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Primacy of the research question, structure of the paper, writing a research article: advice to beginners.

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Thomas V. Perneger, Patricia M. Hudelson, Writing a research article: advice to beginners, International Journal for Quality in Health Care , Volume 16, Issue 3, June 2004, Pages 191–192, https://doi.org/10.1093/intqhc/mzh053

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Writing research papers does not come naturally to most of us. The typical research paper is a highly codified rhetorical form [ 1 , 2 ]. Knowledge of the rules—some explicit, others implied—goes a long way toward writing a paper that will get accepted in a peer-reviewed journal.

A good research paper addresses a specific research question. The research question—or study objective or main research hypothesis—is the central organizing principle of the paper. Whatever relates to the research question belongs in the paper; the rest doesn’t. This is perhaps obvious when the paper reports on a well planned research project. However, in applied domains such as quality improvement, some papers are written based on projects that were undertaken for operational reasons, and not with the primary aim of producing new knowledge. In such cases, authors should define the main research question a posteriori and design the paper around it.

Generally, only one main research question should be addressed in a paper (secondary but related questions are allowed). If a project allows you to explore several distinct research questions, write several papers. For instance, if you measured the impact of obtaining written consent on patient satisfaction at a specialized clinic using a newly developed questionnaire, you may want to write one paper on the questionnaire development and validation, and another on the impact of the intervention. The idea is not to split results into ‘least publishable units’, a practice that is rightly decried, but rather into ‘optimally publishable units’.

What is a good research question? The key attributes are: (i) specificity; (ii) originality or novelty; and (iii) general relevance to a broad scientific community. The research question should be precise and not merely identify a general area of inquiry. It can often (but not always) be expressed in terms of a possible association between X and Y in a population Z, for example ‘we examined whether providing patients about to be discharged from the hospital with written information about their medications would improve their compliance with the treatment 1 month later’. A study does not necessarily have to break completely new ground, but it should extend previous knowledge in a useful way, or alternatively refute existing knowledge. Finally, the question should be of interest to others who work in the same scientific area. The latter requirement is more challenging for those who work in applied science than for basic scientists. While it may safely be assumed that the human genome is the same worldwide, whether the results of a local quality improvement project have wider relevance requires careful consideration and argument.

Once the research question is clearly defined, writing the paper becomes considerably easier. The paper will ask the question, then answer it. The key to successful scientific writing is getting the structure of the paper right. The basic structure of a typical research paper is the sequence of Introduction, Methods, Results, and Discussion (sometimes abbreviated as IMRAD). Each section addresses a different objective. The authors state: (i) the problem they intend to address—in other terms, the research question—in the Introduction; (ii) what they did to answer the question in the Methods section; (iii) what they observed in the Results section; and (iv) what they think the results mean in the Discussion.

In turn, each basic section addresses several topics, and may be divided into subsections (Table 1 ). In the Introduction, the authors should explain the rationale and background to the study. What is the research question, and why is it important to ask it? While it is neither necessary nor desirable to provide a full-blown review of the literature as a prelude to the study, it is helpful to situate the study within some larger field of enquiry. The research question should always be spelled out, and not merely left for the reader to guess.

Typical structure of a research paper

The Methods section should provide the readers with sufficient detail about the study methods to be able to reproduce the study if so desired. Thus, this section should be specific, concrete, technical, and fairly detailed. The study setting, the sampling strategy used, instruments, data collection methods, and analysis strategies should be described. In the case of qualitative research studies, it is also useful to tell the reader which research tradition the study utilizes and to link the choice of methodological strategies with the research goals [ 3 ].

The Results section is typically fairly straightforward and factual. All results that relate to the research question should be given in detail, including simple counts and percentages. Resist the temptation to demonstrate analytic ability and the richness of the dataset by providing numerous tables of non-essential results.

The Discussion section allows the most freedom. This is why the Discussion is the most difficult to write, and is often the weakest part of a paper. Structured Discussion sections have been proposed by some journal editors [ 4 ]. While strict adherence to such rules may not be necessary, following a plan such as that proposed in Table 1 may help the novice writer stay on track.

References should be used wisely. Key assertions should be referenced, as well as the methods and instruments used. However, unless the paper is a comprehensive review of a topic, there is no need to be exhaustive. Also, references to unpublished work, to documents in the grey literature (technical reports), or to any source that the reader will have difficulty finding or understanding should be avoided.

Having the structure of the paper in place is a good start. However, there are many details that have to be attended to while writing. An obvious recommendation is to read, and follow, the instructions to authors published by the journal (typically found on the journal’s website). Another concerns non-native writers of English: do have a native speaker edit the manuscript. A paper usually goes through several drafts before it is submitted. When revising a paper, it is useful to keep an eye out for the most common mistakes (Table 2 ). If you avoid all those, your paper should be in good shape.

Common mistakes seen in manuscripts submitted to this journal

Huth EJ . How to Write and Publish Papers in the Medical Sciences , 2nd edition. Baltimore, MD: Williams & Wilkins, 1990 .

Browner WS . Publishing and Presenting Clinical Research . Baltimore, MD: Lippincott, Williams & Wilkins, 1999 .

Devers KJ , Frankel RM. Getting qualitative research published. Educ Health 2001 ; 14 : 109 –117.

Docherty M , Smith R. The case for structuring the discussion of scientific papers. Br Med J 1999 ; 318 : 1224 –1225.

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New Aspects of Diabetes Research and Therapeutic Development

Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose–lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans.

Significance Statement

Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.

I. Introduction

Diabetes mellitus, a metabolic disease defined by elevated fasting blood glucose levels due to insufficient insulin production, has reached epidemic proportions worldwide (World Health Organization, 2020 ). Type 1 and type 2 diabetes (T1D and T2D, respectively) make up the majority of diabetes cases with T1D characterized by autoimmune destruction of the insulin-producing pancreatic beta cells. The much more prevalent T2D arises in conjunction with peripheral tissue insulin resistance and beta cell failure and is estimated to increase to 21%–33% of the US population by the year 2050 (Boyle et al., 2010 ). To combat this growing health threat and its cardiac, renal, and neurologic comorbidities, new and more effective diabetes drugs and treatments are essential. As the last several years have seen many new developments in the field of diabetes pharmacology and therapy, we determined that a new and up to date review of these advances was in order. Our aim is to provide a careful evaluation of both old and new therapies ( Fig. 1 ) in a manner that we hope will be of interest to both clinical and bench diabetologists. Instead of the usual encyclopedic approach to this topic, we provide here a targeted and selective consideration of the underlying issues, promising new treatments, and a re-examination of more traditional approaches. Thus, we do not discuss less frequently used diabetes agents, such as alpha-glucosidase inhibitors; these were discussed in other recent reviews (Hedrington and Davis, 2019 ; Lebovitz, 2019 ).

Pharmacologic targeting of numerous organ systems for the treatment of diabetes. Treatment of diabetes involves targeting of various organ systems, including the kidney by SGLT2 inhibitors; the liver, gut, and adipose tissue by metformin; and direct actions upon the pancreatic beta cell. Beta cell compounds aim to increase secretion or mass and/or to protect from autoimmunity destruction. Ultimately, insulin therapy remains the final line of diabetes treatment with new technologies under development to more tightly regulate blood glucose levels similar to healthy beta cells. hESC, human embryonic stem cell.

II. Diabetes Therapies

A. metformin.

Metformin is a biguanide originally based on the natural product galegine, which was extracted from the French lilac (Bailey, 1992 ; Rojas and Gomes, 2013 ; Witters, 2001 ). A closely related biguanide, phenformin, was also used initially for its hypoglycemic actions. Based on its successful track record as a safe, effective, and inexpensive oral medication, metformin has become the most widely prescribed oral agent in the world in treating T2D (Rojas and Gomes, 2013 ; He and Wondisford, 2015 ; Witters, 2001 ), whereas phenformin has been largely bypassed due to its unacceptably high association with lactic acidosis (Misbin, 2004 ). Unlike sulfonylureas, metformin lowers blood glucose without provoking hypoglycemia and improves insulin sensitivity (Bailey, 1992 ). Despite these well known beneficial metabolic actions, metformin’s mechanism of action and even its main target organ remain controversial. In fact, metformin has multiple mechanisms of action at the organ as well as the cellular level, which has hindered our understanding of its most important molecular effects on glucose metabolism (Witters, 2001 ). Adding to this, a specific receptor for metformin has never been identified. Metformin has actions on several tissues, although the primary foci of most studies have been the liver, skeletal muscle, and the intestine (Foretz et al., 2014 ; Rena et al., 2017 ). Metformin and phenformin clearly suppress hepatic glucose production and gluconeogenesis, and they improve insulin sensitivity in the liver and elsewhere (Bailey, 1992 ). The hepatic actions of metformin have been the most exhaustively studied to date, and there is little doubt that these actions are of some importance. However, several of the studies remain highly controversial, and there are still open questions.

One of the first reported specific molecular targets of metformin was mitochondrial complex I of the electron transport chain. Inhibition of this complex results in reduced oxidative phosphorylation and consequently decreased hepatic ATP production (El-Mir et al., 2008 ; Evans et al., 2005 ; Owen et al., 2000 ). As is the case in many other studies of metformin, however, high concentrations of the drug were found to be necessary to depress metabolism at this site (El-Mir et al., 2000 ; He and Wondisford, 2015 ; Owen et al., 2000 ). Also controversial is whether metformin works by activating 5′ AMP-activated protein kinase (AMPK), a molecular energy sensor that is known to be a major metabolic sensor in cells, or if not AMPK directly, then one of its upstream regulators such as liver kinase B2 (Zhou et al., 2001 ). Although metformin was shown to activate AMPK in several excellent studies, other studies directly contradicted the AMPK hypothesis. Most dramatic were studies showing that metformin’s actions to suppress hepatic gluconeogenesis persisted despite genetic deletion of the AMPK’s catalytic domain (Foretz et al., 2010 ). More recent studies identified additional or alternative targets, such as cAMP signaling in the liver (Miller et al., 2013 ) or glycogen synthase kinase-3 (Link, 2003 ). Other work showed that the phosphorylation of acetyl-CoA carboxylase and acetyl-CoA carboxylase 2 are involved in regulating lipid homeostasis and improving insulin sensitivity after exposure to metformin (Fullerton et al., 2013 ).

Although there are strong data to support each of these pathways, it is not entirely clear which signaling pathway(s) is most essential to the actions of metformin in hepatocytes. Metformin clearly inhibits complex I and concomitantly decreases ATP and increases AMP. The latter results in AMPK activation, reduced fatty acid synthesis, and improved insulin receptor activation, and increased AMP has been shown to inhibit adenylate cyclase to reduce cAMP and thus protein kinase A activation. Downstream, this reduces the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase via decreased cAMP response element-binding protein, the cAMP-sensitive transcription factor. Decreased PKA also promotes ATP-dependent 6-phosphofructokinase, liver type activity via fructose 2,6-bisphosphate and reduces gluconeogenesis, as fructose-bisphosphatase 1 is inhibited by fructose 2,6-bisphosphate, along with other mechanisms (Rena et al., 2017 ; Pernicova and Korbonits, 2014 ).

More recent work has shown that metformin at pharmacological rather than suprapharmacological doses increases mitochondrial respiration and complex 1 activity and also increases mitochondrial fission, now thought to be critical for maintaining proper mitochondrial density in hepatocytes and other cells. This improvement in respiratory activity occurs via AMPK activation (Wang et al., 2019 ).

Although the liver has historically been the major suspected site of metformin action, recent studies have suggested that the gut instead of the liver is a major target, a concept supported by the increased efficacy of extended-release formulations of metformin that reside for a longer duration in the gut after their administration (Buse et al., 2016 ). An older, but in our view an important observation, is that the intravenous administration of metformin has little or no effect on blood glucose, whereas, in contrast, orally administered metformin is much more effective (Bonora et al., 1984 ). Recent imaging studies using labeled glucose have shown directly that metformin stimulates glucose uptake by the gut in patients with T2D to reduce plasma glucose concentrations (Koffert et al., 2017 ; Massollo et al., 2013 ). Additionally, it is possible that metformin may exert its effect in the gut by inducing intestinal glucagon-like peptide-1 (GLP-1) release (Mulherin et al., 2011 ; Preiss et al., 2017) to potentiate beta cell insulin secretion and by stimulating the central nervous system (CNS) to exert control over both blood glucose and liver function. Indeed, CNS effects produced by metformin have been proposed to occur via the local release of GLP-1 to activate intestinal nerve endings of ascending nerve pathways that are involved in CNS glucose regulation (Duca et al., 2015 ). Lastly, several papers have now implicated that metformin may act by altering the gut microbiome, suggesting that changes in gut flora may be critical for metformin’s actions (McCreight et al., 2016 ; Wu et al., 2017 ; Devaraj et al., 2016 ). A new study proposed that activation of the intestinal farnesoid X receptor may be the means by which microbiota alter hyperglycemia (Sun et al., 2018 ). However, these studies will require more mechanistic detail and confirmation before they can be fully accepted by the field. In addition to the action of metformin on gut flora, the production of imidazole propionate by gut microbes in turn has been shown to interfere with metformin action through a p38-dependent mechanism and AMPK inhibition. Levels of imidazole propionate are especially higher in patients with T2D who are treated with metformin (Koh et al., 2020 ).

In summary, the combined contribution of these various effects of metformin on multiple cellular targets residing in many tissues may be key to the benefits of metformin treatment on lowering blood glucose in patients with type 2 diabetes (Foretz et al., 2019 ). In contrast, exciting new work showing metformin leads to weight loss by increasing circulating levels of the peptide hormone growth differentiation factor 15 and activation of brainstem glial cell-derived neurotropic factor family receptor alpha like receptors to reduce food intake and energy expenditure works independently of metformin’s glucose-lowering effect (Coll et al., 2020 ).

