bluuebunny/crossref_metadata_2025_split huggingface dataset:
Centromere evolution in the fungal genusVerticillium
Authors: Seidl Michael F , Kramer H Martin , Cook David E , Fiorin Gabriel Lorencini , van den Berg Grardy CM , Faino Luigi , Thomma Bart PHJ 
Published: July 2020

ABSTRACTCentromeres are chromosomal regions that are crucial for chromosome segregation during mitosis and meiosis, and failed centromere formation can contribute to chromosomal anomalies. Despite this conserved function, centromeres differ significantly between and even within species. Thus far, systematic studies into the organization and evolution of fungal centromeres remain scarce. In this study, we identified the centromeres in each of the ten species of the fungal genusVerticilliumand characterized their organization and evolution. Chromatin immunoprecipitation of the centromere-specific histone CenH3 (ChIP-seq) and chromatin conformation capture (Hi-C) followed by high-throughput sequencing identified eight conserved, large (∼150 kb), AT-, and repeat-rich regional centromeres that are embedded in heterochromatin in the plant pathogenV. dahliae. Using Hi-C, we similarly identified repeat-rich centromeres in the otherVerticilliumspecies. Strikingly, a single repetitive element is strongly associated with centromeric regions in some but not allVerticilliumspecies. Extensive chromosomal rearrangements occurred duringVerticilliumevolution, yet only a minority could be linked to centromeres, suggesting that centromeres played a minor role in chromosomal evolution. Nevertheless, the size and organization of centromeres differ considerably between species, and centromere size was found to correlate with the genome-wide repeat content. Overall, our study highlights the contribution of repetitive elements to the diversity and rapid evolution of centromeres within the fungal genusVerticillium.IMPORTANCEThe genusVerticilliumcontains ten species of plant-associated fungi, some of which are notorious pathogens.Verticilliumspecies evolved by frequent chromosomal rearrangements that contribute to genome plasticity. Centromeres are instrumental for separation of chromosomes during mitosis and meiosis, and failed centromere functionality can lead to chromosomal anomalies. Here, we used a combination of experimental techniques to identify and characterize centromeres in each of theVerticilliumspecies. Intriguingly, we could strongly associate a single repetitive element to the centromeres of some of theVerticilliumspecies. The presence of this element in the centromeres coincides with increased centromere sizes and genome-wide repeat expansions. Collectively, our findings signify a role of repetitive elements in the function, organization and rapid evolution of centromeres in a set of closely related fungal species.
The transcription factor Pdr802 regulates Titan cell formation, quorum sensing, and pathogenicity ofCryptococcus neoformans
Authors: Reuwsaat Julia C. V. , Agustinho Daniel P. , Motta Heryk , Brown Holly , Chang Andrew L. , Brent Michael R. , Kmetzsch Livia , Doering Tamara L. 
Published: July 2020

ABSTRACTCryptococcus neoformansis a ubiquitous, opportunistic fungal pathogen that kills almost 200,000 people worldwide each year. It is acquired when mammalian hosts inhale the infectious propagules; these are deposited in the lung and, in the context of immunocompromise, may disseminate to the brain and cause lethal meningoencephalitis. Once inside the host,C. neoformansundergoes a variety of adaptive processes, including secretion of virulence factors, expansion of a polysaccharide capsule that impedes phagocytosis, and the production of giant (Titan) cells. The transcription factor Pdr802 is one regulator of these responses to the host environment. Expression of the corresponding gene is highly induced under host-like conditionsin vitroand is critical forC. neoformansdissemination and virulence in a mouse model of infection. Direct targets of Pdr802 include the quorum sensing proteins Pqp1, Opt1 and Liv3; the transcription factors Stb4, Zfc3 and Bzp4, which regulate cryptococcal brain infectivity and capsule thickness; the calcineurin targets Had1 and Crz1, important for cell wall remodeling andC. neoformansvirulence; and additional genes related to resistance to host temperature and oxidative stress, and to urease activity. Notably, cryptococci engineered to lack Pdr802 showed a dramatic increase in Titan cells, which are not phagocytosed and have diminished ability to directly cross biological barriers. This explains the limited dissemination ofpdr802mutant cells to the central nervous system and the consequently reduced virulence of this strain. The role of Pdr802 as a negative regulator of Titan cell formation is thus critical for cryptococcal pathogenicity.IMPORTANCEThe pathogenic yeastCryptococcus neoformanspresents a worldwide threat to human health, especially in the context of immunocompromise, and current antifungal therapy is hindered by cost, limited availability, and inadequate efficacy. After the infectious particle is inhaled,C. neoformansinitiates a complex transcriptional program that integrates cellular responses and enables adaptation to the host lung environment. Here we describe the role of the transcription factor Pdr802 in the response to host conditions and its impact onC. neoformansvirulence. We identified direct targets of Pdr802 and also discovered that it regulates cellular features that influence movement of this pathogen from the lung to the brain, where it causes fatal disease. These findings advance our understanding of a serious disease.
A phenome-wide association study (PheWAS) of COVID-19 outcomes by race using the electronic health records data in Michigan Medicine
Authors: Salvatore Maxwell , Gu Tian , Mack Jasmine A. , Sankar Swaraaj Prabhu , Patil Snehal , Valley Thomas S. , Singh Karandeep , Nallamothu Brahmajee K. , Kheterpal Sachin , Lisabeth Lynda , Fritsche Lars G. , Mukherjee Bhramar 
Published: July 2020

