Pre-challenge gut microbial signature predicts RhCMV/SIV vaccine efficacy in rhesus macaques.

Background: RhCMV/SIV vaccines protect ∼59% of vaccinated rhesus macaques against repeated limiting-dose intra-rectal exposure with highly pathogenic SIVmac239M, but the exact mechanism responsible for the vaccine efficacy is not known. It is becoming evident that complex interactions exist between gut microbiota and the host immune system. Here we aimed to investigate if the rhesus gut microbiome impacts RhCMV/SIV vaccine-induced protection. Methods: Three groups of 15 rhesus macaques naturally pre-exposed to RhCMV were vaccinated with RhCMV/SIV vaccines. Rectal swabs were collected longitudinally both before SIV challenge (after vaccination) and post challenge and were profiled using 16S rRNA based microbiome analysis. Results: We identified ∼2,400 16S rRNA amplicon sequence variants (ASVs), representing potential bacterial species/strains. Global gut microbial profiles were strongly associated with each of the three vaccination groups, and all animals tended to maintain consistent profiles throughout the pre-challenge phase. Despite vaccination group differences, using newly developed compositional data analysis techniques we identified a common gut microbial signature predictive of vaccine protection outcome across the three vaccination groups. Part of this microbial signature persisted even after SIV challenge. We also observed a strong correlation between this microbial signature and an early signature derived from whole blood transcriptomes in the same animals. Conclusions: Our findings indicate that changes in gut microbiomes are associated with RhCMV/SIV vaccine-induced protection and early host response to vaccination in rhesus macaques.

Exploring team dynamics during the development of a multi-institutional cross-disciplinary translational team: Implications for potential best practices.

Introduction: A recent literature review revealed no studies that explored teams that used an explicit theoretical framework for multiteam systems in academic settings, such as the increasingly important multi-institutional cross-disciplinary translational team (MCTT) form. We conducted an exploratory 30-interview grounded theory study over two rounds to analyze participants' experiences from three universities who assembled an MCTT in order to pursue a complex grant proposal related to research on post-acute sequelae of COVID-19, also called "long COVID." This article considers activities beginning with preliminary discussions among principal investigators through grant writing and submission, and completion of reviews by the National Center for Advancing Translational Sciences, which resulted in the proposal not being scored. Methods: There were two stages to this interview study with MCTT members: pre-submission, and post-decision. Round one focused on the process of developing structures to collaborate on proposal writing and assembly, whereas round two focused on evaluation of the complete process. A total of 15 participants agreed to be interviewed in each round. Findings: The first round of interviews was conducted prior to submission and explored issues during proposal writing, including (1) importance of the topic; (2) meaning and perception of "team" within the MCTT context; and (3) leadership at different levels of the team. The second round explored best practices-related issues including (1) leadership and design; (2) specific proposal assembly tasks; (3) communication; and (4) critical events. Conclusion: We conclude with suggestions for developing best practices for assembling MCTTs involving multi-institutional teams.

Disruption of myelin structure and oligodendrocyte maturation in a pigtail macaque model of congenital Zika infection.

Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in non-microcephalic infants, of which the pathogenesis remains poorly understood. We utilized an established pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We found prenatal ZikV exposure led to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses revealed marked decreases in myelin basic protein intensity and myelinated fiber density in ZikV-exposed animals. At the ultrastructural level, the myelin sheath in ZikV-exposed animals showed multi-focal decompaction consistent with perturbation or remodeling of previously formed myelin, occurring concomitant with dysregulation of oligodendrocyte gene expression and maturation. These findings define fetal neuropathological profiles of ZikV-linked brain injury underlying CZS resulting from ZikV exposure in utero. Because myelin is critical for cortical development, ZikV-related perturbations in oligodendrocyte function may have long-term consequences on childhood neurodevelopment, even in the absence of overt microcephaly.

Subtyping Social Determinants of Health in All of Us: Network Analysis and Visualization Approach.