B. Sulfonylureas and Beta Cell Burnout

The class of compounds known as sulfonylureas includes one of the oldest oral antidiabetic drugs in the pharmacopoeia: tolbutamide. Tolbutamide is a “first generation” oral sulfonylurea secretagogue whose clinical usefulness is due to its prompt stimulation of insulin release from pancreatic beta cells. “Second generation” sulfonylureas include drugs such as glyburide, gliclazide, and glipizide. Sulfonylureas act by binding to a high affinity sulfonylurea binding site, the sulfonylurea receptor 1 subunit of the K(ATP) channel, which closes the channel. These drugs mimic the physiologic effects of glucose, which closes the K(ATP) channel by raising cytosolic ATP/ADP. This in turn provokes beta cell depolarization, resulting in increased Ca 2+ influx into the beta cell (Ozanne et al., 1995 ; Ashcroft and Rorsman, 1989 ; Nichols, 2006 ). Importantly, sulfonylureas, and all drugs that directly increase insulin secretion, are associated with hypoglycemia, which can be severe, and which limits their widespread use in the clinic (Yu et al., 2018 ). Meglitinides are another class of oral insulin secretagogues that, like the sulfonylureas, bind to sulfonylurea receptor 1 and inhibit K(ATP) channel activity (although at a different site of action). The rapid kinetics of the meglitinides enable them to effectively blunt the postprandial glycemic excursions that are a hallmark (along with elevated fasting glucose) of T2D (Rosenstock et al., 2004). However, the need for their frequent dosing (e.g., administration before each meal) has limited their appeal to patients.

The efficacy of sulfonylureas is known to decrease over time, leading to failure of the class for effective long-term treatment of T2D (Harrower, 1991 ). More broadly, it is now widely accepted that the number of functional beta cells in humans declines during the progression of T2D. Thus, one would expect that due to this decline, all manner of oral agents intended to target the beta cell and increase its cell function (and especially insulin secretion) will fail over time (RISE Consortium, 2019 ), a process referred to as “beta cell failure” (Prentki and Nolan, 2006 ). Currently, treatments that can expand beta cell mass or improve beta cell function or survival over time are not yet available for use in the clinic. As a result, treatments that may be able to help patients cope with beta cell burnout such as islet cell transplantation, insulin pumps, or stem cell therapy are alternatives that will be discussed below.

C. Ca 2+ Channel Blockers and Type 1 Diabetes

Strategies to treat and prevent T1D have historically focused on ameliorating the toxic consequences of immune dysregulation resulting in autoimmune destruction of pancreatic beta cells. More recently, a concerted focus on alleviating the intrinsic beta cell defects (Sims et al., 2020 ; Soleimanpour and Stoffers, 2013 ) that also contribute to T1D pathogenesis have been gaining traction at both the bench and the bedside. Several recent preclinical studies suggest that Ca 2+ -induced metabolic overload induces beta cell failure (Osipovich et al., 2020 ; Stancill et al., 2017 ; Xu et al., 2012 ), with the potential that excitotoxicity contributes to beta cell demise in both T1D and T2D, similar to the well known connection between excitotoxicity and, concomitantly, increased Ca 2+ loading of the cells and neuronal dysfunction. Indeed, the use of the phenylalkylamine Ca 2+ channel blocker verapamil has been successful in ameliorating beta cell dysfunction in preclinical models of both T1D and T2D (Stancill et al., 2017 ; Xu et al., 2012 ). Verapamil is a well known blocker of L-type Ca 2+ channels, and, in normally activated beta cells, it limits Ca 2+ entry into the beta cell (Ohnishi and Endo, 1981 ; Vasseur et al., 1987 ). This would be expected to, in turn, alter the expression of many Ca 2+ influx–dependent beta cell genes (Stancill et al., 2017 ), and the evidence to date suggests it is likely that verapamil preserves beta cell function in diabetes models by repressing thioredoxin-interacting protein (TXNIP) expression and thus protecting the beta cell. This is somewhat surprising given the physiologic role of Ca 2+ is to acutely trigger insulin secretion; this process would be expected to be inhibited by L-type Ca 2+ channel blockers (Ashcroft and Rorsman, 1989 ; Satin et al., 1995 ).

Hyperglycemia is a well known inducer of TXNIP expression, and a lack of TXNIP has been shown to protect against beta cell apoptosis after inflammatory stress (Chen et al., 2008a ; Shalev et al., 2002 ; Chen et al., 2008b ). Excitingly, the use of verapamil in patients with recent-onset T1D improved beta cell function and improved glycemic control for up to 12 months after the initiation of therapy, suggesting there is indeed promise for targeting calcium and TXNIP activation in T1D. Use of verapamil for a repurposed indication in the preservation of beta cell function in T1D is attractive due its well known safety profile as well as its cardiac benefits (Chen et al., 2009 ). Although the long-term efficacy of verapamil to maintain beta cell function in vivo is unclear, a recently described TXNIP inhibitor may also show promise in suppressing the hyperglucagonemia that also contributes to glucose intolerance in T2D (Thielen et al., 2020 ). As there is a clear need for increased Ca 2+ influx into the beta cell to trigger and maintain glucose-dependent insulin secretion (Ashcroft and Rorsman, 1990 ; Satin et al., 1995 ), it remains to be seen how well regulated insulin secretion is preserved in the presence of L-type Ca 2+ channel blockers like verapamil in the system. One might speculate that reducing but not fully eliminating beta cell Ca 2+ influx might reduce TXNIP levels while preserving enough influx to maintain glucose-stimulated insulin release. Alternatively, these two phenomena may operate on entirely different time scales. At present, these issues clearly will require further investigation.

D. GLP-1 and the Incretins

Studies dating back to the 1960s revealed that administering glucose in equal amounts via the peripheral circulation versus the gastrointestinal tract led to dramatically different amounts of glucose-induced insulin secretion (Elrick et al., 1964 ; McIntyre et al., 1964 ; Perley and Kipnis, 1967 ). Gastrointestinal glucose administration greatly increased insulin secretion versus intravenous glucose, and this came to be known as the “incretin effect” (Nauck et al., 1986a ; Nauck et al., 1986b ). Subsequent work showed that release of the gut hormone GLP-1 mediated this effect such that food ingestion induced intestinal cell hormone secretion. GLP-1 so released would then circulate to the pancreas via the blood to prime beta cells to secrete more insulin when glucose became elevated because these hormones stimulated beta cell cAMP formation (Drucker et al., 1987 ). The discovery that a natural peptide corresponding to GLP-1 could be found in the saliva of the Gila monster, a desert lizard, hastened progress in the field, and ample in vitro studies subsequently confirmed that GLP-1 potentiated insulin secretion in a glucose-dependent manner. GLP-1 has little or no significant action on insulin secretion in the absence of elevated glucose (such as might typically correspond to the postprandial case or during fasting), thus minimizing the likelihood of hypoglycemia provoked by GLP-1 in treated patients (Kreymann et al., 1987 ). Although not completely understood, the glucose dependence of GLP-1 likely reflects the requirement for adenine nucleotides to close glucose-inhibited K(ATP) channels and thus subsequently activate Ca 2+ influx–dependent insulin exocytosis. Besides potentiating GSIS at the level of the beta cell, glucagon-like peptide-1 receptor (GLP-1R) agonists also decrease glucagon secretion from pancreatic islet alpha cells, reduce gastric emptying, and may also increase beta cell proliferation, among other cellular actions (reviewed in Drucker, 2018 ; Muller et al., 2019).

Intense interest in the incretins by basic scientists, clinicians, and the pharma community led to the rapid development of new drugs for treating primarily T2D. These drugs include a range of GLP-1R agonists and inhibitors of the incretin hormone degrading enzyme dipeptidyl peptidase 4 (DPP4), whose targeting increases the half-lives of GLP-1 and gastric inhibitory polypeptide (GIP) and thereby increases protein hormone levels in plasma. GLP-1R agonists have been associated with not only a lowering of plasma glucose but also weight loss, decreased appetite, reduced risk of cardiovascular events, and other favorable outcomes (Gerstein et al., 2019; Hernandez et al., 2018; Husain et al., 2019; Marso et al., 2016a; Marso et al., 2016b ; Buse et al., 2004). Regarding their untoward actions, although hypoglycemia is not a major concern, there have been reports of pancreatitis and pancreatic cancer from use of GLP-1R agonists. However, a recent meta-analysis covering four large-scale clinical trials and over 33,000 participants noted no significantly increased risk for pancreatitis/pancreatic cancer in patients using GLP-1R agonists (Bethel et al., 2018).

Ongoing and future developments in the use of proglucagon-derived peptides such as GLP-1 and glucagon include the use of combined GLP-1/GIP, glucagon/GLP-1, and agents targeting all three peptides in combination (reviewed in Alexiadou and Tan, 2020 ). Although short-term infusions of GLP-1 with GIP failed to yield metabolic benefits beyond those seen with GLP-1 alone (Bergmann et al., 2019 ), several GLP-1/GIP dual agonists are currently in development and have shown promising metabolic results in clinical trials (Frias et al., 2017 ; Frias et al., 2020 ; Frias et al., 2018 ). At the level of the pancreatic islet, beneficial effects of dual GLP-1/GIP agonists may be related to imbalanced and biased preferences of these agonists for the gastric inhibitory polypeptide receptor over the GLP-1R (Willard et al., 2020 ) and possibly were not simply to dual hormone agonism in parallel. Dual glucagon/GLP-1 agonist therapy has also been shown to have promising metabolic effects in humans (Ambery et al., 2018 ; Tillner et al., 2019 ). Oxyntomodulin is a natural dual glucagon/GLP-1 receptor agonist and proglucagon cleavage product that is also secreted from intestinal enteroendocrine cells, which has beneficial effects on insulin secretion, appetite regulation, and body weight in both humans and rodents (Cohen et al., 2003 ; Dakin et al., 2001 ; Dakin et al., 2002 ; Shankar et al., 2018 ; Wynne et al., 2005 ). Interestingly, alpha cell crosstalk to beta cells through the combined effects of glucagon and GLP-1 is necessary to obtain optimal glycemic control, suggesting a potential pathway for therapeutic dual glucagon/GLP-1 agonism within the islets of patients with T2D (Capozzi et al., 2019a ; Capozzi et al., 2019b ). Although the early results appear promising, more studies will be necessary to better understand the mechanistic and clinical impacts of these multiagonist agents.

E. DPP4 Inhibitors

Inhibition of DPP4, the incretin hormone degrading enzyme, is one of the most common T2D treatments to increase GLP-1 and GIP plasma hormone levels. These DPP4 inhibitors or “gliptins” are generally used in conjunction with other T2D drugs such as metformin or sulfonylureas to obtain the positive benefits discussed above (Lambeir et al., 2008 ). DPP4 is a primarily membrane-bound peptidase belonging to the serine peptidase/prolyl oligopeptidase gene family, which cleaves a large number of substrates in addition to the incretin hormones (Makrilakis, 2019 ). DPP4 inhibitors provide glucose-lowering benefits while being generally well tolerated, and the variety of available drugs (including sitagliptin, saxagliptin, vildagliptin, alogliptin, and linagliptin) with slightly different dosing frequency, half-life, and mode of excretion/metabolism allows for use in multiple patient populations (Makrilakis, 2019 ). This includes the elderly and individuals with renal or hepatic insufficiency (Makrilakis, 2019 ).

Although hypoglycemia is not a concern for DPP4 inhibitor use, other considerations should be made. DPP4 inhibitors tend to be more expensive than metformin or other second-line oral drugs in addition to having more modest glycemic effects than GLP-1R agonists (Munir and Lamos, 2017 ). Finally, meta-analysis of randomized and observational studies concluded that heart failure in patients with T2D was not associated with use of DPP4 inhibitors; however, this study was limited by the short follow-up and lack of high-quality data (Li et al., 2016 ). Thus, the US Food and Drug Administration (FDA) did recommend assessing risk of heart failure hospitalization in patients with pre-existing cardiovascular disease, prior heart failure, and chronic kidney disease when using saxagliptin and alogliptin (Munir and Lamos, 2017 ).

F. Sodium Glucose Cotransporter 2 Inhibitors

A recent development in the field of T2D drugs are sodium glucose cotransporter 2 (SGLT2) inhibitors, which have an interesting and very different mechanism of action. Within the proximal tubule of the nephron, SGLT2 transports ingested glucose into the lumen of the proximal tubule between the epithelial layers, thereby reclaiming glucose by this reabsorption process (reviewed in Vallon, 2015 ). SGLT2 inhibitors target this transporter and increase glucose in the tubular fluid and ultimately increase it in the urine. In patients with diabetes, SGLT2 inhibition results in a lowering of plasma glucose with urine glucose content rising substantially (Adachi et al., 2000 ; Vallon, 2015 ). These drugs, although they are relatively new, have become an area of great interest for not only patients with T2D (Grempler et al., 2012 ; Imamura et al., 2012 ; Meng et al., 2008 ; Nomura et al., 2010 ) but also for patients with T1D (Luippold et al., 2012 ; Mudaliar et al., 2012 ). Part of their appeal also rests on reports that their use can lead to a statistically significant decline in cardiac events that are known to occur secondarily to diabetes, possibly independently of plasma glucose regulation (reviewed in Kurosaki and Ogasawara, 2013 ). Although the long-term consequences of their clinical use cannot yet be determined, raising the glucose content of the urogenital tract leads to an increased risk of urinary tract infections and other related infections in some patients (Kurosaki and Ogasawara, 2013 ).

