bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective and retrospective representations of saccadic movements in primate prefrontal cortex
Authors: Calangiu Ioana , Kollmorgen Sepp , Reppas John , Mante Valerio 
Published: September 2022

AbstractDorso-lateral prefrontal cortex (dlPFC) in primates plays a key role in the acquisition and execution of flexible, goal-directed behaviors. Recordings in monkey dlPFC have revealed possible neural correlates of the underlying cognitive processes like attention, planning, or decision-making, both at the single-neuron and population levels. Integrating these observations into a coherent picture of dlPFC function is challenging, as these studies typically focused on neural activity in relation to a few, specific events within a single, fully learned behavioral task. Here we obtain a more comprehensive description of dlPFC activity from a large dataset of population recordings in monkeys across a variety of behavioral contexts. We characterized neural activity in relation to saccades that monkeys made freely, or at different stages of training in multiple tasks involving instructed saccades, perceptual discriminations, and reward-based decisions. Across all contexts, we observed reliable and strong modulations of neural activity in relation to a retrospective representation of the most recent saccadic movement. Prospective, planning-like activity was instead limited to task-related, delayed saccades that were directly eligible for a reward. The link between prospective and retrospective representations was highly structured, potentially reflecting a hard-wired feature of saccade responses in these areas. Only prospective representations were modulated by the recent behavioral history, but neither representations were modulated by learning occurring over days, despite obvious concurrent behavioral changes. Dorso-lateral PFC thus combines tightly linked flexible and rigid representations, with a dominant contribution from retrospective signals maintaining the memory of past actions.
In vitro to in vivo pharmacokinetic translation guidance
Authors: Fagerholm Urban 
Published: September 2022

ABSTRACTBackgroundPharmacokinetics (PK), exposure profiles and doses of candidate drugs in man are commonly predicted using data produced using various in vitro methods, such as hepatocytes (for intrinsic metabolic clearance (CLint)), plasma (for unbound fraction (fu)), Caco-2 (measuring apparent permeability (Papp) for prediction of in vivo fraction absorbed (fa)) and plasma water and buffers (measuring solubility (S) for prediction of in vivo fraction dissolved (fdiss)). For best possible predictions it is required that the clinical relevance of in vitro data is understood (in vitro-in vivo relationships) and that uncertainties have been investigated and considered.MethodsThe aim was to investigate in vitro-in vivo relationships for CLint, Pappvs fa and S vs fdiss and interlaboratory variability for fu, describe the clinical significance and uncertainties at certain levels of in vitro CLint, fu, Papp and S, and (based on the findings) develop a general in vitro-in vivo translation guide.Results and ConclusionIt was possible to finf data for describing how in vivo CLint, fa and fdiss distribute and varies at different levels of in vitro CLint, Papp and S and how fu varies between laboratories and methods at different fu-levels. It is apparent that there are considerable interlaboratory variabilities for CLint, fu and Papp: corresponding to up to 2500-, 700- and 35-fold variability for CLint, fu and fa, respectively. Apparently, S is a poor predictor of fdiss. Proposed S-thresholds do not seem clinically useful (overestimated). It does not seem appropriate to define in vitro CLint of 0.5-2 µL/min/106 cells as good metabolic stability (rather moderate to moderately high). Results shown for CLint, Papp and fu are applicable as general guidelines when internal standard values for reference compounds are unavailable.
Quantitative proteomic analysis of skeletal muscles from wild type and transgenic mice carrying recessive Ryr1 mutations linked to congenital myopathies
Authors: Eckhardt Jan , Ruiz Alexis , Koenig Stéphane , Frieden Maud , Schmidt Alexander , Treves Susan , Zorzato Francesco 
Published: September 2022

