bluuebunny/crossref_metadata_2025 huggingface dataset:
Bromodomain and extraterminal protein inhibitor, apabetalone (RVX-208), reduces ACE2 expression and attenuates SARS-CoV-2 infection in vitro
Authors: Gilham Dean , Smith Audrey L , Fu Li , Moore Dalia Y , Muralidharan Abenaya , Reid St. Patrick M , Stotz Stephanie C , Johansson Jan O , Sweeney Michael , Wong Norman CW , Kulikowski Ewelina , El-Gamal Dalia
Published: March 2021

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infectionin vitroto levels comparable to antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

Graphical Abstract
A novel approach to the detection of unusual mitochondrial protein change suggests low basal metabolism of ancestral anthropoids
Authors: Akpınar Bala Anı , Sharma Vivek , Dunn Cory D.
Published: March 2021

The mitochondrial genome encodes core subunits involved in the process of oxidative phosphorylation. The sequence and structure of these mitochondria-encoded polypeptides are expected to be shaped by bioenergetic requirements linked to diet and environment. Here, we have developed a robust and effective method for highlighting phylogenetic tree edges with unexpectedly rapid, and likely consequential, substitutions within mitochondrial proteins. Further, our approach allows detection of discrete protein substitutions likely to alter enzyme performance. A survey of mammalian taxonomic groups performed using our method indicates that widely conserved residues in mitochondria-encoded proteins are more likely to rapidly mutate toward variants providing lower OXPHOS activity within specific clades. Intriguingly, our data suggest reduced cellular metabolism of ancestral anthropoids, and our findings have potential implications regarding primate encephalization.

Significance Statement

Mitochondria harbor DNA (mtDNA) that encodes proteins important for converting food into energy. The environment and lifestyle of an organism shapes, and is shaped by, the sequences of these mitochondrial genomes. We developed a new approach for the detection of rapid functional change to proteins, and we applied our method to the mitochondria-encoded polypeptides of mammals. We found that primates displayed a general signature of relative hypometabolism that is shared with other mammals characterized by a low metabolic rate. Indications of reduced cellular metabolism extend even to the earliest anthropoids. Our findings have potential implications regarding the evolution of an enlarged primate brain.
Transient Kinetic Proofreading
Authors: Iyengar G. , Perry M.
Published: March 2021

We propose a new stochastic model for understanding the transient kinetic proofreading mechanism in a T-cell. Our model indicates that a stochastic version of absolute ligand discrimination is a consequence of the finite number of receptors on the cell surface; thus, pointing to receptor number control as being critical to T-cell activation. We propose four different metrics to characterize the performance of kinetic proofreading mechanisms. We explore the numerical experiments that explore the trade-offs between speed, specificity, sensitivity, and robustness of T-cell activation as a function of the model parameters. We also consider the impact of receptor clustering on these trade-offs.
In vitroprofiling of orphan G protein coupled receptor (GPCR) constitutive activity
Authors: Watkins Lyndsay R. , Orlandi Cesare
Published: March 2021

Background and Purpose

Members of the G protein coupled receptor (GPCR) family are targeted by a significant fraction of the available FDA-approved drugs. However, the physiological role and pharmacological properties of many GPCRs remain unknown, representing untapped potential in drug design. Of particular interest are ~100 less-studied GPCRs known as orphans because their endogenous ligands are unknown. Intriguingly, disease-causing mutations identified in patients, together with animal studies, have demonstrated that many orphan receptors play crucial physiological roles, and thus, represent attractive drug targets.

Experimental Approach

The majority of deorphanized GPCRs demonstrate coupling to Gi/o, however a limited number of techniques allow the detection of intrinsically small constitutive activity associated with Gi/oprotein activation which represents a significant barrier in our ability to study orphan GPCR signaling. Using luciferase reporter assays, we effectively detected constitutive Gs, Gq, and G12/13protein signaling by unliganded receptors, and introducing various G protein chimeras, we provide a novel, highly-sensitive tool capable of identifying Gi/ocoupling in unliganded orphan GPCRs.

Key Results

Using this approach, we measured the constitutive activity of the entire class C GPCR family that includes 8 orphan receptors, and a subset of 20 prototypical class A GPCR members, including 11 orphans. Excitingly, this approach illuminated the G protein coupling profile of 8 orphan GPCRs (GPR22, GPR137b, GPR88, GPR156, GPR158, GPR179, GPRC5D, and GPRC6A) previously linked to pathophysiological processes.

Conclusion and Implications

We provide a new platform that could be utilized in ongoing studies in orphan receptor signaling and deorphanization efforts.

What is already known

A large group of understudied orphan GPCRs controls a variety of physiological process.

What this study adds

A new strategy to identify G protein signaling associated with orphan GPCRs.

Identification of Gi/ocoupling for 8 orphan GPCRs.

