bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic basis of a spontaneous mutation’s expressivity
Authors: Schell Rachel , Hale Joseph J. , Mullis Martin N. , Matsui Takeshi , Foree Ryan , Ehrenreich Ian M. 
Published: April 2020

AbstractGenetic background often influences the phenotypic consequences of mutations, resulting in variable expressivity. How standing genetic variants collectively cause this phenomenon is not fully understood. Here, we comprehensively identify loci in a budding yeast cross that impact the growth of individuals carrying a spontaneous missense mutation in the nuclear-encoded mitochondrial ribosomal geneMRP20. Initial results suggested that a single large effect locus influences the mutation’s expressivity, with one allele causing inviability in mutants. However, further experiments revealed this simplicity was an illusion. In fact, many additional loci shape the mutation’s expressivity, collectively leading to a wide spectrum of mutational responses. These results exemplify how complex combinations of alleles can produce a diversity of qualitative and quantitative responses to the same mutation.
Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two European cohort studies
Authors: Carmeli Cristian , Kutalik Zoltán , Mishra Pashupati P. , Porcu Eleonora , Delpierre Cyrille , Delaneau Olivier , Kelly-Irving Michelle , Bochud Murielle , Dhayat Nasser A. , Ponte Belen , Pruijm Menno , Ehret Georg , Kähönen Mika , Lehtimäki Terho , Raitakari Olli T. , Vineis Paolo , Kivimäki Mika , Chadeau-Hyam Marc , Dermitzakis Emmanouil , Vuilleumier Nicolas , Stringhini Silvia 
Published: April 2020

ABSTRACTIndividuals growing up during childhood in a socioeconomically disadvantaged family experience a higher rate of inflammation-related diseases later in life. Little is known about the mechanisms linking early life experiences to the functioning of the immune system decades later. Here we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation (C-reactive protein) and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (up to 78%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than DNA methylation potentially regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of pro-inflammatory genes regulation that cannot fully be explained by differential DNA methylation.
Separate Fever Clinics Prevent the Spread of COVID-19 and Offload Emergency Resources: Analysis from a large tertiary hospital in China
Authors: Wang Jiangshan , Zong Liang , Zhang Jinghong , Sun Han , Walline Joseph Harold , Sun Pengxia , Xu Shengyong , Li Yan , Wang Chunting , Liu Jihai , Li Fan , Xu Jun , Li Yi , Yu Xuezhong , Zhu Huadong 
Published: April 2020

AbstractObjectivesCOVID-19 began spreading widely in China in January 2020. Outpatient “Fever Clinics” (FCs), instituted during the SARS epidemic in 2003 were upgraded to provide COVID-19 screening and prevention attached to large tertiary hospitals. We sought to analyze the effect of upgraded FCs to detecting COVID-19 at our institution.DesignA population-based cross-sectional study.ParticipantsA total of 6,365 patients were screened in the FC.MethodsThe FC of Peking Union Medical College Hospital (PUMCH) was upgraded on January 20, 2020. We performed a retrospective study of patients presenting to the FC between December 12, 2019 to February 29, 2020, covering a period of 40 days before and after upgrading the FC. All necessary data, including baseline patient information, diagnoses, follow-up conditions for critical patients, transfer information between the FC and emergency department (ED) were collected and analyzed.Results6,365 patients were screened in the FC, among whom 2,192 patients were screened before January 21, 2020, while 3,453 were screened afterwards. Screening results showed that upper respiratory infection was the major disease associated with fever. Compared to before the outbreak, patients transferred from the FC to ED decreased significantly [39.21% vs 15.75%, p<0.001] and tended to spend more time in the FC [55 vs 203mins, p<0.001]. For critically-ill patients waiting for a screening result, the total length of stay in the FC was 22mins before the outbreak, compared to 442mins after the outbreak (p< 0.001). The number of in-hospital deaths of critical-care patients seen first in the FC was 9 of 29 patients before the outbreak and 21 of 38 after (p<0.050). Nineteen COVID-19 cases were confirmed in the FC, but no other patients or medical care providers were cross-infected.ConclusionThe work-load of the FC increased after the COVID-19 outbreak and effectively prevented COVID-19 from spreading in the hospital,as well as offload ED resources.
Pressure-Regulated Ventilator Splitting (PReVentS) – A COVID-19 Response Paradigm from Yale University
Authors: Brickman Raredon Micha Sam , Fisher Clark , Heerdt Paul , Deshpande Ranjit , Nivison Steven , Fajardo Elaine , Akhtar Shamsuddin , Raredon Thomas , Niklason Laura 
Published: April 2020