Another recent concern about the use of SGLT2 inhibitors has been the development of normoglycemic diabetic ketoacidosis (DKA). Despite the efficacy of SGLT2 inhibitors, observations of hyperglucagonemia in patients with euglycemic DKA has led to a number of recent studies focused on SGLT2 actions on pancreatic islets. Initial studies of isolated human islets treated with small interfering RNA directed against SGLT2 and/or SGLT2 inhibitors demonstrated increased glucagon release. These studies were complemented by the finding of elevations in glucagon release in mice that were administered SGLT2 inhibitors in vivo (Bonner et al., 2015 ). Insights into the possible mechanistic links between SGLT2 inhibition, DKA frequency, and glucagon secretion in humans may relate to the observation of heterogeneity in SGLT2 expression, as SGLT2 expression appears to have a high frequency of interdonor and intradonor variability (Saponaro et al., 2020 ). More recently, both insulin and GLP-1 have been demonstrated to modulate SGLT2-dependent glucagon release through effects on somatostatin release from delta cells (Vergari et al., 2019 ; Saponaro et al., 2019 ), suggesting potentially complex paracrine effects that may affect the efficacy of these compounds.

On the other hand, several recent studies question that the development of euglycemic DKA after SGLT2 inhibitor therapy may be through alpha cell–dependent mechanisms. Three recent studies found no effect of SGLT2 inhibitors to promote glucagon secretion in mouse and/or rat models and could not detect SGLT2 expression in human alpha cells (Chae et al., 2020 ; Kuhre et al., 2019 ; Suga et al., 2019 ). A fourth study demonstrated only a brief transient effect of SGLT2 inhibition to raise circulating glucagon concentrations in immunodeficient mice transplanted with human islets, which returned to baseline levels after longer exposures to SGLT2 inhibitors (Dai et al., 2020 ). Furthermore, SGLT2 protein levels were again undetectable in human islets (Dai et al., 2020 ). These results could suggest alternative islet-independent mechanisms by which patients develop DKA, including alterations in ketone generation and/or clearance, which underscore the additional need for further studies both in molecular models and at the bedside. Nevertheless, SGLT2 inhibitors continue to hold promise as a valuable therapy for T2D, especially in the large segment of patients who also have superimposed cardiovascular risk (McMurray et al., 2019; Wiviott et al., 2019; Zinman et al., 2015).

G. Thiazolidinediones

Once among the most commonly used oral agents in the armamentarium to treat T2D, thiazolidinediones (TZDs) were clinically popular in their utilization to act specifically as insulin sensitizers. TZDs improve peripheral insulin sensitivity through their action as peroxisome proliferator-activated receptor (PPAR) γ agonists, but their clinical use fell sharply after studies suggested a connection between cardiovascular toxicity with rosiglitazone and bladder cancer risk with pioglitazone (Lebovitz, 2019 ). Importantly, an FDA panel eventually removed restrictions related to cardiovascular risk with rosiglitazone in 2013 (Hiatt et al., 2013 ). Similarly, concerns regarding use of bladder cancer risk with pioglitazone were later abated after a series of large clinical studies found that pioglitazone did not increase bladder cancer (Lewis et al., 2015 ; Schwartz et al., 2015 ). However, usage of TZDs had already substantially decreased and has not since recovered.

Although concerns regarding edema, congestive heart failure, and fractures persist with TZD use, there have been several studies suggesting that TZDs protect beta cell function. In the ADOPT study, use of rosiglitazone monotherapy in patients newly diagnosed with T2D led to improved glycemic control compared with metformin or sulfonylureas (Kahn et al., 2006). Later analyses revealed that TZD-treated subjects had a slower deterioration of beta cell function than metformin- or sulfonylurea-treated subjects (Kahn et al., 2011). Furthermore, pioglitazone use improved beta cell function in the prevention of T2D in the ACT NOW study (Defronzo et al., 2013; Kahn et al., 2011). Mechanistically, it is unclear if TZDs lead to beneficial beta cell function through direct effects or through indirect effects of reduced beta cell demand due to enhanced peripheral insulin sensitivity. Indeed, a beta cell–specific knockout of PPAR γ did not impair glucose homeostasis, nor did it impair the antidiabetic effects of TZD use in mice (Rosen et al., 2003 ). However, other reports demonstrated PPAR-responsive elements within the promoters of both glucose transporter 2 and glucokinase that enhance beta cell glucose sensing and function, which could explain beta cell–specific benefits for TZDs (Kim et al., 2002 ; Kim et al., 2000 ). Furthermore, TZDs have been shown to improve beta cell function by upregulating cholesterol transport (Brunham et al., 2007 ; Sturek et al., 2010 ). Additionally, use of TZDs in the nonobese diabetic (NOD) mouse model of T1D augmented the beta cell unfolded protein response and prevented beta cell death, suggesting potential benefits for TZDs in both T1D and T2D (Evans-Molina et al., 2009 ; Maganti et al., 2016 ). With a now refined knowledge of demographics in which to avoid TZD treatment due to adverse effects, together with genetic approaches to identify candidates more likely to respond effectively to TZD therapy (Hu et al., 2019 ; Soccio et al., 2015 ), it remains to be seen if TZD therapy will return to more prominent use in the treatment of diabetes.

H. Insulin and Beyond: The Use of “Smart” Insulin and Closed Loop Systems in Diabetes Treatment

Due to recombinant DNA technology, numerous insulin analogs are now available in various forms ranging from fast acting crystalline insulin to insulin glargine; all of these analogs exhibit equally effective insulin receptor binding. Most are generated by altering amino acids in the B26–B30 region of the molecule (Kurtzhals et al., 2000 ). The American Diabetes Association delineates these insulins by their 1) onset or time before insulin reaches the blood stream, 2) peak time or duration of maximum blood glucose–lowering efficacy, and 3) the duration of blood glucose–lowering time. Insulin administration is independent of the residuum of surviving and/or functioning beta cells in the patient and remains the principal pharmacological treatment of both T1D and T2D. The availability of multiple types of delivery methods, i.e., insulin pens, syringes, pumps, and inhalants, provides clinicians with a solid and varied tool kit with which to treat diabetes. The downsides, however, are that 1) hypoglycemia is a constant threat, 2) proper insulin doses are not trivial to calculate, 3) compliance can vary especially in children and young adults, and 4) there can be side effects of a variety of types. Nonetheless, insulin therapy remains a mainstay treatment of diabetes.

To eliminate the downsides of insulin therapy, research in the past several decades has worked toward generating glucose-sensitive or “smart” insulin molecules. These molecules change insulin bioavailability and become active only upon high blood glucose using glucose-binding proteins such as concanavalin A, glucose oxidase to alter pH sensitivity, and phenylboronic acid (PBA), which forms reversible ester linkages with diol-containing molecules including glucose itself (reviewed in Rege et al., 2017 ). Indeed, promising recent studies included various PBA moieties covalently bonded to an acylated insulin analog (insulin detemir, which contains myristic acid coupled to Lys B29 ). The detemir allows for binding to serum albumin to prolong insulin’s half-life in the circulation, and PBA provided reversible glucose binding (Chou et al., 2015 ). The most promising of the PBA-modified conjugates showed higher potency and responsiveness in lowering blood glucose levels compared with native insulin in diabetic mouse models and decreased hypoglycemia in healthy mice, although the molecular mechanisms have not yet been determined (Chou et al., 2015 ).

An additional active area of research includes structurally defining the interaction between insulin and the insulin receptor ectodomain. Importantly, a major conformational change was discovered that may be exploited to impair insulin receptor binding under hypoglycemic conditions (Menting et al., 2013 ; Rege et al., 2017 ). Challenges in the design, testing, and execution of glucose-responsive insulins may be overcome by the adaptation of novel modeling approaches (Yang et al., 2020 ), which may allow for more rapid screening of candidate compounds.

Technologies have also progressed in the field of artificial pancreas design and development. Currently two “closed loop” systems are now available: Minimed 670G from Medtronic and Control-IQ from Tandem Diabetes Care. Both systems use a continuous glucose monitor, insulin pump, and computer algorithm to predict correct insulin doses and administer them in real time. Such algorithm systems also take into account insulin potency, the rate of blood glucose increase, and the patient’s heart rate and temperature to adjust insulin delivery levels during exercise and after a meal. In addition, so-called “artificial pancreas” systems have also been clinically tested, which use both insulin and glucagon and as such result in fewer reports of hypoglycemic episodes (El-Khatib et al., 2017 ). These types of systems will continue to become more popular as the development of room temperature–stable glucagon analogs continue, such as GVOKE by Xeris Pharmaceuticals (currently available in an injectable syringe) and Baqsimi, a nasally administered glucagon from Eli Lilly.

I. Present and Future Therapies: Beta Cell Transplantation, Replication, and Immune Protection

1. islet transplantation.

The idea to use pancreatic allo/xenografts to treat diabetes remarkably dates back to the late 1800s (Minkowski, 1892 ; Pybus, 1924 ; Williams, 1894 ). Before proceeding to the discovery of insulin (together with Best, MacLeod, and Collip), Frederick Banting also postulated the potential for transplantation of pancreatic tissue emulsions to treat diabetes in dog models in a notebook entry in 1921 (Bliss, 1982 ). Decades later, Paul Lacy, David Scharp, and colleagues successfully isolated intact functional pancreatic islets and transplanted them into rodent models (Kemp et al., 1973 ). These studies led to the initial proof of concept studies for humans, with the first successful islet transplant in a patient with T1D occurring in 1977 (Sutherland et al., 1978 ). A rapid expansion of islet transplantation, inspired by these original studies led to key observations of successfully prolonged islet engraftment by the “Edmonton protocol” whereby corticosteroid-sparing immunosuppression was applied, and islets from at least two allogeneic donors were used to achieve insulin independence (Shapiro et al., 2000 ). More recent work has focused on improving upon the efficiency and long-term engraftment of allogeneic transplants leading to more prolonged graft function (to the 5-year mark) and successful transplantation from a single islet donor (Hering et al., 2016; Hering et al., 2005 ; Rickels et al., 2013 ). Critical to these efforts to improve the success rate was the recognition that the earlier generation of immunosuppressive agents to counter tissue rejection was toxic to islets (Delaunay et al., 1997 ; Paty et al., 2002 ; Soleimanpour et al., 2010 ) and that more appropriate and less toxic agents were needed (Hirshberg et al., 2003 ; Soleimanpour et al., 2012 ).

Certainly, islet transplantation as a therapeutic approach for patients with T1D has been scrutinized due to several challenges, including (but not limited to) the lack of available donor supply to contend with demand, limited long-term functional efficacy of islet allografts, the potential for re-emergence of autoimmune islet destruction and/or metabolic overload-induced islet failure, and significant adverse effects of prolonged immunosuppression (Harlan, 2016 ). Furthermore, although islet transplantation is not currently available for individuals with T2D, simultaneous pancreas-kidney transplantation in T2D had similar favorable outcomes to simultaneous pancreas-kidney transplantation in T1D; therefore, islet-kidney transplantation may eventually be a feasible option to treat T2D, as patients will already be on immunosuppressors (Sampaio et al., 2011 ; Westerman et al., 1983 ). An additional significant obstacle is the tremendous expense associated with islet transplantation therapy. Indeed, the maintenance, operation, and utilization of an FDA-approved and Good Manufacturing Practice–compliant islet laboratory can lead to operating costs at nearly $150,000 per islet transplant, which is not cost effective for the vast majority of patients with T1D (Naftanel and Harlan, 2004 ; Wallner et al., 2016 ). At present, the focus has been to obtain FDA approval for islet allo-transplantation as a therapy for T1D to allow for insurance compensation (Hering et al., 2016; Rickels and Robertson, 2019 ). In the interim, the islet biology, stem cell, immunology, and bioengineering communities have continued the development of cell-based therapies for T1D by other approaches to overcome the challenges identified during the islet transplantation boom of the 1990s and 2000s.

2. Pharmacologic Induction of Beta Cell Replication

Besides transplantation, progress in islet cell biology and especially in developmental biology of beta cells over several decades raised the additional possibility that beta cell mass reduction in diabetes might be countered by increasing beta cell number through mitogenic means. A key method to expand pancreatic beta cell mass is through the enhancement of beta cell replication. Although the study of pancreatic beta cell replication has been an area of intense focus in the beta cell biology field for several decades, only recently has this seemed truly feasible. Seminal studies identified that human beta cells are essentially postmitotic, with a rapid phase of growth occurring in the prenatal period that dramatically tapers off shortly thereafter (Gregg et al., 2012 ; Meier et al., 2008 ). The plasticity of rodent beta cells is considerably higher than that of human beta cells (Dai et al., 2016 ), which has led to a renewed focus on validation of pharmacologic agents to enhance rodent beta cell replication using isolated and/or engrafted human islets (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). Indeed, a large percentage of agents that were successful when applied to rodent systems were largely unsuccessful at inducing replication in human beta cells (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). However, several recent studies have begun to make significant progress on successfully pushing human beta cells to replicate.

Several groups have reported successful human beta cell proliferation, both in vitro and in vivo, in response to inhibitors of the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). These inhibitors include harmine, INDY, GNF4877, 5-iodotubericidin, leucettine-42, TG003, AZ191, CC-401, and more specific, recently developed DYRK1A inhibitors (Ackeifi et al., 2020 ). Although DYRK1A is conclusively established as the important mediator of human beta cell proliferation, comprehensively determining other cellular targets and if additional gene inhibition amplifies the proliferative response is still in process. New evidence from Wang and Stewart shows dual specificity tyrosine phosphorylation-regulated kinase 1B to be an additional mitogenic target and also describes variability in the range of activated kinases within cells and/or levels of inhibition for the many DYRK1A inhibitors listed above (Ackeifi et al., 2020 ). Interestingly, opposite to these human studies, earlier mouse studies from the Scharfmann group demonstrated that Dyrk1a haploinsufficiency leads to decreased proliferation and loss of beta cell mass (Rachdi et al., 2014b ). In addition, overexpression of Dyrk1a in mice led to beta cell mass expansion with increased glucose tolerance (Rachdi et al., 2014a ).