AbstractBackgroundWe perform a phenome-wide scan to identify pre-existing conditions related to COVID-19 susceptibility and prognosis across the medical phenome and how they vary by race.MethodsThe study is comprised of 53,853 patients who were tested/positive for COVID-19 between March 10 and September 2, 2020 at a large academic medical center.ResultsPre-existing conditions strongly associated with hospitalization were renal failure, pulmonary heart disease, and respiratory failure. Hematopoietic conditions were associated with ICU admission/mortality and mental disorders were associated with mortality in non-Hispanic Whites. Circulatory system and genitourinary conditions were associated with ICU admission/mortality in non-Hispanic Blacks.ConclusionsUnderstanding pre-existing clinical diagnoses related to COVID-19 outcomes informs the need for targeted screening to support specific vulnerable populations to improve disease prevention and healthcare delivery.
Modeling the early phase of the Belgian COVID-19 epidemic using a stochastic compartmental model and studying its implied future trajectories
Authors: Abrams Steven , Wambua James , Santermans Eva , Willem Lander , Kuylen Elise , Coletti Pietro , Libin Pieter , Faes Christel , Petrof Oana , Herzog Sereina A. , Beutels Philippe , Hens Niel 
Published: July 2020

AbstractFollowing the onset of the ongoing COVID-19 pandemic throughout the world, a large fraction of the global population is or has been under strict measures of physical distancing and quarantine, with many countries being in partial or full lockdown. These measures are imposed in order to reduce the spread of the disease and to lift the pressure on healthcare systems. Estimating the impact of such interventions as well as monitoring the gradual relaxing of these stringent measures is quintessential to understand how resurgence of the COVID-19 epidemic can be controlled for in the future. In this paper we use a stochastic age-structured discrete time compartmental model to describe the transmission of COVID-19 in Belgium. Our model explicitly accounts for age-structure by integrating data on social contacts to (i) assess the impact of the lockdown as implemented on March 13, 2020 on the number of new hospitalizations in Belgium; (ii) conduct a scenario analysis estimating the impact of possible exit strategies on potential future COVID-19 waves. More specifically, the aforementioned model is fitted to hospital admission data, data on the daily number of COVID-19 deaths and serial serological survey data informing the (sero)prevalence of the disease in the population while relying on a Bayesian MCMC approach. Our age-structured stochastic model describes the observed outbreak data well, both in terms of hospitalizations as well as COVID-19 related deaths in the Belgian population. Despite an extensive exploration of various projections for the future course of the epidemic, based on the impact of adherence to measures of physical distancing and a potential increase in contacts as a result of the relaxation of the stringent lockdown measures, a lot of uncertainty remains about the evolution of the epidemic in the next months.
Effects of simulated cochlear-implant processing on voice quality distinction: Evidence from analysis of disordered voices
Authors: Arjmandi Meisam K. , Ghasemzadeh Hamzeh , Dilley Laura C. 
Published: July 2020

