bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimicrobial copper as an effective and practical deterrent to surface transmission of SARS-CoV-2
Authors: Vera-Otarola Jorge , Mendez Nicolas , Martínez-Valdebenito Constanza , Mannheim Rodolfo , Rhodes Steve , Lu Kenneth 
Published: August 2022

AbstractThe aerosols are critical for SARS-CoV-2 transmission, however in areas with high confluence of people the contaminated surfaces take an important role that we could attack using antimicrobial surfaces including copper. In this study, we wanted to challenge infectious SARS-CoV-2 with two samples of copper surfaces and one plastic surface as control at different direct times contact. To evaluate and quantify virucidal activity of copper against SARS-CoV-2, two methods of experimental infection were performed, TCID50 and plaque assays on VeroE6 cells, showing significant inactivation of high titer of SARS-CoV-2 within minutes reaching 99.9 % of inactivation of infectivity on both copper surfaces. Daily high demand surfaces contamination is an issue that we have to worry about not only during the actual pandemic time but also for future, where copper or its alloys will have a pivotal role.ImportanceQuantitative data obtained of TCID50 and plaque assay with infectious SARS-CoV-2 virus showed that after direct contact with copper or copper alloys, viruses were inactivated within minutes. Notably, the SARS-CoV-2 virus used in these assays was in high titer (106 PFU/mL) showing strong copper inactivation of the infectious SARS-CoV-2.
Using adversarial networks to extend brain computer interface decoding accuracy over time
Authors: Ma Xuan , Rizzoglio Fabio , Perreault Eric J. , Miller Lee E. , Kennedy Ann 
Published: August 2022

AbstractExisting intracortical brain computer interfaces (iBCIs) transform neural activity into control signals capable of restoring movement to persons with paralysis. However, the accuracy of the “decoder” at the heart of the iBCI typically degrades over time due to turnover of recorded neurons. To compensate, decoders can be recalibrated, but this requires the user to spend extra time and effort to provide the necessary data, then learn the new dynamics. As the recorded neurons change, one can think of the underlying movement intent signal being expressed in changing coordinates. If a mapping can be computed between the different coordinate systems, it may be possible to stabilize the original decoder’s mapping from brain to behavior without recalibration. We previously proposed a method based on Generalized Adversarial Networks (GANs), called “Adversarial Domain Adaptation Network” (ADAN), which aligns the distributions of latent signals within underlying low-dimensional neural manifolds. However, ADAN was tested on only a very limited dataset. Here we propose a method based on Cycle-Consistent Adversarial Networks (Cycle-GAN), which aligns the distributions of the full-dimensional neural recordings. We tested both Cycle-GAN and ADAN on data from multiple monkeys and behaviors and compared them to a linear method based on Procrustes Alignment of axes provided by Factor Analysis (PAF). Both GAN-based methods outperformed PAF. Cycle-GAN and ADAN (like PAF) are unsupervised and require little data, making them practical in real life. Overall, Cycle-GAN had the best performance and was easier to train and more robust than ADAN, making it ideal for stabilizing iBCI systems over time.Significance StatementThe inherent instabilities in the neural signals acquired by intracortical microelectrode arrays cause the performance of an intracortical brain computer interface (iBCI) decoder to drop over time, as the movement intent signal must essentially be recorded from neurons representing an ever-changing coordinate system. Here, we address this problem using Generative Adversarial Networks (GANs) to align these coordinates and compare their success to another, recently proposed linear method that uses Factor Analysis and Procrustes alignment. Our proposed methods are fully unsupervised, can be trained quickly, and require remarkably little new data. These methods should give iBCI users access to decoders with unchanging dynamics, and without the need for periodic supervised recalibration.
Timeline of changes in spike conformational dynamics in emergent SARS-CoV-2 variants reveal progressive stabilization of trimer stalk and enhanced NTD dynamics
Authors: Braet Sean M. , Buckley Theresa S. C. , Venkatakrishnan Varun , Dam Kim-Marie A. , Bjorkman Pamela J. , Anand Ganesh S. 
Published: August 2022

