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eScholarship@UMassChan is a digital repository for UMass Chan Medical School's research and scholarship, including journal articles, theses, datasets and more. We welcome submissions from our faculty, staff, and students. eScholarship@UMassChan is a service of the Lamar Soutter Library, Worcester, MA, USA.
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Unraveling the Roles of C. elegans Vasa Homologs, GLH Proteins, in Argonaute Pathway Specificity and Transcriptome SurveillanceEpigenetic regulation of gene expression empowers organisms to alter phenotypic information without affecting DNA sequence. Germline Argonaute proteins, complexed with their cognate small-RNAs, are essential for transcriptome surveillance and maintenance of heritable gene silencing. In C. elegans, PIWI Argonaute PRG-1 employs piRNAs to screen thousands of germline transcripts through microRNA-like base pairing. Upon target recognition, RNA-directed RNA polymerases (RdRPs) are recruited to generate abundant antisense small RNAs (22G-RNAs), which are subsequently loaded onto worm-specific Argonautes (WAGOs) to establish long-term epigenetic memory. Both small RNA amplification and Argonaute surveillance are thought to occur within perinuclear liquid-like condensates called nuage or P granules. The precise mechanism by which the nearly one million different perinuclear Argonaute/guide complexes engage their targets to mediate gene regulation remain unclear. In this dissertation, we explore the functions of a family of VASA homologs, Germ Line Helicases (GLHs) in diverse germline small-RNA pathways. Our genetic and biochemical investigations reveal that these perinuclear-localized DEAD-box proteins engage germline transcripts and promote piRNA- and RNA interference-mediated transgenerational silencing in C. elegans. We provide evidence that GLH proteins scaffold multiple Argonautes responsible for epigenetic silencing, competing with paralogs for direct binding to target mRNAs. Additionally, GLHs enhance the specificity of Argonuate pathways by preventing WAGO/22G-RNA misrouting. Through examining mutants without severe P-granule disruptions, we sought to separate GLH-1 scaffolding and enzymatic functions. We found that the GLH-1 ATPase cycle promotes RNA duplex unwinding and the biogenesis of WAGO-bound 22G-RNAs while many P-granule components remain properly localized. Moreover, we show that GLH-1 N-terminal domains containing both FG repeats and zinc fingers are crucial for binding Argonautes and RNA substrates. Taken together, our findings support a model in which Argonautes recruit GLH proteins for target mRNA binding and retention, enabling GLHs to regulate pathway-specific small-RNA signals and transgenerational inheritance.
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Vascular Extremity Venous UltrasoundThis presentation is part of the PEER Liberia Radiology Lecture Series. It provides an overview of vascular extremity venous ultrasound, including: normal presentation; tips and tricks for successful, high quality scanning; basic scanning protocol; image interpretation; and understanding the importance of accurate sonographic image interpretation as it relates to the development of patient care plans.
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Applying for a Job: The Young Adults Guide, Revised 2023This is a tip sheet for youth and young adults with serious mental health conditions about finding, applying for, and interviewing for jobs. This tip sheet was originally published in 2011. It has been updated for 2023.
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COVID-19 and the Cardiovascular System: Requiem for a Medical MinotaurThe world has finally emerged from the great medical, economic, and social calamity of 2020 to 2022, the COVID-19 pandemic. This Compendium of 10 articles describes various aspects of the effects of SARS-CoV-2 on the cardiovascular system, focusing on the heart. The Minotaur from Greek mythology is an apt metaphor, because this half bull/half man spike-adorned gain of function mutant slaughtered the innocent was nearly impossible to eradicate in his labyrinthian environs, inspired mass fear of the unknown, and ultimately was eliminated by resourceful, determined collaborators.1 Although SARS-CoV-2 infection has not been eliminated, it has been contained to the point of acquiring the status of a manageable infectious disease.
