bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Receptor Tyrosine Kinases Regulate Dengue Infection of Hepatocytes
Authors: Bourgeois Natasha M. , Wei Ling , Ho Nhi N. T. , Neal Maxwell L. , Seferos Denali , Tongogara Tinotenda , Mast Fred D. , Aitchison John D. , Kaushansky Alexis 
Published: July 2023

ABSTRACTDengue is an arboviral disease causing severe illness in over 500,000 people each year. Currently, there is no way to constrain dengue in the clinic. Host kinase regulators of dengue virus (DENV) infection have the potential to be disrupted by existing therapeutics to prevent infection and/or disease progression. To evaluate kinase regulation of DENV infection, we performed kinase regression (KiR), a machine learning approach that predicts kinase regulators of infection using existing drug-target information and a small drug screen. We infected hepatocytes with DENVin vitroin the presence of a panel of 38 kinase inhibitors then quantified the effect of each inhibitor on infection rate. We employed elastic net regularization on these data to obtain predictions of which of 300 kinases are regulating DENV infection. Thirty-six kinases were predicted to have a functional role. Intriguingly, seven of the predicted kinases – EPH receptor A4 (EPHA4), EPH receptor B3 (EPHB3), EPH receptor B4 (EPHB4), erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 2 (FGFR2), Insulin like growth factor 1 receptor (IGF1R), and ret proto-oncogene (RET) – belong to the receptor tyrosine kinase (RTK) family, which are already therapeutic targets in the clinic. We demonstrate that predicted RTKs are expressed at higher levels in DENV infected cells. Knockdown of ERBB2, FGFR2 and IGF1R reduces DENV infection in hepatocytes. Finally, we observe differential temporal induction of ERBB2 and IGF1R following DENV infection, highlighting their unique roles in regulating DENV. Collectively, our findings underscore the significance of multiple RTKs in DENV infection and advocate further exploration of RTK-oriented interventions against dengue.
A test of time-resolved functional MRI with sub-second event durations
Authors: Wong Alvin P.H. , Wu Esther X.W. , Rogers Baxter P. , Asplund Christopher L. 
Published: July 2023

AbstractFunctional neuroimaging (fMRI) signals are famously sluggish, unfolding over several seconds after even brief sensory (and neural) events. Relative timing differences between different evoking conditions, however, can distinguish between changes in the duration or intensity of neural activity (Henson et al., 2002). Specifically, increases in stimulus duration cause a delayed response peak with a greater amplitude, whereas increases in stimulus intensity affect the peak magnitude alone. These relationships have been empirically demonstrated using stimulus durations of several seconds (Friston, 2005), but many processes relevant to cognitive psychology occur on sub-second timescales. Here we tested whether the predicted relationship between stimulus properties and the hemodynamic response held for sub-second stimuli and sub-second changes in stimulus duration. In Experiment 1 (n=15), we presented visual and auditory stimuli at three durations (100, 300, and 900 ms) and three intensities in a slow event-related design with a rapid TR (625 ms). In Experiment 2 (n=14), the stimulus durations were extended (1000, 1200, and 1800 ms) to increase the evoked signal. By fitting the observed fMRI signals to parameterised hemodynamic response functions, we found that changes in stimulus duration caused differences in peak latency and magnitude, whereas changes in stimulus intensity affected only peak magnitude. Significant effects were found for duration differences as small as 200 ms, with clearer results when a sufficiently large base signal was evoked and when a bootstrap resampling technique was used. Our results support the validity of existing models of the hemodynamic response. They also support the use of time-resolved fMRI for mental chronometry in cognitive neuroscience, thereby allowing researchers to draw additional inferences about brief mental events.
Highly effective gene inactivation in tetraploidXenopus laeviswith low-temperature-active engineered Cas12a
Authors: Yun Seongmin , Kim Seohyun , Hong Juyeon , Choi Jiwon , Shin Jeong-Sik , Choi Subin , Lee Hyun-Shik , Cho Seung Woo , Park Tae Joo , Kwon Taejoon 
Published: July 2023