Background: Social determinants of health (SDoH), such as financial resources and housing stability, account for between 30-55% of people's health outcomes. While many studies have identified strong associations among specific SDoH and health outcomes, most people experience multiple SDoH that impact their daily lives. Analysis of this complexity requires the integration of personal, clinical, social, and environmental information from a large cohort of individuals that have been traditionally underrepresented in research, which is only recently being made available through the All of Us research program. However, little is known about the range and response of SDoH in All of Us, and how they co-occur to form subtypes, which are critical for designing targeted interventions. Objective: To address two research questions: (1) What is the range and response to survey questions related to SDoH in the All of Us dataset? (2) How do SDoH co-occur to form subtypes, and what are their risk for adverse health outcomes? Methods: For Question-1, an expert panel analyzed the range of SDoH questions across the surveys with respect to the 5 domains in Healthy People 2030 (HP-30), and analyzed their responses across the full All of Us data (n=372,397, V6). For Question-2, we used the following steps: (1) due to the missingness across the surveys, selected all participants with valid and complete SDoH data, and used inverse probability weighting to adjust their imbalance in demographics compared to the full data; (2) an expert panel grouped the SDoH questions into SDoH factors for enabling a more consistent granularity; (3) used bipartite modularity maximization to identify SDoH biclusters, their significance, and their replicability; (4) measured the association of each bicluster to three outcomes (depression, delayed medical care, emergency room visits in the last year) using multiple data types (surveys, electronic health records, and zip codes mapped to Medicaid expansion states); and (5) the expert panel inferred the subtype labels, potential mechanisms that precipitate adverse health outcomes, and interventions to prevent them. Results: For Question-1, we identified 110 SDoH questions across 4 surveys, which covered all 5 domains in HP-30. However, the results also revealed a large degree of missingness in survey responses (1.76%-84.56%), with later surveys having significantly fewer responses compared to earlier ones, and significant differences in race, ethnicity, and age of participants of those that completed the surveys with SDoH questions, compared to those in the full All of Us dataset. Furthermore, as the SDoH questions varied in granularity, they were categorized by an expert panel into 18 SDoH factors. For Question-2, the subtype analysis (n=12,913, d=18) identified 4 biclusters with significant biclusteredness (Q=0.13, random-Q=0.11, z=7.5, P<0.001), and significant replication (Real-RI=0.88, Random-RI=0.62, P<.001). Furthermore, there were statistically significant associations between specific subtypes and the outcomes, and with Medicaid expansion, each with meaningful interpretations and potential targeted interventions. For example, the subtype Socioeconomic Barriers included the SDoH factors not employed, food insecurity, housing insecurity, low income, low literacy, and low educational attainment, and had a significantly higher odds ratio (OR=4.2, CI=3.5-5.1, P-corr<.001) for depression, when compared to the subtype Sociocultural Barriers. Individuals that match this subtype profile could be screened early for depression and referred to social services for addressing combinations of SDoH such as housing insecurity and low income. Finally, the identified subtypes spanned one or more HP-30 domains revealing the difference between the current knowledge-based SDoH domains, and the data-driven subtypes. Conclusions: The results revealed that the SDoH subtypes not only had statistically significant clustering and replicability, but also had significant associations with critical adverse health outcomes, which had translational implications for designing targeted SDoH interventions, decision-support systems to alert clinicians of potential risks, and for public policies. Furthermore, these SDoH subtypes spanned multiple SDoH domains defined by HP-30 revealing the complexity of SDoH in the real-world, and aligning with influential SDoH conceptual models such as by Dahlgren-Whitehead. However, the high-degree of missingness warrants repeating the analysis as the data becomes more complete. Consequently we designed our machine learning code to be generalizable and scalable, and made it available on the All of Us workbench, which can be used to periodically rerun the analysis as the dataset grows for analyzing subtypes related to SDoH, and beyond.

"Technical" Contributors and Authorship Distribution in Health Science.

In health sciences, technical contributions may be undervalued and excluded in the author byline. In this paper, I demonstrate how authorship is a historical construct which perpetuates systemic injustices including technical undervaluation. I make use of Pierre Bourdieu's conceptual work to demonstrate how the power dynamics at play in academia make it very challenging to change the habitual state or "habitus". To counter this, I argue that we must reconceive technical contributions to not be a priori less important based on its nature when assigning roles and opportunities leading to authorship. I make this argument based on two premises. First, science has evolved due to major information and biotechnological innovation; this requires 'technicians' to acquire and exercise a commensurate high degree of both technical and intellectual expertise which in turn increases the value of their contribution. I will illustrate this by providing a brief historical view of work statisticians, computer programmers/data scientists and laboratory technicians. Second, excluding or undervaluing this type of work is contrary to norms of responsibility, fairness and trustworthiness of the individual researchers and of teams in science. Although such norms are continuously tested because of power dynamics, their importance is central to ethical authorship practice and research integrity. While it may be argued that detailed disclosure of contributions (known as contributorship) increases accountability by clearly identifying who did what in the publication, I contend that this may unintentionally legitimize undervaluation of technical roles and may decrease integrity of science. Finally, this paper offers recommendations to promote ethical inclusion of technical contributors.

