bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE INTESTINAL AND ORAL MICROBIOMES ARE ROBUST PREDICTORS OF COVID-19 SEVERITY THE MAIN PREDICTOR OF COVID-19-RELATED FATALITY
Authors: Ward Doyle V. , Bhattarai Shakti , Rojas-Correa Mayra , Purkayastha Ayan , Holler Devon , Da Qu Ming , Mitchell William G. , Yang Jason , Fountain Samuel , Zeamer Abigail , Forconi Catherine , Fujimori Gavin , Odwar Boaz , Cawley Caitlin , McCormick Beth A. , Moormann Ann , Wessolossky Mireya , Bucci Vanni , Maldonado-Contreras Ana 
Published: January 2021

ABSTRACTThe reason for the striking differences in clinical outcomes of SARS-CoV-2 infected patients is still poorly understood. While most recover, a subset of people become critically ill and succumb to the disease. Thus, identification of biomarkers that can predict the clinical outcomes of COVID-19 disease is key to help prioritize patients needing urgent treatment. Given that an unbalanced gut microbiome is a reflection of poor health, we aim to identify indicator species that could predict COVID-19 disease clinical outcomes. Here, for the first time and with the largest COVID-19 patient cohort reported for microbiome studies, we demonstrated that the intestinal and oral microbiome make-up predicts respectively with 92% and 84% accuracy (Area Under the Curve or AUC) severe COVID-19 respiratory symptoms that lead to death. The accuracy of the microbiome prediction of COVID-19 severity was found to be far superior to that from training similar models using information from comorbidities often adopted to triage patients in the clinic (77% AUC). Additionally, by combining symptoms, comorbidities, and the intestinal microbiota the model reached the highest AUC at 96%. Remarkably the model training on the stool microbiome found enrichment of Enterococcus faecalis, a known pathobiont, as the top predictor of COVID-19 disease severity. Enterococcus faecalis is already easily cultivable in clinical laboratories, as such we urge the medical community to include this bacterium as a robust predictor of COVID-19 severity when assessing risk stratification of patients in the clinic.
Potential Blood Transfusion Adverse Events Can be Found in Unstructured Text in Electronic Health Records using the “Shakespeare Method”
Authors: Bright Roselie A , Rankin Summer K , Dowdy Katherine , Blok Sergey V , Bright-Ponte Susan J , Palmer Lee Anne 
Published: January 2021

ABSTRACTBackgroundText in electronic health records (EHRs) and big data tools offer the opportunity for surveillance of adverse events (patient harm associated with medical care) (AEs) in the unstructured notes. Writers may explicitly state an apparent association between treatment and adverse outcome (“attributed”) or state the simple treatment and outcome without an association (“unattributed”). We chose the case of transfusion adverse events (TAEs) and potential TAEs (PTAEs) because real dates were obscured in the study data, and new TAE types were becoming recognized during the study data period.ObjectiveDevelop a new method to identify attributed and unattributed potential adverse events using the unstructured text of EHRs.MethodsWe used EHRs for adult critical care admissions at a major teaching hospital, 2001-2012. We formed a transfusion (T) group (21,443 admissions treated with packed red blood cells, platelets, or plasma), excluded 2,373 ambiguous admissions, and formed a comparison (C) group of 25,468 admissions. We concatenated the text notes for each admission, sorted by date, into one document, and deleted replicate sentences and lists. We identified statistically significant words in T vs. C. T documents were filtered to those words, followed by topic modeling on the T filtered documents to produce 45 topics.For each topic, the three documents with the maximum topic scores were manually reviewed to identify events that occurred shortly after the first transfusion; documents with clear alternative explanations for heart, lung, and volume overload problems (e.g., advanced cancer, lung infection) were excluded. We also reviewed documents with the most topics, as well as 20 randomly selected T documents without alternate explanations.ResultsTopics centered around medical conditions. The average number of significant topics was 6.1. Most PTAEs were not attributed to transfusion in the notes.Admissions with a top-scoring cardiovascular topic (heart valve repair, tapped pericardial effusion, coronary artery bypass graft, heart attack, or vascular repair) were more likely than random T admissions to have at least one heart PTAE (heart rhythm changes or hypotension, proportion difference = 0.47, p = 0.022). Admissions with a top-scoring pulmonary topic (mechanical ventilation, acute respiratory distress syndrome, inhaled nitric oxide) were more likely than random T admissions (proportion difference = 0.37, p = 0.049) to have at least one lung PTAE (hypoxia, mechanical ventilation, bilateral pulmonary effusion, or pulmonary edema).ConclusionsThe “Shakespeare Method” could be a useful supplement to AE reporting and surveillance of structured EHR data. Future improvements should include automation of the manual review process.
SERF deletion modifies amyloid aggregation in a mouse model of Alzheimer’s disease
Authors: Stroo E. , Janssen L. , Sin O. , Hogewerf W. , Koster M. , Harkema L. , Youssef S.A. , Beschorner N. , Wolters A.H.G. , Bakker B. , Becker Lore , Garrett L , Marschall Susan , Hoelter Sabine M , Wurst Wolfgang , Fuchs Helmut , Gailus-Durner Valerie , de Angelis Martin Hrabe , Thathiah A. , Foijer F. , van de Sluis B. , van Deursen J. , Jucker M. , de Bruin A. , Nollen E.A.A. 
Published: January 2021