AbstractSARS-CoV-2 emergent variants are characterized by increased transmissibility and each show multiple mutations predominantly localized to the spike (S) protein. Here, amide hydrogen/deuterium exchange mass spectrometry has been applied to track correlative changes in S dynamics from multiple SARS-CoV-2 variants. Our results highlight large differences across variants at two loci with impacts on S dynamics and stability. A significant enhancement in stabilization first occurred with the emergence of D614G S followed by smaller, progressive stabilization in Omicron BA.1 S traced through Alpha S and Delta S variants. Stabilization preceded progressive enhancement in dynamics in the N-terminal domain, wherein Omicron BA.1 S showed the largest magnitude increases relative to other preceding variants. Changes in stabilization and dynamics resulting from specific S mutations detail the evolutionary trajectory of S protein in emerging variants. These carry major implications for SARS-CoV-2 viral fitness and offer new insights into variant-specific therapeutic development.
Orchestration of Proteins in cyanobacterial Circadian Clock System 1
Authors: Sugiyama Masaaki , Morishima Ken , Yunoki Yasuhiro , Inoue Rintaro , Sato Nobuhiro , Yagi Hirokazu , Kato Koichi 
Published: August 2022

ABSTRACTCircadian rhythm by Cyanobacteria is one of the simplest biological clocks: the clock consists of only three proteins, KaiA, KaiB, and KaiC. Their oligomers, KaiA dimer (A2), KaiB tetramer (B4), and KaiC hexamer (C6) oscillate an association–disassociation cycle with 24-hr period. In a widely accepted model, the oscillation process is as follows. From the viewpoint of a base unit (C6), C6 homo-oligomer → A2C6 complex → B6C6 complex → AnB6C6 complex (n≤12) →C6 homo-oligomer. In this study, Small-Angle X-ray Scattering, Contrast Matching-Small-Angle Neutron Scattering, Analytical Ultracentrifuge, and phosphorylation-analysis PAGE measurements were performed to reveal the kinetics not only of KaiC hexamer but also of all components in a working Kai clock. The complementary analysis disclosed that the oscillation is not the single process as the widely accepted model but composed with synchronized multiple association-dissociation reactions between components. Namely, there are various reactions between components, which proceed simultaneously, in a working Kai-clock.
Robust phylogenetic regression
Authors: Adams Richard , Cain Zoe , Assis Raquel , DeGiorgio Michael 
Published: August 2022

AbstractModern comparative biology owes much to phylogenetic regression. At its conception, this technique sparked a revolution that armed biologists with phylogenetic comparative methods (PCMs) for combatting evolutionary pseudoreplication, which arises inherently from trait data sampled across related species. Over the past few decades, the phylogenetic regression framework has become a paradigm of modern comparative biology that has been widely embraced as a remedy for evolutionary pseudoreplication. However, recent evidence has sown doubt over the efficacy of phylogenetic regression, and PCMs more generally, with the suggestion that many of these methods fail to provide an adequate defense against unreplicated evolution—the primary justification for using them in the first place. Importantly, some of the most compelling examples of biological innovation in nature result from abrupt, lineage-specific evolutionary shifts, which current regression models are largely ill-equipped to deal with. Here we explore a solution to this problem by applying robust linear regression to comparative trait data. We formally introduce robust phylogenetic regression to the PCM toolkit with linear estimators that are less sensitive to model violations while still retaining high power to detect true trait associations. Our analyses also highlight an ingenuity of the original algorithm for phylogenetic regression based on independent contrasts, whereby robust estimators are particularly effective. Collectively, we find that robust estimators hold promise for improving tests of trait associations and offer a path forward in scenarios where classical approaches may fail. Our study joins recent arguments for increased vigilance against pseudoreplication and a better understanding of evolutionary model performance in challenging–yet biologically important–settings.
Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease
Authors: Birolini Giulia , Valenza Marta , Ottonelli Ilaria , Talpo Francesca , Minoli Lucia , Cappelleri Andrea , Bombaci Mauro , Caccia Claudio , Canevari Caterina , Trucco Arianna , Leoni Valerio , Passoni Alice , Favagrossa Monica , Nucera Maria Rosaria , Colombo Laura , Paltrinieri Saverio , Bagnati Renzo , Duskey Jason Thomas , Caraffi Riccardo , Vandelli Maria Angela , Taroni Franco , Salmona Mario , Scanziani Eugenio , Biella Gerardo , Ruozi Barbara , Tosi Giovanni , Cattaneo Elena 
Published: August 2022