ABSTRACTSkeletal muscle is a highly structured and differentiated tissue responsible for voluntary movement and metabolic regulation. Muscles however, are heterogeneous and depending on their location, speed of contraction, fatiguability and function, can be broadly subdivided into fast and slow twitch as well as subspecialized muscles, with each group expressing common as well as specific proteins. Congenital myopathies are a group of non-inflammatory non-dystrophic muscle diseases caused by mutations in a number of genes, leading to a weak muscle phenotype. In most cases specific muscles types are affected, with preferential involvement of fast twitch muscles as well as extraocular and facial muscles. Here we performed relative and absolute quantitative proteomic analysis of EDL, soleus and extraocular muscles from wild type and transgenic mice carrying compound heterozygous mutations in Ryr1 identified in a patient with a severe congenital myopathy. Our quantitative proteomic study shows that recessive Ryr1 mutations not only decrease the content of RyR1 protein in muscle, but also impact the content of many other proteins; in addition, we provide important insight into the pathological mechanism of congenital myopathies linked to mutations in other genes encoding components of the excitation contraction coupling molecular complex.
Complex plumages spur rapid color diversification in island kingfishers (Aves: Alcedinidae)
Authors: Eliason Chad M. , McCullough Jenna M. , Hackett Shannon J. , Andersen Michael J. 
Published: September 2022

AbstractOceanic islands are cradles for diversity. Differences in predation pressures and lack of competition on islands are thought to drive both phenotypic and species diversification. While most work exploring these patterns has focused on life history, behavioral and morphological traits, many island species are uniquely colorful. Yet, a recent study of island bird coloration found that insular species are duller than continental species. Whether such shifts in color are associated with increased rates of color evolution on islands remains unknown. Here, we incorporate geometric morphometric techniques to study plumage color diversity in a speciose clade of colorful birds that inhabit nearly all areas of the globe—kingfishers (Aves: Alcedinidae). In particular, we test two hypotheses: (i) that plumage complexity enhances interspecific rates of color evolution and (ii) that plumage color diversity is elevated on islands. Our results show that more complex plumages result in more diverse colors among species and plumage color evolves faster on islands. Importantly, we found that insular species did not have more complex plumages than their continental relatives. Thus, complexity may be a key innovation that facilitates response to divergent (or relaxed) selection pressures on islands. Lack of support for competition driving rates of evolution along different color axes hints at an allopatric model of color evolution in which species adapt to local conditions on different islands. This work demonstrates how a truly multivariate treatment of color data can reveal evolutionary patterns that might otherwise go unnoticed.
Population Structure and Migration in the Eastern Highlands of Papua New Guinea; a Region Impacted by the kuru Epidemic
Authors: Quinn Liam , Moltke Ida , Whitfield Jerome , Alpers Michael , Campbell Tracy , Hummerich Holger , Pomat William , Siba Peter , Koki George , Collinge John , Hellenthal Garrett , Mead Simon 
Published: September 2022

AbstractPopulations of the Eastern Highlands of Papua New Guinea (EHPNG, area 11,157 km2) lived in relative isolation from the rest of the world until the mid-20th century, and the region contains a wealth of linguistic and cultural diversity. Notably, several populations of EHPNG were devastated by an epidemic prion disease, kuru, which at its peak in the mid-twentieth century led to some villages being almost depleted of adult women. Until now, population genetic analyses to learn about genetic diversity, migration, admixture and the impact of the kuru epidemic have been restricted to a small number of variants or samples. Here, we present a population genetic analysis of the region based on genome-wide genotype data of 943 individuals from 21 linguistic groups and 68 villages in EHPNG, including 34 villages in the South Fore linguistic group, which the group most affected by kuru. We find a striking degree of genetic population structure in the relatively small region (average FST between linguistic groups 0.024; area similar to Jamaica). The genetic population structure correlates well with linguistic grouping, with some noticeable exceptions. Also, we find evidence of a series of discrete admixture events that appear to coincide with previously expected introduction dates and movement of the sweet potato in the region. Finally, we find signatures of more recent migration within the EHPNG region and observe a substantial excess of female migration into the heavily kuru-affected South Fore linguistic group (p=0.0017, Chi Squared Test), likely reflecting the sex-bias in incidence of kuru. These data provide an in-depth look at the population genetics of a region devastated by a prion disease epidemic and which was until recently relatively isolated from the rest of the world.
GutMeta: online microbiome analysis and interactive visualization with build-in curated human gut microbiome database
Authors: Jiang Yiqi , Wang Yanfei , Che Lijia , Zhou Qian , Li Shuaicheng 
Published: September 2022