What is the clinical significance

Many orphan GPCRs are associated with pathological conditions and represent promising druggable targets.
Seasonal dynamics and repeatability of gastrointestinal parasite burdens in wild Soay sheep
Authors: Sweeny Amy R. , Corripio-Miyar Yolanda , Bal Xavier , Hayward Adam , Pilkington Jill G. , Pemberton Josephine M. , McNeilly Tom N. , Nussey Daniel H. , Kenyon Fiona
Published: March 2021

Seasonality is a ubiquitous feature of wildlife disease ecology, but is determined by a complex interplay of environmental, parasitological and host factors. Gastrointestinal parasites often exhibit strong seasonal dynamics in wild vertebrate populations due to, for example, environmental influences on free-living or vectored life stages, and variation in the physiological and immune status of hosts across their annual cycle. At the same time, wild populations are typically infected with multiple parasites. The seasonal dynamics of co-infecting parasites may differ depending on age and reproductive status, and associations among parasites may be driven by short-term within-individual changes or longer-term interactions that are consistent among hosts. Here, we used faecal samples and egg counts collected repeatedly from individually marked and monitored wild Soay sheep that were part of a long-term study to investigate seasonal dynamics of six gastrointestinal parasite groups (strongyle nematodes, coccidian protozoa,Capillaria, Strongyloides, Nematodirus, andMoniezia). Prevalence and abundance generally tended to be higher spring and summer, and burdens were higher in lambs than adults. Within the highly prevalent strongyle nematode group, we found differences in seasonality of egg counts depending on adult reproductive status. Reproductive ewes had increased counts in spring around the time of birth followed by a drop in abundance in summer, while barren ewes showed little evidence of seasonality. Males showed a sustained rise in egg counts through spring and summer, and sex differences were only strongly apparent in summer. In contrast, in similarly prevalent coccidia we found a peak in faecal oocyst counts in spring but no differences in seasonality among males, barren and pregnant ewes. Using multivariate mixed-effects models, we went on to show that both strongyle and coccidia counts are moderately repeatable across seasons among individuals. We further show that apparent positive correlation between strongyle and coccidia counts was driven by short-term within-individual changes in both parasite burdens rather than long-term among-individual covariation. Overall, our results demonstrate that seasonality varies across demographic and parasite groups and highlight the value of investigating fluctuating susceptibility and exposure over time for understanding epidemiology of a population.
Genomic Prediction in Family Bulks Using Different Traits and Cross-Validations in Pine
Authors: Rios Esteban F. , Andrade Mario H. M. L. , Resende Marcio F.R. , Kirst Matias , de Resende Marcos D.V. , de Almeida Filho Janeo E. , Gezan Salvador A. , Munoz Patricio
Published: March 2021

Genomic prediction (GP) integrates statistical, genomic and computational tools to improve the estimation of breeding values and increase genetic gain. Due to the broad diversity in biology, breeding scheme, propagation method, and unit of selection, no universal GP approach can be applied in all crops. In a genome-wide family prediction (GWFP) approach, the family bulk is the basic unit of selection. We tested GWFP in two loblolly pine (Pinus taedaL.) datasets: a breeding population composed of 63 full-sib families (5-20 individuals per family), and a simulated population with the same pedigree structure. In both populations, phenotypic and genomic data was pooled at the family levelin silico. Marker effects were estimated to compute genomic estimated breeding values at the individual (GEBV) and family (GWFP) levels. Less than six individuals per family produced inaccurate estimates of family phenotypic performance and allele frequency. Tested across different scenarios, GWFP predictive ability was higher than those for GEBV in both populations. Validation sets composed of families with similar phenotypic mean and variance as the training population yielded predictions consistently higher and more accurate than other validation sets. Results revealed potential for applying GWFP in breeding programs whose selection unit are family bulks, and for systems where family can serve as training sets. The GWFP approach is well suited for crops that are routinely genotyped and phenotyped at the plot-level, but it can be extended to other breeding programs. Higher predictive ability obtained with GWFP would motivate the application of GP in these situations.
REGEN-COV protects against viral escape in preclinical and human studies
Authors: Copin Richard , Baum Alina , Wloga Elzbieta , Pascal Kristen E. , Giordano Stephanie , Fulton Benjamin O. , Zhou Anbo , Negron Nicole , Lanza Kathryn , Chan Newton , Coppola Angel , Chiu Joyce , Ni Min , Wei Yi , Atwal Gurinder S. , Hernandez Annabel Romero , Saotome Kei , Zhou Yi , Franklin Matthew C. , Hooper Andrea T. , McCarthy Shane , Hamon Sara , Hamilton Jennifer D. , Staples Hilary M. , Alfson Kendra , Carrion Ricardo , Ali Shazia , Norton Thomas , Karakaya Selin Somersan- , Sivapalasingam Sumathi , Herman Gary A. , Weinreich David M. , Lipsich Leah , Stahl Neil , Murphy Andrew J. , Yancopoulos George D. , Kyratsous Christos A.
Published: March 2021

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in COVID-19 patients or identified from preclinical in vitro and in vivo studies. This study demonstrates that a combination of non-competing antibodies, REGEN-COV, not only provides full coverage against current variants of concern/interest but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.
A small fraction of progenitors differentiate into mature adipocytes due to constraints on the cell structure change
Authors: Ahmed Mahmoud , Lai Trang Huyen , Kim Deok Ryong
Published: March 2021