ABSTRACTThe ability to discern variations in voice quality from speech is important for effective talker identification and robust speech processing; yet, little is known about how faithfully acoustic information relevant to variations in talkers’ voice quality is transmitted through a cochlear implant (CI) device. The present study analyzed unprocessed and CI-simulated versions of sustained /a/ vowel sounds from two groups of individuals with normal and disordered voice qualities in order to explore the effects of CI speech processing on acoustic information relevant for the distinction of voice quality. The CI-simulated voices were created by processing the vowel sounds along with 4-, 8-, 12-, 16-, 22-, and 32-channel noise-vocoders. The variations in voice quality for each voice sound was characterized by calculating mel-frequency cepstral coefficients (MFCCs). The effects of simulated CI speech processing on the acoustic distinctiveness between normal and disordered voices were then measured by calculating the Mahalanobis distance (MD) metric, as well as accuracy of support vector machines (SVMs) applied to MFCC features. The results showed that CI speech processing, as simulated by noise vocoding, is highly detrimental to the acoustic information involved in conveying voice quality distinctions. This supports the view that listeners with CIs will likely experience difficulties in perceiving voice quality variations due to the reduced spectral resolution, shedding light on challenges listeners with CIs may face for effective recognition and processing of talkers’ voices.
Nested PCR for the detection of Taenia solium DNA in stool samples
Authors: Franco-Muñoz C , Arévalo A , Duque-Beltran S 
Published: July 2020

ABSTRACTThe traditional parasitological method to diagnose taeniasis is the microscopic observation of eggs in stool samples. However, this method does not allow differentiation between Taenia saginata and Taenia solium. This aim of this study was to achieve the detection of T. solium DNA by polymerase chain reaction (PCR) and to evaluate the cross-reaction with other species of the genus Taenia and other intestinal parasites. DNA was extracted from adult T. solium cestodes by cryolysis in liquid nitrogen and with the DNA stool extraction kit from Qiagen. The detection limit of the test was evaluated by DNA dilutions in water and in stool samples. DNA was extracted from proglottids of T. saginata and T. crassiceps and from stool samples containing other intestinal parasites using ethanol treatment, alkaline lysis, and the DNA stool extraction kit. Nested PCR was used to amplify a previously described fragment of the Tso31 gene, and the PCR products were analyzed by electrophoresis in 2% agarose gels followed by staining with GelRed. The nested PCR of the Tso31 gene allowed the detection of T. solium DNA in stool samples with a detection limit of 20 pg of parasite DNA. PCR showed no cross-reaction with T. saginata, T. crassiceps, or other intestinal parasites of public health importance in Colombia.
Empirical Evidence for Cognitive Subgroups in Body Dysmorphic Disorder
Authors: Malcolm Amy , Brennan Sarah N. , Grace Sally A. , Pikoos Toni D. , Toh Wei Lin , Labuschagne Izelle , Buchanan Ben , Kaplan Ryan A. , Castle David J. , Rossell Susan L. 
Published: July 2020

AbstractObjectiveCurrent understanding of cognitive functioning in body dysmorphic disorder (BDD) is limited, owing to few studies, small sample sizes, and assessment across only limited cognitive domains. Existing research has also shown inconsistent findings, with both intact and impaired cognition reported in BDD, which might point toward cognitive heterogeneity in the disorder. This study aimed to examine the cognitive profile of BDD in a large sample across eight cognitive domains, and to explore whether cognitive subgroups might be identified within BDD.MethodsCognitive domains of inhibition/flexibility, working memory, speed of processing, reasoning and problem-solving, visual and verbal learning, attention/vigilance and social cognition were assessed and compared between 65 BDD patients and 70 healthy controls. Then, hierarchical clustering analysis was conducted on the BDD group’s cognitive data.ResultsGroup-average comparisons demonstrated significantly poorer cognitive functioning in BDD than healthy controls in all domains except for attention/vigilance and social cognition. Cluster analysis identified two divergent cognitive subgroups within our BDD cohort characterised by i) broadly intact cognitive function with mild selective impairments (72.3%), and ii) broadly impaired cognitive function (27.7%). However, the clusters did not significantly differ on clinical parameters or most sociodemographic characteristics.ConclusionCognitively diverse subgroups were identified within BDD, yet these were obscured in group-average comparisons. However, subgroup profiles of cognitive functioning seem unrelated to the clinical presentation of BDD. Further research into the underlying mechanisms of cognition in BDD is warranted.Significant OutcomesCognitive function varies widely among people with body dysmorphic disorder (BDD) and includes subgroups characterised by broadly intact or broadly impaired cognitive profiles.However, reduced performances in visual learning and working memory as relative to healthy participants were identified across both BDD cognitive subgroups to differing degrees.Clinical characteristics were not significantly different among the two BDD cognitive subgroups; what role cognitive functioning may play in the aetiology or presentation of BDD remains unclear.LimitationsThe output of clustering analysis is sensitive to the choice of variables entered and requires replication with analogous measures of cognition.Psychiatric comorbidities and medications could have impacted cognitive performances in the BDD group in an unaccounted-for manner.Data availability statementAuthor elects to not share data.
Spatial and single-cell transcriptional landscape of human cerebellar development
Authors: Aldinger Kimberly A. , Thomson Zach , Haldipur Parthiv , Deng Mei , Timms Andrew E. , Hirano Matthew , Santpere Gabriel , Roco Charles , Rosenberg Alexander B. , Lorente-Galdos Belen , Gulden Forrest O. , O’Day Diana , Overman Lynne M. , Lisgo Steven N. , Alexandre Paula , Sestan Nenad , Doherty Dan , Dobyns William B. , Seelig Georg , Glass Ian A. , Millen Kathleen J. 
Published: July 2020