AbstractIn the current COVID-19 crisis, the US and many countries in the world are suffering acute shortages of modern ventilators to care for desperately ill patients. Since modern ICU ventilators are powerful devices that can deliver very high gas flow rates and pressures, multiple physicians have attempted to ventilate more than one patient on a single ventilator – so-called “vent splitting”. Early applications of this approach have utilized simple concatenations of ventilator tubing and T-pieces, to provide flow to more than one patient. Additional approaches using custom flow splitters – sometimes made using 3D printing technologies – have also advanced into the clinic with FDA approval. However, heretofore there has been less progress made on controlling individual ventilatory pressures for patients with severe lung disease. Given the inherent variability and instability of lung compliance amongst patients with COVID-19, there remains an important need to provide a means of extending ventilator usefulness to more than one patient, but in a way that provides more tailored pressures that can be titrated over time. In this descriptive report, we provide the basis for a ventilator circuit that can support two patients with individualized peak inspiratory and end-expiratory pressures. The circuit is comprised of exclusively “off the shelf” materials and is inexpensive to produce. The circuit can be used with typical ICU ventilators, and with anesthesia ventilators used in operating rooms. Inspiratory and end-expiratory pressures for each patient can be titrated over time, without changes for one patient affecting the ventilation parameters of the other patient. Using in-line spirometry, individual tidal volumes can be measured for each patient. This Pressure-Regulated Ventilator Splitting (PReVentS) Yale University protocol operates under a pressure-control ventilatory mode, and may function optimally when patients are not triggering breaths from the ventilator.This method has been tested thus far only in the laboratory with mock lungs, and has not yet been deployed in animals or in patients. However, given the novelty and potential utility of this approach, we deemed it appropriate to provide this information to the broader critical care community at the present time. In coming days and weeks, we will continue to characterize and refine this approach, using large animal models and proof-of-principle human studies.
Peripheral Zone Enlargement: a newly described entity on MRI
Authors: Wasserman Neil F. , Murguan Paari , Spilseth Ben , Metzger Gregory J. , Sanghvi Tina 
Published: April 2020

AbstractPurposeA retrospective study was performed to describe and characterize a previously unreported finding on T2-weighted magnetic resonance imaging (MRI) of peripheral zone enlargement (PZE) associated with total prostatic enlargement without necessary association with benign prostatic hyperplasia (BPH) or lower urinary tract symptoms.MethodsT2-weighted MRI were reviewed from 2012-2018. Patients were referred for elevated serum prostatic specific antigen (PSA) levels, prostatic enlargement, or abnormal digital rectal examination (DRE) suggestive of adenocarcinoma. Enlargement of the thickness of the peripheral zone (PZ) was defined as a measurement of postero-lateral thickness (PLPZ) of ≥ 15.8 mm in the maximal transaxial plane. Endorectal coils were used in 2 patients. Microscopic pathology was described in 3 patients.ResultsThere were 22 patients who met the criteria out of 2871 subjects (<1%). Mean age was 63 years, Mean PLPZ was 17.7 mm (CI=0.45, range, 15.8-21.3). mean total prostatic volume was 55.1 cc (range, 19.9-127.2 cc), mean transition zone volume was 20.6 cc (range, 2.7-71.9 cc), mean transition zone index (TZI) was 0.34 (range, 0.31-0.68), mean prostatic specific antigen (PSA) was 13.9 ng/mL (range, 0.28-144.7), mean body mass index was 28.9 (range 23.0-36.3).. Enlargement was described in 14 of 20 (70%). Pathological findings showed marked glandular distention and atrophy with interstitial edema and chronic inflammatory cells. Significance of these results is discussed.
Maternal Continuous Oral Oxycodone Self-Administration Alters Pup Affective/Social Communication but not Spatial Learning or Sensory-Motor Function
Authors: Zanni Giulia , Robinson-Drummer Patrese A. , Dougher Ashlee A. , Deutsch Hannah M. , DeSalle Matthew J. , Teplitsky David , Vemulapalli Aishwarya , Sullivan Regina M. , Eisch Amelia J. , Barr Gordon A. 
Published: April 2020

