bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and Virologic Factors associated with Outcomes of COVID-19 before and after Vaccination among Veterans: Retrospective Analysis from Six New England States
Authors: Lee Megan , Cosentino Danielle , Kyriakides Tassos C. , Cavallaro Tricia , Stack Gary , Gupta Shaili 
Published: February 2022

AbstractBackgroundA region-wide analysis of COVID-19 outcomes in New England has not been done. We aimed to characterize clinical, demographic, and vaccination status affecting COVID-19 clinical outcomes and describe viral epidemiology.MethodsClinical variables of Veterans with COVID-19 in Veterans Administration healthcare systems in six New England states from April 8, 2020, to September 2, 2021 were correlated with outcomes of 30-day mortality, non-psychiatric hospitalization, intensive care unit admission (ICU-care), and post-vaccination infection. We sequenced 754 whole viral genomes and 197 partial genomes.ResultsOf 4,170 Veterans with COVID-19, 81% were White, 8% women, mean age was 60.1 ±17.7 years, and 2,399 became fully vaccinated. Overall, 19% Veterans needed hospitalization, 2.8% required ICU-care, and 3.7% died. Veterans with post-vaccination COVID-19 were older, with higher rates of tobacco/drug use, CKD, and malignancy, and 0.38% died. Among the unvaccinated, ICU-care and mortality correlated with age, while hospitalization correlated with age, male sex, black race, drug use, chronic heart disease, COPD, CKD, and chronic liver disease. Age, CKD, and alcohol use correlated with hospitalization in vaccinated patients.Most New England Veterans (>97%) were infected with B.1 sub-lineages with the D614G mutation in 2020 and early 2021. B.1.617.2 lineage (71%) predominated after July 2021, including the post-vaccination infections.ConclusionIn New England Veterans with mean age of 60 years, age and CKD significantly correlated with hospitalization regardless of vaccination-status. Age correlated with mortality and ICU-care among the unvaccinated. The Delta variant of SARS-CoV-2 (B.1.617.2) dominated post-vaccination infections.
Current status and future opportunities in modeling Multiple Sclerosis clinical characteristics
Authors: Liu Joshua , Kelly Erin , Bielekova Bibiana 
Published: February 2022

AbstractDevelopment of effective treatments requires understanding of disease mechanisms. For diseases of the central nervous system (CNS), like Multiple sclerosis (MS), human pathology studies and animal models tend to identify candidate disease mechanisms. However, these studies cannot easily link identified processes to clinical outcomes, such as MS severity, required for causality assessment of candidate mechanisms. Technological advances now allow generation of thousands of biomarkers in living human subjects, derived from genes, transcripts, medical images and proteins or metabolites in biological fluids. These biomarkers can be assembled into computational models of clinical value, provided such models are generalizable. Reproducibility of models increases with technical rigor of study design, such as blinding, implementing controls, using large cohorts that encompass entire spectrum of disease phenotypes and, most importantly, validating models in independent cohort(s).To facilitate growth of this important research area, we performed a meta-analysis of publications that model MS clinical outcomes (n=302), extracting effect sizes, while also scoring technical quality of study design using pre-defined criteria. Finally, we generated a Shiny-App-based website that allows dynamic exploration of data using selective filtering.On average, published studies fulfilled only one out of seven criteria of study design rigor. Only 15.2% of studies used any validation strategy, and only 8% used the gold standard of independent cohort validation. Many studies also used small cohorts, e.g., for MRI and blood biomarker predictors the median sample size was below 100 subjects. We observed inverse relationships between reported effect sizes and the numbers of study design criteria fulfilled, expanding analogous reports from non-MS fields, that studies that fail to limit bias over-estimate effect sizes.In conclusion, the presented meta-analysis represents a useful tool for researchers, reviewers, and funders to improve design of future modeling studies in MS and to easily compare new studies with published literature. We expect that this will accelerate research in this important area, leading to development of robust models with proven clinical value.
Elevated fecal mitochondrial DNA from symptomatic norovirus infections suggests potential health relevance of human mitochondrial DNA in fecal source tracking
Authors: Zhu Kevin J. , Suttner Brittany , Knee Jackie , Capone Drew , Moe Christine L. , Stauber Christine E. , Konstantinidis Kostas T. , Wallach Thomas E. , Pickering Amy J. , Brown Joe 
Published: February 2022