Differentiating 3T3-L1 pre-adipocytes are a mixture of non-identical culture cells. It is vital to identify the cell types that respond to the induction stimulus to understand the pre-adipocyte potential and the mature adipocyte behavior. To test this hypothesis, we deconvoluted the gene expression profiles of the cell culture of MDI-induced 3T3-L1 cells. Then we estimated the fractions of the sub-populations and their changes in time. We characterized the sub-populations based on their specific expression profiles. Initial cell cultures comprised three distinct phenotypes. A small fraction of the starting cells responded to the induction and developed into mature adipocytes. Unresponsive cells were probably under structural constraints or were committed to differentiating into alternative phenotypes. Using the same population gene markers, similar proportions were found in induced human primary adipocyte cell cultures. The three sub-populations had diverse responses to treatment with various drugs and compounds. Only the response of the maturating sub-population resembled that estimated from the profiles of the mixture. We then showed that even at a low division rate, a small fraction of cells could increase its share in a dynamic two-populations model. Finally, we used a cell cycle expression index to validate that model. To sum, pre-adipocytes are a mixture of different cells of which a limited fraction become mature adipocytes.
Permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver
Authors: Nair Anjana Ramdas , Lakhiani Priyanka , Zhang Chi , Macchi Filippo , Sadler Kirsten C.
Published: March 2021

Proteostatic stress initiates a transcriptional response that is unique to the stress condition, yet the regulatory mechanisms underlying the distinct gene expression patterns observed in stressed cells remains unknown. Using a functional genomic approach, we investigated how activating transcription factor 6 (ATF6), a key transcription factor in the unfolded protein response (UPR), regulates target genes. We first designed a computational strategy to define Atf6 target genes based on the evolutionary conservation of predicted ATF6 binding in gene promoters, identifying 652 conserved putative Atf6 target (CPAT) genes. CPATs were overrepresented for genes functioning in the UPR, however, the majority functioned in cellular processes unrelated to proteostasis, including small molecule metabolism and development. Functional studies of stress-independent and toxicant based Atf6 activation in zebrafish livers showed that the pattern of CPAT expression in response to Atf6 overexpression, alcohol and arsenic was unique. Only 34 CPATs were differentially expressed in all conditions, indicating that Atf6 is sufficient to regulate a small subset of CPATs. Blocking Atf6 using Ceapins in zebrafish demonstrated that Atf6 is necessary for activation of these genes in response to arsenic. We investigated CPAT during physiologically mediated hepatocyte stress using liver regeneration in mice as a model. Over half of all CPATs were differentially expressed during this process. This was attributed to the permissive chromatin environment in quiescent livers on the promoters of these genes, characterized by the absence of H3K27me3 and enrichment of H3K4me3. Taken together, these data uncover a complex transcriptional response to Atf6 activation and implicate a permissive epigenome as a mechanism by which distinct transcriptional responses are regulated by Atf6.
Phodopus roborovskii SH101 as a systemic infection model of SARS-CoV-2
Authors: Zhai Chongkai , Wang Mingda , Chung Hea-Jong , Hassan Md. Mehedi , Lee Seungkoo , Kim Hyeon-Jin , Hong Seong-Tshool
Published: March 2021

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide threat with its unusually high transmission rates and rapid evolution into diverse strains. Unlike typical respiratory viruses, SARS-CoV-2 frequently causes systemic infection by breaking the boundaries of the respiratory systems. The development of animal models recapitulating the clinical manifestations of COVID-19 is of utmost importance not only for the development of vaccines and antivirals but also for understanding the pathogenesis. However, there has not been developed an animal model for systemic infection of SARS-CoV-2 representing most aspects of the clinical manifestations of COVID-19 with systemic symptoms. Here we report that a hamster strain of Phodopus roborovskii SH101, a laboratory inbred hamster strain of P. roborovskii, displayed most symptoms of systemic infection upon SARS-CoV-2 infection as in the case of the human counterpart, unlike current COVID-19 animal models. P. roborovskii SH101 post-infection of SARS-CoV-2 represented most clinical symptoms of COVID-19 such as snuffling, dyspnea, cough, labored breathing, hunched posture, progressive weight loss, and ruffled fur, in addition to high fever following shaking chills. Histological examinations also revealed a serious right-predominated pneumonia as well as slight organ damages in the brain and liver, manifesting systemic COVID-19 cases. Considering the merit of a small animal as well as its clinical manifestations of SARS-CoV-2 infection in human, this hamster model seems to provide an ideal tool to investigate COVID-19.

