bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transmission event of SARS-CoV-2 Delta variant reveals multiple vaccine breakthrough infections
Authors: Farinholt Timothy , Doddapaneni Harsha , Qin Xiang , Menon Vipin , Meng Qingchang , Metcalf Ginger , Chao Hsu , Gingras Marie-Claude , Farinholt Paige , Agrawal Charu , Muzny Donna M. , Piedra Pedro A. , Gibbs Richard A. , Petrosino Joseph 
Published: July 2021

AbstractImportanceVaccine breakthrough by an emergent SARS-CoV-2 variant poses a great risk to global public health.ObjectiveTo determine the SARS-CoV-2 variant responsible for 6 cases of vaccine breakthrough.DesignNasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 by qPCR for Wuhan-Hu1 and Alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant.SettingTransmission event occurred at events surrounding a wedding outside of Houston, TX. Two patients from India, likely transmitted the Delta variant to other guests.ParticipantsFollowing a positive SARS-CoV-2 qPCR test at a third-party site, six fully vaccinated patients were investigated. Three males and three females ranged from 53 to 69 years old. One patient suffered from diabetes while three others were classified as overweight. No significant other comorbidities were identified. None of the patients had a history of failed vaccination.Key PointsQuestionWhich SARS-CoV-2 variant is responsible for 6 cases of vaccine breakthrough, one interventional monoclonal antibody treatment, and one death?FindingsViral sequencing revealed 6 vaccinated patients were infected with the Delta SARS-CoV-2 variant. With no histories of vaccine breakthrough, this suggests Delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152.MeaningDelta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with increased transmissibility over Alpha variant and possible vaccine breakthrough.
A classification model to predict specialty drug use
Authors: Ni Xianglian , Fairless Andrew , McCammon Jasmine M. , Rahmanian Farbod , Lavoie Heather 
Published: July 2021

ABSTRACTObjectivePredicting who is likely to become utilizers of specialty drugs allows care managers to have an early intervention and payers to have financial preparation for the upcoming spending. Our administrative claims-based predictive model is to predict the members who might use specialty drugs.Materials and MethodsA national database* and a commercial health plan claim data were used to select a total 6.5 million people who were not taking any specialty drugs before the Target Prediction Window. There were about 136,700 members who were older than 65 in the study. We extracted 81 features from past history of medical, pharmacy claims, and demographic data to predict the specialty drug use in the following year. Members having at least three-month continuous enrollment either under medical or pharmacy plan in the previous year immediately before the start of the target prediction window and with no specialty drug taking history were eligible for this study. We trained and tuned on 75% of the data using an extreme gradient boosting binary classifier. We used the remaining 25% of the data to predict the outcomes and evaluate the performance. We also recorded the performance for the age group older than 65 years old.ResultsThere were 3% of members who used specialty drugs in the cohort under the current study. The important features for prediction included age, monthly pharmacy payment, monthly medical payment, diseases, procedure, or drug-related codes. On the test data with members of all ages, model performance for the area under the receiving operator characteristics curve (AUROC) was 78.6%. For the test set on members older than 65 (prevalence rate 3.6%), we had an AUROC of 79.3%.DiscussionThere is no similar machine learning model in the field to predict specialty drug use. Our model provides an unparalleled opportunity to allow early intervention for people who might develop diseases that require specialty drug use. It is also important for health plans and providers to know their covered population who might use specialty drugs and predict the increased cost in the next year.ConclusionA predictive model of specialty drug use can be helpful for both payers and providers to prepare for a spending spike or have an early intervention. In return, this helps to improve patients’ overall satisfaction.
Impact of regional heterogeneity on the severity of COVID-19
Authors: Tsuzuki Shinya , Asai Yusuke , Matsunaga Nobuaki , Ishioka Haruhiko , Akiyama Takayuki , Ohmagari Norio 
Published: July 2021