AbstractBackgroundGene knockout using the CRISPR/Cas (clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein) system revolutionized reverse genetic (or targeted mutagenesis) studies in model and non-model organisms because almost all genetic elements can be targeted with few limitations. Although the CRISPR/Cas system incorporating SpCas9 (Cas9 derived fromStreptococcus pyogenes) remains the most popular for genome editing, another CRISPR/Cas system with Cas12a (Cpf1) has expanded its application. However, Cas12a is difficult to use in some aquatic model organisms, such asXenopus, because of its low activity at the temperatureXenopusis normally raised (lower than 25°C). Recently, an engineered Cas12a called Cas12a-Ultra was developed, which has improvedin vivoendonuclease activity with less temperature dependency, and several commercial products were introduced to the market.ResultsWe evaluated the performance of these engineered Cas12a enzymes inXenopusembryos. We first confirmed that they were more active than SpCas9 at the low temperature thatX. laevisembryos are mostly raised (20–22°C) based onin vitrodigestion experiments. Then, we evaluated theirin vivoactivities by disrupting the tyrosinase enzyme (tyr), which induces albino-like phenotypes. LbCpf1 (Cpf1 derived fromLachnospiraceaebacterium)-Ultra outperformed the other enzymes, producing more than 80% of embryos with severely defective phenotypes even in low-temperature conditions. In addition, duplicated copies of two paralogous lysine demethylases (kdm5bandkdm5c) were successfully disrupted, which recapitulated the previously reported phenotypes observed upon morpholino-mediated knockdown.ConclusionsNewly engineered Cas12a is valuable for gene function studies inXenopusand other model organisms with low growth temperatures.
Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress
Authors: Taylor Bethany C. , Steinthal Loic H. , Dias Michelle , Yalamanchili Hari K. , Ochsner Scott A. , Zapata Gladys E. , Mehta Nitesh R. , McKenna Neil J. , Young Nicolas L. , Nuotio-Antar Alli M. 
Published: July 2023

AbstractRegulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top- down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28.8°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression data suggest a role for epigenetic modification of DNA in gene regulation in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT. Taken together, our results reveal global epigenetically-regulated transcriptional “on” and “off” signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.
PACS allows comprehensive dissection of multiple factors governing chromatin accessibility from snATAC-seq data
Authors: Miao Zhen , Wang Jianqiao , Park Kernyu , Kuang Da , Kim Junhyong 
Published: July 2023

AbstractSingle nucleus ATAC-seq (snATAC-seq) experimental designs have become increasingly complex with multiple factors that might affect chromatin accessibility, including genotype, cell type, tissue of origin, sample location, batch, etc., whose compound effects are difficult to test by existing methods. In addition, current snATAC-seq data present statistical difficulties due to their sparsity and variations in individual sequence capture. To address these problems, we present a zero-adjusted statistical model, Probability model of Accessible Chromatin of Single cells (PACS), that can allow complex hypothesis testing of factors that affect accessibility while accounting for sparse and incomplete data. For differential accessibility analysis, PACS controls the false positive rate and achieves on average a 17% to 122% higher power than existing tools. We demonstrate the effectiveness of PACS through several analysis tasks including supervised cell type annotation, compound hypothesis testing, batch effect correction, and spatiotemporal modeling. We apply PACS to several datasets from a variety of tissues and show its ability to reveal previously undiscovered insights in snATAC-seq data.
disperseNN2: a neural network for estimating dispersal distance from georeferenced polymorphism data
Authors: Smith Chris C. R. , Kern Andrew D. 
Published: July 2023

AbstractSpatial genetic variation is shaped in part by an organism’s dispersal ability. We present a deep learning tool,disperseNN2, for estimating the mean per-generation dispersal distance from georeferenced polymorphism data. Our neural network performs feature extraction on pairs of genotypes, and uses the geographic information that comes with each sample. These attributes leddisperseNN2to outperform a state-of-the-art deep learning method that does not use explicit spatial information: the mean relative absolute error was reduced by 33% and 48% using sample sizes of 10 and 100 individuals, respectively.disperseNN2is particularly useful for non-model organisms or systems with sparse genomic resources, as it uses unphased, single nucleotide polymorphisms as its input. The software is open source and available fromhttps://github.com/kr-colab/disperseNN2, with documentation located athttps://dispersenn2.readthedocs.io/en/latest/.
A transcriptome-wide meta-analysis reveals lack of cancer-cell intrinsic determinants of response to immune checkpoint blockade
Authors: Guo Yu Amanda , Kulshrestha Tanmay , Chang Mei Mei , Kassam Irfahan , Revkov Egor , Rizzetto Simone , Tan Aaron C. , Tan Daniel S.W. , Tan Iain Beehuat , Skanderup Anders Jacobsen 
Published: July 2023