AbstractThe broad use and misuse of prescription opioids during pregnancy has resulted in a surge of infants diagnosed with Neonatal Opioid Withdrawal Syndrome (NOWS). Short-term irritability and neurological complications are hallmarks of NOWS, but the long-term consequences are unknown. Our newly-developed preclinical model of oxycodone self-administration enables adult female rats to readily drink oxycodone (0.06-0.12 mg/ml, ∼10/mg/kg/day) continuously before and during pregnancy and after delivery, to achieve similar liquid intake in oxycodone moms relative to water-only controls. Oxycodone levels were detected in the serum of mothers and pups. Growth parameters in dams and pups, and litter mass and size were similar to controls. Maternal behavior at postnatal day 1 (PN1) was unchanged by perinatal oxycodone consumption. Regarding the plantar thermal response, there were no differences in paw retraction latency between oxycodone and control pups at PN2 or PN14. Oxycodone and control pups had similar motor coordination, cliff avoidance, righting time, pivoting, and olfactory spatial learning from PN3 through PN13. Separation-induced ultrasonic vocalizations at PN8 revealed higher call frequency in oxycodone pups relative to controls. Finally, during naltrexone precipitated withdrawal at PN9, oxycodone males vocalized more than control pups, consistent with a previously-published withdrawal phenotype. Thus, our rat model of continuous oral oxycodone self-administration in pregnancy shows exacerbated affect/social communication in pups in a sex-dependent manner but spared cognition and locomotion. Our preclinical, high face validity NOWS model reproduces key aspects of human opioid use during pregnancy, enabling longitudinal analysis of how maternal oxycodone changes emotional behavior in the offspring.HIGHLIGHTSFemale rats self-administered oxycodone at clinically relevant doses before and during pregnancy and for the first two weeks after parturition.Both dams and pups, for the14 day postnatal experimental period, had detectable levels of oxycodone in their bloodDams drinking oxycodone only or water only did not differ in weight gain, water intake, or the number of pups born and their pups did not differ in weight throughout.Sensory and motor function in the pups was not altered, nor was hippocampal dependent spatial learning.Oxycodone exposed pups were physically dependent and displayed increased withdrawal behaviors with or without the opioid antagonist naltrexone.Pups expressed more negative affect, expressed by increased ultrasonic vocalizations, following naltrexone precipitated withdrawal or when separated from their mother.
ZNF423patient variants, truncations, and in-frame deletions in mice define an allele-dependent range of midline brain abnormalities
Authors: Deshpande Ojas , Lara Raquel Z. , Zhang Oliver R. , Concepcion Dorothy , Hamilton Bruce A. 
Published: April 2020