AbstractIn age-related neurodegenerative disease, like Alzheimer’s and Parkinson’s disease, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm- and human cell models for disease. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown. Here, we generated SERF2 brain-specific knockout mice which, unlike full body knockout mice, were viable, and showed no major behavioral and cognitive abnormalities. We combined these knockout mice with the APPPS1 mouse model for human amyloid beta aggregation. Using structure-specific amyloid dyes, previously used to distinguish amyloid polymorphisms in human brain, we show that knockout of SERF2 alters the structure of amyloid fibrils and deposits. Moreover, scanning transmission electron microscopy revealed thicker, shorter and more densely packed amyloid in absence of SERF2. Altogether, our data reveal pleiotropic functions of SERF in development and aging and support a function as a modifier of amyloid aggregation in mammalian brain. Our results indicate that single cellular factors like SERF can determine the structural outcome of amyloid aggregation, offering possibilities for polymorphism-based disease interventions.
No Evidence for a Single Oscillator Underlying Discrete Visual Percepts
Authors: Morrow Audrey , Samaha Jason 
Published: January 2021

AbstractTheories of perception based on discrete sampling posit that visual consciousness is reconstructed based on snapshot-like perceptual moments, as opposed to being updated continuously. According to a model proposed by Schneider (2018), discrete sampling can explain both the flash-lag and the Fröhlich illusion, whereby a lag in the conscious updating of a moving stimulus alters its perceived spatial location in comparison to a stationary stimulus. The alpha-band frequency, which is associated with phasic modulation of stimulus detection and the temporal resolution of perception, has been proposed to reflect the duration of perceptual moments. The goal of this study was to determine whether a single oscillator (e.g., alpha) is underlying the duration of perceptual moments, which would predict that the point of subjective equality (PSE) in the flash-lag and Fröhlich illusions are positively correlated across individuals. Although our displays induced robust flash-lag and Fröhlich effects, virtually zero correlation was seen between the PSE in the two illusions, indicating that the illusion magnitudes are unrelated across observers. These findings suggest that, if discrete sampling theory is true, these illusory percepts either rely on different oscillatory frequencies or not on oscillations at all. Alternatively, discrete sampling may not be the mechanism underlying these two motion illusions or our methods were ill-suited to test the theory.
Corticospinal correlates of hand preference for reaching during whole-body motion
Authors: Wijdenes Leonie Oostwoud , Wynn Syanah C. , Roesink Béla S. , Schutter Dennis J.L.G. , Selen Luc P.J. , Medendorp W. Pieter 
Published: January 2021