AbstractImmune-checkpoint therapy (ICB) has conferred significant and durable clinical benefit to some cancer patients. However, most patients do not respond to ICB, and reliable biomarkers of ICB response are needed to improve patient stratification. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors from ICB-treated patients and tumors with expected ICB outcomes based on microsatellite status. Using a robust transcriptome deconvolution approach, we inferred cancer and stroma-specific gene expression differences and identified cell-type specific features of ICB response across cancer types. Consistent with current knowledge, stromal expression ofCXCL9,CXCL13, andIFNGwere the top determinants of favorable ICB response. In addition, we identified a group of potential immune-suppressive genes, includingFCER1A, associated with poor response to ICB. Strikingly, PD-L1 expression in stromal cells, but not cancer cells, is correlated with ICB response across cancer types. Furthermore, the unbiased transcriptome-wide analysis failed to identify cancer-cell intrinsic features of ICB response conserved across tumor types. Overall, our results challenge the prevailing dogma that cancer cells present tissue-agnostic molecular markers that modulate immune activity and ICB treatment response. These results have implications for the development of improved ICB treatments and diagnostics.
Modelling The Brain’s Response To Natural Scenes In The Bottleneck Space
Authors: Ndubuaku Henry 
Published: July 2023

AbstractComputational models that mirror the brain’s behaviour can help us understand human intelligence and SOTA techniques for modelling the brain’s response to visual stimuli use deep neural networks. However, the best-performing vision models are compute-intensive and functional brain activities are represented by high-dimensional matrices which exacerbate this inefficiency. To this end, we propose a novel approach which showed significant performance improvements by 1) Projecting both the visual stimuli features and brain responses to low-dimensional vectors and using a non-linear neural network to learn the mapping in the latent space. 2) Simultaneously modelling all vertices in the visual cortices of both the left and right hemispheres using an objective we call “Racing Loss”. 3) Incorporating tiny leaks of the ground truth during training of this network. 4) First pre-training this network on all subjects then fine-tuning on each. We show that our method additionally achieved 12% higher Noise-Normalized Mean Correlation Scores compared to fully fine-tuning large vision models to the high-dimensional brain responses.
Missing microbial eukaryotes and misleading meta-omic conclusions
Authors: Krinos Arianna I. , Brisbin Margaret Mars , Hu Sarah K. , Cohen Natalie R. , Rynearson Tatiana A. , Follows Michael J. , Schulz Frederik , Alexander Harriet 
Published: July 2023

AbstractMeta-omics has become commonplace in the study of microbial eukaryotes. The explosion of available data has inspired large-scale analyses, including species or taxonomic group distribution mapping, gene catalog construction, and inference on the functional roles and activities of microbial eukaryotesin situ. However, genome and transcriptome databases are prone to misannotation biases, and meta-omic inventories may have no recoverable taxonomic annotation for more than half of assembled contigs or predicted proteins. Direct mapping solely to organisms of interest might introduce a problematic misattribution bias, while full databases can annotate any cataloged organism but may be imbalanced between taxa. Here, we explore the potential pitfalls of common approaches to taxonomic annotation of protistan meta-omic datasets. We argue that ongoing curation of genetic resources is critical in accurately annotating protistsin situin meta-omic datasets. Moreover, we propose that precise taxonomic annotation of meta-omic data is a clustering problem rather than a feasible alignment problem. We show that taxonomic membership of sequence clusters demonstrates more accurate estimated community composition than returning exact sequence labels, and overlap between clusters can address database shortcomings. Clustering approaches can be applied to diverse environments while continuing to exploit the wealth of annotation data collated in databases, and database selection and evaluation is a critical part of correctly annotating protistan taxonomy in environmental datasets. We re-analyze three environmental datasets at three levels of taxonomic hierarchy in order to illustrate the critical importance of both database completeness and curation in enabling accurate environmental interpretation.
Genetic consequences of improved river connectivity in brown trout (Salmo trutta, L.)
Authors: Moccetti Paolo , Dodd Jamie R. , Joyce Domino A. , Nunn Andy D. , Gillespie Ben , Bolland Jonathan D. 
Published: July 2023

AbstractFragmentation of watercourses poses a significant threat to biodiversity, particularly for migratory fish species. Mitigation measures such as fishways, have been increasingly implemented to restore river connectivity and support fish migration. The effects of such restoration efforts are typically tested using telemetry and fisheries methods, which do not fully capture the broader population movements that may have important consequences for population viability. We performed a before-and-after control-impact (BACI) study using genetic tools (SNPs) to investigate the effect of a newly implemented fishway, aiming to enhance upstream spawning migration of brown trout (Salmo trutta, Linnaeus) in a reservoir with two headwater tributaries fragmented by man-made weirs. Another reservoir with two barrier-free tributaries was also analysed as a control. Our results showed that the isolated brown trout population was spawning in the reservoir before the installation of the fishway, and we found genetic structuring and differentiation between fragmented headwater tributaries before the fishway construction, but not in the control reservoir. Unexpectedly, after the fishway construction we observed signals consistent with increased genetic differentiation between populations of newly recruited juvenile fish in the reservoir tributary and fish in the reservoir. We propose this was caused by newly enabled philopatric behaviour of brown trout to their natal spawning tributary. In contrast, we did not find any genetic changes in the tributary without a fishway or in the barrier-free reservoir system. Given the scarcity of similar studies, we advocate for an increased use of genetic analyses in BACI studies to monitor and evaluate the effect of efforts to restore habitat connectivity and inform future management strategies.
The Endosomal pH Regulator NHE6 is Required for Insulin-Stimulated Glucose Uptake in Adipocytes
Authors: Mekile Allatah X. , Makena Monish Ram , Gupta Ruby , White Cory J. , Bowman Ray Wesley , Patnayak Rachana L. , Lorenzo Damaris N. , Rao Rajini 
Published: July 2023