Author summary

Although the current animal models supported SARS-CoV-2 replication and displayed varying degrees of illness after SARS-CoV-2 infection, the infections of SARS-CoV-2 were mainly limited to the respiratory systems of these animals, including hACE2 transgenic mice, hamsters, ferrets, fruit bats, guinea pigs, African green monkey, Rhesus macaques, and Cynomolgus macaques. While these animal models can be a modest model for the respiratory infection, there is a clear limit for use them in the study of COVID-19 that also displays multiple systemic symptoms. Therefore, the development of an animal model recapitulating COVID-19-specific symptoms such as the right-predominated pneumonia would be the utmost need to overcome the imminent threat posed by COVID-19. We identified a very interesting hamster strain, Phodopus roborovskii SH101, which mimics almost all aspects of the clinical manifestations of COVID-19 upon SARS-CoV-2 infection. Unlike the current animal models, SARS-CoV-2-infected P. roborovskii SH101 not only displayed the symptoms of respiratory infection but also clinical manifestations specific to human COVID-19 such as high fever following shaking chills, serious right-predominated pneumonia, and minor organ damages in the brain and liver.
Counterproductive effects of Daratumumab and checkpoint inhibitor for the treatment of patients with relapsing NK/T lymphoma
Authors: Lee Wendy W.L. , Lim Jing Quan , Tang Tiffany P.L , Tan Daryl , Joo Puan Kia , Tan Kim Peng , Wang Liang Wei , Koh Ser Mei , Ong Choon Kiat , Rotzschke Olaf
Published: March 2021

Natural killer/T cell lymphoma (NK/T L) is an aggressive malignancy associated with poor prognosis in relapsed patients. Although L-asparaginase based treatments are recommended as first-line treatment in relapsed patients, advances in immunotherapies such as checkpoint inhibitions have provided new therapeutic alternatives. However, as clinical outcomes for checkpoint inhibitors seemed to vary between NK/T L patients, combination therapies have been suggested to improve treatment efficacy. Here, we compared the effects of Daratumumab (anti-CD38)/anti-PD-1 combination therapy versus anti-PD-1 monotherapy on two relapsed NK/T L patients. Anti-PD-1 triggered an upregulation of CD38 on activated T cells, leading to depletion by Daratumumab. Concomittantly, EBV-specific antibody titer was also reduced alongside with depletion of CD38+ B cells and antibody-producing plasmablasts. Taken together, combining anti-CD38 and anti-PD-1 is likely to be antithetic.
Risk, clinical course and outcome of ischemic stroke in patients hospitalized with COVID-19: a multicenter cohort study
Authors: Sluis Wouter M. , Linschoten Marijke , Buijs Julie E. , Biesbroek J. Matthijs , Hertog Heleen M. den , Ribbers Tessa , Nieuwkamp Dennis , Houwelingen Reinier C. van , Dias Andreas , Uden Ingeborg W.M. van , Kerklaan Joost P. , Bienfait H. Paul , Vermeer Sarah E. , de Jong Sonja W. , Ali Mariam , Wermer Marieke J.H. , de Graaf Marieke T. , Brouwers Paul J.A.M. , Asselbergs Folkert W. , Kappelle L. Jaap , van der Worp H. Bart , Algra Annemijn M.
Published: March 2021

Background and purpose

The frequency of ischemic stroke in patients with COVID-19 varies in the current literature, and risk factors are unknown. We assessed the incidence, risk factors, and outcomes of acute ischemic stroke in hospitalized patients with COVID-19.

Methods

We included patients with a laboratory confirmed SARS-CoV-2 infection admitted in 16 hospitals participating in the international CAPACITY-COVID registry between March 1st and August 1st, 2020. Patients were screened for the occurrence of acute ischemic stroke. We calculated the cumulative incidence of ischemic stroke and compared risk factors, cardiovascular complications, and in-hospital mortality in patients with and without ischemic stroke.

Results

We included 2147 patients with COVID-19, of whom 586 (27.3%) needed treatment at an intensive care unit (ICU). Thirty-eight patients (1.8%) had an ischemic stroke. Patients with stroke were older, but did not differ in sex or cardiovascular risk factors. Median time between onset of COVID-19 symptoms and diagnosis of stroke was two weeks. The incidence of ischemic stroke was higher among patients who were treated at an ICU (16/586; 2.7% versus 22/1561; 1.4%; p=0.039). Pulmonary embolism was more common in patients with (8/38; 21.1%) than in those without stroke (160/2109; 7.6%; adjusted RR: 2.08; 95%CI:1.52-2.84). Twenty-seven patients with ischemic stroke (71.1%) died during admission or were functional dependent at discharge and in-hospital mortality. Patients with ischemic stroke were at a higher risk of in-hospital mortality (adjusted RR 1.56; 95%CI:1.13-2.15) than patients without stroke.

Conclusions

In this multicenter cohort study, the cumulative incidence of acute ischemic stroke in hospitalized patients with COVID-19 was approximately 2%, with a higher risk in patients treated at an ICU. The majority of stroke patients had a poor outcome. The association between ischemic stroke and pulmonary embolism warrants further investigation.
Predicting the onset of freezing of gait in de novo Parkinson’s disease
Authors: Wang Fengting , Pan Yixin , Zhang Miao , Hu Kejia
Published: March 2021