AbstractBehavioral studies have shown that humans account for inertial acceleration in their decisions of hand choice when reaching during body motion. Physiologically, it is unclear at what stage of movement preparation information about body motion is integrated in the process of hand selection. Here, we addressed this question by applying transcranial magnetic stimulation over motor cortex (M1) of human participants who performed a preferential reach task while they were sinusoidally translated on a linear motion platform. If M1 only represents a read-out of the final hand choice, we expect the body motion not to affect the MEP amplitude. If body motion biases the hand selection process prior to target onset, we expect corticospinal excitability to modulate with the phase of the motion, with larger MEP amplitudes for phases that show a bias to using the right hand. Behavioral results replicate our earlier findings of a sinusoidal modulation of hand choice bias with motion phase. MEP amplitudes also show a sinusoidal modulation with motion phase, suggesting that body motion influences corticospinal excitability which may ultimately reflect changes of hand preference. The modulation being present prior to target onset suggests that competition between hands is represented throughout the corticospinal tract. Its phase relationship with the motion profile suggests that other processes after target onset take up time until the hand selection process has been completely resolved, and the reach is initiated. We conclude that the corticospinal correlates of hand preference are modulated by body motion.
Super-resolution shadow imaging reveals local remodeling of astrocytic microstructures and brain extracellular space after osmotic challenge
Authors: Arizono Misa , Inavalli V.V.G. Krishna , Nägerl U. Valentin 
Published: January 2021

The extracellular space (ECS) plays a central role for brain physiology, shaping the time course and spread of neurochemicals, ions and nutrients that ensure proper brain homeostasis and neuronal communication. Astrocytes are the most abundant type of glia cell in the brain, whose processes densely infiltrate the brain’s parenchyma. As astrocytes are highly sensitive to changes in osmotic pressure, they are capable of exerting a potent physiological influence on the ECS.However, little is known about the spatial distribution and temporal dynamics of the ECS that surrounds astrocytes, owing mostly to a lack of appropriate techniques to visualize the ECS in live brain tissue. Mitigating this technical limitation, we applied the recent SUper-resolution SHadow Imaging technique (SUSHI) to astrocyte-labeled organotypic hippocampal brain slices, which allowed us to concurrently image the complex morphology of astrocytes and the ECS with nanoscale resolution in a live experimental setting.Focusing on ring-like astrocytic microstructures in the spongiform domain, we found them to enclose sizable pools of interstitial fluid and cellular structures like dendritic spines. Upon an experimental osmotic challenge, these microstructures remodeled and swelled up at the expense of the pools, effectively increasing the physical contact between astrocytic and cellular structures.Our study reveals novel facets of the dynamic microanatomical relationships between astrocytes, neuropil and the ECS in living brain tissue, which could be of functional relevance for neuronglia communication in a variety of (patho)physiological settings, e.g. LTP induction, epileptic seizures or acute ischemic stroke, where osmotic disturbances are known to occur.
Evidence, evolution and pattern of contractile elements in villous vascular walls and stroma of human placentas of premature infants of different gestational ages. An immuno-morphologic comparative study
Authors: Vellone Valerio Gaetano , Paudice Michele , Bianchi Rita , Scaglione Giulia , Biatta Chiara Maria , Buffi Davide , Buffelli Francesca , Barra Fabio , Ferrero Simone , Fulcheri Ezio 
Published: January 2021

AbstractThe contractile elements of the human placenta villous tree represent a topic of interest and many issues persist still open. Histology of the stroma and muscular wall and their evolution, in relation with the gestational age, remains to be clarified for a deeper understanding of the adaptive potential and pathogenetic mechanisms.In our study, 56 premature placentas (21-36 wks) were considered, sub-divided into four groups based on age of gestation and compared to 23 at-term placentas (37-40 wks). All cases were tested with anti-smooth muscle actin (SMA) and anti-desmin antibodies to identify the contractile elements in the stroma and in vascular walls of villi.SMA and desmin staining show evident decreased expressions during the pregnancy (temporal variation) and from proximal to distal part of the villous tree (spatial variation) being higher in the stem villi.Both pre-term and at-term placentas showed persisting, although variable, positivity for SMA and desmin staining in the stroma and in the vessel walls of the mature intermediate and terminal villi. This represents an unexpected finding and nothing alike has been previously reported in literature.Both highly premature and term placentas seem to maintain contractile components within each type of villi, represented by both myofibroblasts and mature smooth muscular cells. These components may be present in both villous vascular walls and stroma, albeit with different staining intensity.This finding allows us to imagine an active function in the regulation of the blood flow, not only in stem and intermediate immature villi but even in smaller villi.
Human induced pluripotent stem cell-derived three-dimensional cardiomyocyte tissues ameliorate the rat ischemic myocardium by remodeling the extracellular matrix and cardiac protein phenotype
Authors: Yokoyama Junya , Miyagawa Shigeru , Akagi Takami , Akashi Mitsuru , Sawa Yoshiki 
Published: January 2021