ABSTRACTInterpreting rare variants remains a challenge in personal genomics, especially for disorders with several causal genes and for genes that cause multiple disorders.ZNF423encodes a transcriptional regulatory protein that intersects several developmental pathways.ZNF423has been implicated in rare neurodevelopmental disorders, consistent with midline brain defects inZfp423-mutant mice, but pathogenic potential of most patient variants remains uncertain. We engineered ~50 patient-derived and small deletion variants into the highly-conserved mouse ortholog and examined neuroanatomical measures for 791 littermate pairs. Three substitutions previously asserted pathogenic appeared benign, while a fourth was effectively null. Heterozygous premature termination codon (PTC) variants showed mild haploabnormality, consistent with loss-of-function intolerance inferred from human population data. In-frame deletions of specific zinc fingers showed mild to moderate abnormalities, as did low-expression variants. These results affirm the need for functional validation of rare variants in biological context and demonstrate cost-effective modeling of neuroanatomical abnormalities in mice.AUTHOR SUMMARYGene identification in rare disorders is typically supported by finding different mutations of the same gene in multiple families with the same disorder. However, causal evidence for any specific mutation found in one or a few related individuals is weaker, especially if the disorder can be caused by any of several genes and the functional effect of the mutation is not certain. Experimental models can be helpful in testing causal effects, but only to the extent that the model is validated to recapitulate one or more aspects of the disorder. We used CRISPR/Cas9-based genome engineering to create a wide range of mutations in mouseZfp423, whose human cognate is implicated in neurodevelopmental disorders, especially cerebellar vermis hypoplasia and Joubert syndrome. This large collection of animal models shows that both reducedZfp423expression, including heterozygosity for loss-of-function mutations, and normally-expressed domain deletions, including specific zinc finger domains, produce measureable abnormalities in midline development. Despite this high level of validation, most patient-derived amino acid substitution variants tested do not produce measureable effects. The single exception is a substitution, H1277Y, that destroys a structural element in the last zinc finger domain and results in dramatic loss of steady-state Zfp423 protein level.
Behavioral thermal tolerance predicts distribution pattern but not habitat use in sympatric Neotropical frogs
Authors: Diaz-Ricaurte Juan C. , Serrano Filipe C. , Guevara-Molina Estefany Caroline , Araujo Cybele , Martins Marcio 
Published: April 2020

AbstractEnvironmental temperatures are a major constraint on ectotherm abundance and diversity, influencing their distribution and natural history. Comparing thermal tolerances with environmental temperatures is a simple way to estimate thermal constraints on species distributions. We investigate the potential effects of thermal tolerance on anuran local (habitat) and global distribution patterns and associated behavioral responses. We tested for differences in Voluntary Thermal Maximum of two sympatric frog species of the genusPhysalaemusin the Cerrado ecoregion. For each species, we constructed models to assess the effects of period of day, duration of experiment, initial body mass, initial body temperature and heating rate on the VTMax. We mapped the difference between VTMaxand maximum daily temperature (VTMax- ETMax) for each occurrence point.Physalaemus nattererihad a significantly higher VTMaxthanP. cuvieri. ForP. nattereri, the model including only period of day was chosen as the best to explain variation in the VTMax. ForP. cuvieri, no model was selected as best to predict VTMax. The VTMax- ETMaxvalues were significantly different between species, withP. nattererimostly found in localities that attain maximum temperatures lower than its VTMaxandP. cuvierishowing the reverse pattern. Regarding habitat use, we foundP. cuvierito be slightly more abundant in open habitats than in non-open habitats, whereasP. nattererishows the reverse pattern. The difference in VTMaxvalues between these two species might be related to their different body sizes, but additionally might reflect their natural history, especially the way they use their habitats, and phylogenetic constraints (the species studied are in different clades withinPhysalaemus). Our study indicates that differences in behavioral thermal tolerance may be important in shaping local and regional distribution patterns. Furthermore, small-scale habitat use might reveal a link between behavioral thermal tolerance and natural history strategies.
A benzene-mapping approach for uncovering cryptic pockets in membrane-bound proteins
Authors: Zuzic Lorena , Marzinek Jan K , Warwicker Jim , Bond Peter J 
Published: April 2020

ABSTRACTMolecular dynamics (MD) simulations in combination with small organic probes present in the solvent have previously been used as a method to reveal cryptic pockets that may not have been identified in experimental structures. We report such a method implemented within the CHARMM forcefield to effectively explore cryptic pockets on the surfaces of membrane-embedded proteins using benzene as a probe molecule. This relies on modified non-bonded parameters in addition to repulsive potentials between membrane lipids and benzene molecules. The method was tested on part of the outer shell of the dengue virus (DENV), for which research into a safe and effective neutralizing antibody or drug molecule is still ongoing. In particular, the envelope (E) protein, associated with the membrane (M) protein, is a lipid membrane-embedded complex which forms a dimer in the mature viral envelope. Solvent mapping was performed for the full, membrane-embedded EM protein complex and compared with similar calculations performed for the isolated, soluble E protein ectodomain dimer in solvent. Ectodomain-only simulations with benzene exhibited unfolding effects not observed in the more physiologically relevant membrane-associated systems. A cryptic pocket which has been experimentally shown to bindn-octyl-β-D-glucoside detergent was consistently revealed in all benzene-containing simulations. The addition of benzene also enhanced the flexibility and hydrophobic exposure of cryptic pockets at a key, functional interface in the E protein, and revealed a novel, potentially druggable pocket that may be targeted to prevent conformational changes associated with viral entry into the cell.GRAPHICAL ABSTRACT
OptiFlex: video-based animal pose estimation using deep learning enhanced by optical flow
Authors: Liu XiaoLe , Yu Si-yang , Flierman Nico , Loyola Sebastian , Kamermans Maarten , Hoogland Tycho M. , De Zeeuw Chris I. 
Published: April 2020