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Integrating evolution and genomics to investigate social development in wolf-dog hybridsDomesticated dogs separated from wolves around ~5000-7000 generations ago, with major differences in early social development that have enabled them to survive, and thrive, in close proximity to humans. Due to their unique evolutionary history and accessibility, canines serve as a natural model system to study the genetic factors underlying behavior adaptation within and between subspecies. The wolf/dog system can not only advance the understanding of evolutionary processes, but also help to better understand the neurogenetic pathways involved in human psychiatric disorders. Although wolves and dogs split relatively recently in evolutionary time, they are genetically distinct populations with numerous differences across their genome. This population structure makes it impossible to confidently associate particular genomic variants with domestication-related traits by simply comparing dogs and wolves. In this dissertation, I identified genes and pathways associated with domestication-related behavior using an unusual admixed population of wolf-dog hybrids housed in sanctuaries across the United States. I developed methods and approaches to map behavioral phenotypes in wolf-dog hybrids, and explored the overlap with dog social behaviors, and human psychiatric conditions. I first characterized the population history of wolf-dog hybrids using techniques including exploratory principal component analysis, ancestry calling, and population differentiation test. I defined the behavioral phenotypes by dimensional reduction analysis of coded video data, and identified associations between genes and regulatory elements with those phenotypes using admixture mapping and association test. Finally, I investigated the functional and biological mechanisms underlying the associated regions by gene-set analysis. I discovered that regions associated with domestication-related behavioral differences are enriched for brain expressed genes, especially those enriched in early infancy. To further investigate the candidate regions associated with canine domestication, I leveraged a powerful new data resource comparing the genomes of 240 mammalian species. Using data from massively parallel reporter assay experiments in human cells, I confirmed that this resource can distinguish which bases have regulatory function. Overall, variants in highly constrained positions are more likely to alter cellular function. In addition, I showed that dogs with ancestry from a single breed, which have shorter lifespans than outbred dogs, are also more likely to carry variants in constrained positions, suggesting they impact fitness. In the wolf-dog hybrids, I cataloged candidate causal variants that differed between dogs and wolves and were highly constrained across mammals. Overall, this thesis demonstrates how new genomic tools and data resources can be leveraged to investigate exceptional evolutionary adaptations in other species that may offer insight into human diseases. By utilizing the wolf-dog hybrid population, we can re-trace the ancient genetic changes of domestication that led to divergence of canine social and developmental behaviors, and potentially uncover genetic pathways that contribute to social behavioral disorders such as autism spectrum disorders.
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UMCCTS Newsletter, May 2023This is the May 2023 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.
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Renewal of oligodendrocyte lineage reverses dysmyelination and CNS neurodegeneration through corrected N-acetylaspartate metabolismMyelinating oligodendrocytes are essential for neuronal communication and homeostasis of the central nervous system (CNS). One of the most abundant molecules in the mammalian CNS is N-acetylaspartate (NAA), which is catabolized into L-aspartate and acetate by the enzyme aspartoacylase (ASPA) in oligodendrocytes. The resulting acetate moiety is thought to contribute to myelin lipid synthesis. In addition, affected NAA metabolism has been implicated in several neurological disorders, including leukodystrophies and demyelinating diseases such as multiple sclerosis. Genetic disruption of ASPA function causes Canavan disease, which is hallmarked by increased NAA levels, myelin and neuronal loss, large vacuole formation in the CNS, and early death in childhood. Although NAA's direct role in the CNS is inconclusive, in peripheral adipose tissue, NAA-derived acetate has been found to modify histones, a mechanism known to be involved in epigenetic regulation of cell differentiation. We hypothesize that a lack of cellular differentiation in the brain contributes to the disruption of myelination and neurodegeneration in diseases with altered NAA metabolism, such as Canavan disease. Our study demonstrates that loss of functional Aspa in mice disrupts myelination and shifts the transcriptional expression of neuronal and oligodendrocyte markers towards less differentiated stages in a spatiotemporal manner. Upon re-expression of ASPA, these oligodendrocyte and neuronal lineage markers are either improved or normalized, suggesting that NAA breakdown by Aspa plays an essential role in the maturation of neurons and oligodendrocytes. Also, this effect of ASPA re-expression is blunted in old mice, potentially due to limited ability of neuronal, rather than oligodendrocyte, recovery.