AbstractThe extracellular matrix (ECM) plays a key role in the viability and survival of implanted human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We hypothesized that coating of three-dimensional (3D) cardiac tissue-derived hiPSC-CMs with the ECM protein fibronectin (FN) would improve the survival of transplanted cells in the heart and improve heart function in a rat model of ischemic heart failure. To test this hypothesis, we first explored the tolerance of FN-coated hiPSC-CMs to hypoxia in anin vitrostudy. Forin vivoassessments, we constructed 3D-hiPSC cardiac tissues (3D-hiPSC-CTs) using a layer-by-layer technique, and then the cells were implanted in the hearts of a myocardial infarction rat model (3D-hiPSC-CTs, n = 10; sham surgery control group (without implant), n = 10). Heart function and histology were analyzed 4 weeks after transplantation. In thein vitroassessment, cell viability and lactate dehydrogenase assays showed that FN-coated hiPSC-CMs had improved tolerance to hypoxia compared with the control cells.In vivo, the left ventricular ejection fraction of hearts implanted with 3D-hiPSC-CT was significantly better than that of the sham control hearts. Histological analysis showed clear expression of collagen type IV and plasma membrane markers such as desmin and dystrophinin vivoafter implantation of 3D-hiPSC-CT, which were not detected in 3D-hiPSC-CMsin vitro. Overall, these results indicated that FN-coated 3D-hiPSC-CT could improve distressed heart function in a rat myocardial infarction model with a well-expressed cytoskeletal or basement membrane matrix. Therefore, FN-coated 3D-hiPSC-CT may serve as a promising replacement for heart transplantation and left ventricular assist devices and has the potential to improve survivability and therapeutic efficacy in cases of ischemic heart disease.
Transient response of basal ganglia network in healthy and low-dopamine state
Authors: Chakravarty Kingshuk , Roy Sangheeta , Sinha Aniruddha , Nambu Atsushi , Chiken Satomi , Kotaleski Jeanette Hellgren , Kumar Arvind 
Published: January 2021

AbstractThe basal ganglia (BG) are crucial for a variety of motor and cognitive functions. Changes induced by persistent low-dopamine (e.g. in Parkinson’s disease), result in aberrant changes in steady-state population activity (β-band oscillations) and transient response of the BG. Typically, brief cortical stimulation results in a triphasic response in the substantia nigra pars reticulata (SNr, output of the BG). The properties of the triphasic responses are shaped by dopamine levels. While it is relatively well understood how changes in BG result in aberrant steady state activity, it is not clear which BG interactions are crucial for the aberrant transient responses in the BG. Moreover, it is also not clear whether the same or different mechanisms underlie the aberrant changes in steady-state activity and aberrant transient response. Here we used numerical simulations of a network model of BG to identify the key factors that determine the shape of the transient responses. We show that an aberrant transient response of the SNr in low-dopamine state, involves changes in both, the direct pathway and the recurrent interactions within the globus pallidus externa (GPe) and between GPe and sub-thalamic nucleus. We found that the connections from D2-type spiny projection neurons to GPe are most crucial in shaping the transient response and by restoring them to their healthy level, we could restore the shape of transient response even in low-dopamine state. Finally, we show that the changes in BG that result in aberrant transient response are also sufficient to generate pathological oscillatory activity.Significance statementTo understand how changes induced by low-dopamine (e.g. in Parkinson’s disease, PD) affect basal ganglia (BG) function, we need to identify the factors that determine the shape of BG responses to brief cortical stimuli. We show that transient response of the BG is also affected by recurrent interactions within the subnuclei of the BG, and not just feedforward pathways. We found that input and local connectivity within the globus pallidus externa are crucial for shaping the transient response. We also show that the same network changes may underlie both, pathologicalβ-band oscillations and aberrant transient responses. Our results highlight the importance of the recurrent connectivity within the BG and provide a coherent view of emergence of pathological activity in PD.
Virus-associated organosulfur metabolism in human and environmental systems
Authors: Kieft Kristopher , Breister Adam M. , Huss Phil , Linz Alexandra M. , Zanetakos Elizabeth , Zhou Zhichao , Rahlff Janina , Esser Sarah P. , Probst Alexander J. , Raman Srivatsan , Roux Simon , Anantharaman Karthik 
Published: January 2021