Although important differences in beta cell proliferative capacity have been shown between human and rodent species, there are also significant differences in the mitogenic capacity of beta cells from juvenile, adult, and pregnant individuals. This demonstrates that proliferative stimuli appear to act within the complex islet, pancreas, and whole-body environments unique to each time point. For example, the administration of the hormones platelet-derived growth factor alpha or GLP-1 result in enhanced proliferation in juvenile human beta cells yet are ineffective in adult human beta cells (Chen et al., 2011 ; Dai et al., 2017 ). This has been shown to be due to a loss of platelet-derived growth factor alpha receptor expression as beta cells age but appears to be unrelated to GLP-1 receptor expression levels (Chen et al., 2011 ). Indeed, the GLP-1 receptor is highly expressed in adult beta cells, and GLP-1 secretion increases insulin secretion, as detailed previously; however, the induction of proliferative factors such as nuclear factor of activated T cells, cytoplasmic 1; forkhead box protein 1; and cyclin A1 is only seen in juvenile islets (Dai et al., 2017 ). Human studies using cadaveric pancreata from pregnant donors also showed increased beta cell mass, yet lactogenic hormones from the pituitary or placenta (prolactin, placental lactogen, or growth hormone) are unable to stimulate proliferation in human beta cells despite their ability to produce robust proliferation in mouse beta cells (reviewed in Baeyens et al., 2016 ). Experiments overexpressing mouse versus human signal transducer and activator of transcription 5, the final signaling factor inducing beta cell adaptation, in human beta cells allows for prolactin-mediated proliferation revealing fundamental differences in prolactin pathway competency in human (Chen et al., 2015 ). Overcoming the barrier of recapitulating human pregnancy’s effect on beta cells through isolating placental cells or blood serum during pregnancy may result in the discovery of a factor(s) that facilitates the increase in beta cell mass observed during human pregnancy.

Mechanisms that stimulate beta cell proliferation have also been discovered from studying genetic mutations that result in insulinomas, spontaneous insulin-producing beta cell adenomas. The most common hereditary mutation occurs in the multiple endocrine neoplasia type 1 (MEN1) gene. Indeed, administration of a MEN1 inhibitor in addition to a GLP-1 agonist (which cannot induce proliferation alone) is able to increase beta cell proliferation in isolated human islets through synergistic activation of KRAS proto-oncogene, GTPase downstream signals (Chamberlain et al., 2014 ). Interestingly, MEN1 mutations are uncommon in sporadic insulinomas, yet assaying genomic and epigenetic changes in a large cohort of non-MEN1 insulinomas found alterations in trithorax and polycomb chromatin modifying genes that were functionally related to MEN1 (Wang et al., 2017 ). Stewart and colleagues hypothesized that changes in histone 3 lysine 27 and histone 3 lysine 4 methylation status led to increased enhancer of zeste homolog 2 and lysine demethylase 6A, decreased cyclin-dependent kinase inhibitor 1C, and thereby increased beta cell proliferation, among other phenotypes. They also proposed that these findings help to explain why increased proliferation always occurs despite broad heterogeneity of mutations found between individual insulinomas (Wang et al., 2017 ).

Although factors that induce proliferation are continuing to be discovered, there are drawbacks that still limit their clinical application. Harmine and other DYRK1A inhibitors are not beta cell specific, nor have all their cellular targets been determined (Ackeifi et al., 2020 ). Targeting other pathways to induce human beta cell proliferation such as modulation of prostaglandin E2 receptors (i.e., inhibition of prostaglandin E receptor 3 alone or in combination with prostaglandin E receptor 4 activation) showed promising increases in proliferative rate yet suffers from the same lack of specificity (Carboneau et al., 2017 ). Induction of proliferation may also come at the expense of glucose sensing as in insulinomas, which have an increased expression of “disallowed genes” and alterations in glucose transporter and hexokinase expression (Wang et al., 2017 ). A further untoward consequence that must be avoided is the production of cancerous cells through unchecked proliferation. Finally, increasing beta cell mass through low rates of proliferation may increase the pool of functional insulin-secreting cells in T2D, but without additional measures, these beta cells will still ultimately be targeted for immune cell destruction in T1D.

3. Beta Cell Stress Relieving Therapies

Metabolic, inflammatory, and endoplasmic reticulum (ER) stress contribute to beta cell dysfunction and failure in both T1D and T2D. Although reduction of metabolic overload of beta cells by early exogenous insulin therapy or insulin sensitizers can temporarily reduce loss of beta cell mass/function early in diabetes, a focus on relieving ER and inflammatory stress is also of interest to preserve beta cell health.

ER stress is a well known contributor to beta cell demise both in T1D and T2D (Laybutt et al., 2007 ; Marchetti et al., 2007 ; Marhfour et al., 2012 ; Tersey et al., 2012 ) and a target of interest in the prevention of beta cell loss in both diseases. Preclinical studies suggest that the use of chemical chaperones, including 4-phenylbutyric acid and tauroursodeoxycholic acid (TUDCA), to alleviate ER stress improves beta cell function and insulin sensitivity in mouse models of T2D (Cnop et al., 2017 ; Ozcan et al., 2006 ). Furthermore, TUDCA has been shown to preserve beta cell mass and reduce ER stress in mouse models of T1D (Engin et al., 2013 ). Interestingly, TUDCA has shown promise at improving insulin action in obese nondiabetic human subjects, yet beta cell function and insulin secretion were not assessed (Kars et al., 2010 ). A clinical trial regarding the use of TUDCA for humans with new-onset T1D is also ongoing ( {"type":"clinical-trial","attrs":{"text":"NCT02218619","term_id":"NCT02218619"}} NCT02218619 ). However, a note of caution regarding use of ER chaperones is that they may prevent low level ER stress necessary to potentiate beta cell replication during states of increased insulin demand (Sharma et al., 2015 ), suggesting that the broad use of ER chaperone therapies should be carefully considered.

The blockade of inflammatory stress has long been an area of interest for treatments of both T1D and T2D (Donath et al., 2019 ; Eguchi and Nagai, 2017 ). Indeed, use of nonsteroidal anti-inflammatory drugs (NSAIDs), which block cyclooxygenase, have been observed to improve metabolic control in patients with diabetes since the turn of the 20th century (Williamson, 1901 ). Salicylates have been shown to improve insulin secretion and beta cell function in both obese human subjects and those with T2D (Fernandez-Real et al., 2008; Giugliano et al., 1985 ). However, another NSAID, salsalate, has not been shown to improve beta cell function while improving other metabolic outcomes (Kim et al., 2014 ; Penesova et al., 2015 ), possibly suggesting distinct mechanisms of action for anti-inflammatory compounds. The regular use of NSAIDs to enhance metabolic outcomes is also often limited to the tolerability of long-term use of these agents due to adverse effects. Recently, golilumab, a monoclonal antibody against the proinflammatory cytokine tumor necrosis factor alpha, was demonstrated to improve beta cell function in new-onset T1D, suggesting that targeting the underlying inflammatory milieu may have benefits to preserve beta cell mass and function in T1D (Quattrin et al., 2020). Taken together, both new and old approaches to target beta cell stressors still remain of long-term interest to improve beta cell viability and function in both T1D and T2D.

3. New Players to Induce Islet Immune Protection

Countless researchers have expended intense industry to determine T1D disease etiology and treatments focused on immunotherapy and tolerogenic methods. Multiple, highly comprehensive reviews are available describing these efforts (Goudy and Tisch, 2005 ; Rewers and Gottlieb, 2009 ; Stojanovic et al., 2017 ). Here we will focus on the protection of beta cells through programmed cell death protein-1 ligand (PD-L1) overexpression, major histocompatibility complex class I, A, B, C (HLA-A,B,C) mutated human embryonic stem cell–derived beta cells, and islet encapsulation methods.

Cancer immunotherapies that block immune checkpoints are beneficial for treating advanced stage cancers, yet induction of autoimmune diseases, including T1D, remains a potential side effect (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). A subset of these drugs target either the programmed cell death-1 protein on the surface of activated T lymphocytes or its receptor PD-L1 (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). PD-L1 expression was found in insulin-positive beta cells from T1D but not insulin-negative islets or nondiabetic islets, leading to the hypothesis that PD-L1 is upregulated in an attempt to drive immune cell attenuation (Osum et al., 2018 ; Colli et al., 2018 ). Adenoviral overexpression of PD-L1 specifically in beta cells rescued hyperglycemia in the NOD mouse model of T1D, but these animals eventually succumbed to diabetes by the study’s termination (El Khatib et al., 2015 ). A more promising report from Ben Nasr et al. ( 2017 ) demonstrated that pharmacologically or genetically induced overexpression of PD-L1 in hematopoietic stem and progenitor cells inhibited beta cell autoimmunity in the NOD mouse as well as in vitro using human hematopoietic stem and progenitor cells from patients with T1D.

As mentioned above, islet transplantation to treat T1D is limited by islet availability, cost, and the requirement for continuous immunosuppression. Islet cells generated by differentiating embryonic or induced pluripotent stem (iPS) cells could circumvent these limitations. Ideally, iPS-derived beta cells could be manipulated to eliminate the expression of polymorphic HLA-A,B,C molecules, which were found to be upregulated in T1D beta cells (Bottazzo et al., 1985 ; Richardson et al., 2016 ). These molecules allow peptide presentation to CD8+ T cells or cytotoxic T lymphocytes and may lead to beta cell removal. Interestingly, remaining insulin-positive cells in T1D donor pancreas are not HLA-A,B,C positive (Nejentsev et al., 2007; Rodriguez-Calvo et al., 2015 ). However, current differentiation protocols are still limited in their ability to produce fully glucose-responsive beta cells without transplantation into animal models to induce mature characteristics. Additionally, use of iPS-derived beta cells will still lead to concerns regarding DNA mutagenesis resulting from the methods used to obtain pluripotency or teratoma formation from cells that have escaped differentiation.

Encapsulation devices would protect islets or stem cells from immune cell infiltration while allowing for the proper exchange of nutrients and hormones. Macroencapsulation uses removable devices that would help assuage fears surrounding mutation or tumor formation; indeed, the first human trial using encapsulated hESC-derived beta cells will be completed in January 2021 ( {"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}} NCT02239354 ). Macroencapsulation of islets prior to transplantation using various alginate-based hydrogels has historically been impeded by a strong in vivo foreign body immune response (Desai and Shea, 2017 ; Doloff et al., 2017 ; Pueyo et al., 1993 ). More recently, chemically modified forms of alginate that avoid macrophage recognition and fibrous deposition have been successfully used in rodents and for up to 6 months in nonhuman primates (Vegas et al., 2016 ). Indeed, Bochenek et al. ( 2018 ) successfully transplanted alginate protected islets for 4 months without immunosuppression in the bursa omentalis of nonhuman primates demonstrating the feasibility for this approach to be extended to humans. It remains to be seen if these devices will be successful for long-term use, perhaps decades, in patients with diabetes.

III. Summary

Although existing drug therapies using classic oral antidiabetic drugs like sulfonylureas and metformin or injected insulin remain mainstays of diabetes treatment, newer drugs based on incretin hormone actions or SGLT2 inhibitors have increased the pharmacological armamentarium available to diabetologists ( Fig. 1 ). However, the explosion of progress in beta cell biology has identified potential avenues that can increase beta cell mass in sophisticated ways by employing stem cell differentiation or enhancement of beta cell proliferation. Taken together, there should be optimism that the increased incidence of both T1D and T2D is being matched by the creativity and hard work of the diabetes research community.

Abbreviations

Authorship Contributions

Wrote and contributed to the writing of the manuscript: Satin, Soleimanpour, Walker

This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Grant R01-DK46409] (to L.S.S.), [Grant R01-DK108921] (to S.A.S.), and [Grant P30-DK020572 pilot and feasibility grant] (to S.A.S.), the Juvenile Diabetes Research Foundation (JDRF) [Grant CDA-2016-189] (to L.S.S. and S.A.S.), [Grant SRA-2018-539] (to S.A.S.), and [Grant COE-2019-861] (to S.A.S.), and the US Department of Veterans Affairs [Grant I01 BX004444] (to S.A.S.). The JDRF Career Development Award to S.A.S. is partly supported by the Danish Diabetes Academy and the Novo Nordisk Foundation.

https://doi.org/10.1124/pharmrev.120.000160

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How to Write a Research Paper | A Beginner's Guide

A research paper is a piece of academic writing that provides analysis, interpretation, and argument based on in-depth independent research.

Research papers are similar to academic essays , but they are usually longer and more detailed assignments, designed to assess not only your writing skills but also your skills in scholarly research. Writing a research paper requires you to demonstrate a strong knowledge of your topic, engage with a variety of sources, and make an original contribution to the debate.

This step-by-step guide takes you through the entire writing process, from understanding your assignment to proofreading your final draft.

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Table of contents

Understand the assignment, choose a research paper topic, conduct preliminary research, develop a thesis statement, create a research paper outline, write a first draft of the research paper, write the introduction, write a compelling body of text, write the conclusion, the second draft, the revision process, research paper checklist, free lecture slides.

Completing a research paper successfully means accomplishing the specific tasks set out for you. Before you start, make sure you thoroughly understanding the assignment task sheet:

• Read it carefully, looking for anything confusing you might need to clarify with your professor.
• Identify the assignment goal, deadline, length specifications, formatting, and submission method.
• Make a bulleted list of the key points, then go back and cross completed items off as you’re writing.