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International Inter-observer Variability of Breast Density AssessmentObjective: To determine variability in visually assessed mammographic breast density categorization among radiologists practicing in Indonesia, the Netherlands, South Africa, and the United States. Methods: Two-hundred consecutive 2D full field digital screening mammograms performed from September-December 2017 were selected and retrospectively reviewed from four global locations for a total of 800 mammograms. Three breast radiologists in each location (team) provided consensus density assessments of all 800 mammograms using BI-RADS® density categorization. Inter-reader agreement was compared using Gwet's AC2 with quadratic weighting across all four density categories and Gwet's AC1 for binary comparison of combined not dense versus dense categories. Variability of distribution between teams was calculated using the Stuart-Maxwell test of marginal homogeneity across all four categories and using McNemar's test for not dense versus dense categories. To compare readers from a particular country on their own 200 mammograms versus the other three teams, density distribution was calculated using conditional logistic regression. Results: For all 800 mammograms, inter-reader weighted agreement for distribution among four density categories is 0.86 (Gwet's AC2 with quadratic weighting 95%, CI 0.85-0.88) and for not dense vs dense categories it is 0.66 (Gwet's AC1 95%, CI 0.63-0.70). Density distribution across four density categories was significantly different when teams were compared to each other and one team versus the other three teams combined (p<0.001). Overall, all readers placed the largest number of mammograms in the scattered and heterogeneous categories. Conclusion: While reader teams from four different global locations had almost perfect inter-reader agreement in BI-RADS® density categorization, variability in density distribution across four categories remains statistically significant.
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Phosphoregulation of Cell Cycle Transcription Factors by Cyclin-Dependent KinaseTo prevent the development of cancer, cells must regulate the cell division cycle. Cell cycle events are coordinated by an oscillatory gene expression program, established by a conserved transcription factor (TF) network. Most TFs in the network are phosphorylated by cyclin-dependent kinases (CDKs), which regulate their activity. However, the physiological consequences of disrupting TF phosphorylation remain poorly understood. The budding yeast repressive TFs Yhp1 and Yox1 are degraded following multisite phosphorylation by CDK. Surprisingly, I discovered that blocking phosphorylation of Yhp1 and Yox1 increased fitness compared to wild type cells, despite decreased expression of several essential cell cycle genes. We found that cells expressing non-phosphorylatable Yhp1 and Yox1 accelerated the G1/S transition and delayed mitotic exit. This suggests that by lengthening mitosis mutant cells have more time to correct chromosome segregation errors, which confers a fitness advantage to cells. Although hundreds of CDK targets have been identified, it is challenging to determine which phosphosites within a domain are required to regulate protein function. The conserved S-phase TF Hcm1 is activated by CDK-dependent phosphorylation of eight sites in its transactivation domain (TAD). Like Yox1 and Yhp1, disruption of Hcm1 TAD phosphorylation impacts cellular fitness. I leveraged these fitness phenotypes to develop a high-throughput approach, Phosphosite Scanning, that determines the importance of each phosphosite within a multisite phosphorylated domain. I identified multiple combinations of phosphosites that can activate Hcm1 and found that specific phosphorylations are required for phosphorylation throughout the TAD. These results highlight the importance of precise TF phosphoregulation and demonstrate that disruption of phosphoregulatory networks can have unexpected consequences on cellular physiology.
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Rigid Plate Fixation for Reconstruction of Symptomatic Sternal Nonunion: A Retrospective ReviewBackground: Median sternotomy, the most common approach to open cardiac surgery, is performed in over 500,000 patients annually in the United States. This approach involves an incision from the manubrium to xyphoid and vertical division of the bony sternum. Wire cerclage remains the standard technique for sternal closure after median sternotomy. Complications following median sternotomy include infection, hematoma, seroma, and sternal nonunion or dehiscence. Sternal nonunion occurs when either significant bony motion, fracture, or separation occurs with the two sternal halves. It is clinically defined as greater than 6 months of pain, clicking, or sternal instability. This represents a failure of primary cerclage “fixation.” Risk factors for nonunion after sternotomy include obesity, bilateral internal mammary artery harvesting, diabetes, and off-midline sternotomy. While sternal nonunion has an incidence of less than 1%, this complication can serve as a nidus for life-threatening infection and can cause significant discomfort for the patient. There is currently no standard-of-care treatment for sternal nonunion after median sternotomy. In fact, sternal nonunion most commonly goes untreated, leaving patients