Cost-effectiveness analysis of different screening and diagnostic strategies for sexually transmitted infections and bacterial vaginosis in women attending primary health care facilities in Cape Town.

Background: Genital inflammation associated with sexually transmitted infections (STIs) and bacterial vaginosis (BV) is considered a key driver in the HIV epidemic. A new rapid point-of-care test (POC) that detects genital inflammation in women-Genital InFlammation Test (GIFT)-was recently developed by researchers at the University of Cape Town. The objective of this study was to establish the cost-effectiveness of this novel intervention relative to other relevant screening and diagnostic strategies for the management of STIs and BV in women seeking care in the public health sector in South Africa. Methods: A decision analysis model was developed for five different screening and diagnostic strategies for women incorporating syndromic management, screening with GIFT and using etiological diagnosis. A decision tree was constructed using Microsoft Excel Office 365, and cost and effectiveness parameters were obtained from published literature and market prices. The model incorporated all clinic-level and treatment costs associated with diagnosing and treating a single episode of disease. The effectiveness of each approach was proxied by its sensitivity. One-way and threshold sensitivity analyses were conducted to test key uncertainties and assumptions in the model. Results: Screening with GIFT, and following with antibiotic treatment according to syndromic management guidelines for GIFT-positive cases, was the most cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of USD 11.08 per women diagnosed with an STI(s) and/or BV and provided treatment. This strategy resulted in lower rates of overtreatment compared to syndromic management, but higher rates compared to etiological diagnosis using nucleic acid amplification tests and microscopy. However, following a GIFT positive test with etiological diagnosis prior to treatment did not increase the effectiveness, but dramatically increased the cost. Conclusion: Screening with GIFT and treating positive cases according to syndromic management guidelines is the most cost-effective strategy for the management of STIs and BV. GIFT has a potential to significantly improve the management of STIs and BV in women by identifying asymptomatic women and reducing their risk of HIV infection. This analysis presents a first step in establishing the cost-effectiveness of these interventions and paves the way for further research to develop optimal context-specific implementation strategies.

Duration of viral infectiousness and correlation with symptoms and diagnostic testing in non-hospitalized adults during acute SARS-CoV-2 infection: A longitudinal cohort study.

BACKGROUND: Guidelines for SARS-CoV-2 have relied on limited data on duration of viral infectiousness and correlation with COVID-19 symptoms and diagnostic testing. METHODS: We enrolled ambulatory adults with acute SARS-CoV-2 infection and performed serial measurements of COVID-19 symptoms, nasal swab viral RNA, nucleocapsid (N) and spike (S) antigens, and replication-competent SARS-CoV-2 by viral growth in culture. We determined average time from symptom onset to a first negative test result and estimated risk of infectiousness, as defined by positive viral growth in culture. RESULTS: Among 95 adults, median [interquartile range] time from symptom onset to first negative test result was 9 [5] days, 13 [6] days, 11 [4] days, and >19 days for S antigen, N antigen, culture growth, and viral RNA by RT-PCR, respectively. Beyond two weeks, virus growth and N antigen titers were rarely positive, while viral RNA remained detectable among half (26/51) of participants tested 21-30 days after symptom onset. Between 6-10 days from symptom onset, N antigen was strongly associated with culture positivity (relative risk=7.61, 95% CI: 3.01-19.22), whereas neither viral RNA nor symptoms were associated with culture positivity. During the 14 days following symptom onset, the presence of N antigen remained strongly associated (adjusted relative risk=7.66, 95% CI: 3.96-14.82) with culture positivity, regardless of COVID-19 symptoms. CONCLUSIONS: Most adults have replication-competent SARS-CoV-2 for 10-14 after symptom onset. N antigen testing is a strong predictor of viral infectiousness and may be a more suitable biomarker, rather than absence of symptoms or viral RNA, to discontinue isolation within two weeks from symptom onset.