Freezing of gait (FoG) is a debilitating symptom of Parkinson’s disease (PD) related to higher risks of falls and poor quality of life. In this study, we predicted the onset of FoG in PD patients using a battery of risk factors from patients enrolled in the Parkinson’s Progression Markers Initiative (PPMI) cohort. The endpoint was the presence of FoG, which was assessed every year during the five-year follow-up visit. Overall, 212 PD patients were included in analysis. Seventy patients (33.0%) developed FoG during the visit (pre-FoG group). Age, bradykinesia, TD/PIGD classification, fatigue, cognitive impairment, impaired autonomic functions and sleep disorder were found to be significantly different in patients from pre-FoG and non-FoG groups at baseline. The logistic regression model showed that motor factors such as TD/PIGD classification (OR = 2.67, 95% CI = 1.41-5.09), MDS-UPDRS part III score (OR = 1.05, 95% CI = 1.01-1.09) were associated with FoG occurrence. Several indicators representing non-motor symptoms such as SDMT total score (OR = 0.95, 95% CI = 0.91-0.98), HVLT immediate/Total recall (OR = 0.91, 95% CI = 0.86-0.97), MOCA (OR = 0.87, 95% CI = 0.76-0.99), Epworth Sleepiness Scale (OR = 1.13, 95% CI = 1.03-1.24), fatigue(OR = 1.98, 95% CI = 1.32-3.06), SCOPA-AUT gastrointestinal score (OR = 1.27, 95% CI = 1.09-1.49) and SCOPA-AUT urinary score (OR = 1.18, 95% CI = 1.06-1.32) were found to have the predictive value. PD patients that developed FoG showed a significant reduction of DAT uptake in the striatum. However, no difference at baseline was observed in genetic characteristics and CSF biomarkers between the two patient sets. Our model indicated that TD/PIGD classification, MDS-UPDRS total score, and Symbol Digit Modalities score were independent risk factors for the onset of FoG in PD patients. In conclusion, the combination of motor and non-motor features including the akinetic subtype and poor cognitive functions should be considered in identifying PD patients with high risks of FoG onset.
Analysis of Accumulated SARS-CoV-2 Seroconversion in North Carolina: The COVID-19 Community Research Partnership
Authors: Williamson John C. , Wierzba Thomas F , Santacatterina Michele , Munawar Iqra , Seals Austin L , Ballard Christine Ann Pittman , Alexander-Miller Martha , Runyon Michael S , McCurdy Lewis H , Gibbs Michael A , Ahmed Amina , Lagarde William H , Maguire Patrick D , King-Thiele Robin , Hamrick Terri , Ihmeidan Abdalla , Henderson Shakira , Uschner Diane , Herrington David M , Sanders John W
Published: March 2021

Introduction

The COVID-19 Community Research Partnership is a population-based longitudinal syndromic and sero-surveillance study. The study includes over 17,000 participants from six healthcare systems in North Carolina who submitted over 49,000 serology results. The purpose of this study is to use these serology data to estimate the cumulative proportion of the North Carolina population that has either been infected with SARS-CoV-2 or developed a measurable humoral response to vaccination.

Methods

Adult community residents were invited to participate in the study between April 2020 and February 2021. Demographic information was collected and daily symptom screen was completed using a secure, HIPPA-compliant, online portal. A portion of participants were mailed kits containing a lateral flow assay to be used in-home to test for presence of anti-SARS-CoV-2 IgM or IgG antibodies. The cumulative proportion of participants who tested positive at least once during the study was calculated. A standard Cox proportional hazards model was constructed to illustrate the probability of seroconversion over time up to December 20, 2020 (before vaccines available). A separate analysis was performed to describe the influence of vaccines during an extended period through February 15, 2021.

Results

17,688 participants contributed at least one serology result. Approximately two-thirds of the population were female and almost three-quarters were between 30 and 64 years of age. The average number of serology test results submitted per participant was 3.0 (±1.9). At December 20, 2020, the overall probability of seropositivity in the CCRP population was 32.6%. At February 15, 2021 the probability among healthcare workers and non-healthcare workers was 83% and 49%, respectively. An inflection upward in the probability of seropositivity was demonstrated around the end of December, suggesting an influence of vaccinations, especially for healthcare workers. Among healthcare workers, those in the oldest age category (60+ years) were 38% less likely to have seroconverted by February 15, 2021.

Conclusions

Results of this study suggest more North Carolina residents may have been infected with SARS-CoV-2 than the number of documented cases as determined by positive RNA or antigen tests. The influence of vaccinations on seropositivity among North Carolina residents is also demonstrated. Additional research is needed to fully characterize the impact of seropositivity on immunity and the ultimate course of the pandemic.
COVID-19 and Medical Education in Ghana: Assessing the Impact
Authors: Asumanu Edward , Tsevi Linda
Published: March 2021

Medical education in Ghana has been affected in many ways by the onslaught of the COVID-19 pandemic. Though the pandemic has affected both preclinical and clinical segments of medical education, the effect has been felt more at the clinical stage. Medical students on vacation who started their clinical training abroad could not return to their destination of study to complete their programme because of COVID-19 linked travel restrictions. This qualitative study examined how COVID-19 impacted on teaching and learning at a public higher education institution offering clinical medical education in Ghana for over 200 medical students. These medical students were from three different higher education institutions with varied curriculum outcomes. Thus, for them to be considered as a single group required innovativeness on the part of administrators. Open-ended interviews were held with administrators and the outcome indicated that salient aspects of the clinical training process had been impacted. These included administration of clinical education, curriculum, student learning, student assessment and code of practice. As a result of the pandemic, student learning shifted from traditional face to face interaction to online learning at the beginning. Some of the administrative challenges that ensued included the need for reduced number of students per tutor and introduction of afternoon sessions with a limited budget. The paper concludes that COVID-19 has been disruptive to traditional medical education in Ghana. However, the novel learning processes may provide opportunities to increase access to medical education using a phased system of learning. The findings from this study should have implications for policy and contribute to the discourse on blended learning in medical education in Ghana while ensuring that quality is maintained in all instances.
Smartphone-based videoconference visits are easy to implement, effective, and feasible in Crohn’s Disease Patients: A prospective cohort study
Authors: Yilmaz Hasan , Duman Ali Erkan
Published: March 2021