SummaryViruses influence the fate of nutrients and human health by killing microorganisms and altering metabolic processes. Organosulfur metabolism and biologically-derived hydrogen sulfide play dynamic roles in manifestation of diseases, infrastructure degradation, and essential biological processes. While microbial organosulfur metabolism is well-studied, the role of viruses in organosulfur metabolism is unknown. Here we report the discovery of 39 gene families involved in organosulfur metabolism encoded by 3,749 viruses from diverse ecosystems, including human microbiomes. The viruses infect organisms from all three domains of life. Six gene families encode for enzymes that degrade organosulfur compounds into sulfide, while others manipulate organosulfur compounds and may influence sulfide production. We show that viral metabolic genes encode key enzymatic domains, are translated into protein, are maintained after recombination, and that sulfide provides a fitness advantage to viruses. Our results reveal viruses as drivers of organosulfur metabolism with important implications for human and environmental health.
Emergent organization of multiple visuotopic maps without a feature hierarchy
Authors: Konkle Talia 
Published: January 2021

AbstractThe primate visual system is comprised of multiple visual areas. Despite their foundational relevance, there are no normative accounts for why there are multiple areas nor why they have their signature “mirrored map” topography. Here I show that the stereotyped cortical organization of multiple mirrored areas naturally emerges in simulated cortex, in which self-organizing processes are used to map a multi-scale representation of visual space smoothly onto a two-dimensional cortical sheet. Predominant accounts of multiple areas emphasize hierarchical processing, where each area extends and elaborates on the previous areas’ representation. Here, no explicit hierarchical relationships were required to manifest this multi-areal organization, suggesting that feature hierarchies may be the derived rather than the driving force of this organization. This modeling work thus provides a simple computational explanation for the hallmark features of early visual topography, and the presence of multiple areas, as emergent from a single functional goal — to smoothly represent the visual field at multiple spatial scales.One Sentence SummaryThis work presents a formal model of simulated cortex with multiple visual areas, where purely spatial relationships underlie the large-scale motifs of visual cortex.
Vangl2, a core component of the WNT/PCP pathway, regulates adult hippocampal neurogenesis and age-related decline in cognitive flexibility
Authors: Koehl M , Ladevèze E , Montcouquiol M , Abrous DN 
Published: January 2021

AbstractDecline in episodic memory is one of the hallmarks of aging and represents one of the most important health problems facing western societies. A key structure in episodic memory is the hippocampal formation and the dentate gyrus in particular, as the continuous production of new dentate granule neurons in this brain region was found to play a crucial role in memory and in age-related decline in memory. As such, understanding the molecular processes that regulate the relationship between adult neurogenesis and aging of memory function holds great therapeutic potential. Recently, we found that Vang-gogh like 2 (Vangl2), a core component of the planar cell polarity signaling pathway, is enriched in the dentate gyrus of adult mice. In this context, we sought to evaluate the involvement of this effector of the Wnt/PCP pathway in both adult neurogenesis and memory abilities in adult and middle-aged mice. Using a heterozygous mouse model carrying a dominant negative mutation in Vangl2 gene, we show that alteration in Vangl2 expression decreases the survival of adult-born granule cells and advances the onset of decrease in cognitive flexibility. Inability of mutant mice to erase old irrelevant information to the benefit of new relevant ones highlights a key role of Vangl2 in interference-based forgetting. Taken together, our findings show for the first that Vangl2 activity may constitute an interesting target to prevent age-related decline in hippocampal plasticity and memory.