Should authorship on scientific publications be treated as a right?

Sometimes researchers explicitly or implicitly conceive of authorship in terms of moral or ethical rights to authorship when they are dealing with authorship issues. Because treating authorship as a right can encourage unethical behaviours, such as honorary and ghost authorship, buying and selling authorship, and unfair treatment of researchers, we recommend that researchers not conceive of authorship in this way but view it as a description about contributions to research. However, we acknowledge that the arguments we have given for this position are largely speculative and that more empirical research is needed to better ascertain the benefits and risks of treating authorship on scientific publications as a right.

Multi-year monitoring of Piping Plovers (Charadriusmelodus) and other shorebirds in The Bahamas.

Background: The Bahamas provides a wide range of crucial coastal habitats to many declining resident and migratory birds. Amongst these species is the Piping Plover (Charadriusmelodus), whose breeding populations are all listed as federally threatened or endangered in the United States and Canada. This species winters in the southern U.S. and the Caribbean, including The Bahamas, spending most of the year on the wintering grounds. Nonetheless, prior to the census data presented here, reports of Piping Plovers from The Bahamas were few and incidental. Therefore, repeated surveys are essential to increase understanding of the distribution, abundance and movement patterns of Piping Plovers and other shorebirds in the Bahamian territory. This dataset provides information on the abundance and distribution of the Piping Plover across multiple islands and much of the suitable habitat that exists in The Bahamas. It also provides some information on the variability of Piping Plover count data and presence of other shorebird species. Furthermore, these data may serve as baseline information on Piping Plover abundance and shorebird site occupancy by which to assess key candidate sites for protection and also future impacts of climate change, such as sea level rise and hurricanes. New information: The National Audubon Society (NAS), Environment and Climate Change Canada (ECCC) and the United States Geological Survey (USGS) conducted a multi-year shorebird census in The Bahamas. Surveys initiated by ECCC and many other collaborators were also part of a multi-year survival study. Censuses were conducted across 16 different islands between the years 2006 and 2020. These surveys were performed with the cooperation of the Bahamas National Trust (BNT), volunteer biologists and scientists from the United States and Canada. Biologists working with NAS, ECCC and USGS used satellite imagery, historical records and local knowledge from Bahamian residents to identify sites with suitable habitat for Piping Plovers. Experienced researchers visited each site during winter (November-February), identified and counted Piping Plovers and, when possible, other bird species in each of the sampled locations. In total, the resulting database holds 2,684 observations of 62 bird species, of which 77% belong to 24 shorebird species. Approximately 30% of all presence records belong to the Piping Plover. It is important to emphasise that the counts reported in this dataset represent minimum estimates of local shorebird assemblages. Since abundance and distribution of birds vary with changing conditions, representative estimates are best achieved via repeated surveys that reflect a range of conditions including timing (day, year, month), weather (wind direction and speed, precipitation), tide state etc.

Research integrity during the COVID-19 pandemic: Perspectives of health science researchers at an Academic Health Science Center.

During the coronavirus disease 2019 pandemic, a complex mix of political pressure, social urgency, public panic, and scientific curiosity has significantly impacted the context of research and development. The goal of this study is to understand if and how researchers are shifting their practices and adjusting norms and beliefs regarding research ethics and integrity. We have conducted 31 interviews with Health Science Researchers at the University of Texas Medical Branch which were then analyzed using integrated deductive and inductive coding. We categorized participant views into four main areas: 1) limitations to the research design, 2) publication, 3) duplication of studies, and 4) research pipeline. Although certain researchers were in keeping to the status quo, more were willing to modify norms to address social need and urgency. Notably, they were more likely to opt for systemic change rather than modifications within their own research practices.

For the "good of the lab": Insights from three focus groups concerning the ethics of managing a laboratory or research group.