Background

Crohn’s Disease patients require life-long follow-up resulting frequent hospital visits. Usefulness of telehealth has been established in remote management of Crohn’s disease but mobile technology’s role is missing. We aimed to determine the feasibility and effectiveness of smartphone-based real-time video visits.

Methods

We prospectively studied 139 patients either at a traditional (FTF) or online clinic (OLV) in a university hospital between March 2020-September 2020. We measured patients’ satisfactions, disease activity, visit outcomes, socioeconomic parameters, and travel expenses to assess the effectiveness and acceptance of OLV.

Results

Satisfaction scores were significantly higher at OLV compared to FTF (89.58±9.93 vs 70.85±18.51, p<0.001). The Cronbach Alpha reliability coefficient of the VSQ9 scale was 0.878. Median 47km travel distance and 49 minutes travel time per visit saved with OLV. An average of US$12.24 potential travel costs were saved per appointment. Eighty-five per cent of the patients met the needs at online visits and did not require a face-to-face visit.

Conclusions

Smartphone-based real-time video visit telehealth model for distant management of Crohn’ disease had high acceptance. The model was easy to implement, effective and saved travel cost and time.
Sleep quality mediates the relationship between risk of obstructive sleep apnea and acute stress in young adults
Authors: Aggarwal Kunal , Akhtar Nasreen , Mallick Hrudananda
Published: March 2021

Purpose

Intermittent hypoxia and transient arousals in obstructive sleep apnea (OSA) can lead to poor sleep quality and acute stress. Rising levels of obesity and increased incidence of OSA in young adults predisposes them to acute stress. We propose a mediation model to assess if risk of OSA is associated with acute stress and if the relationship between risk for OSA and acute stress is mediated by sleep quality.

Methods

493 healthy individuals (F=237, M=256) from 18-25 years of age (mean age=20.3±1.53 years) were screened for OSA, sleep quality and acute stress using STOP-BANG questionnaire, Pittsburg Sleep Quality Index and American Psychiatry Association’s National Stressful Events Survey Acute Stress Disorder Short Scale (NSESS-S) respectively. Binary and logistic regression were used establish the relationships between the variables. Sobel test for mediation analysis was conducted.

Results

73 participants (17.3%) were found at an intermediate and high risk of OSA by STOP BANG questionnaire. 79 (16%) participants reported level of stress as ‘None’. Mild, moderate and severe stress was present in 248 (50.3%), 109 (22.1%), 51 (10.3%) and 16 (3.2%) participants respectively. The odds of having severe and extreme stress among those at risk of sleep apnea is 2.18 times higher than that among those not at risk of sleep apnea (OR: 2.18, 95% Confidence Interval: 1.37-3.51). Sobel test established that the relationship between OSA and acute stress is mediated by sleep quality.

Conclusion

Sleep quality mediates the relationship between risk for sleep apnea and acute stress. This highlights the importance of screening for OSA in young adults, particularly young men with high BMI, presenting with high stress levels.
Automated Production of Research Data Marts from a Canonical Fast Healthcare Interoperability Resource (FHIR) Data Repository: Applications to COVID-19 Research
Authors: Lenert Leslie A , Ilatovskiy Andrey V. , Agnew James , Rudsill Patricia , Jacobs Jeff , Weatherston Duncan , Deans Kenneth
Published: March 2021

Objective

Objective: The COVID-19 pandemic has enhanced the need for timely real-world data (RWD) for research. To meet this need, several large clinical consortia have developed networks for access to RWD from electronic health records (EHR), each with its own common data model (CDM) and custom pipeline for extraction, transformation, and load operations for production and incremental updating. However, the demands of COVID-19 research for timely RWD (e.g., 2-week delay) make this less feasible.

Methods and Materials

We describe the use of the Fast Healthcare Interoperability Resource (FHIR) data model as a canonical model for representation of clinical data for automated transformation to the Patient-Centered Outcomes Research Network (PCORnet) and Observational Medical Outcomes Partnership (OMOP) CDMs and the near automated production of linked clinical data repositories (CDRs) for COVID-19 research using the FHIR subscription standard. The approach was applied to healthcare data from a large academic institution and was evaluated using published quality assessment tools.

Results

Six years of data (1.07M patients, 10.1M encounters, 137M laboratory results), were loaded into the FHIR CDR producing 3 linked real-time linked repositories: FHIR, PCORnet, and OMOP. PCORnet and OMOP databases were refined in subsequent post processing steps into production releases and met published quality standards. The approach greatly reduced CDM production efforts.