continuously symptomatic. Rigid plate fixation (RPF) has been employed in certain cases for primary sternal closure in patients at higher risk for sternal healing complications. RPF has been shown to significantly reduce the incidence of complications and mortality after median sternotomy in high-risk patients when compared to wire cerclage. We have recently employed traditional orthopedic techniques of bony debridement, anatomic bony reduction, and have extended the use of RPF to patients with symptomatic sternal nonunion. Objectives: The goal of this retrospective review is to investigate and describe long term clinical outcomes in patients at our institution who have undergone RPF for sternal nonunion after median sternotomy. Our objectives are to investigate long term outcomes and complications in patients at our institution who have undergone rigid plate fixation for sternal nonunion after median sternotomy. Methods: All patients who underwent sternal reconstruction for sterile sternal nonunion between 2017 and 2023 were reviewed. Patients were excluded if they underwent prophylactic RPF during primary sternotomy or if they did not meet the clinical definition of sternal nonunion. Data regarding demographics, risk factors, initial sternotomy procedure, nonunion presentation, reconstructive procedure, and clinical and radiographic follow up. For sternal reconstruction, all patients underwent debridement of nonviable sternal tissue, rigid fixation with locking plates and screws with or without pectoralis muscle advancement flaps, layered closure, and incisional negative pressure wound therapy (NPWT). A total of 18 eligible patients, 14 male and 4 female, were identified. Average age was 63 years. Preoperative risk factors included obesity (n = 14), smoking (n = 9), diabetes (n = 8), and LIMA harvest (n = 16). Indication for median sternotomy included coronary artery bypass grafting (n = 16) and aortic valve replacement (n = 2). Patients presented with symptoms of sternal nonunion an average of 4.5 months after initial sternotomy. The most common presenting symptoms were pain (n = 17) and sternal clicking (n = 14). 8 patients (44%) showed evidence of fractured sternal wires. Results: Average time from symptom presentation to sternal reconstruction was 3.2 months. Average time from initial sternotomy to reconstruction was 7.7 months. Regarding the sternal reconstruction procedure, 100% of patients underwent debridement of sternal edges and rigid plate fixation using locking plates and screws. Bilateral pectoralis advancement flaps were performed in 17 patients (94%). The average clinical follow-up period was 3 years, ranging from 39 days to 4.9 years. 100% of patients had sternal nonunion confirmed by CT scan and demonstrated clinical evidence of sternal healing. Complications following RPF included seroma (n=3), hematoma (n = 2), and wound infections (n = 2). One patient presented with osteomyelitis/mediastinitis one month post sternal reconstruction, with full resolution after receiving IV and oral antibiotics. Another patient had all hardware removed after presenting with cellulitis and CT evidence of perihardware infection 3 months post reconstruction. Sternal union was noted at time of hardware removal. Conclusion: Rigid plate fixation is a reliable method of treatment for symptomatic sternal nonunion and should be offered to all patients demonstrating signs and symptoms of sternal nonunion after median sternotomy.
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The Molecular Mechanism of RIPK1-Induced Cell Death And Its Impact On The Immune ResponseReceptor-interacting serine/threonine protein kinase 1 (RIPK1) is a critical adapter protein with pleiotropic functions that regulate cell survival and death. RIPK1 is essential for immune homeostasis and thus is closely controlled during development and inflammation. RIPK1 overexpression has been implicated in multiple inflammatory disorders such as multiple sclerosis, atherosclerosis, cardiovascular disease, obesity, psoriasis, and tumor growth. To study the effects of the overactivation of RIPK1, a system was established that drives its overexpression in mouse fibroblasts. Remarkably, the overexpression of RIPK1 resulted in the induction of both apoptosis and necroptosis. While apoptosis is known to be immunologically silent, necroptosis is highly inflammatory. Additional assays using chemical inhibitors and genetic knockout mice established that RIPK1 kinase activity promotes both types of cell death. Furthermore, RIPK1-induced apoptosis and necroptosis require caspase 8 and MLKL, respectively, and the absence of both caspase 8 and MLKL inhibits RIPK1-induced cell death. RIPK1 induction activates NF-κB/MAPK and increases cytokine/chemokine production driven by cell death. This system was further explored to elucidate the effects of RIPK1-induced cell death on immune effector cells, revealing that RIPK1-induced apoptosis and necroptosis can promote DC activation. Lastly, to study the role of RIPK1 in DCs and its contribution to intestinal homeostasis and injury, mice lacking RIPK1 in the DC population were characterized. Importantly, RIPK1 functions in DCs to support colon homeostasis, but also plays a detrimental role during DSS-induced colitis. Collectively, these data further provide novel insights into the multifaceted functions of RIPK1 in cell death and inflammation, highlighting its critical contributions to the immune response.