AbstractObjectiveTrafficking ofGLUcoseTransporter isoform4(GLUT4) from the adipocyte vesicular pool to the cell surface is tightly regulated by insulin to maintain glucose homeostasis in response to changing demands in energy consumption. Previously, endosomal Na+/H+exchanger 6 (NHE6, gene nameSLC9A6) was identified in adipocyte plasma membranes and shown to associate with GLUT4-positive vesicles. However, the functional contribution of NHE6 to GLUT4 trafficking and glucose uptake remained uncharacterized.MethodsNHE6 was knocked down in 3T3L1 cells either before or after differentiation into adipocytes using lentiviral delivery of shRNA. Uptake of [3H] 2-deoxyglucose into adipocytes was quantified in response to insulin. We used epitope tagged constructs to distinguish between localization of vesicular and surface levels of NHE6 and GLUT4 proteins. Protein and transcript levels of components of the glucose signaling pathway were monitored by qPCR and Western analysis, respectively, in response to NHE6 knockdown and/or treatment with chemical modulators of endosomal pH.ResultsWe show that insulin-stimulated glucose uptake in adipocytes is severely impaired upon NHE6 depletion. Correspondingly, insulin-stimulated surface expression of GLUT4 at the adipocyte plasma membrane was diminished in NHE6 knockdown cells due to a post-transcriptional decrease in basal GLUT4. Metformin response of GLUT4 was also muted in the absence of NHE6. Further, we demonstrate diminished activation of the GLUT4 translocation pathway in the absence of NHE6 via reduced expression of the insulin receptor and reduced phosphorylation of the downstream effector kinase Akt. Components of GLUT4 storage vesicles, including GLUT4, LRP1 and sortilin were downregulated in NHE6-knockdown adipocytes under basal conditions. Proteostatic control of key components of the insulin signaling pathway (insulin receptor, GLUT4) could be restored by chemical bypass of NHE6 using the V-ATPase inhibitor bafilomycin or the Na+/H+exchanger mimetic monensin.ConclusionsThus, NHE6 is critical for proper expression and trafficking of GLUT4. Basal expression of both insulin receptor and GLUT4 in NHE6 knockdown cells could be restored by bafilomycin-inhibition of the H+-ATPase or the H+ionophore monensin pointing to pH dysregulation as the underlying defect. We suggest that NHE6 is a component of GLUT4 storage vesicles where it regulates proteostasis. These findings establish NHE6 as a novel contributor to glucose homeostasis and energy metabolism with implications for Christianson syndrome patients who carry loss of function mutations in theSLC9A6gene.Graphical Abstract
Context-invariant beliefs are supported by dynamic reconfiguration of single unit functional connectivity in prefrontal cortex
Authors: Noel Jean-Paul , Balzani Edoardo , Savin Cristina , Angelaki Dora E. 
Published: July 2023

AbstractNatural behaviors occur in closed action-perception loops and are supported by dynamic and flexible beliefs abstracted away from our immediate sensory milieu. How this real-world flexibility is instantiated in neural circuits remains unknown. Here we have macaques navigate in a virtual environment by primarily leveraging sensory (optic flow) signals, or by more heavily relying on acquired internal models. We record single-unit spiking activity simultaneously from the dorsomedial superior temporal area (MSTd), parietal area 7a, and the dorso-lateral prefrontal cortex (dlPFC). Results show that while animals were able to maintain adaptive task-relevant beliefs regardless of sensory context, the fine-grain statistical dependencies between neurons, particularly in 7a and dlPFC, dynamically remapped with the changing computational demands. In dlPFC, but not 7a, destroying these statistical dependencies abolished the area’s ability for cross-context decoding. Lastly, correlation analyses suggested that the more unit-to-unit couplings remapped in dlPFC, and the less they did so in MSTd, the less were population codes and behavior impacted by the loss of sensory evidence. We conclude that dynamic functional connectivity between prefrontal cortex neurons maintains a stable population code and context-invariant beliefs during naturalistic behavior with closed action-perception loops.