Carefully consider your timeframe and word limit: be realistic, and plan enough time to research, write, and edit.

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There are many ways to generate an idea for a research paper, from brainstorming with pen and paper to talking it through with a fellow student or professor.

You can try free writing, which involves taking a broad topic and writing continuously for two or three minutes to identify absolutely anything relevant that could be interesting.

You can also gain inspiration from other research. The discussion or recommendations sections of research papers often include ideas for other specific topics that require further examination.

Once you have a broad subject area, narrow it down to choose a topic that interests you, m eets the criteria of your assignment, and i s possible to research. Aim for ideas that are both original and specific:

• A paper following the chronology of World War II would not be original or specific enough.
• A paper on the experience of Danish citizens living close to the German border during World War II would be specific and could be original enough.

Note any discussions that seem important to the topic, and try to find an issue that you can focus your paper around. Use a variety of sources , including journals, books, and reliable websites, to ensure you do not miss anything glaring.

Do not only verify the ideas you have in mind, but look for sources that contradict your point of view.

• Is there anything people seem to overlook in the sources you research?
• Are there any heated debates you can address?
• Do you have a unique take on your topic?
• Have there been some recent developments that build on the extant research?

In this stage, you might find it helpful to formulate some research questions to help guide you. To write research questions, try to finish the following sentence: “I want to know how/what/why…”

A thesis statement is a statement of your central argument — it establishes the purpose and position of your paper. If you started with a research question, the thesis statement should answer it. It should also show what evidence and reasoning you’ll use to support that answer.

The thesis statement should be concise, contentious, and coherent. That means it should briefly summarize your argument in a sentence or two, make a claim that requires further evidence or analysis, and make a coherent point that relates to every part of the paper.

You will probably revise and refine the thesis statement as you do more research, but it can serve as a guide throughout the writing process. Every paragraph should aim to support and develop this central claim.

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A research paper outline is essentially a list of the key topics, arguments, and evidence you want to include, divided into sections with headings so that you know roughly what the paper will look like before you start writing.

A structure outline can help make the writing process much more efficient, so it’s worth dedicating some time to create one.

Your first draft won’t be perfect — you can polish later on. Your priorities at this stage are as follows:

• Maintaining forward momentum — write now, perfect later.
• Paying attention to clear organization and logical ordering of paragraphs and sentences, which will help when you come to the second draft.
• Expressing your ideas as clearly as possible, so you know what you were trying to say when you come back to the text.

You do not need to start by writing the introduction. Begin where it feels most natural for you — some prefer to finish the most difficult sections first, while others choose to start with the easiest part. If you created an outline, use it as a map while you work.

Do not delete large sections of text. If you begin to dislike something you have written or find it doesn’t quite fit, move it to a different document, but don’t lose it completely — you never know if it might come in useful later.

Paragraph structure

Paragraphs are the basic building blocks of research papers. Each one should focus on a single claim or idea that helps to establish the overall argument or purpose of the paper.

Example paragraph

George Orwell’s 1946 essay “Politics and the English Language” has had an enduring impact on thought about the relationship between politics and language. This impact is particularly obvious in light of the various critical review articles that have recently referenced the essay. For example, consider Mark Falcoff’s 2009 article in The National Review Online, “The Perversion of Language; or, Orwell Revisited,” in which he analyzes several common words (“activist,” “civil-rights leader,” “diversity,” and more). Falcoff’s close analysis of the ambiguity built into political language intentionally mirrors Orwell’s own point-by-point analysis of the political language of his day. Even 63 years after its publication, Orwell’s essay is emulated by contemporary thinkers.

Citing sources

It’s also important to keep track of citations at this stage to avoid accidental plagiarism . Each time you use a source, make sure to take note of where the information came from.

You can use our free citation generators to automatically create citations and save your reference list as you go.

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The research paper introduction should address three questions: What, why, and how? After finishing the introduction, the reader should know what the paper is about, why it is worth reading, and how you’ll build your arguments.

What? Be specific about the topic of the paper, introduce the background, and define key terms or concepts.

Why? This is the most important, but also the most difficult, part of the introduction. Try to provide brief answers to the following questions: What new material or insight are you offering? What important issues does your essay help define or answer?

How? To let the reader know what to expect from the rest of the paper, the introduction should include a “map” of what will be discussed, briefly presenting the key elements of the paper in chronological order.

The major struggle faced by most writers is how to organize the information presented in the paper, which is one reason an outline is so useful. However, remember that the outline is only a guide and, when writing, you can be flexible with the order in which the information and arguments are presented.

One way to stay on track is to use your thesis statement and topic sentences . Check:

• topic sentences against the thesis statement;
• topic sentences against each other, for similarities and logical ordering;
• and each sentence against the topic sentence of that paragraph.

Be aware of paragraphs that seem to cover the same things. If two paragraphs discuss something similar, they must approach that topic in different ways. Aim to create smooth transitions between sentences, paragraphs, and sections.

The research paper conclusion is designed to help your reader out of the paper’s argument, giving them a sense of finality.

Trace the course of the paper, emphasizing how it all comes together to prove your thesis statement. Give the paper a sense of finality by making sure the reader understands how you’ve settled the issues raised in the introduction.

You might also discuss the more general consequences of the argument, outline what the paper offers to future students of the topic, and suggest any questions the paper’s argument raises but cannot or does not try to answer.

You should not :

• Offer new arguments or essential information
• Take up any more space than necessary
• Begin with stock phrases that signal you are ending the paper (e.g. “In conclusion”)

There are four main considerations when it comes to the second draft.

• Check how your vision of the paper lines up with the first draft and, more importantly, that your paper still answers the assignment.
• Identify any assumptions that might require (more substantial) justification, keeping your reader’s perspective foremost in mind. Remove these points if you cannot substantiate them further.
• Be open to rearranging your ideas. Check whether any sections feel out of place and whether your ideas could be better organized.
• If you find that old ideas do not fit as well as you anticipated, you should cut them out or condense them. You might also find that new and well-suited ideas occurred to you during the writing of the first draft — now is the time to make them part of the paper.

The goal during the revision and proofreading process is to ensure you have completed all the necessary tasks and that the paper is as well-articulated as possible. You can speed up the proofreading process by using the AI proofreader .

Global concerns

• Confirm that your paper completes every task specified in your assignment sheet.
• Check for logical organization and flow of paragraphs.
• Check paragraphs against the introduction and thesis statement.

Fine-grained details

Check the content of each paragraph, making sure that:

• each sentence helps support the topic sentence.
• no unnecessary or irrelevant information is present.
• all technical terms your audience might not know are identified.

Next, think about sentence structure , grammatical errors, and formatting . Check that you have correctly used transition words and phrases to show the connections between your ideas. Look for typos, cut unnecessary words, and check for consistency in aspects such as heading formatting and spellings .

Finally, you need to make sure your paper is correctly formatted according to the rules of the citation style you are using. For example, you might need to include an MLA heading  or create an APA title page .

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Checklist: Research paper

I have followed all instructions in the assignment sheet.

My introduction presents my topic in an engaging way and provides necessary background information.

My introduction presents a clear, focused research problem and/or thesis statement .

My paper is logically organized using paragraphs and (if relevant) section headings .

Each paragraph is clearly focused on one central idea, expressed in a clear topic sentence .

Each paragraph is relevant to my research problem or thesis statement.

I have used appropriate transitions  to clarify the connections between sections, paragraphs, and sentences.

My conclusion provides a concise answer to the research question or emphasizes how the thesis has been supported.

My conclusion shows how my research has contributed to knowledge or understanding of my topic.

My conclusion does not present any new points or information essential to my argument.

I have provided an in-text citation every time I refer to ideas or information from a source.

I have included a reference list at the end of my paper, consistently formatted according to a specific citation style .

I have thoroughly revised my paper and addressed any feedback from my professor or supervisor.

I have followed all formatting guidelines (page numbers, headers, spacing, etc.).

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The top 10 journal articles of 2020

In 2020, APA’s 89 journals published more than 5,000 articles—the most ever and 25% more than in 2019. Here’s a quick look at the 10 most downloaded to date.

Vol. 52 No. 1 Print version: page 24

1. Me, My Selfie, and I: The Relations Between Selfie Behaviors, Body Image, Self-Objectification, and Self-Esteem in Young Women

Veldhuis, j., et al..

Young women who appreciate their bodies and consider them physical objects are more likely to select, edit, and post selfies to social media, suggests this study in Psychology of Popular Media (Vol. 9, No. 1). Researchers surveyed 179 women, ages 18 to 25, on how often they took selfies, how they selected selfies to post, how often they used filters and editing techniques, and how carefully they planned their selfie postings. They also assessed participants’ levels of body appreciation and dissatisfaction, self-objectification, and self-esteem. Higher levels of self-objectification were linked to more time spent on all selfie behaviors, while body appreciation was related to more time spent selecting selfies to post, but not frequency of taking or editing selfies. Body dissatisfaction and self-esteem were not associated with selfie behaviors. DOI: 10.1037/ppm0000206

2. A Closer Look at Appearance and Social Media: Measuring Activity, Self-Presentation, and Social Comparison and Their Associations With Emotional Adjustment

Zimmer-gembeck, m. j., et al..

This Psychology of Popular Media (online first publication) article presents a tool to assess young people’s preoccupation with their physical appearance on social media. Researchers administered a 21-item survey about social media to 281 Australian high school students. They identified 18 items with strong inter-item correlation centered on three categories of social media behavior: online self-presentation, appearance-related online activity, and appearance comparison. In a second study with 327 Australian university students, scores on the 18-item survey were found to be associated with measures of social anxiety and depressive symptoms, appearance-related support from others, general interpersonal stress, coping flexibility, sexual harassment, disordered eating, and other factors. The researchers also found that young women engaged in more appearance-related social media activity and appearance comparison than did young men. DOI: 10.1037/ppm0000277

3. The Novel Coronavirus (COVID-2019) Outbreak: Amplification of Public Health Consequences by Media Exposure

Garfin, d. r., et al..

Repeated media exposure to the COVID-19 pandemic may be associated with psychological distress and other public health consequences, according to this commentary in Health Psychology (Vol. 39, No. 5). The authors reviewed research about trends in health behavior and psychological distress as a response to media coverage of crises, including terrorist attacks, school shootings, and disease outbreaks. They found that repeated media exposure to collective crises was associated with increased anxiety and heightened acute and post-traumatic stress, with downstream effects on health outcomes such as new incidence of cardiovascular disease. Moreover, misinformation can further amplify stress responses and lead to misplaced or misguided health-protective and help-seeking behaviors. The authors recommended public health agencies use social media strategically, such as with hashtags, to keep residents updated during the pandemic. They also urged the public to avoid sensationalism and repeated coverage of the same information. DOI: 10.1037/hea0000875

4. Barriers to Mental Health Treatment Among Individuals With Social Anxiety Disorder and Generalized Anxiety Disorder

Goetter, e. m., et al..

This study in Psychological Services (Vol. 17, No. 1) indicates that 3 in 4 people who suffer from anxiety do not receive proper care. Researchers recruited 226 participants in the United States who were previously diagnosed with social anxiety disorder or generalized anxiety disorder and assessed their symptom severity and asked them to self-report any barriers to treatment. Shame and stigma were the highest cited barriers, followed by logistical and financial barriers and not knowing where to seek treatment. Participants with more severe symptoms reported more barriers to treatment than those with milder symptoms. Racial and ethnic minorities reported more barriers than racial and ethnic majorities even after controlling for symptom severity. The researchers called for increased patient education and more culturally sensitive outreach to reduce treatment barriers. DOI: 10.1037/ser0000254

5. The Construction of “Critical Thinking”: Between How We Think and What We Believe

This History of Psychology (Vol. 23, No. 3) article examines the emergence of “critical thinking” as a psychological concept. The author describes how, between World War I and World War II in the United States, the concept emerged out of growing concerns about how easily people’s beliefs could be changed and was constructed in a way that was independent of what people believed. The author delves into how original measurements of critical thinking avoided assumptions about the accuracy of specific real-world beliefs and details how subsequent critical thinking tests increasingly focused on logical abilities, often favoring outcome (what we believe) over process (how we think). DOI: 10.1037/hop0000145

6. Treatment of Alcohol Use Disorder: Integration of Alcoholics Anonymous and Cognitive Behavioral Therapy

Breuninger, m. m., et al..

This article in Training and Education in Professional Psychology (Vol. 14, No. 1) details how to work with alcohol use disorder patients who are participating in both cognitive behavioral therapy (CBT) and Alcoholics Anonymous (AA). The authors point to distinctions between AA and CBT: The goal of AA is total abstinence and the primary therapeutic relationship is with a peer in recovery, while CBT takes a less absolute approach and the primary relationship is with a psychotherapist. The authors also point to commonalities: both approaches emphasize identifying and replacing dysfunctional beliefs and place value in social support. The authors recommend clinicians and trainees become more educated about AA and recommend a translation of the 12-step language into CBT terminology to bridge the gap. DOI: 10.1037/tep0000265

7. Positivity Pays Off: Clients’ Perspectives on Positive Compared With Traditional Cognitive Behavioral Therapy for Depression

Geschwind, n., et al..

Positive cognitive behavioral therapy, a version of CBT focused on exploring exceptions to the problem rather than the problem itself, personal strengths, and embracing positivity, works well to counter depressive symptoms and build well-being, according to this study in Psychotherapy (Vol. 57, No. 3). Participants received a block of eight sessions of traditional CBT and a block of eight sessions of positive CBT. Researchers held in-depth interviews with 12 of these participants. Despite initial skepticism, most participants reported preferring positive CBT but indicated experiencing a steeper learning curve than with traditional CBT. Researchers attributed positive CBT’s favorability to four factors: feeling empowered, benefiting from effects of positive emotions, learning to appreciate baby steps, and rediscovering optimism as a personal strength. DOI: 10.1037/pst0000288

8. Targeted Prescription of Cognitive-Behavioral Therapy Versus Person-Centered Counseling for Depression Using a Machine Learning Approach

Delgadillo, j., & gonzalez salas duhne, p..