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Pilot study of implementing the Shared Healthcare Actions & Reflections Electronic systems in Survivorship (SHARE-S) program in coordination with clinical careIntroduction: Initial cancer survivorship care planning efforts focused on information sharing demonstrated limited impact on patient health outcomes. We designed the Shared Healthcare Actions & Reflections Electronic Systems in survivorship (SHARE-S) program to enhance survivorship guideline implementation by transitioning some effort from clinicians to technology and patients through supporting health self-management (e.g., healthy lifestyles). Methods: We conducted a single-group hybrid implementation-effectiveness pilot study. SHARE-S incorporated three strategies: (1) e-referral from the clinical team for patient engagement, (2) three health self-management coach calls, and (3) text messages to enhance coaching. Our primary implementation measure was the proportion of patients e-referred who enrolled (target >30%). Secondary implementation measures assessed patient engagement. We also measured effectiveness by describing changes in patient health outcomes. Results: Of the 118 cancer survivor patients e-referred, 40 engaged in SHARE-S (proportion enrolled = 34%). Participants had a mean age of 57.4 years (SD = 15.7), 73% were female, 23% were Black/African American, and 5 (12.5%) were from a rural location. Patient-level adherence to coach calls was >90%. Changes from baseline to follow-up showed at least a small effect (Cohen's d = 0.2) for improvements in: mindful attention, alcohol use, physical activity, fruit and vegetable intake, days of mindfulness practice, depressive symptoms, ability to participate in social roles and activities, cancer-specific quality of life, benefits of having cancer, and positive feelings. Conclusion: The SHARE-S program successfully engaged cancer survivor patients. Once enrolled, patients showed promising improvements in health outcomes. Supporting patient self-management is an important component of optimizing delivery of cancer survivorship care.
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TIR-1/SARM1 inhibits axon regeneration and promotes axon degenerationGrowth and destruction are central components of the neuronal injury response. Injured axons that are capable of repair, including axons in the mammalian peripheral nervous system and in many invertebrate animals, often regenerate and degenerate on either side of the injury. Here we show that TIR-1/dSarm/SARM1, a key regulator of axon degeneration, also inhibits regeneration of injured motor axons. The increased regeneration in tir-1 mutants is not a secondary consequence of its effects on degeneration, nor is it determined by the NADase activity of TIR-1. Rather, we found that TIR-1 functions cell-autonomously to regulate each of the seemingly opposite processes through distinct interactions with two MAP kinase pathways. On one side of the injury, TIR-1 inhibits axon regeneration by activating the NSY-1/ASK1 MAPK signaling cascade, while on the other side of the injury, TIR-1 simultaneously promotes axon degeneration by interacting with the DLK-1 mitogen-activated protein kinase (MAPK) signaling cascade. In parallel, we found that the ability to cell-intrinsically inhibit axon regeneration is conserved in human SARM1. Our finding that TIR-1/SARM1 regulates axon regeneration provides critical insight into how axons coordinate a multidimensional response to injury, consequently informing approaches to manipulate the response toward repair.
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Artificial Intelligence for the Diagnosis of Pediatric Appendicitis: A Systematic ReviewBACKGROUND: While acute appendicitis is the most frequent surgical emergency in children, its diagnosis remains complex. Artificial intelligence (AI) and machine learning (ML) tools have been employed to improve the accuracy of various diagnoses, including appendicitis. The purpose of this study was to systematically review the current body of evidence regarding the efficacy of AL and ML approaches for the diagnosis of acute pediatric appendicitis. METHODS: This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify articles from Pubmed, Scopus, and iEEE Xplore. Eligible articles included full text, English-language articles assessing the use of AI technologies for the diagnosis of acute pediatric appendicitis. Study quality of reporting was appraised using The Transparent Reporting of a multivariable prediction model of Individual Prognosis Or Diagnosis (TRIPOD) statement. RESULTS: A total of fourteen studies were included in the final analysis of which ten were published after 2019. Two studies originated in the United States while half were carried out in Europe. Artificial Neural Network and Random Forest AI methods were the most commonly used modeling approaches. Commonly used predictors were pain and laboratory blood findings. The average area under the curve that was reported among the fourteen studies was greater than 80%. CONCLUSIONS: AI and ML technologies have the potential to improve the accuracy of acute appendicitis diagnosis in pediatric patients. Further investigation is needed to identify barriers to adoption of these technologies and to assess their efficacy in real world usage once integrated into clinical workflows.