ABSTRACTCerebellar development and function require precise regulation of molecular and cellular programs to coordinate motor functions and integrate network signals required for cognition and emotional regulation. However, molecular understanding of human cerebellar development is limited. Here, we combined spatially resolved and single-cell transcriptomics to systematically map the molecular, cellular, and spatial composition of early and mid-gestational human cerebellum. This enabled us to transcriptionally profile major cell types and examine the dynamics of gene expression within cell types and lineages across development. The resulting‘Developmental Cell Atlas of the Human Cerebellum’demonstrates that the molecular organization of the cerebellar anlage reflects cytoarchitecturally distinct regions and developmentally transient cell types that are insufficiently captured in bulk transcriptional profiles. By mapping disease genes onto cell types, we implicate the dysregulation of specific cerebellar cell types, especially Purkinje cells, in pediatric and adult neurological disorders. These data provide a critical resource for understanding human cerebellar development with implications for the cellular basis of cerebellar diseases.
SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response
Authors: Huang Jessie , Hume Adam J. , Abo Kristine M. , Werder Rhiannon B. , Villacorta-Martin Carlos , Alysandratos Konstantinos-Dionysios , Beermann Mary Lou , Simone-Roach Chantelle , Lindstrom-Vautrin Jonathan , Olejnik Judith , Suder Ellen L. , Bullitt Esther , Hinds Anne , Sharma Arjun , Bosmann Markus , Wang Ruobing , Hawkins Finn , Burks Eric J. , Saeed Mohsan , Wilson Andrew A. , Mühlberger Elke , Kotton Darrell N. 
Published: July 2020

ABSTRACTThe most severe and fatal infections with SARS-CoV-2 result in the acute respiratory distress syndrome, a clinical phenotype of coronavirus disease 2019 (COVID-19) that is associated with virions targeting the epithelium of the distal lung, particularly the facultative progenitors of this tissue, alveolar epithelial type 2 cells (AT2s). Little is known about the initial responses of human lung alveoli to SARS-CoV-2 infection due in part to inability to access these cells from patients, particularly at early stages of disease. Here we present anin vitrohuman model that simulates the initial apical infection of the distal lung epithelium with SARS-CoV-2, using AT2s that have been adapted to air-liquid interface culture after their derivation from induced pluripotent stem cells (iAT2s). We find that SARS-CoV-2 induces a rapid global transcriptomic change in infected iAT2s characterized by a shift to an inflammatory phenotype predominated by the secretion of cytokines encoded by NF-kB target genes, delayed epithelial interferon responses, and rapid loss of the mature lung alveolar epithelial program. Over time, infected iAT2s exhibit cellular toxicity that can result in the death of these key alveolar facultative progenitors, as is observedin vivoin COVID-19 lung autopsies. Importantly, drug testing using iAT2s confirmed an antiviral dose-response to remdesivir and demonstrated the efficacy of TMPRSS2 protease inhibition, validating a putative mechanism used for viral entry in human alveolar cells. Our model system reveals the cell-intrinsic responses of a key lung target cell to infection, providing a physiologically relevant platform for further drug development and facilitating a deeper understanding of COVID-19 pathogenesis.
Direct visualization of translational GTPase factor-pool formed around the archaeal ribosomal P-stalk by high-speed atomic force microscopy
Authors: Imai Hirotatsu , Uchiumi Toshio , Kodera Noriyuki 
Published: July 2020

