bluuebunny/crossref_metadata_2025_split huggingface dataset:
The importance of a consistent workflow to estimate muscle-tendon lengths based on joint angles from the conventional gait model
Authors: Kainz Hans , Schwartz Michael H 
Published: March 2021

AbstractBackgroundMusculoskeletal models enable us to estimate muscle-tendon length, which has been shown to improve clinical decision-making and outcomes in children with cerebral palsy. Most clinical gait analysis services, however, do not include muscle-tendon length estimation in their clinical routine. This is due, in part, to a lack of knowledge and trust in the musculoskeletal models, and to the complexity involved in the workflow to obtain the muscle-tendon length.Research questionCan the joint angles obtained with the conventional gait model (CGM) be used to generate accurate muscle-tendon length estimates?MethodsThree-dimensional motion capture data of 15 children with cerebral palsy and 15 typically developing children were retrospectively analyzed and used to estimate muscle-tendon length with the following four modelling frameworks: (1) 2392-OSM-IK-angles: standard OpenSim workflow including scaling, inverse kinematics and muscle analysis; (2) 2392-OSM-CGM-angle: generic 2392-OpenSim model driven with joint angles from the CGM; (3) modif-OSM-IK-angles: standard OpenSim workflow including inverse kinematics and a modified model with segment coordinate systems and joint degrees-of-freedom similar to the CGM; (4) modif-OSM-CGM-angles: modified model driven with joint angles from the CGM. Joint kinematics and muscle-tendon length were compared between the different modelling frameworks.ResultsLarge differences in hip joint kinematics were observed between the CGM and the 2392-OpenSim model. The modif-OSM showed similar kinematics as the CGM. Muscle-tendon length obtained with modif-OSM-IK-angles and modif-OSM-CGM-angles were similar, whereas large differences in some muscle-tendon length were observed between 2392-OSM-IK-angles and 2392-OSM-CGM-angles.SignificanceThe modif-OSM-CGM-angles framework enabled us to estimate muscle-tendon lengths without the need for scaling a musculoskeletal model and running inverse kinematics. Hence, muscle-tendon length estimates can be obtained simply, without the need for the complexity, knowledge and time required for musculoskeletal modeling and associated software. An instruction showing how the framework can be used in a clinical setting is provided on https://github.com/HansUniVie/MuscleLength.
Evaluation of Measles Surveillance System amidst Covid – 19 pandemic in Asutifi North District, Ahafo Region, Ghana
Authors: Owusu Sekyere Stephen , Dam-Park Laar Salam 
Published: March 2021

AbstractBackgroundMeasles is a disease of public health importance earmarked for elimination by all WHO Regions. Globally, more than 140 000 people died from Measles in 2018 affecting mostly children under 5 years, despite the availability of safe and effective vaccine.MethodsA descriptive cross-sectional survey was conducted. Disease surveillance focal persons were interviewed using semi-structured questionnaire on the system operations and use of Measles case definitions. Measles case-based investigation forms from 2015 – 2020 were reviewed for its timeliness and data quality. CDC updated guidelines for surveillance system evaluation was used to assess its usefulness and attributes. Data was analyzed for frequencies and proportions and results presented in tables and graphs.ResultsMeasles surveillance system was timely as 100% (69/69) of the suspected cases were reported on time. Also, the level of representativeness was good as all the 14 health facilities in the District were participating in the Measles Surveillance system. Majority 73.1 (44/60) of the case-based investigation forms filled were incomplete with some columns wrongly filled.ConclusionDespite the outbreak of Covid – 19 with most districts battling with how to contain the virus, measles surveillance system was still meeting its objectives of early detection and prompt reporting but with poor data quality.
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

AbstractEffective 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

AbstractThe 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 StatementMitochondria 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

AbstractWe 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

AbstractBackground and PurposeMembers 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 ApproachThe 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 ResultsUsing 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 ImplicationsWe provide a new platform that could be utilized in ongoing studies in orphan receptor signaling and deorphanization efforts.What is already knownA large group of understudied orphan GPCRs controls a variety of physiological process.What this study addsA new strategy to identify G protein signaling associated with orphan GPCRs.Identification of Gi/ocoupling for 8 orphan GPCRs.What is the clinical significanceMany 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

AbstractSeasonality 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

AbstractGenomic 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

SummaryMonoclonal 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

AbstractDifferentiating 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

ABSTRACTProteostatic 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

AbstractSevere 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 summaryAlthough 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.