AbstractBackgroundWe aimed to assess the impact of regional heterogeneity on the severity of COVID-19 in Japan.MethodsWe included 27,865 cases registered between January 2020 and February 2021 in the COVID-19 Registry of Japan to examine the relationship between the National Early Warning Score (NEWS) of COVID-19 patients on the day of admission and the prefecture where the patients live. A hierarchical Bayesian model was used to examine the random effect of each prefecture in addition to the patients’ backgrounds. In addition, we compared the results of two models; one model included the number of beds secured for COVID-19 patients in each prefecture as one of the fixed effects, and the other model did not.ResultsThe results indicated that the prefecture had a substantial impact on the severity of COVID-19 on admission. Even when considering the effect of the number of beds separately, the heterogeneity caused by the random effect of each prefecture affected the severity of the case on admission.ConclusionsOur analysis revealed a possible association between regional heterogeneity and increased/decreased risk of severe COVID-19 infection on admission. This heterogeneity was derived not only from the number of beds secured in each prefecture but also from other factors.
COVID-19 vaccines dampen genomic diversity of SARS-CoV-2: Unvaccinated patients exhibit more antigenic mutational variance
Authors: Niesen Michiel J.M. , Anand Praveen , Silvert Eli , Suratekar Rohit , Pawlowski Colin , Ghosh Pritha , Lenehan Patrick , Hughes Travis , Zemmour David , O’Horo John C. , Yao Joseph D. , Pritt Bobbi S. , Norgan Andrew , Hurt Ryan T. , Badley Andrew D. , Venkatakrishnan AJ , Soundararajan Venky 
Published: July 2021

AbstractVariants of SARS-CoV-2 are evolving under a combination of immune selective pressure in infected hosts and natural genetic drift, raising a global alarm regarding the durability of COVID-19 vaccines. Here, we conducted longitudinal analysis over 1.8 million SARS-CoV-2 genomes from 183 countries or territories to capture vaccination-associated viral evolutionary patterns. To augment this macroscale analysis, we performed viral genome sequencing in 23 vaccine breakthrough COVID-19 patients and 30 unvaccinated COVID-19 patients for whom we also conducted machine-augmented curation of the electronic health records (EHRs). Strikingly, we find the diversity of the SARS-CoV-2 lineages is declining at the country-level with increased rate of mass vaccination (n = 25 countries, mean correlation coefficient = −0.72, S.D. = 0.20). Given that the COVID-19 vaccines leverage B-cell and T-cell epitopes, analysis of mutation rates shows neutralizing B-cell epitopes to be particularly more mutated than comparable amino acid clusters (4.3-fold, p < 0.001). Prospective validation of these macroscale evolutionary patterns using clinically annotated SARS-CoV-2 whole genome sequences confirms that vaccine breakthrough patients indeed harbor viruses with significantly lower diversity in known B cell epitopes compared to unvaccinated COVID-19 patients (2.3-fold, 95% C.I. 1.4-3.7). Incidentally, in these study cohorts, vaccinated breakthrough patients also displayed fewer COVID-associated complications and pre-existing conditions relative to unvaccinated COVID-19 patients. This study presents the first known evidence that COVID-19 vaccines are fundamentally restricting the evolutionary and antigenic escape pathways accessible to SARS-CoV-2. The societal benefit of mass vaccination may consequently go far beyond the widely reported mitigation of SARS-CoV-2 infection risk and amelioration of community transmission, to include stemming of rampant viral evolution.
Megafaunal extinctions—not climate change—seem to explain Holocene genetic diversity declines inNumeniusshorebirds
Authors: Tan Hui Zhen , Jansen Justin J.F.J. , Allport Gary A. , Garg Kritika M. , Chattopadhyay Balaji , Irestedt Martin , Pang Sean E.H. , Chilton Glen , Gwee Chyi Yin , Rheindt Frank E. 
Published: July 2021

AbstractUnderstanding the relative contributions of historical and anthropogenic factors to declines in genetic diversity is important for informing conservation action. Using genome-wide DNA of fresh and historic specimens, including that of two species widely thought to be extinct, we investigated fluctuations in genetic diversity and present the first complete phylogenomic tree for all nine species of the threatened shorebird genusNumenius, known as whimbrels and curlews. Most species faced sharp declines in effective population size, a proxy for genetic diversity, soon after the Last Glacial Maximum (around 20,000 years ago). These declines occurred prior to the Anthropocene and in spite of an increase in breeding area predicted by environmental niche modelling, suggesting that they were not caused by climatic or recent anthropogenic factors. Crucially, these genetic diversity declines coincide with mass extinctions of mammalian megafauna in the Northern Hemisphere. Demise of ecosystem-engineering megafauna which maintained open habitats would have been detrimental for grassland and tundra-breedingNumeniusshorebirds. Our work suggests that the impact of historical factors such as megafaunal extinction may have had wider repercussions on present-day population dynamics of open habitat biota than previously appreciated.
Efficacy and safety of cyclosporine in the management of coronavirus disease 2019: A protocol for systematic review and meta-analysis
Authors: Abdallah Ibtihal , Aabdien Mohamed , Danjuma Mohammed 
Published: July 2021