To obtain some exploratory, qualitative data on ethical issues and values in managing a research laboratory, we conducted three focus groups with experienced investigators and laboratory managers. After validating the focus group transcripts for accuracy, two coders used deductive and inductive coding to develop themes from the text. Participants regarded ethics as important in managing a laboratory (or research group) for various reasons, ranging from conducting research with integrity to exhibiting leadership and promoting an ethical research climate. Participants identified many different types of ethical issues that arise in managing a research laboratory, including issues involving the management people, financial and material resources, projects, and data. An overarching ethical dilemma identified by participants was balancing the desire for productivity against apparently competing values, such as treating people fairly and promoting the wellbeing of individuals. Participants also indicated that graduate and post-graduate education and training did not prepare them to deal with the ethical, financial, interpersonal, and other issues related to managing a research laboratory, and that communication and leadership are crucial to managing a research laboratory ethically.

Scientific priorities and relational dynamics during the COVID-19 pandemic: A qualitative study.

To rapidly respond to the COVID-19 public health crisis, researchers have been called upon to prioritize pandemic research, while simultaneously modifying their existing research to maintain the safety of all stakeholders. This study aims to explore the experiences of health science researchers in their scientific practices, research priorities, and professional relational dynamics due to COVID-19. Specifically, we interviewed 31 researchers from diverse fields at the University of Texas Medical Branch. Participants worked on COVID-19, non-COVID-19 related research, or both. We integrated inductive and deductive coding using a thematic coding method. The following four themes were explored: 1) impact of research, 2) research priorities, 3) professional relationships and 4) contextual influences on science. Participants were drawn to COVID-19 work for a diversity of reasons including social need, scientific interest, professional duty, and increased access to funding opportunities. While collaborations have increased for COVID-19 researchers, interpersonal relationships have been challenging for participants. Additionally, political, familial, and personal stresses due to the pandemic have taken a toll on researchers in very different and often inequitable ways. To ensure team cohesion, there is a need to develop research practices, policies and systems that value empathy, flexibility, and interdependence.

Cytomegalovirus-vaccine-induced unconventional T cell priming and control of SIV replication is conserved between primate species.

Strain 68-1 rhesus cytomegalovirus expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) primes MHC-E-restricted CD8+ T cells that control SIV replication in 50%-60% of the vaccinated rhesus macaques. Whether this unconventional SIV-specific immunity and protection is unique to rhesus macaques or RhCMV or is intrinsic to CMV remains unknown. Here, using cynomolgus CMV vectors expressing SIV antigens (CyCMV/SIV) and Mauritian cynomolgus macaques, we demonstrate that the induction of MHC-E-restricted CD8+ T cells requires matching CMV to its host species. RhCMV does not elicit MHC-E-restricted CD8+ T cells in cynomolgus macaques. However, cynomolgus macaques vaccinated with species-matched 68-1-like CyCMV/SIV mounted MHC-E-restricted CD8+ T cells, and half of the vaccinees stringently controlled SIV post-challenge. Protected animals manifested a vaccine-induced IL-15 transcriptomic signature that is associated with efficacy in rhesus macaques. These findings demonstrate that the ability of species-matched CMV vectors to elicit MHC-E-restricted CD8+ T cells that are required for anti-SIV efficacy is conserved in nonhuman primates, and these data support the development of HCMV/HIV for a prophylactic HIV vaccine.

Innate immune regulation in HIV latency models.

BACKGROUND: Innate immunity and type 1 interferon (IFN) defenses are critical for early control of HIV infection within CD4 + T cells. Despite these defenses, some acutely infected cells silence viral transcription to become latently infected and form the HIV reservoir in vivo. Latently infected cells persist through antiretroviral therapy (ART) and are a major barrier to HIV cure. Here, we evaluated innate immunity and IFN responses in multiple T cell models of HIV latency, including established latent cell lines, Jurkat cells latently infected with a reporter virus, and a primary CD4 + T cell model of virologic suppression. RESULTS: We found that while latently infected T cell lines have functional RNA sensing and IFN signaling pathways, they fail to induce specific interferon-stimulated genes (ISGs) in response to innate immune activation or type 1 IFN treatment. Jurkat cells latently infected with a fluorescent reporter HIV similarly demonstrate attenuated responses to type 1 IFN. Using bulk and single-cell RNA sequencing we applied a functional genomics approach and define ISG expression dynamics in latent HIV infection, including HIV-infected ART-suppressed primary CD4 + T cells. CONCLUSIONS: Our observations indicate that HIV latency and viral suppression each link with cell-intrinsic defects in specific ISG induction. We identify a set of ISGs for consideration as latency restriction factors whose expression and function could possibly mitigate establishing latent HIV infection.