Amachine learning algorithm can identify which patients would derive more benefit from cognitive behavioral therapy (CBT) versus counseling for depression, suggests research in this Journal of Consulting and Clinical Psychology (Vol. 88, No. 1) article. Researchers retrospectively explored data from 1,085 patients in the United Kingdom treated with either CBT or counseling for depression and discovered six patient characteristics—age, employment status, disability, and three diagnostic measures of major depression and social adjustment—relevant to developing an algorithm for prescribing the best approach. The researchers then used the algorithm to determine which therapy would work best for an additional 350 patients with depression. They found that patients receiving their optimal treatment type were twice as likely to improve significantly. DOI: 10.1037/ccp0000476

9. Traumatic Stress in the Age of COVID-19: A Call to Close Critical Gaps and Adapt to New Realities

Horesh, d., & brown, a. d..

This article in Psychological Trauma: Theory, Research, Practice, and Policy (Vol. 12, No. 4) argues that COVID-19 should be examined from a post-traumatic stress perspective. The authors call for mental health researchers and clinicians to develop better diagnoses and prevention strategies for COVID-related traumatic stress; create guidelines and talking points for the media and government officials to use when speaking to an anxious, and potentially traumatized, public; and provide mental health training to professionals in health care, education, childcare, and occupational support in order to reach more people. DOI: 10.1037/tra0000592

10. Emotional Intelligence Predicts Academic Performance: A Meta-Analysis

Maccann, c., et al..

Students with high emotional intelligence get better grades and score higher on standardized tests, according to the research presented in this article in Psychological Bulletin (Vol. 146, No. 2). Researchers analyzed data from 158 studies representing more than 42,529 students—ranging in age from elementary school to college—from 27 countries. The researchers found that students with higher emotional intelligence earned better grades and scored higher on achievement tests than those with lower emotional intelligence. This finding was true even when controlling for intelligence and personality factors, and the association held regardless of age. The researchers suggest that students with higher emotional intelligence succeed because they cope well with negative emotions that can harm academic performance; they form stronger relationships with teachers, peers, and family; and their knowledge of human motivations and socialinteractions helps them understand humanities subject matter. DOI: 10.1037/bul0000219

5 interviews to listen to now

Psychology’s most innovative thinkers are featured on APA’s Speaking of Psychology podcast , which highlights important research and helps listeners apply psychology to their lives. The most popular episodes of 2020, as measured by the number of downloads in the first 30 days, were: 

• How to have meaningful dialogues despite political differences , with  Tania Israel, PhD
• Canine cognition and the survival of the friendliest , with  Brian Hare, PhD  
• The challenges faced by women in leadership , with  Alice Eagly, PhD
• How to choose effective, science-based mental health apps , with  Stephen Schueller, PhD  
• Psychedelic therapy , with Roland Griffiths, PhD  

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Home » Research Paper – Structure, Examples and Writing Guide

Research Paper – Structure, Examples and Writing Guide

Table of Contents

Research Paper

Definition:

Research Paper is a written document that presents the author’s original research, analysis, and interpretation of a specific topic or issue.

It is typically based on Empirical Evidence, and may involve qualitative or quantitative research methods, or a combination of both. The purpose of a research paper is to contribute new knowledge or insights to a particular field of study, and to demonstrate the author’s understanding of the existing literature and theories related to the topic.

Structure of Research Paper

The structure of a research paper typically follows a standard format, consisting of several sections that convey specific information about the research study. The following is a detailed explanation of the structure of a research paper:

The title page contains the title of the paper, the name(s) of the author(s), and the affiliation(s) of the author(s). It also includes the date of submission and possibly, the name of the journal or conference where the paper is to be published.

The abstract is a brief summary of the research paper, typically ranging from 100 to 250 words. It should include the research question, the methods used, the key findings, and the implications of the results. The abstract should be written in a concise and clear manner to allow readers to quickly grasp the essence of the research.

Introduction

The introduction section of a research paper provides background information about the research problem, the research question, and the research objectives. It also outlines the significance of the research, the research gap that it aims to fill, and the approach taken to address the research question. Finally, the introduction section ends with a clear statement of the research hypothesis or research question.

Literature Review

The literature review section of a research paper provides an overview of the existing literature on the topic of study. It includes a critical analysis and synthesis of the literature, highlighting the key concepts, themes, and debates. The literature review should also demonstrate the research gap and how the current study seeks to address it.

The methods section of a research paper describes the research design, the sample selection, the data collection and analysis procedures, and the statistical methods used to analyze the data. This section should provide sufficient detail for other researchers to replicate the study.

The results section presents the findings of the research, using tables, graphs, and figures to illustrate the data. The findings should be presented in a clear and concise manner, with reference to the research question and hypothesis.

The discussion section of a research paper interprets the findings and discusses their implications for the research question, the literature review, and the field of study. It should also address the limitations of the study and suggest future research directions.

The conclusion section summarizes the main findings of the study, restates the research question and hypothesis, and provides a final reflection on the significance of the research.

The references section provides a list of all the sources cited in the paper, following a specific citation style such as APA, MLA or Chicago.

How to Write Research Paper

You can write Research Paper by the following guide:

• Choose a Topic: The first step is to select a topic that interests you and is relevant to your field of study. Brainstorm ideas and narrow down to a research question that is specific and researchable.
• Conduct a Literature Review: The literature review helps you identify the gap in the existing research and provides a basis for your research question. It also helps you to develop a theoretical framework and research hypothesis.
• Develop a Thesis Statement : The thesis statement is the main argument of your research paper. It should be clear, concise and specific to your research question.
• Plan your Research: Develop a research plan that outlines the methods, data sources, and data analysis procedures. This will help you to collect and analyze data effectively.
• Collect and Analyze Data: Collect data using various methods such as surveys, interviews, observations, or experiments. Analyze data using statistical tools or other qualitative methods.
• Organize your Paper : Organize your paper into sections such as Introduction, Literature Review, Methods, Results, Discussion, and Conclusion. Ensure that each section is coherent and follows a logical flow.
• Write your Paper : Start by writing the introduction, followed by the literature review, methods, results, discussion, and conclusion. Ensure that your writing is clear, concise, and follows the required formatting and citation styles.
• Edit and Proofread your Paper: Review your paper for grammar and spelling errors, and ensure that it is well-structured and easy to read. Ask someone else to review your paper to get feedback and suggestions for improvement.
• Cite your Sources: Ensure that you properly cite all sources used in your research paper. This is essential for giving credit to the original authors and avoiding plagiarism.

Research Paper Example

Note : The below example research paper is for illustrative purposes only and is not an actual research paper. Actual research papers may have different structures, contents, and formats depending on the field of study, research question, data collection and analysis methods, and other factors. Students should always consult with their professors or supervisors for specific guidelines and expectations for their research papers.

Research Paper Example sample for Students:

Title: The Impact of Social Media on Mental Health among Young Adults

Abstract: This study aims to investigate the impact of social media use on the mental health of young adults. A literature review was conducted to examine the existing research on the topic. A survey was then administered to 200 university students to collect data on their social media use, mental health status, and perceived impact of social media on their mental health. The results showed that social media use is positively associated with depression, anxiety, and stress. The study also found that social comparison, cyberbullying, and FOMO (Fear of Missing Out) are significant predictors of mental health problems among young adults.

Introduction: Social media has become an integral part of modern life, particularly among young adults. While social media has many benefits, including increased communication and social connectivity, it has also been associated with negative outcomes, such as addiction, cyberbullying, and mental health problems. This study aims to investigate the impact of social media use on the mental health of young adults.

Literature Review: The literature review highlights the existing research on the impact of social media use on mental health. The review shows that social media use is associated with depression, anxiety, stress, and other mental health problems. The review also identifies the factors that contribute to the negative impact of social media, including social comparison, cyberbullying, and FOMO.

Methods : A survey was administered to 200 university students to collect data on their social media use, mental health status, and perceived impact of social media on their mental health. The survey included questions on social media use, mental health status (measured using the DASS-21), and perceived impact of social media on their mental health. Data were analyzed using descriptive statistics and regression analysis.

Results : The results showed that social media use is positively associated with depression, anxiety, and stress. The study also found that social comparison, cyberbullying, and FOMO are significant predictors of mental health problems among young adults.

Discussion : The study’s findings suggest that social media use has a negative impact on the mental health of young adults. The study highlights the need for interventions that address the factors contributing to the negative impact of social media, such as social comparison, cyberbullying, and FOMO.

Conclusion : In conclusion, social media use has a significant impact on the mental health of young adults. The study’s findings underscore the need for interventions that promote healthy social media use and address the negative outcomes associated with social media use. Future research can explore the effectiveness of interventions aimed at reducing the negative impact of social media on mental health. Additionally, longitudinal studies can investigate the long-term effects of social media use on mental health.

Limitations : The study has some limitations, including the use of self-report measures and a cross-sectional design. The use of self-report measures may result in biased responses, and a cross-sectional design limits the ability to establish causality.

Implications: The study’s findings have implications for mental health professionals, educators, and policymakers. Mental health professionals can use the findings to develop interventions that address the negative impact of social media use on mental health. Educators can incorporate social media literacy into their curriculum to promote healthy social media use among young adults. Policymakers can use the findings to develop policies that protect young adults from the negative outcomes associated with social media use.

References :

• Twenge, J. M., & Campbell, W. K. (2019). Associations between screen time and lower psychological well-being among children and adolescents: Evidence from a population-based study. Preventive medicine reports, 15, 100918.
• Primack, B. A., Shensa, A., Escobar-Viera, C. G., Barrett, E. L., Sidani, J. E., Colditz, J. B., … & James, A. E. (2017). Use of multiple social media platforms and symptoms of depression and anxiety: A nationally-representative study among US young adults. Computers in Human Behavior, 69, 1-9.
• Van der Meer, T. G., & Verhoeven, J. W. (2017). Social media and its impact on academic performance of students. Journal of Information Technology Education: Research, 16, 383-398.

Appendix : The survey used in this study is provided below.

Social Media and Mental Health Survey

• How often do you use social media per day?
• Less than 30 minutes
• 30 minutes to 1 hour
• 1 to 2 hours
• 2 to 4 hours
• More than 4 hours
• Which social media platforms do you use?
• Others (Please specify)
• How often do you experience the following on social media?
• Social comparison (comparing yourself to others)
• Cyberbullying
• Fear of Missing Out (FOMO)
• Have you ever experienced any of the following mental health problems in the past month?
• Do you think social media use has a positive or negative impact on your mental health?
• Very positive
• Somewhat positive
• Somewhat negative
• Very negative
• In your opinion, which factors contribute to the negative impact of social media on mental health?
• Social comparison
• In your opinion, what interventions could be effective in reducing the negative impact of social media on mental health?
• Education on healthy social media use
• Counseling for mental health problems caused by social media
• Social media detox programs
• Regulation of social media use

Thank you for your participation!

Applications of Research Paper

Research papers have several applications in various fields, including:

• Advancing knowledge: Research papers contribute to the advancement of knowledge by generating new insights, theories, and findings that can inform future research and practice. They help to answer important questions, clarify existing knowledge, and identify areas that require further investigation.
• Informing policy: Research papers can inform policy decisions by providing evidence-based recommendations for policymakers. They can help to identify gaps in current policies, evaluate the effectiveness of interventions, and inform the development of new policies and regulations.
• Improving practice: Research papers can improve practice by providing evidence-based guidance for professionals in various fields, including medicine, education, business, and psychology. They can inform the development of best practices, guidelines, and standards of care that can improve outcomes for individuals and organizations.
• Educating students : Research papers are often used as teaching tools in universities and colleges to educate students about research methods, data analysis, and academic writing. They help students to develop critical thinking skills, research skills, and communication skills that are essential for success in many careers.
• Fostering collaboration: Research papers can foster collaboration among researchers, practitioners, and policymakers by providing a platform for sharing knowledge and ideas. They can facilitate interdisciplinary collaborations and partnerships that can lead to innovative solutions to complex problems.

When to Write Research Paper

Research papers are typically written when a person has completed a research project or when they have conducted a study and have obtained data or findings that they want to share with the academic or professional community. Research papers are usually written in academic settings, such as universities, but they can also be written in professional settings, such as research organizations, government agencies, or private companies.

Here are some common situations where a person might need to write a research paper:

• For academic purposes: Students in universities and colleges are often required to write research papers as part of their coursework, particularly in the social sciences, natural sciences, and humanities. Writing research papers helps students to develop research skills, critical thinking skills, and academic writing skills.
• For publication: Researchers often write research papers to publish their findings in academic journals or to present their work at academic conferences. Publishing research papers is an important way to disseminate research findings to the academic community and to establish oneself as an expert in a particular field.
• To inform policy or practice : Researchers may write research papers to inform policy decisions or to improve practice in various fields. Research findings can be used to inform the development of policies, guidelines, and best practices that can improve outcomes for individuals and organizations.
• To share new insights or ideas: Researchers may write research papers to share new insights or ideas with the academic or professional community. They may present new theories, propose new research methods, or challenge existing paradigms in their field.