Conclusions

FHIR and FHIR CDRs can play an important role in enhancing the availability of RWD from EHR systems. The above approach leverages 21st Century Cures Act mandated standards and could greatly enhance the availability of datasets for research.
Two Genomic Loci Control Three Eye Colors in the Domestic Pigeon (Columba livia)
Authors: Maclary Emily T. , Phillips Bridget , Wauer Ryan , Boer Elena F. , Bruders Rebecca , Gilvarry Tyler , Holt Carson , Yandell Mark , Shapiro Michael D.
Published: March 2021

The iris of the eye shows striking color variation across vertebrate species, and may play important roles in crypsis and communication. The domestic pigeon (Columba livia)has three common iris colors, orange, pearl (white), and bull (dark brown), segregating in a single species, thereby providing a unique opportunity to identify the genetic basis of iris coloration. We used comparative genomics and genetic mapping in laboratory crosses to identify two candidate genes that control variation in iris color in domestic pigeons. We identified a nonsense mutation in the solute carrierSLC2A11Bthat is shared among all pigeons with pearl eye color, and a locus associated with bull eye color that includesEDNRB2, a gene involved in neural crest migration and pigment development. However, bull eye is likely controlled by a heterogeneous collection of alleles across pigeon breeds. We also found that theEDNRB2region is associated with regionalized plumage depigmentation (piebalding). Our results establish a genetic link between iris and plumage color, two traits that were long known by pigeon breeders to co-occur, and demonstrate the importance of gene duplicates in establishing possibilities and constraints in the evolution of color and color pattern among vertebrates.
Whole-organism 3D Quantitative Characterization of Zebrafish Melanin by Silver Deposition Micro-CT
Authors: Katz Spencer R. , Yakovlev Maksim A. , Vanselow Daniel J. , Ding Yifu , Lin Alex Y. , Parkinson Dilworth Y. , Wang Yuxin , Canfield Victor A. , Ang Khai C. , Cheng Keith C.
Published: March 2021

Melanin-rich zebrafish melanophores are used to study pigment development, human skin color, and as a large-scale screening phenotype. To facilitate more detailed whole-body, computational analyses of melanin content and morphology, we have combined X-ray microtomography (micro-CT), a non-destructive, full-volume imaging modality, with a novel application of ionic silver staining to characterize melanin distribution in whole zebrafish larvae. Normalized micro-CT reconstructions of silver-stained fish consistently reproduced pigment patterns seen by light microscopy, and allowed direct quantitative comparisons of melanin content across wild-type and mutant samples, for both dramatic and subtle phenotypes not previously described. Silver staining of melanin for micro-CT provides proof-of-principle for whole-body, three-dimensional computational phenomic analysis of a particular cell type at cellular resolution, with potential applications in other model organisms and human melanoma biopsies. Whole-organism, high-resolution phenotyping is a challenging ideal, but provides superior context for functional studies of mutations, diseases, and environmental influences.
A cell-ECM mechanism for connecting the ipsilateral eye to the brain
Authors: Su Jianmin , Liang Yanping , Sabbagh Ubadah , Olejníková Lucie , Russell Ashley L. , Chen Jiang , Pan Yuchin Albert , Triplett Jason W. , Fox Michael A.
Published: March 2021

Information about features in the visual world are parsed by circuits in the retina and are then transmitted to the brain by distinct subtypes of retinal ganglion cells (RGCs). Axons from RGC subtypes are stratified in retinorecipient brain nuclei, such as the superior colliculus (SC), to provide a segregated relay of parallel and feature-specific visual streams. Here, we sought to identify the molecular mechanisms that direct the stereotyped laminar targeting of these axons. We focused on ipsilateral-projecting subtypes of RGCs (ipsiRGCs) whose axons target a deep SC sublamina. We identified an extracellular glycoprotein, Nephronectin (NPNT), whose expression is restricted to this ipsiRGC-targeted sublamina. SC-derived NPNT and integrin receptors generated by ipsiRGCs are both required for the targeting of ipsiRGC axons to the deep sublamina of SC. Thus, a cell-extracellular matrix (ECM) recognition mechanism specifies precise laminar targeting of ipsiRGC axons and the assembly of eye-specific parallel visual pathways.

Significance Statement

Distinct features of the visual world are transmitted from the retina to the brain through anatomically segregated circuits. Despite this being an organizing principle of visual pathways in mammals, we lack an understanding of the signaling mechanisms guiding axons of different types of retinal neurons into segregated layers of brain regions. We explore this question by identifying how axons from the ipsilateral retina innervate a specific lamina of the superior colliculus. Our studies reveal a unique cell-extracellular matrix (ECM) recognition mechanism that specifies precise targeting of these axons to the superior colliculus. Loss of this mechanism not only resulted in the absence of this eye-specific visual circuit, but it led to an impairment of innate predatory visual behavior as well.
A survey of the mouse hindbrain in the fed and fasted state using single-nucleus RNA sequencing
Authors: Dowsett Georgina K.C. , Lam Brian Y.H. , Tadross John , Cimino Irene , Rimmington Debra , Coll Anthony P. , Polex-Wolf Joseph , Knudsen Lotte Bjerre , Pyke Charles , Yeo Giles S.H.
Published: March 2021

Objective

The area postrema (AP) and the nucleus tractus solitaris (NTS), located in the hindbrain, are key nuclei that sense and integrate peripheral nutritional signals and, consequently, regulate feeding behaviour. While single cell transcriptomics have been used in mice to reveal the gene expression profile and heterogeneity of key hypothalamic populations, similar in-depth studies have not yet been performed in the hindbrain.