AbstractIntroductionCyclosporine may improve the clinical course and outcomes of Coronavirus disease 2019 (COVID-19) due to its antiviral and anti-cytokine effects as shown in vitro. A few ongoing trials are exploring the benefit of adding it to the standard of care (SOC) of COVID-19 patients.ObjectivesThe primary objective is to evaluate the severity of COVID-19, determined by oxygen saturation, intensive care unit (ICU) admission, or the World Health Organization COVID-19 clinical severity scale in patients treated with oral or intravenous cyclosporine added to SOC compared SOC alone or placebo. Secondary objectives include mortality, length of hospitalization, length of ICU stay, and laboratory measurements as well as the safety outcomes of cyclosporine.MethodologyA systematic review and meta-analysis of randomized clinical trials and observational studies that compared cyclosporine to placebo or SOC in COVID-19 patients will be conducted. PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, Google Scholar, and ClinicalTrials.gov will be explored for studies that satisfy pre-specified inclusion criteria. Quality assessment of all included studies will be performed. Meta-analyses will be done utilizing random effect models to estimate the effect of cyclosporine on the severity of COVID-19. Heterogeneity will be assessed utilizing Q statistics. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed.ResultsThe result of this synthesis will inform potential changes in the management of COVID-19 patients, especially regarding the role of calcineurin inhibitors. Additionally, it will serve as hypothesis generating for potential future prospective studies.
Promoter architecture links gene duplication with transcriptional divergence
Authors: Fraimovitch Evgeny , Hagai Tzachi 
Published: July 2021

SummaryGene duplication is thought to be a central mechanism in evolution to gain new functions, but gene families vary greatly in their rates of gene duplication and long-term retention. Here, we discover a link between the promoter architecture of vertebrate genes and their rate of duplication: Genes that harbor CpG Islands in their promoters (CGI genes) – nearly 60% of our genes – have rarely duplicated in recent evolutionary times, and most CGI gene duplication events predate the emergence of CGI as a major regulatory element of vertebrate genes. In contrast, CGI-less genes predominate duplications that have occurred since the divergence of vertebrates. Furthermore, CGI-less paralogs are transcriptionally more divergent than CGI paralogs, even when comparing CGI and CGI-less paralogs that have duplicated at similar evolutionary times – suggesting greater capacity of CGI-less promoters to enable divergence in expression. This higher divergence between CGI-less paralogs is also reflected in lower similarity of transcription factors that bind to the promoters of CGI-less paralog pairs in comparison with CGI paralogs. Finally, CGI-less paralogs have a greater tendency to sub- and neo-functionalize, and they transcriptionally diversify faster following duplication. Our results highlight the links between promoter architecture, gene expression plasticity and their impact on gene expansion, and unravel an unappreciated role of CGI elements in shaping genome evolution.Significance statementGene duplication generates extra gene copies, providing material for evolution of new functions. However, many duplicated genes are eliminated due to functional and regulatory constraints. The evolutionary processes that govern the elimination and persistence of duplicated genes are not well understood. Here, we focus on CpG Islands (CGIs) – important elements that occur in the majority of gene promoters. We show that genes with CGIs in their promoters have duplicated almost exclusively in ancient times, and nearly all recent duplications involve CGI-less genes. Furthermore, duplicated CGI-less genes diverge more in expression and display more distinctive transcription and cis-regulation compared to duplicated CGI-genes. Our results demonstrate how promoter structure influences transcriptional evolvability and, in turn, the retention of new genes.
Behavioral performance requirements for division of labor influence adaptive brain mosaicism in a socially complex ant
Authors: Muratore I.B. , Fandozzi E.M. , Traniello J.F.A. 
Published: July 2021