Purpose of Research Paper

The purpose of a research paper is to present the results of a study or investigation in a clear, concise, and structured manner. Research papers are written to communicate new knowledge, ideas, or findings to a specific audience, such as researchers, scholars, practitioners, or policymakers. The primary purposes of a research paper are:

• To contribute to the body of knowledge : Research papers aim to add new knowledge or insights to a particular field or discipline. They do this by reporting the results of empirical studies, reviewing and synthesizing existing literature, proposing new theories, or providing new perspectives on a topic.
• To inform or persuade: Research papers are written to inform or persuade the reader about a particular issue, topic, or phenomenon. They present evidence and arguments to support their claims and seek to persuade the reader of the validity of their findings or recommendations.
• To advance the field: Research papers seek to advance the field or discipline by identifying gaps in knowledge, proposing new research questions or approaches, or challenging existing assumptions or paradigms. They aim to contribute to ongoing debates and discussions within a field and to stimulate further research and inquiry.
• To demonstrate research skills: Research papers demonstrate the author’s research skills, including their ability to design and conduct a study, collect and analyze data, and interpret and communicate findings. They also demonstrate the author’s ability to critically evaluate existing literature, synthesize information from multiple sources, and write in a clear and structured manner.

Characteristics of Research Paper

Research papers have several characteristics that distinguish them from other forms of academic or professional writing. Here are some common characteristics of research papers:

• Evidence-based: Research papers are based on empirical evidence, which is collected through rigorous research methods such as experiments, surveys, observations, or interviews. They rely on objective data and facts to support their claims and conclusions.
• Structured and organized: Research papers have a clear and logical structure, with sections such as introduction, literature review, methods, results, discussion, and conclusion. They are organized in a way that helps the reader to follow the argument and understand the findings.
• Formal and objective: Research papers are written in a formal and objective tone, with an emphasis on clarity, precision, and accuracy. They avoid subjective language or personal opinions and instead rely on objective data and analysis to support their arguments.
• Citations and references: Research papers include citations and references to acknowledge the sources of information and ideas used in the paper. They use a specific citation style, such as APA, MLA, or Chicago, to ensure consistency and accuracy.
• Peer-reviewed: Research papers are often peer-reviewed, which means they are evaluated by other experts in the field before they are published. Peer-review ensures that the research is of high quality, meets ethical standards, and contributes to the advancement of knowledge in the field.
• Objective and unbiased: Research papers strive to be objective and unbiased in their presentation of the findings. They avoid personal biases or preconceptions and instead rely on the data and analysis to draw conclusions.

Advantages of Research Paper

Research papers have many advantages, both for the individual researcher and for the broader academic and professional community. Here are some advantages of research papers:

• Contribution to knowledge: Research papers contribute to the body of knowledge in a particular field or discipline. They add new information, insights, and perspectives to existing literature and help advance the understanding of a particular phenomenon or issue.
• Opportunity for intellectual growth: Research papers provide an opportunity for intellectual growth for the researcher. They require critical thinking, problem-solving, and creativity, which can help develop the researcher’s skills and knowledge.
• Career advancement: Research papers can help advance the researcher’s career by demonstrating their expertise and contributions to the field. They can also lead to new research opportunities, collaborations, and funding.
• Academic recognition: Research papers can lead to academic recognition in the form of awards, grants, or invitations to speak at conferences or events. They can also contribute to the researcher’s reputation and standing in the field.
• Impact on policy and practice: Research papers can have a significant impact on policy and practice. They can inform policy decisions, guide practice, and lead to changes in laws, regulations, or procedures.
• Advancement of society: Research papers can contribute to the advancement of society by addressing important issues, identifying solutions to problems, and promoting social justice and equality.

Limitations of Research Paper

Research papers also have some limitations that should be considered when interpreting their findings or implications. Here are some common limitations of research papers:

• Limited generalizability: Research findings may not be generalizable to other populations, settings, or contexts. Studies often use specific samples or conditions that may not reflect the broader population or real-world situations.
• Potential for bias : Research papers may be biased due to factors such as sample selection, measurement errors, or researcher biases. It is important to evaluate the quality of the research design and methods used to ensure that the findings are valid and reliable.
• Ethical concerns: Research papers may raise ethical concerns, such as the use of vulnerable populations or invasive procedures. Researchers must adhere to ethical guidelines and obtain informed consent from participants to ensure that the research is conducted in a responsible and respectful manner.
• Limitations of methodology: Research papers may be limited by the methodology used to collect and analyze data. For example, certain research methods may not capture the complexity or nuance of a particular phenomenon, or may not be appropriate for certain research questions.
• Publication bias: Research papers may be subject to publication bias, where positive or significant findings are more likely to be published than negative or non-significant findings. This can skew the overall findings of a particular area of research.
• Time and resource constraints: Research papers may be limited by time and resource constraints, which can affect the quality and scope of the research. Researchers may not have access to certain data or resources, or may be unable to conduct long-term studies due to practical limitations.

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Title: scalable diffusion models with transformers.

Abstract: We explore a new class of diffusion models based on the transformer architecture. We train latent diffusion models of images, replacing the commonly-used U-Net backbone with a transformer that operates on latent patches. We analyze the scalability of our Diffusion Transformers (DiTs) through the lens of forward pass complexity as measured by Gflops. We find that DiTs with higher Gflops -- through increased transformer depth/width or increased number of input tokens -- consistently have lower FID. In addition to possessing good scalability properties, our largest DiT-XL/2 models outperform all prior diffusion models on the class-conditional ImageNet 512x512 and 256x256 benchmarks, achieving a state-of-the-art FID of 2.27 on the latter.

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OpenAI Offers a Peek Inside the Guts of ChatGPT

ChatGPT developer OpenAI’s approach to building artificial intelligence came under fire this week from former employees who accuse the company of taking unnecessary risks with technology that could become harmful.

Today, OpenAI released a new research paper apparently aimed at showing it is serious about tackling AI risk by making its models more explainable. In the paper , researchers from the company lay out a way to peer inside the AI model that powers ChatGPT. They devise a method of identifying how the model stores certain concepts—including those that might cause an AI system to misbehave.

Although the research makes OpenAI’s work on keeping AI in check more visible, it also highlights recent turmoil at the company. The new research was performed by the recently disbanded “superalignment” team at OpenAI that was dedicated to studying the technology’s long-term risks.

The former group’s coleads, Ilya Sutskever and Jan Leike—both of whom have left OpenAI —are named as coauthors. Sutskever, a cofounder of OpenAI and formerly chief scientist, was among the board members who voted to fire CEO Sam Altman last November, triggering a chaotic few days that culminated in Altman’s return as leader.

ChatGPT is powered by a family of so-called large language models called GPT, based on an approach to machine learning known as artificial neural networks. These mathematical networks have shown great power to learn useful tasks by analyzing example data, but their workings cannot be easily scrutinized as conventional computer programs can. The complex interplay between the layers of “neurons” within an artificial neural network makes reverse engineering why a system like ChatGPT came up with a particular response hugely challenging.

“Unlike with most human creations, we don’t really understand the inner workings of neural networks,” the researchers behind the work wrote in an accompanying blog post . Some prominent AI researchers believe that the most powerful AI models, including ChatGPT, could perhaps be used to design chemical or biological weapons and coordinate cyberattacks. A longer-term concern is that AI models may choose to hide information or act in harmful ways in order to achieve their goals.

OpenAI’s new paper outlines a technique that lessens the mystery a little, by identifying patterns that represent specific concepts inside a machine learning system with help from an additional machine learning model. The key innovation is in refining the network used to peer inside the system of interest by identifying concepts, to make it more efficient.

OpenAI proved out the approach by identifying patterns that represent concepts inside GPT-4, one of its largest AI models. The company released code related to the interpretability work, as well as a visualization tool that can be used to see how words in different sentences activate concepts, including profanity and erotic content, in GPT-4 and another model. Knowing how a model represents certain concepts could be a step toward being able to dial down those associated with unwanted behavior, to keep an AI system on the rails. It could also make it possible to tune an AI system to favor certain topics or ideas.

By Scott Gilbertson

By Simon Hill

By Julian Chokkattu

By Brenda Stolyar

Even though LLMs defy easy interrogation, a growing body of research suggests they can be poked and prodded in ways that reveal useful information. Anthropic, an OpenAI competitor backed by Amazon and Google, published similar work on AI interpretability last month. To demonstrate how the behavior of AI systems might be tuned, the company's researchers created a chatbot obsessed with San Francisco's Golden Gate Bridge . And simply asking an LLM to explain its reasoning can sometimes yield insights .

“It’s exciting progress,” says David Bau , a professor at Northeastern University who works on AI explainability, of the new OpenAI research. “As a field, we need to be learning how to understand and scrutinize these large models much better.”

Bau says the OpenAI team’s main innovation is in showing a more efficient way to configure a small neural network that can be used to understand the components of a larger one. But he also notes that the technique needs to be refined to make it more reliable. “There’s still a lot of work ahead in using these methods to create fully understandable explanations,” Bau says.

Bau is part of a US government-funded effort called the National Deep Inference Fabric , which will make cloud computing resources available to academic researchers so that they too can probe especially powerful AI models. “We need to figure out how we can enable scientists to do this work even if they are not working at these large companies,” he says.

OpenAI’s researchers acknowledge in their paper that further work needs to be done to improve their method, but also say they hope it will lead to practical ways to control AI models. “We hope that one day, interpretability can provide us with new ways to reason about model safety and robustness, and significantly increase our trust in powerful AI models by giving strong assurances about their behavior,” they write.

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The best new science fiction books of May 2024

A new Stephen King short story collection, an Ursula K. Le Guin reissue and a celebration of cyberpunk featuring writing from Philip K. Dick and Cory Doctorow are among the new science fiction titles published this month

By Alison Flood

A new short story collection from Stephen King, You Like It Darker, is out in May

Shane Leonard

Every month, I trawl through publishers’ catalogues so I can tell you about the new science fiction being released. And every month, I’m disappointed to see so much more fantasy on publishers’ lists than sci-fi. I know it’s a response to the huge boom in readers of what’s been dubbed “ romantasy ”, and I’m not knocking it – I love that sort of book too. But it would be great to see more good, hard, mind-expanding sci-fi in the offing as well.

In the meantime, there is definitely enough for us sci-fi fans to sink our teeth into this month, whether it’s a reissue of classic writing from Ursula K. Le Guin, some new speculative short stories from Stephen King or murder in space from Victor Manibo and S. A. Barnes.

Last month, I tipped Douglas Preston’s Extinction and Sofia Samatar’s The Practice, the Horizon, and the Chain as books I was looking forward to. I can report that they were both excellent: Extinction was a lot of good, clean, Jurassic Park -tinged fun, while Samatar’s offering was a beautiful and thought-provoking look at life on a generation ship.

The Language of the Night: Essays on writing, science fiction, and fantasy by Ursula K. Le Guin

There are few sci-fi and fantasy writers more brilliant (and revered) than Ursula K. Le Guin. This reissue of her first full-length collection of essays features a new introduction from Hugo and Nebula award-winner Ken Liu and covers the writing of The Left Hand of Darkness and A Wizard of Earthsea , as well as her advocacy for sci-fi and fantasy as legitimate literary mediums. I’ve read some of these essays but not all, and I won’t be missing this collection.

Nuclear War: A Scenario by Annie Jacobsen

This isn’t science fiction, not quite, but it is one of the best and most important books I have read for some time. It sees Jacobsen lay out, minute by minute, what would happen if an intercontinental ballistic missile hit Washington DC. How would the US react? What, exactly, happens if deterrence fails? Jacobsen has spoken to dozens of military experts to put together what her publisher calls a “non-fiction thriller”, and what I call the scariest book I have possibly ever read (and I’m a Stephen King fan; see below). We’re currently reading it at the New Scientist Book Club, and you can sign up to join us here .

New Scientist book club

Love reading? Come and join our friendly group of fellow book lovers. Every six weeks, we delve into an exciting new title, with members given free access to extracts from our books, articles from our authors and video interviews.

The Big Book of Cyberpunk (Vol 1 & 2)

Forty years ago, William Gibson published Neuromancer . Since then, it has entranced millions of readers right from its unforgettable opening line: “The sky above the port was the color of television, tuned to a dead channel…”. Neuromancer gave us the literary genre that is cyberpunk, and we can now welcome a huge, two-volume anthology celebrating cyberpunk’s best stories, by writers from Cory Doctorow to Justina Robson, and from Samuel R. Delaney to Philip K. Dick. I have both glorious-sounding volumes, brought together by anthologist Jared Shurin, on my desk (using up most of the space on it), and I am looking forward to dipping in.

You Like It Darker by Stephen King

You could categorise Stephen King as a horror writer. I see him as an expert chronicler of the dark side of small-town America, and from The Tommyknockers and its aliens to Under the Dome with its literally divisive trope, he frequently slides into sci-fi. Even the horror at the heart of It is some sort of cosmic hideousness. He is one of my favourite writers, and You Like It Darker is a new collection of short stories that moves from “the folds in reality where anything can happen” to a “psychic flash” that upends dozens of lives. There’s a sequel to Cujo , and a look at “corners of the universe best left unexplored”. I’ve read the first story so far, and I can confirm there is plenty for us sci-fi fans here.

Enlightenment by Sarah Perry

Not sci-fi, but fiction about science – and from one of the UK’s most exciting writers (if you haven’t read The Essex Serpent yet, you’re in for a treat). This time, Perry tells the story of Thomas Hart, a columnist on the Essex Chronicle who becomes a passionate amateur astronomer as the comet Hale-Bopp approaches in 1997. Our sci-fi columnist Emily Wilson is reviewing it for New Scientist ’s 11 May issue, and she has given it a vigorous thumbs up (“a beautiful, compassionate and memorable book,” she writes in a sneak preview just for you guys).

Ghost Station by S.A. Barnes

Dr Ophelia Bray is a psychologist and expert in the study of Eckhart-Reiser syndrome, a fictional condition that affects space travellers in terrible ways. She’s sent to help a small crew whose colleague recently died, but as they begin life on an abandoned planet, she realises that her charges are hiding something. And then the pilot is murdered… Horror in space? Mysterious planets? I’m up for that.