Methods

Using single-nucleus RNA sequencing, we provide a detailed survey of 16,034 cells within the AP and NTS of the mouse, in the fed and fasted state.

Results

Of these, 8910 are neurons that group into 30 clusters, with 4289 coming from mice fedad libitumand 4621 from overnight fasted mice. 7124 nuclei are from non-neuronal cells, including oligodendrocytes, astrocytes and microglia. Interestingly, we identified that the oligodendrocyte population was particularly transcriptionally sensitive to an overnight fast. The receptors GLP1R, GIPR, GFRAL and CALCR, which bind GLP1, GIP, GDF15 and amylin respectively, are all expressed in the hindbrain and are major targets for anti-obesity therapeutics. We characterise the transcriptomes of these four populations and show that their gene expression profiles are not dramatically altered by an overnight fast. Notably, we find that roughly half of cells that express GIPR are oligodendrocytes. Additionally, we profile POMC expressing neurons within the hindbrain and demonstrate that 84% of POMC neurons express either PCSK1, PSCK2 or both, implying that melanocortin peptides are likely produced by these neurons.

Conclusion

We provide a detailed single-cell level characterisation of AP and NTS cells expressing receptors for key anti-obesity drugs that are either already approved for human use or are in clinical trials. This resource will help delineate the mechanisms underlying the effectiveness of these compounds, and also prove useful in the continued search for other novel therapeutic targets.
A quantitative landscape of cell fate transitions identifies principles of cellular decision-making
Authors: Sáez M. , Blassberg R. , Camacho-Aguilar E. , Siggia E. D. , Rand D. , Briscoe J.
Published: March 2021

Fate decisions in developing tissues involve cells transitioning between a set of discrete cell states, each defined by a distinct gene expression profile. Geometric models, often referred to as Waddington landscapes, in which developmental paths are given by the gradient and cell states by the minima of the model, are an appealing way to describe differentiation dynamics and developmental decisions. To construct and validate accurate dynamical landscapes, quantitative methods based on experimental data are necessary. To this end we took advantage of the differentiation of neural and mesodermal cells from pluripotent mouse embryonic stem cells exposed to different combinations and durations of signalling factors. We developed a principled statistical approach using flow cytometry data to quantify differentiating cell states. Then, using a framework based on Catastrophe Theory and approximate Bayesian computation, we constructed the corresponding dynamical landscape. The result was a quantitative model that accurately predicted the proportions of neural and mesodermal cells differentiating in response to specific signalling regimes. Analysis of the geometry of the landscape revealed two distinct ways in which cells make a binary choice between one of two fates. We discuss the biological relevance of these mechanisms and suggest that they represent general archetypal designs for developmental decisions. Taken together, the approach we describe is broadly applicable for the quantitative analysis of differentiation dynamics and for determining the logic of developmental cell fate decisions.
Complementary evolution of coding and noncoding sequence underlies mammalian hairlessness
Authors: Kowalczyk Amanda , Chikina Maria , Clark Nathan
Published: March 2021

Body hair is a defining mammalian characteristic, but several mammals, such as whales, naked mole-rats, and humans, have notably less hair than others. To find the genetic basis of reduced hair quantity, we used our evolutionary-rates-based method, RERconverge, to identify coding and noncoding sequences that evolve at significantly different rates in so-called hairless mammals compared to hairy mammals. Using RERconverge, we performed an unbiased, genome-wide scan over 62 mammal species using 19,149 genes and 343,598 conserved noncoding regions to find genetic elements that evolve at significantly different rates in hairless mammals compared to hairy mammals. We show that these rate shifts resulted from relaxation of evolutionary constraint on hair-related sequences in hairless species. In addition to detecting known and potential novel hair-related genes, we also discovered hundreds of putative hair-related regulatory elements. Computational investigation revealed that genes and their associated noncoding regions show different evolutionary patterns and influence different aspects of hair growth and development. Many genes under accelerated evolution are associated with the structure of the hair shaft itself, while evolutionary rate shifts in noncoding regions also included the dermal papilla and matrix regions of the hair follicle that contribute to hair growth and cycling. Genes that were top-ranked for coding sequence acceleration included known hair and skin genesKRT2, KRT35, PKP1, andPTPRMthat surprisingly showed no signals of evolutionary rate shifts in nearby noncoding regions. Conversely, accelerated noncoding regions are most strongly enriched near regulatory hair-related genes and microRNAs, such asmir205, ELF3, andFOXC1, that themselves do not show rate shifts in their protein-coding sequences. Such dichotomy highlights the interplay between the evolution of protein sequence and regulatory sequence to contribute to the emergence of a convergent phenotype.