AbstractBrain evolution is hypothesized to be driven by neuroarchitectural requirements for behavioral performance. Assessments of such needs should be informed by the nature of sensory and motor processes underpinning behavior. We developed a novel metric to estimate the relative neuroanatomical investments required to perform tasks varying in sensorimotor and processing demands across polymorphic and polyethic workers of the leafcutter antAtta cephalotesand quantified brain size and structure to examine their correspondence with our computational approximations. Investment in multi-sensory integration and motor requirements for task performance was estimated to be greatest for media workers whose leaf-harvesting repertoire involves the most diverse and demanding sensory and motor processes, including plant discrimination, leaf cutting, and fragment transportation. Volumetric analysis of confocal brain images revealed that absolute brain size increased with worker size and compartmental scaling allometries among functionally specialized brain compartments differed among polymorphic workers. The mushroom bodies, centers of sensory integration and learning, and the antennal lobes, which process olfactory inputs, were significantly larger in medias than in minim workers (fungal gardeners) and major workers (“soldiers”), which had lower estimated task-related neural demands. Minims had a proportionally larger central complex, perhaps to control navigation in subterranean fungal garden chambers. These results indicate that variation in task performance requirements has selected for adaptive variation in brain size and mosaic scaling.
Multifaceted roles of SAMHD1 in cancer
Authors: McLaughlin Katie-May , Cinatl Jindrich , Wass Mark N. , Michaelis Martin 
Published: July 2021

AbstractSAMHD1 is discussed as a tumour suppressor protein, but its potential role in cancer has only been investigated in very few cancer types. Here, we performed a systematic analysis of the TCGA (adult cancer) and TARGET (paediatric cancer) databases, the results of which did not suggest that SAMHD1 should be regarded as abona fidetumour suppressor. SAMHD1 mutations that interfere with SAMHD1 function were not associated with poor outcome, which would be expected for a tumour suppressor. High SAMHD1 tumour levels were associated with increased survival in some cancer entities and reduced survival in others. Moreover, the data suggested differences in the role of SAMHD1 between males and females and between different races. Often, there was no significant relationship between SAMHD1 levels and cancer outcome. Taken together, our results indicate that SAMHD1 may exert pro-or anti-tumourigenic effects and that SAMHD1 is involved in the oncogenic process in a minority of cancer cases. These findings seem to be in disaccord with a perception and narrative forming in the field suggesting that SAMHD1 is a tumour suppressor. A systematic literature review confirmed that most of the available scientific articles focus on a potential role of SAMHD1 as a tumour suppressor. The reasons for this remain unclear but may include confirmation bias and publication bias. Our findings emphasise that hypotheses, perceptions, and assumptions need to be continuously challenged by using all available data and evidence.
Three-dimensional drug screen identifies HDAC inhibitors as therapeutic agents in mTORC1-driven lymphangioleiomyomatosis
Authors: Pietrobon Adam , Yockell-Lelièvre Julien , Melong Nicole , Smith Laura J. , Delaney Sean P. , Azzam Nadine , Xue Chang , Merwin Nishanth , Lian Eric , Camacho-Magallanes Alberto , Doré Carole , Musso Gabriel , Julian Lisa M. , Kristof Arnold S. , Tam Roger Y. , Berman Jason N. , Shoichet Molly S. , Stanford William L. 
Published: July 2021