AbstractAn end goal of fecal source tracking (FST) is to provide information on risk of transmission of waterborne illnesses associated with fecal contamination. Ideally, concentrations of FST markers in ambient waters would reflect exposure risk. Human mtDNA is an FST marker that is exclusively human in origin and may be elevated in feces of individuals experiencing gastrointestinal inflammation. In this study, we examined whether human mtDNA is elevated in fecal samples from individuals with symptomatic norovirus infections using samples from the US, Mozambique, and Bangladesh. We quantified hCYTB484 (human mtDNA) and HF183/BacR287 (human-associated Bacteroides) FST markers using droplet digital PCR. We observed the greatest difference in concentrations of hCYTB484 when comparing samples from individuals with symptomatic norovirus infections versus individuals without norovirus infections or diarrhea symptoms: log10 increase of 1.42 in US samples (3,820% increase, p-value = 0.062), 0.49 in Mozambique (308% increase, p-value = 0.061), and 0.86 in Bangladesh (648% increase, p-value = 0.035). We did not observe any trends in concentrations of HF183/BacR287 in the same samples. These results suggest concentrations of fecal mtDNA increase during symptomatic norovirus infection and that mtDNA in environmental samples may represent an unambiguously human source-tracking marker that correlates with enteric pathogen exposure risk.
Why Risk Factors Minimally Change the ROC Curve AUC
Authors: Stern Ralph H. 
Published: February 2022

AbstractNovel risk factors that improve statistical measures of fit on addition to established clinical prediction models often minimally change measures of discrimination (ROC curve AUC or c-index). As a result, measures of discrimination have been suggested to be insensitive in the evaluation of such models.To understand this phenomenon, it is necessary to focus on the population risk distributions produced by models with and without the risk factor. This is because these risk distribution fully determines the risk distributions of cases/patients and controls/nonpatients, which in turn fully determine the ROC curve and its AUC. Broader population risk distributions result in larger ROC curve AUCs.A fully independent risk factor with a relative risk of 2 added to the standard cardiovascular risk model produces risk distributions of those with or without the risk that are clearly different (which is evaluated by statistical measures of fit), while minimally broadening the population risk distributions (which is evaluated by measures of discrimination). The reason for this is that although addition of the risk factor replaces every risk stratum with higher and lower risk strata, this depopulated risk stratum is largely repopulated by similar splitting in neighboring risk strata. The interweaving of the the up and down migration paths to and from every point on the risk distribution results in a largely compensatory shuffling of risk assignments with minimal changes in the ROC curve AUC.
An open, analysis-ready, and quality controlled resource for pediatric brain white-matter research
Authors: Richie-Halford Adam , Cieslak Matthew , Ai Lei , Caffarra Sendy , Covitz Sydney , Franco Alexandre R. , Karipidis Iliana I. , Kruper John , Milham Michael , Avelar-Pereira Bárbara , Roy Ethan , Sydnor Valerie J. , Yeatman Jason ,   The Fibr Community Science Consortium, Satterthwaite Theodore D. , Rokem Ariel 
Published: February 2022

AbstractWe created resources to facilitate research on the role of human brain microstructure in the development of mental health disorders, based on openly-available diffusion MRI (dMRI) data from the Healthy Brain Network (HBN) study. First, we curated the HBN dMRI data (N=2747) into the Brain Imaging Data Structure and preprocessed it according to best-practices, including denoising and correcting for motion effects, susceptibility-related distortions, and eddy currents. Preprocessed, analysis-ready data was made openly available. Data quality plays a key role in the analysis of dMRI, and we provide automated quality control (QC) scores for every scan, as part of the data release. To scale QC to this large dataset, we trained a neural network through the combination of a small data subset scored by experts and a larger set scored by community scientists. The network performs QC highly concordant with that of experts on a held out set (ROC-AUC = 0.947). A further analysis of the neural network demonstrates that it relies on image features with relevance to QC. Altogether, this work both delivers a resource for transdiagnostic research in brain connectivity and pediatric mental health and serves as a novel tool for automated QC of large datasets.
A three-dimensional human adipocyte model of fatty acid-induced obesity
Authors: Pieters Vera M. , Rjaibi Saifedine T. , Singh Kanwaldeep , Li Nancy T. , Khan Safwat T. , Nunes Sara S. , Dal Cin Arianna , Gilbert Penney M. , McGuigan Alison P. 
Published: February 2022