In Hey, Zoey, the protagonist finds an animatronic sex doll hidden in her garage

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Hey, Zoey by Sarah Crossan

Hot on the heels of Sierra Greer’s story about a sex robot wondering what it means to be human in Annie Bot , the acclaimed young adult and children’s author Sarah Crossan has ventured into similar territory. In Hey, Zoey , Dolores finds an animatronic sex doll hidden in her garage and assumes it belongs to her husband David. She takes no action – but then Dolores and Zoey begin to talk, and Dolores’s life changes.

How to Become the Dark Lord and Die Trying by Django Wexler

Davi has tried to take down the Dark Lord before, rallying humanity and making the final charge – as you do. But the time loop she is stuck in always defeats her, and she loses the battle in the end. This time around, Davi decides that the best thing to do is to become the Dark Lord herself. You could argue that this is fantasy, but it has a time loop, so I’m going to count it as sci-fi. It sounds fun and lighthearted: quotes from early readers are along the lines of “A darkly comic delight”, and we could all use a bit of that these days.

Escape Velocity by Victor Manibo

It’s 2089, and there’s an old murder hanging over the clientele of Space Habitat Altaire, a luxury space hotel, while an “unforeseen threat” is also brewing in the service corridors. A thriller in space? Sounds excellent – and I’m keen to see if Manibo makes use of the latest research into the angle at which blood might travel following violence in space, as reported on by our New Scientist humour columnist Marc Abrahams recently.

The best new science fiction books of March 2024

With a new Adrian Tchaikovsky, Mars-set romance from Natasha Pulley and a high-concept thriller from Stuart Turton due to hit shelves, there is plenty of great new science fiction to be reading in March

In Our Stars by Jack Campbell

Part of the Doomed Earth series, this follows Lieutenant Selene Genji, who has been genetically engineered with partly alien DNA and has “one last chance to save the Earth from destruction”. Beautifully retro cover for this space adventure – not to judge a book in this way, of course…

The Downloaded by Robert J. Sawyer

Two sets of people have had their minds uploaded into a quantum computer in the Ontario of 2059. Astronauts preparing for the world’s first interstellar voyage form one group; the other contains convicted murderers, sentenced to a virtual-reality prison. Naturally, disaster strikes, and, yup, they must work together to save Earth from destruction. Originally released as an Audible Original with Brendan Fraser as lead narrator, this is the first print edition of the Hugo and Nebula award-winning Sawyer’s 26 th novel.

The Ferryman by Justin Cronin

Just in case you still haven’t read it, Justin Cronin’s gloriously dreamy novel The Ferryman , set on an apparently utopian island where things aren’t quite as they seem, is out in paperback this month. It was the first pick for the New Scientist Book Club, and it is a mind-bending, dreamy stunner of a read. Go try it – and sign up for the Book Club in the meantime!

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After Affirmative Action Ban, They Rewrote College Essays With a Key Theme: Race

The Supreme Court’s ruling intended to remove the consideration of race during the admissions process. So students used their essays to highlight their racial background.

By Bernard Mokam

Bernard Mokam interviewed dozens of high school students, parents and counselors about preparing college applications in a new landscape.

Astrid Delgado first wrote her college application essay about a death in her family. Then she reshaped it around a Spanish book she read as a way to connect to her Dominican heritage.

Deshayne Curley wanted to leave his Indigenous background out of his essay. But he reworked it to focus on an heirloom necklace that reminded him of his home on the Navajo Reservation.

The first draft of Jyel Hollingsworth’s essay explored her love for chess. The final focused on the prejudice between her Korean and Black American families and the financial hardships she overcame.

All three students said they decided to rethink their essays to emphasize one key element: their racial identities. And they did so after the Supreme Court last year struck down affirmative action in college admissions, leaving essays the only place for applicants to directly indicate their racial and ethnic backgrounds.

High school students graduating this year worked on their college applications, due this month, in one of the most turbulent years in American education. Not only have they had to prepare them in the backdrop of the Israel-Hamas war — which sparked debates about free speech and antisemitism on college campuses, leading to the resignation of two Ivy League presidents — but they also had to wade through the new ban on race-conscious admissions.

“It has been a lot to take in,” said Keteyian Cade, a 17-year-old from St. Louis. “There is so much going on in the world right now.”

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The social media platforms of the twenty-first century have an enormous role in regulating speech in the USA and worldwide 1 . However, there has been little research on platform-wide interventions on speech 2 , 3 . Here we evaluate the effect of the decision by Twitter to suddenly deplatform 70,000 misinformation traffickers in response to the violence at the US Capitol on 6 January 2021 (a series of events commonly known as and referred to here as ‘January 6th’). Using a panel of more than 500,000 active Twitter users 4 , 5 and natural experimental designs 6 , 7 , we evaluate the effects of this intervention on the circulation of misinformation on Twitter. We show that the intervention reduced circulation of misinformation by the deplatformed users as well as by those who followed the deplatformed users, though we cannot identify the magnitude of the causal estimates owing to the co-occurrence of the deplatforming intervention with the events surrounding January 6th. We also find that many of the misinformation traffickers who were not deplatformed left Twitter following the intervention. The results inform the historical record surrounding the insurrection, a momentous event in US history, and indicate the capacity of social media platforms to control the circulation of misinformation, and more generally to regulate public discourse.

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Ideological differences in the expanse of the moral circle

Misunderstanding the harms of online misinformation

Determinants of behaviour and their efficacy as targets of behavioural change interventions

Data availability.

Aggregate data used in the analysis are publicly available at the OSF project website ( https://doi.org/10.17605/OSF.IO/KU8Z4 ) to any researcher for purposes of reproducing or extending the analysis. The tweet-level data and specific user demographics cannot be publicly shared owing to privacy concerns arising from matching data to administrative records, data use agreements and platforms’ terms of service. Our replication materials include the code used to produce the aggregate data from the tweet-level data, and the tweet-level data can be accessed after signing a data-use agreement. For access requests, please contact D.M.J.L.

Code availability

All code necessary for reproduction of the results is available at the OSF project site https://doi.org/10.17605/OSF.IO/KU8Z4 .

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Acknowledgements

The authors thank N. Grinberg, L. Friedland and K. Joseph for earlier technical work on the development of the Twitter dataset. Earlier versions of this paper were presented at the Social Media Analysis Workshop, UC Riverside, 26 August 2022; at the Annual Meeting of the American Political Science Association, 17 September 2022; and at the Center for Social Media and Politics, NYU, 23 April 2021. Special thanks go to A. Guess for suggesting the DID analysis. D.M.J.L. acknowledges support from the William & Flora Hewlett Foundation and the Volkswagen Foundation. S.D.M. was supported by the John S. and James L. Knight Foundation through a grant to the Institute for Data, Democracy & Politics at the George Washington University.

Author information

These authors contributed equally: Stefan D. McCabe, Diogo Ferrari

Authors and Affiliations

Institute for Data, Democracy & Politics, George Washington University, Washington, DC, USA

Stefan D. McCabe

Department of Political Science, University of California, Riverside, Riverside, CA, USA

Diogo Ferrari & Kevin M. Esterling

Department of Political Science, Duke University, Durham, NC, USA

Network Science Institute, Northeastern University, Boston, MA, USA

David M. J. Lazer

Institute for Quantitative Social Science, Harvard University, Cambridge, MA, USA

School of Public Policy, University of California, Riverside, Riverside, CA, USA

Kevin M. Esterling

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Contributions

The order of author listed here does not indicate level of contribution. Conceptualization of theory and research design: S.D.M., D.M.J.L., D.F., K.M.E. and J.G. Data curation: S.D.M. and J.G. Methodology: D.F. Visualization: D.F. Funding acquisition: D.M.J.L. Project administration: K.M.E., S.D.M. and D.M.J.L. Writing, original draft: K.M.E. and D.M.J.L. Writing, review and editing: K.M.E., D.F., S.D.M., D.M.J.L. and J.G.

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Correspondence to David M. J. Lazer .

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Extended data figures and tables

Extended data fig. 1 replication of the did results varying the number of deplatformed accounts..

DID estimates where the intervention depends on the number of deplatformed users that were followed by the not-deplatformed misinformation sharers. Results are two-way fixed effect point estimates (dots) and 95% confidence intervals (bars) of the difference-in-differences for all activity levels combined. Estimates use ordinary least squares with clustered standard errors at user-level. The Figure shows results including and excluding Trump followers (color code). The x-axis shows the minimum number of deplatformed accounts the user followed from at least one (1+) to at least ten (10+). Total sample sizes for each dosage level: Follow Trump (No): 1: 625,865; 2: 538,460; 3: 495,723; 4: 470,380; 5: 451,468; 6: 437,574; 7: 426,772; 8: 417,200; 9: 408,672; 10: 401,467; Follow Trump (Yes): 1: 688,174; 2: 570,637; 3: 514,352; 4: 481,684; 5: 460,676; 6: 444,656; 7: 432,659; 8: 421,924; 9: 413,241; 10: 405,766.

Extended Data Fig. 2 SRD results for total (bottom row) and average (top row) misinformation tweets and retweets, for deplatformed and not-deplatformed users.

Sample size includes 546 observations (days) on average across groups (x-axis), 404 before and 136 after. The effective number of observations is 64.31 days before and after on average. The estimation excludes data between Jan 6 (cutoff point) and 12 (included). January 6th is the score value 0, and January 12th the score value 1. Optimal bandwidth of 32.6 days with triangular kernel and order-one polynomial. Bars indicate 95% robust bias-corrected confidence intervals.

Extended Data Fig. 3 Time series of the daily mean of non-misinformation URL sharing.

Degree five polynomial regression (fitted line) before and after the deplatforming intervention, separated by subgroup (panel rows), for liberal-slant news (right column), and conservative-slant news (left column) sharing activity. Shaded area around the fitted line is the 95% confidence interval of the fitted values. As a placebo test we evaluate the effect of the intervention on sharing non-fake news for each of our subgroups. Since sharing non-misinformation does not violate Twitter’s Civic Integrity policy – irrespective of the ideological slant of the news – we do not expect the intervention to have an impact on this form of Twitter engagement; see SI for how we identify liberal and conservative slant of these domains from ref. 52 . Among the subgroups, users typically did not change their sharing of liberal or conservative non-fake news. Taking these results alongside those in Fig. 2 implies that these subgroups of users did not substitute non-misinformation conservative news sharing during and after the insurrection in place of misinformation.

Extended Data Fig. 4 Time series of misinformation tweets and retweets (panel columns), separately for high, medium and low activity users (panel rows).

Fitted straight lines describe a linear regression fitted using ordinary least squares of daily total misinformation retweeted standardized (y-axis) on days (x-axis) before January 6th and after January 12th. Shaded areas around the fitted line are 95% confidence intervals.

Extended Data Fig. 5 Replicates Fig. 5 but with adjustment covariates.

Corresponding regression tables are Supplementary Information Tables 1 to 3 . Two-way fixed effect point estimates (dots) and 95% confidence intervals (bars) of the difference-in-differences for high, moderate, and low activity users, as well as all these levels combined (x-axis). P-values (stars) are from two-sided t-tests based on ordinary least squares estimates with clustered standard errors at user-level. Estimates compare followers (treated group) and not-followers (reference group) of deplatformed users after January 12th (post-treatment period) and before January 6th (pre-treatment period). No multiple test correction was used. See Supplementary Information Tables 1 – 3 for exact values with all activity level users combined. Total sample sizes of not-followers (reference) and Trump-only followers: combined: 306,089, high: 53,962, moderate: 219,375, low: 32,003; Followers: combined: 662,216, high: 156,941, moderate: 449,560, low: 53,442; Followers (4+): combined: 463,176, high: 115,264, moderate: 302,907, low: 43,218.

Extended Data Fig. 6 Placebo test of SRD results for total (bottom row) and average (top row) shopping and sports tweets and retweets at the deplatforming intervention, among those not deplatformed.

Sample size includes 545 observations (days), 404 before the intervention and 141 after. Optimal bandwidth of 843.6 days with triangular kernel and order-one polynomial. Cutoff points on January 6th (score 0) and January 12th (score 1). Bars indicate 95% robust bias-corrected confidence intervals. These are placebo tests since tweets about sports and shoppings should not be affected by the insurrection or deplatforming.

Extended Data Fig. 7 Placebo test of SRD results for total (bottom row) and average (top row) misinformation tweets and retweets using December 20th as an arbitrary cutoff point.

Sample size includes 551 observations (days), 387 before the intervention and 164 after. Optimal bandwidth of 37.2 days with triangular kernel and order-one polynomial. Bars indicate 95% robust bias-corrected confidence intervals about the SRD coefficients. This is a placebo test of the intervention period.

Extended Data Fig. 8 Placebo test of SRD results for total (bottom row) and average (top row) misinformation tweets and retweets using January 18th as a cutoff point.

The parameters are very similar to Extended Data Fig. 7 .

Supplementary information

Supplementary information.

Supplementary Figs. 1–5 provide descriptive information about our subgroups, a replication of the panel data using the Decahose, and robustness analyses for the SRD. Supplementary Tables 1–5 show full parameter estimates for the DID models, summary statistics for follower type and activity level, and P values for the DID analyses under different multiple comparisons corrections.

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McCabe, S.D., Ferrari, D., Green, J. et al. Post-January 6th deplatforming reduced the reach of misinformation on Twitter. Nature 630 , 132–140 (2024). https://doi.org/10.1038/s41586-024-07524-8

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Received : 27 October 2023

Accepted : 06 May 2024

Published : 05 June 2024

Issue Date : 06 June 2024

DOI : https://doi.org/10.1038/s41586-024-07524-8

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