AbstractThe ribosomal stalk protein plays an essential role in the recruitment of translational GTPase factors EF1A and EF2 to the ribosome and their GTP hydrolysis for efficient translation elongation. However, due to the flexible nature of the ribosomal stalk, its structural dynamics and mechanism of action remain unclear. Here, we applied high-speed atomic force microscopy (HS-AFM) to directly visualize the action of the archaeal ribosomal stalk (P-stalk). HS-AFM movies clearly demonstrated the wobbling motion of the P-stalk on the large ribosomal subunit, where the stalk base adopted two conformational states, a predicted canonical state, and a newly identified flipped state. Intriguingly, archaeal aEF1A and aEF2 molecules spontaneously assembled around the ribosomal P-stalk up to the maximum number of available binding sites. These results provide the first visual evidence for the factor-pooling mechanism and reveal that the ribosomal P-stalk promotes translation elongation by increasing the local concentration of translational GTPase factors.
Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM
Authors: Xu Cong , Wang Yanxing , Liu Caixuan , Zhang Chao , Han Wenyu , Hong Xiaoyu , Wang Yifan , Hong Qin , Wang Shutian , Zhao Qiaoyu , Wang Yalei , Yang Yong , Chen Kaijian , Zheng Wei , Kong Liangliang , Wang Fangfang , Zuo Qinyu , Huang Zhong , Cong Yao 
Published: July 2020

AbstractThe recent outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid international spread pose a global health emergency. The trimeric spike (S) glycoprotein interacts with its receptor human ACE2 to mediate viral entry into host-cells. Here we present cryo-EM structures of an uncharacterized tightly closed SARS-CoV-2 S-trimer and the ACE2-bound-S-trimer at 2.7-Å and 3.8-Å-resolution, respectively. The tightly closed S-trimer with inactivated fusion peptide may represent the ground prefusion state. ACE2 binding to the up receptor-binding domain (RBD) within S-trimer triggers continuous swing-motions of ACE2-RBD, resulting in conformational dynamics of S1 subunits. Noteworthy, SARS-CoV-2 S-trimer appears much more sensitive to ACE2-receptor than SARS-CoV S-trimer in terms of receptor-triggered transformation from the closed prefusion state to the fusion-prone open state, potentially contributing to the superior infectivity of SARS-CoV-2. We defined the RBD T470-T478 loop and residue Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2, and provided structural basis of the spike D614G-mutation induced enhanced infectivity. Our findings offer a thorough picture on the mechanism of ACE2-induced conformational transitions of S-trimer from ground prefusion state towards postfusion state, thereby providing important information for development of vaccines and therapeutics aimed to block receptor binding.
Stochastic Analysis Demonstrates the Dual Role of Hfq in ChaperoningE. coliSugar Shock Response
Authors: Bianchi David M. , Brier Troy A. , Poddar Anustup , Azam Muhammad S. , Vanderpool Carin K. , Ha Taekjip , Luthey-Schulten Zaida 
Published: July 2020

AbstractSmall RNAs (sRNAs) play a crucial role in the regulation of bacterial gene expression by silencing the translation of target mRNAs. SgrS is an sRNA that relieves glucose-phosphate stress, or “sugar shock” inE. coli. The power of single cell measurements is their ability to obtain population level statistics that illustrate cell-to-cell variation. Here, we utilize single molecule super-resolution microscopy in singleE. colicells coupled with stochastic modeling to analyze glucose-phosphate stress regulation by SgrS. We present a kinetic model that captures the combined effects of transcriptional regulation, gene replication and chaperone mediated RNA silencing in the SgrS regulatory network. This more complete kinetic description, simulated stochastically, recapitulates experimentally observed cellular heterogeneity and characterizes the binding of SgrS to the chaperone protein Hfq as a slow process that not only stabilizes SgrS but also may be critical in restructuring the sRNA to facilitate association with its targetptsGmRNA.