AbstractObesity prevalence has reached pandemic proportions, leaving individuals at high risk for the development of diseases such as cancer and type 2 diabetes. In obesity, to accommodate excess lipid storage, adipocytes become hypertrophic, which is associated with an increased pro-inflammatory cytokine secretion and dysfunction of metabolic processes such as insulin signaling and lipolysis. Targeting adipocyte dysfunction is an important strategy to prevent the development of obesity-associated disease. However, it is unclear how accurately animal models reflect human biology, and the long-term culture of human hypertrophic adipocytes in an in vitro 2D monolayer is challenging due to the buoyant nature of adipocytes. Here we describe the development of a human 3D in vitro disease model that recapitulates hallmarks of obese adipocyte dysfunction. First, human primary adipose-derived stromal cells are embedded in hydrogel, and infiltrated into a thin cellulose scaffold. The thin microtissue profile allows for efficient assembly and image-based analysis. After adipocyte differentiation, the scaffold is stimulated with oleic or palmitic acid to mimic caloric overload. Using functional assays, we demonstrated that this treatment induced important obese adipocyte characteristics such as a larger lipid droplet size, increased basal lipolysis, insulin resistance and activation of macrophages through adipocyte-conditioned media. This 3D disease model mimics physiologically relevant hallmarks of obese adipocytes, to enable investigations into the mechanisms by which dysfunctional adipocytes contribute to disease.
Variation in supplemental carbon dioxide requirements defines lineage-specific antibiotic resistance acquisition in Neisseria gonorrhoeae
Authors: Rubin Daniel H.F. , Ma Kevin C. , Westervelt Kathleen A. , Hullahalli Karthik , Waldor Matthew K. , Grad Yonatan H. 
Published: February 2022

AbstractThe evolution of the obligate human pathogen Neisseria gonorrhoeae has been shaped by selective pressures from diverse host niche environments1,2 as well as antibiotics3,4. The varying prevalence of antibiotic resistance across N. gonorrhoeae lineages5 suggests that underlying metabolic differences may influence the likelihood of acquisition of specific resistance mutations6,7. We hypothesized that the requirement for supplemental CO2, present in approximately half of isolates8, reflects one such example of metabolic variation. Here, using a genome-wide association study and experimental investigations, we show that CO2-dependence is attributable to a single substitution in a β-carbonic anhydrase, canB. CanB19E is necessary and sufficient for growth in the absence of CO2, and the hypomorphic CanB19G variant confers CO2-dependence. Furthermore, ciprofloxacin resistance is correlated with CanB19G in clinical isolates, and the presence of CanB19G increases the likelihood of acquisition of ciprofloxacin resistance. Together, our results suggest that metabolic variation has impacted the acquisition of fluoroquinolone resistance.
A nucleation-and-growth model for the packaging of genome in linear virus-like particles: impact of multiple packaging signals
Authors: de Bruijn René , Wielstra P.C.M. , Calcines-Cruz Carlos , van Waveren Tom , Hernandez-Garcia Armando , van der Schoot Paul 
Published: February 2022

ABSTRACTInspired by recent experiments on the spontaneous assembly of virus-like particles from a solution containing a synthetic coat protein and double-stranded DNA, (1) we put forward a kinetic model that has as main ingredients a stochastic nucleation and a deterministic growth process. The efficiency and rate of the packaging of the DNA turn out to strongly increase by introducing proteins onto the DNA template that are modified using CRISPR-Cas techniques to bind specifically at predesignated locations, mimicking assembly signals in viruses. Our model shows that treating these proteins as nucleation-inducing diffusion barriers is sufficient to explain experimentally observed increase in encapsulation efficiency, but only if the nucleation rate is sufficiently high. We find an optimum in the encapsulation kinetics for conditions where the number of packaging signals is equal to the number of nucleation events that can occur during time required to fully encapsulate the DNA template, presuming that the nucleation events can only take place adjacent to a packaging signal. Our theory is in satisfactory agreement with the available experimental data.SIGNIFICANCEThe rate and efficiency of the encapsulation of double-stranded DNA by synthetic coat proteins was recently found to be strongly enhanced by the presence of specifically positioned protein molecules on the DNA that mimic so-called packaging signals. We present a kinetic theory based on the initial stochastic nucleation and subsequent deterministic elongation of the protein coat with the aim to explain these findings. We find that equidistantly placed nucleation sites that also act as diffusion barriers on the DNA have profound and non-trivial effects, and they can either slow down or speed up encapsulation, depending on how fast nucleation is on the time scale of the elongation process. Our findings may contribute to the rational design of linear virus-like particles.
A key role of orientation in the coding of visual motion direction
Authors: Moon Jongmin , Tadin Duje , Kwon Oh-Sang 
Published: February 2022