AbstractBackgroundThe human gut microbiome is associated with numerous human diseases. The whole-genome shotgun metagenomics sequencing helps accumulate a massive amount of gut microbiome data. However, few curated integrated platforms are available to explore the vast dataset. Advances in data generation pose new challenges to researchers attempting to analyze, visualize, and reuse published data.ResultGutMeta (human GUT whole-genome shotgun METAgenomics data analysis platform) is a one-stop online human gut metagenomic research platform that integrates a curated database, analyses, and visualizations.First, we built the Human Gut Metagenomics Database (HGMD), which contained taxonomy profiling and metadata of the metagenomics. HGMD collected the published human gut microbiome samples with whole metagenome shotgun (WMGS) sequencing data and consistently performed taxonomy classification using MetaPhlan3 for each sample. The various related metadata information was curated, and phenotypes were according to the MeSH ID. At this moment, HGMD contains 20,898 samples from 91 projects related to 65 diseases. Embedded tools could help users to explore the samples by keywords. Second, GutMeta provides researchers with user-friendly metagenomics analysis modules, including community diversity calculation, differential testing, dimension reduction, disease classifier construction, etc. Then, GutMeta provides corresponding interactive visualizations which can download as Scalable Vector Graphics (SVG), providing high-quality images. Further, GutMeta supplies two additional visualizations for the multi-level taxonomy overview for advanced investigations. GutMeta also supports online editing, including attribute adjustment, recoloring, reordering, and drag-and-drop. Third, GutMeta supports users in building their metagenomics analysis workspaces, including standard profiles uploading and built-in HGMD data import for online customized analyses and visualization.ConclusionGutMeta offers a solution to improve reproducibility in metagenomic research, with the standardized procedure from input data to downstream analysis and visualization. GutMeta is a free access analysis platform that integrates human gut WMGS sequencing data, nine online bioinformatics analysis and data visualization modules/pipelines, and a customized workspace. GutMeta is avaiable at https://GutMeta.deepomics.org.
Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease
Authors: Godoy Andre Schutzer , Nakamura Aline Minalli , Douangamath Alice , Song Yun , Noske Gabriela Dias , Gawriljuk Victor Oliveira , Fernandes Rafaela Sachetto , Muniz Pereira Humberto D. , Zagato Oliveira Ketllyn Irene , Fearon Daren , Dias Alexandre , Krojer Tobias , Fairhead Michael , Powell Alisa , Dunnet Louise , Brandao-Neto Jose , Skyner Rachael , Chalk Rod , von Delft Frank , Bajusz Dávid , Bege Miklós , Borbás Anikó , Miklós Keserű György , Oliva Glaucius 
Published: September 2022

AbstractSARS-CoV-2 is the causative agent of COVID-19. The highly conserved viral NSP15 endoribonuclease, NendoU, is a key enzyme involved in viral immune evasion, and a promising target for the development of new classes of antivirals. Yet, the broad variety of recognition sequences, complex assembly and kinetics, and lack of structural complexes hampers the development of new competitive or allosteric inhibitors for this target. Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index of 2. By using cryo-EM at distinct pH’s combined with X-ray crystallography and structural analysis, we demonstrate the potential for NendoU to shift between open and closed states, and assembly in larger supramolecular entities, which might serve as a mechanism of self-regulation. Further, we report results from a large fragment screening campaign against NendoU, revealing multiple new allosteric sites for the development of inhibitors.
An ABM of biting midge dynamics to understand Bluetongue outbreaks
Authors: Gladson Shane L. , Stepien Tracy L. 
Published: September 2022