AbstractDeep learning based animal pose estimation tools have greatly improved animal behaviour quantification. However, those tools all make predictions on individual video frames and do not account for variability of animal body shape in their model designs. Here, we introduce the first video-based animal pose estimation architecture, referred to as OptiFlex, which integrates a flexible base model to account for variability in animal body shape with an optical flow model to incorporate temporal context from nearby video frames. This approach can be combined with multi-view information, generating prediction enhancement using all four dimensions (3D space and time). To evaluate OptiFlex, we adopted datasets of four different lab animal species (mouse, fruit fly, zebrafish, and monkey) and proposed a more intuitive evaluation metric - percentage of correct key points (aPCK). Our evaluations show that OptiFlex provides the best prediction accuracy amongst current deep learning based tools, and that it can be readily applied to analyse a wide range of behaviours.
Glycogen synthase kinase 3 alpha/beta deletion induces precocious growth plate remodeling and cell loss in mice
Authors: Bali Supinder Kour , Bryce Dawn , Prein Carina , Woodgett James R. , Beier Frank 
Published: April 2020

ABSTRACTGlycogen synthase kinase (GSK) 3 acts to negatively regulate multiple signaling pathways, including canonical Wnt signaling. The two mammalian GSK3 proteins (alpha and beta) are at least partially redundant. WhileGsk3aKO mice are viable and display a metabolic phenotype, abnormal neuronal development and accelerated aging,Gsk3bKO animals die late in embryogenesis or at birth. SelectiveGsk3bKO in bone delayed development of some bones, whereas cartilage-specificGsk3bKO mice are normal except for elevated levels of GSK3alpha protein. However, the collective role of these two GSK3 proteins in cartilage was not evaluated. To address this, we generated tamoxifen-inducible, cartilage-specificGsk3a/Gsk3bKO in juvenile mice and investigated their skeletal phenotypes. We found that cartilage-specificGsk3a/Gsk3bdeletion in young, skeletally immature mice causes precocious growth plate remodeling, culminating in shorter long bones and hence, growth retardation. These mice exhibit inefficient breathing patterns at later stages and fail to survive. The disrupted growth plates in KO mice showed progressive loss of cellular and proteoglycan components and Sox9 positive cells, with increased staining for osteocalcin and type II collagen. In addition, an increase in osteoclast recruitment and cell apoptosis was observed in growth plates. Surprisingly, changes in articular cartilage ofGsk3a/Gsk3bKO mice were mild compared to growth plates, signifying differential regulation of articular cartilage vs growth plate tissues. Taken together, these findings emphasize a crucial role of two GSK3 proteins in skeletal development, in particular in the maintenance and function of growth plates.SignificanceGrowth plate cartilage dynamics determine the rate of endochondral bone growth and thus, our final height. These processes are disturbed in many genetic and acquired diseases, but the intracellular mechanisms responsible for normal growth plate function, as well as the cessation of growth plate activity in puberty, are poorly understood. Here, we demonstrate that specific removal of both GSK3 genes (Gsk3aandGsk3b) in postnatal cartilage of mice leads to a severe reduction of endochondral bone growth, premature remodelling of the growth plate, and early death. In contrast, articular cartilage is only mildly affected by deletion of both genes. These studies identify GSK3 signaling as a key regulator of growth plate dynamics and endochondral bone growth.