AbstractDespite the fundamental importance of visual motion processing, our understanding of how the brain represents basic aspects of motion is incomplete. While it is generally believed that direction is the main representational feature of motion, motion processing is also influenced by non-directional orientation signals that are present in most motion stimuli. Here, we aimed to test whether this non-directional motion axis determines motion perception even when orientation is completely absent from the stimulus. Using stimuli with and without orientation signals, we found that serial dependence in a simple motion direction estimation task was predominantly determined by the orientation of the previous motion stimulus. Moreover, the observed attraction profiles closely matched the characteristic pattern of serial attraction found in orientation perception. Evidently, the sequential integration of motion signals depends solely on the orientation of motion, indicating a fundamental role of non-directional orientation in the coding of visual motion direction.
Dissecting the effects of adaptive encoding and predictive inference on a single perceptual estimation
Authors: Moon Jongmin , Kwon Oh-Sang 
Published: February 2022

AbstractThe human visual system exploits continuity in the visual environment, which induces two contrasting perceptual phenomena: repulsive aftereffects and attractive serial dependences. Recent studies have theorized that these two effects concurrently arise in perceptual processing, but empirical evidence that directly supports this hypothesis lacks. Here we show that the two effects concurrently modulate estimation behavior in a typical sequence of perceptual tasks. We first demonstrate that observers’ estimation error as a function of both the previous stimulus and response cannot be fully described by either attractive or repulsive bias but is instead well captured by a summation of repulsion from the previous stimulus and attraction toward the previous response. We then reveal that the repulsive bias is centered on the observer’s sensory encoding of the previous stimulus, which is again repelled away from the preceding trials, whereas the attractive bias is centered precisely on the previous response, which is the observer’s best prediction about the incoming stimuli. Our findings provide strong evidence that sensory coding is shaped by dynamic tuning of the system to the past stimuli, inducing repulsive aftereffects, and followed by inference incorporating the prediction from the past estimation, leading to attractive serial dependence.
A role for thalamic projection GABAergic neurons in circadian responses to light
Authors: Brock O. , Gelegen C.E. , Salgarella I. , Sully P. , Jager P. , Menage L. , Mehta I. , Jęczmień-Łazur J. , Djama D. , Strother L. , Coculla A. , Vernon A. , Brickley S. , Holland P. , Cooke S. , Delogu A. 
Published: February 2022