Engineered Cas12i2 is a versatile high-efficiency platform for therapeutic genome editing.

The CRISPR-Cas type V-I is a family of Cas12i-containing programmable nuclease systems guided by a short crRNA without requirement for a tracrRNA. Here we present an engineered Type V-I CRISPR system (Cas12i), ABR-001, which utilizes a tracr-less guide RNA. The compact Cas12i effector is capable of self-processing pre-crRNA and cleaving dsDNA targets, which facilitates versatile delivery options and multiplexing, respectively. We apply an unbiased mutational scanning approach to enhance initially low editing activity of Cas12i2. The engineered variant, ABR-001, exhibits broad genome editing capability in human cell lines, primary T cells, and CD34+ hematopoietic stem and progenitor cells, with both robust efficiency and high specificity. In addition, ABR-001 achieves a high level of genome editing when delivered via AAV vector to HEK293T cells. This work establishes ABR-001 as a versatile, specific, and high-performance platform for ex vivo and in vivo gene therapy.

The gendered nature of authorship.

Authorship is the primary form of symbolic capital in science. Despite this, authorship is rife with injustice and malpractice, with women expressing concerns regarding the fair attribution of credit. Based on an international survey, we examine gendered practices in authorship communication, disagreement, and fairness. Our results demonstrate that women were more likely to experience authorship disagreements and experience them more often. Their contributions to research papers were more often devalued by both men and women. Women were more likely to discuss authorship with coauthors at the beginning of the project, whereas men were more likely to determine authorship unilaterally at the end. Women perceived that they received less credit than deserved, while men reported the opposite. This devaluation of women's work in science creates cumulative disadvantages in scientific careers. Open discussion regarding power dynamics related to gender is necessary to develop more equitable distribution of credit for scientific labor.

Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy.

Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge.

Reimagining the peer-review system for translational health science journals.

Retractions of coronavirus disease 2019 (COVID-19) papers in high impact journals, such as The Lancet and the New England Journal of Medicine, have been panned as major scientific fraud in public media. The initial reaction to this news was to seek out scapegoats and blame individual authors, peer-reviewers, editors, and journals for wrong doing. This paper suggests that scapegoating a few individuals for faulty science is a myopic approach to the more profound problem with peer-review. Peer-review in its current limited form cannot be expected to adequately address the scope and complexity of large interdisciplinary science research collaboration, which is central in translational research. In addition, empirical studies on the effectiveness of traditional peer-review reveal its very real potential for bias and groupthink; as such, expectations regarding the capacity and effectiveness of the current peer review process are unrealistic. This paper proposes a new vision of peer-review in translational science that, on the one hand, would allow for early release of a manuscript to ensure expediency, whereas also creating a forum or a collective of various experts to actively comment, scrutinize, and even build on the research under review. The aim would be to not only generate open discussion and oversight respecting the quality and limitations of the research, but also to assess the extent and the means for that knowledge to translate into social benefit.

SARS-CoV-2 Infects Human Pluripotent Stem Cell-Derived Cardiomyocytes, Impairing Electrical and Mechanical Function.

COVID-19 patients often develop severe cardiovascular complications, but it remains unclear if these are caused directly by viral infection or are secondary to a systemic response. Here, we examine the cardiac tropism of SARS-CoV-2 in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and smooth muscle cells (hPSC-SMCs). We find that that SARS-CoV-2 selectively infects hPSC-CMs through the viral receptor ACE2, whereas in hPSC-SMCs there is minimal viral entry or replication. After entry into cardiomyocytes, SARS-CoV-2 is assembled in lysosome-like vesicles and egresses via bulk exocytosis. The viral transcripts become a large fraction of cellular mRNA while host gene expression shifts from oxidative to glycolytic metabolism and upregulates chromatin modification and RNA splicing pathways. Most importantly, viral infection of hPSC-CMs progressively impairs both their electrophysiological and contractile function, and causes widespread cell death. These data support the hypothesis that COVID-19-related cardiac symptoms can result from a direct cardiotoxic effect of SARS-CoV-2.