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NeuroimagingThis presentation is part of the PEER Liberia Radiology Lecture Series. It provides an overview for clinicians of neuroimaging, including anatomy and summary of various cases.
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Implications of Non-Specific Effects for Testing, Approving, and Regulating VaccinesThe current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.
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A pilot study of robotic surgery case videos for first-year medical student anatomyThere has been a recent shift in medical student anatomy education with greater incorporation of virtual resources. Multiple approaches to virtual anatomy resources have been described, but few involve video or images from surgical procedures. In this pilot study, a series of surgical case videos was created using robotic surgery video footage for a first-year medical student anatomy course. Five operations were included that covered thoracic, abdominal, and pelvic anatomy. Students were surveyed at the end of the course regarding their experience with the videos and their perceptions towards a surgical career. Overall, participants agreed that the videos were an effective learning tool, were useful regardless of career interest, and that in the future it would be useful to incorporate additional surgical case videos. Respondents highlighted the importance of audio narration with future videos and provided suggestions for future operations that they would like to see included. In summary, this pilot study describes the creation and implementation of a surgical video anatomy curriculum and student survey results suggest this may be an effective approach to video-based anatomy education for further curricular development.
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Balance in the In-BetweenIntroduction: This week we hear from our most avid writer - Pam Adelstein, former resident of Family Health Center of Worcester, and now Medical Director at Fenway Health. She writes regularly for Pulse. Today's piece was previously published there. It takes on the notion of transitions since she has recently experienced a big one. How does one embrace transitions - whether it is from one job to another, or simply from one exam room to another or just getting from work to home. When I graduated from University, the minister at our graduation week ceremony pleaded with us to focus on transitions - that is where the good stuff will happen. Let's see what Pam has to add.
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Cryo-EM structure of the human cardiac myosin filament [preprint]Pumping of the heart is powered by filaments of the motor protein myosin, which pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly 1 . Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years 2 . Here, we have solved the structure of the main (cMyBP-C-containing) region of the human cardiac filament to 6 Å resolution by cryo-EM. The reconstruction reveals the architecture of titin and cMyBP-C for the first time, and shows how myosin's motor domains (heads) form 3 different types of motif (providing functional flexibility), which interact with each other and with specific domains of titin and cMyBP-C to dictate filament architecture and regulate function. A novel packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps generate the cardiac super-relaxed state 3 , how titin and cMyBP-C may contribute to length-dependent activation 4 , and how mutations in myosin and cMyBP-C might disrupt interactions, causing disease 5, 6 . A similar structure is likely in vertebrate skeletal myosin filaments. The reconstruction resolves past uncertainties, and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.
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Retracted Covid-19 articles: significantly more cited than other articles within their journal of originWith the expansion of research volume, coinciding with the age of the internet, the retraction of published papers from scientific journals has become crucial to preserving scientific integrity. Since the beginning of the COVID-19 pandemic, both public and professional interest in scientific literature has grown as people attempt to educate themselves on the virus. The Retraction Watch Database COVID-19 blog was accessed in June and November of 2022 and analyzed to ensure articles met inclusion criteria. Articles were then accessed on Google Scholar and the Scopus database to find number of citations and SJR/CiteScore. The average SJR and CiteScore for a journal that published one of the articles was 1.531 and 7.3 respectively. The retracted articles were cited an average of 44.8 times, which was significantly higher than the average CiteScore (p = 0.01). Between June and November, retracted COVID-19 articles gained a total of 728 new citations, presence of "withdrawn" or "retracted" before article title did not affect citation rates. COPE guidelines for retraction statements were not met for 32% of articles. We believe retracted COVID-19 publications may have been more likely to include bold claims that garnered a disproportionately high amount of attention within the scientific community. Additionally, we found many journals were not forthright with explanations for why articles had been retracted. Retractions could be a tool used to add to the scientific discourse, but currently we are only getting half the data, the what and not the why.