ABSTRACTLymphangioleiomyomatosis (LAM) is a rare disease involving cystic lung destruction by invasive LAM cells. These cells harbor loss-of-function mutations in TSC2, conferring constitutive mTORC1 signaling. Rapamycin is the only clinically approved disease-modifying treatment, but its action is cytostatic and disease progresses upon its withdrawal. There is a critical need to identify novel agents that prevent the invasive phenotype and/or eradicate the neoplastic LAM cells. Here, we employed novel cellular and extracellular models to screen for candidate therapeutics in a physiologically relevant setting. We observed that lung-mimetic hydrogel culture of pluripotent stem cell-derived diseased cells more faithfully recapitulates human LAM biology compared to conventional culture on two-dimensional tissue culture plastic. Leveraging our culture system, we conducted a three-dimensional drug screen using a custom 800-compound library, tracking cytotoxicity and invasion modulation phenotypes at the single cell level. We identified histone deacetylase (HDAC) inhibitors as a group of anti-invasive agents that are also selectively cytotoxic towards TSC2-/- cells. Unexpectedly, we observed that next generation ATP-competitive mTORC1/2 inhibitors potentiate invasion. We determined anti-invasive effects of HDAC inhibitors to be independent of genotype, while selective cell death is mTORC1-dependent and mediated by apoptosis. Drug performance was subsequently evaluated at the single cell level in zebrafish xenografts. We observed consistent therapeutic efficacy in vivo at equivalent concentrations to those used in vitro, substantiating HDAC inhibitors as potential therapeutic candidates for pursuit in patients with LAM.One Sentence SummaryWe performed a drug screen in 3D and discovered HDAC inhibitors exhibit therapeutic efficacy in models of the lung disease lymphangioleiomyomatosis.
Mechanics defines the spatial pattern of compensatory proliferation
Authors: Kawaue Takumi , Yow Ivan , Le Anh Phuong , Lou Yuting , Loberas Mavis , Shagirov Murat , Prost Jacques , Hiraiwa Tetsuya , Ladoux Benoit , Toyama Yusuke 
Published: July 2021

AbstractThe number of cells in tissues is tightly controlled by cell division and cell death, and misregulation of cell numbers could lead to pathological conditions such as cancer. To maintain cell numbers in a tissue, a cell elimination process named programmed cell death or apoptosis, stimulates the proliferation of neighboring cells. This mechanism is called apoptosis-induced compensatory proliferation, which was originally reported more than 40 years ago. While only a limited number of the neigboring cells need to divide to compensate for apoptotic cell loss, the mechanisms that select cells for undergoing division remain an open question. Here we found that the spatial inhomogeneity in mechanotransduction through a growth-promoting transcription co-activator Yes-associated protein (YAP) in the neighboring tissue, accounts for the inhomogeneity of compensatory proliferation. Such inhomogeneous mechanotransduction arises from the combination of the non-uniform distribution of nuclear size, which is inherent in tissues, and the non-uniform pattern of mechanical force applied to the neighboring cells upon apoptosis. Our findings from a mechanical perspective complement the current biochemical understanding of compensatory growth and provide additional insights into cellular functions of how tissue precisely maintains its homeostasis.
Frequency-specific coactivation patterns in resting-state and their alterations in schizophrenia: an fMRI study
Authors: Yang Hang , Zhang Hong , Di Xin , Wang Shuai , Meng Chun , Tian Lin , Biswal Bharat 
Published: July 2021

AbstractThe resting-state human brain is a dynamic system that shows frequency-specific characteristics. Coactivation pattern (CAP) analysis has been recently used to identify recurring brain states sharing similar coactivation configurations. However, whether and how CAPs differ across different sub-frequency bands are unknown. In the current study, in addition to the typical low-frequency range (0.01 - 0.08 Hz), the spatial and temporal characteristics of CAPs in four sub-frequency bands, slow-5 (0.01 - 0.027 Hz), slow-4 (0.027 - 0.073 Hz), slow-3 (0.073 - 0.198 Hz), and slow-2 (0.198 - 0.25 Hz), were studied. Six CAP states were obtained for each band., The CAPs from the typical frequency range were spatially largely overlapped with those in slow-5, slow-4 and slow-3 but not with those in slow-2. With the increase of frequency, the CAP state became more unstable and resulted in an overall shorter persistence. The spatial and temporal characteristics of slow-4 and slow-5 were further compared, because they constitute most power of the resting-state fMRI signals. In general, slow-4 showed stronger coactivations or co-deactivations in subcortical regions, while slow-5 showed stronger coactivations or co-deactivations in large-scale cortical networks such as the dorsal attention network. Lastly, frequency-dependent dynamic alterations were also observed in schizophrenia patients. Combining the information obtained from both slow-5 and slow-4 increased the classification accuracy of schizophrenia patients than only using the typical range. In conclusion, our results revealed that the spatial and temporal characteristics of CAP state varied at different frequency bands, which could be helpful for identifying brain alterations in schizophrenia.