AbstractThe thalamus is an important hub for sensory information and participates in sensory perception, regulation of attention, arousal and sleep. These functions are executed primarily by glutamatergic thalamocortical neurons that extend axons to the cortex and initiate cortico-thalamocortical connectional loops. However, the thalamus also contains projection GABAergic neurons that do not engage in direct communication with the cortex. Here, we have harnessed recent insight into the development of the intergeniculate (IGL), the ventrolateral geniculate (LGv) and the perihabenula (pHB) to specifically target and manipulate thalamic projection GABAergic neurons in female and male mice. Our results show that thalamic GABAergic neurons of the IGL and LGv receive retinal input from diverse classes of ipRGCs, but not from the M1 ipRGC type, while those in the pHB lack direct retinal input. We describe the synergistic role of the photoreceptor melanopsin and the thalamic neurons of the IGL/LGv in circadian entrainment to dim light. We identify a requirement for the thalamic IGL/LGv in the rapid changes in vigilance states associated with circadian light transitions. Furthermore, we map a previously undescribed thalamic network of developmentally related GABAergic neurons in the IGL/LGv complex and the pHB potentially involved in light-dependent mood regulation.Significance statementThe intergeniculate leaflet and ventral geniculate nucleus are part of the extended circadian system and mediate some non-image-forming visual functions. Here we show that each of these structures has a thalamic (dorsal) as well as prethalamic (ventral) developmental origin. We map the retinal input to thalamus-derived cells in the IGL/LGv complex and discover that while ipRGC input is dominant, this is not likely to originate from M1-ipRGCs. We describe the extent of similarity in synaptic input to developmentally related cells in the IGL/LGv and in the perihabenula nucleus (pHB). We implicate thalamic cells in the IGL/LGv in vigilance state transitions at circadian light changes and in overt behavioural entrainment to dim light, the latter exacerbated by concomitant loss of melanopsin expression.
Thymidine rescues ATR kinase inhibition induced deoxyuridine contamination in genomic DNA, cell death, and Type 1 interferon expression
Authors: Sugitani Norie , Vendetti Frank P. , Cipriano Andrew J. , Pandya Pinakin , Deppas Joshua J. , Moiseeva Tatiana N. , Schamus-Haynes Sandra , Wang Yiyang , Palmer Drake , Osmanbeyoglu Hatice U. , Bostwick Anna , Snyder Nathaniel W. , Gong Yi-Nan , Aird Katherine M. , Delgoffe Greg M. , Beumer Jan H. , Bakkenist Christopher J. 
Published: February 2022

SUMMARYATR kinase is a central regulator of the DNA damage response (DDR) and cell cycle checkpoints. ATR kinase inhibitors (ATRi’s) combine with radiation to generate CD8+ T cell-dependent responses in mouse models of cancer. We show that ATRi’s induce CDK1-dependent origin firing across active replicons in CD8+ T cells activated ex vivo while simultaneously decreasing the activity of rate-limiting enzymes for nucleotide biosynthesis. These pleiotropic effects of ATRi induce deoxyuridine (dU) contamination in genomic DNA, R loops, RNA-DNA polymerase collisions, and type-1 interferons (IFN-1). Remarkably, thymidine rescues ATRi-induced dU contamination, cell death, and IFN-1 expression in proliferating CD8+ T cells. Thymidine also rescues ATRi-induced cancer cell death. We propose that ATRi-induced dU contamination contributes to dose-limiting leukocytopenia and inflammation in the clinic and CD8+ T cell dependent anti-tumor responses in mouse models. We conclude that ATR is essential to limit dU contamination in genomic DNA and IFN-1 expression.
Model-free analysis in the spectral domain of postmortem mouse brain EPSI reveals inconsistencies with model-based analyses of the free induction decay
Authors: Trinkle Scott , Wildenberg Gregg , Kasthuri Narayanan , Rivière Patrick La , Foxley Sean 
Published: February 2022

AbstractPurposeDysmyelinating disorders lead to abnormalities in myelin structure that produce detectable effects in an echo-planar spectroscopic imaging (EPSI) signal. To estimate the voxel-wise proportion of myelin, data are typically fit to compartmental models in the time domain. This work characterizes limitations in these models by comparing high-resolution water spectra measured in postmortem fixed mouse brains to spectra predicted from time-domain models fit to the same data, specifically by comparing spectra from control and shiverer mice, a model for dysmyelination.MethodsPerfusion-fixed, resected control (n = 5) and shiverer (n = 4) mouse brains were imaged using 3D EPSI with 100 µm isotropic resolution. The free induction decay (FID) was sampled every 2.74 ms over 192 echoes and Fourier transformed to produce water spectra with 1.9 Hz resolution. FIDs were also fit to two biophysical models and the resulting fits were converted to spectra with a Fourier transform. Spectral asymmetry was computed and compared before and after fitting the data to models.ResultsSpectra derived from both models did not show the magnitude of asymmetric broadening observed in the raw data. Correlations between data- and model-derived asymmetries and estimated frequency shifts are weak, leading to a reduction in spectral sensitivity to changes in white-matter structure after fitting the data to models.ConclusionThe results demonstrate spectral inconsistencies between biophysical model predictions and measured data, promoting the further incorporation of spectral analysis methods to develop and benchmark new model-based approaches.