AbstractBluetongue (BT) is a well-known vector-borne disease that infects ruminants such as sheep, cattle, and deer with high mortality rates. Recent outbreaks in Europe highlight the importance of understanding vector-host dynamics and potential courses of action to mitigate the damage that can be done by BT. We present an agent-based model (ABM), entitled MidgePy, that focuses on the movement of individualCulicoidesspp. biting midges and their interactions with ruminants to understand their role as vectors in BT outbreaks, especially in regions that do not regularly experience outbreaks. Sensitivity analysis is performed and results indicate that midge survival rate has a significant impact on the probability of a BTV outbreak as well as its severity. Parameter regions where outbreaks are more likely to occur are determined, with an increase in environmental temperature corresponding with an increased probability of outbreak, where midge flight activity is used as a proxy for temperature. This suggests that future methods to control BT spread could combine large-scale vaccination programs with biting midge population control measures such as the use of pesticides. Spatial heterogeneity in the environment is also explored to give insight on optimal farm layouts to reduce the potential for BT outbreaks.
External validation and further exploration of fall prediction models based on questionnaires and daily-life trunk accelerometry
Authors: Zhang Yuge , Weijer Roel H.A. , van Schooten Kimberley S. , Bruijn Sjoerd M. , Pijnappels Mirjam 
Published: September 2022

AbstractBackgroundAmbulatory measurements of trunk accelerations can provide valuable insight into the amount and quality of daily life activities. Such information has been used to create models that aim to identify individuals at high risk of falls. However, external validation of such prediction models is lacking, yet crucial for clinical implementation. We externally validated three previously described fall prediction models (van Schooten et al., 2015a).MethodsComplete questionnaires and one week of trunk acceleration data were obtained in 263 community-dwelling people (mean age 71.8 years, 68.1% female). To validate models, we first used the coefficients and optimal cut-offs from original cohort, then recalibrated the original models, as well as optimized parameters based on our new cohort.ResultsAmong all participants, 39.9% experienced falls during 6-month follow-up. All models showed poor precision (0.20-0.49), poor sensitivity (0.32-0.58), and good specificity (0.45-0.89). Calibration of the original models had limited effect on model performance. Using coefficients and cut-offs optimized on the external cohort also had limited benefit. Last, the odds ratios in our cohort were different from those in the original cohort and indicated that gait characteristics, except for index of harmonicity ML, were not statistically significantly associated with falls.ConclusionsPrediction of fall risk in our cohort was not as effective as in the original cohort. Recalibration as well as optimized model parameters resulted in limited increase in accuracy. Fall prediction models are highly specific to the cohort studied. This highlights the need for large representative cohorts, preferably with an external validation cohort.
Antagonistic H3K79me-H3K9ac crosstalk determines elongation at housekeeping genes to promote pluripotency
Authors: Wille Coral K. , Zhang Xiaoya , Haws Spencer A. , Denu John M. , Sridharan Rupa 
Published: September 2022

ABSTRACTPluripotent embryonic stem cells (ESCs) have a transcriptionally permissive chromatin environment enriched for gene activation-associated histone modifications as compared to somatic cells. A striking exception is DOT1L-mediated H3K79 methylation that is considered a positive regulator of transcription. Here we find that ESCs maintain low H3K79 methylation to facilitate RNA polymerase II (RNAPII) elongation for greater nascent transcription. Inhibiting DOT1L during the reprogramming of somatic to induced pluripotent stem cells (iPSCs) enables ESC-like RNAPII and transcriptional status. Mechanistically, DOT1L inhibition causes a local gain of histone acetylation at genes that lose the most H3K79me, which unexpectedly are ubiquitously expressed genes that perform essential functions in every cell, rather than lineage specifying genes. Maintenance of this elevated histone acetylation is required for the enhanced conversion to iPSCs upon DOT1L inhibition. Remarkably, increasing global DOT1L or site-specific tethering of DOT1L is sufficient to decrease H3K9ac in ESCs. We discover a high H3ac-low H3K79me epigenetic mechanism that promotes transcription elongation at ubiquitously expressed genes to enforce pluripotent cell identity.
The Effect of P2X7 Antagonism on Subcortical Spread of Optogenetically-Triggered Cortical Spreading Depression and Neuroinflammation
Authors: Uzay Burak , Donmez-Demir Buket , Ozcan Sinem Yilmaz , Kocak Emine Eren , Yemisci Muge , Ozdemir Yasemin Gursoy , Dalkara Turgay , Karatas Hulya 
Published: September 2022

AbstractMigraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in opening of pannexin-1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light. Here, we investigated the role of purinergic P2X7 receptors on the subcortical spread of CSD and its consequent neuroinflammation using a potent and selective P2X7 antagonist, JNJ-47965567. P2X7 antagonism had no effect on the CSD threshold and characteristics but increased the latency to hypothalamic voltage deflection following CSD showing that ATP acts as a mediator in the subcortical spread. P2X7 antagonism also prevented hypothalamic neuronal activation following CSD, revealed by bilateral decrease in hypothalamic c-fos positive neuron count. P2X7 antagonism further stopped the CSD-induced neuroinflammation revealed by decreased nuclear translocation of NF-kappa B-p65 in astrocytes and decreased HMGB1 release. Following CSD we observed an increase in neuronal cytoplasmic P2X7R signal in cortex and subcortical structures (thalamus, hypothalamus, striatum, hippocampus) concordant with the neuroinflammation which is also prevented by P2X7R antagonism. In conclusion, our data suggest that P2X7R plays an imperative role in CSD-induced neuroinflammation, subcortical spread of CSD and CSD-induced hypothalamic neuronal activation hence can be a potential target in migraine treatment.
Optical Biopsy using a neural network to predict functional state from photos of wounds
Authors: Teague Joe , Socia Damien , An Gary , Badylak Stephen , Johnson Scott , Jiang Peng , Vodovotz Yoram , Cockrell R. Chase 
Published: September 2022

AbstractBackgroundThe clinical characterization of the functional status of active wounds remains a considerable challenge that at present, requires excision of a tissue biopsy. In this pilot study, we use a convolutional Siamese neural network architecture to predict the functional state of a wound using digital photographs of wounds in a canine model of volumetric muscle loss (VML).Materials and MethodsImages of volumetric muscle loss injuries and tissue biopsies were obtained in a canine model of VML. Gene expression profiles for each image were obtained using RNAseq. These profiles were then converted to functional profiles using a manual review of validated gene ontology databases. A Siamese neural network was trained to regress functional profile expression values as a function of the data contained in an extracted image segment showing the surface of a small tissue biopsy. Network performance was assessed in a test set of images using Mean Absolute Percentage Error (MAPE).ResultsThe network was able to predict the functional expression of a range of functions based with a MAPE ranging from ∼5% to ∼50%, with functions that are most closely associated with the early-state of wound healing to be those best-predicted.ConclusionsThese initial results suggest promise for further research regarding this novel use of ML regression on medical images. The regression of functional profiles, as opposed to specific genes, both addresses the challenge of genetic redundancy and gives a deeper insight into the mechanistic configuration of a region of tissue in wounds. As this preliminary study focuses on the first 14 days of wound healing, future work will focus on extending the training data to include longer time periods which would result in additional functions, such as tissue remodeling, having a larger presence in the training data.
Shared and unique responses in the microbiome of allopatric lizards reared in a standardized environment
Authors: Assis Braulio A. , Bell Terrence H. , Engler Heather I. , King William L. 
Published: September 2022

AbstractThe gut microbiome can influence host fitness and, consequently, the ecology and evolution of natural populations. Microbiome composition can be driven by environmental exposure but also by the host’s genetic background and phenotype. To contrast environmental and genetic effects on the microbiome we leverage preserved specimens of eastern fence lizards from allopatric lineages east and west of the Mississippi River but reared in standardized conditions. Bacterial composition was indistinguishable between lineages but responded significantly to host age – a proxy for environmental exposure. This was accompanied by a continuous decrease in bacterial diversity in both lineages, partially driven by decreasing evenness seen only in western lizards. These findings indicate that longer exposure to a homogeneous habitat may have a depreciating effect on microbiome diversity in eastern fence lizards, a response shared by both lineages. We highlight the importance of such effects when extrapolating patterns from laboratory experiments to the natural world.