AbstractEvidence that Huntington’s disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing (“early treatment”) or reversing (“late treatment”) HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally.We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic (“early treatment”) or symptomatic (“late treatment”) stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments (“2 cycle treatment”) lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions.Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates.These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients.
Target-enriched enzymatic methyl sequencing: flexible, scalable and inexpensive hybridization capture for quantifying DNA methylation
Authors: Rubenstein Dustin R. , Solomon Joseph 
Published: August 2022

AbstractThe increasing interest in studying DNA methylation to understand how traits or diseases develop requires new and flexible approaches for quantifying DNA methylation in a diversity of organisms. In particular, we need efficient yet cost-effective ways to measure CpG methylation states over large and complete regions of the genome. Here, we develop TEEM-Seq (target-enriched enzymatic methyl sequencing), a method that combines enzymatic methyl sequencing with a custom-designed hybridization capture bait set that can be scaled to reactions including large numbers of samples in any species for which a reference genome is available. Using DNA from a passerine bird, the superb starling (Lamprotornis superbus), we show that TEEM-Seq is able to quantify DNA methylation states similarly well to the more traditional approaches of whole-genome and reduced-representation sequencing. Moreover, we demonstrate its reliability and repeatability, as duplicate libraries from the same samples were highly correlated. Importantly, the downstream bioinformatic analysis for TEEM-Seq is the same as for any sequence-based approach to studying DNA methylation, making it simple to incorporate into a variety of workflows. We believe that TEEM-Seq could replace traditional approaches for studying DNA methylation in candidate genes and pathways, and be effectively paired with other whole-genome or reduced-representation sequencing approaches to increase project sample sizes. In addition, TEEM-Seq can be combined with mRNA sequencing to examine how DNA methylation in promoters or other regulatory regions is related to the expression of individual genes or gene networks. By maximizing the number of samples in the hybridization reaction, TEEM-Seq is an inexpensive and flexible sequence-based approach for quantifying DNA methylation in species where other capture-based methods are unavailable or too expensive, particularly for non-model organisms.
Computational Modeling of the Human Compound Action Potential
Authors: Alamri Yousef , Jennings Skyler G. 
Published: August 2022

ABSTRACTThe auditory nerve (AN) compound action potential (CAP) is an important tool for assessing auditory disorders and monitoring the health of the auditory periphery during surgical procedures. The CAP has been mathematically conceptualized as the convolution of a unit response (UR) waveform with the firing rate of a population of AN fibers. Here, an approach for predicting experimentally-recorded CAPs in humans is proposed, which involves the use of human-based computational models to simulate AN activity. CAPs elicited by clicks, chirps, and amplitude-modulated carriers were simulated and compared with empirically recorded CAPs from human subjects. In addition, narrowband CAPs derived from noise-masked clicks and tone bursts were simulated. Many morphological, temporal, and spectral aspects of human CAPs were captured by the simulations for all stimuli tested. These findings support the use of model simulations of the human CAP to refine existing human-based models of the auditory periphery, aid in the design and analysis of auditory experiments, and predict the effects of hearing loss, synaptopathy, and other auditory disorders on the human CAP.
Mitochondrial Phosphatidylethanolamine Directly Regulates UCP1 to Promote Brown Adipose Thermogenesis
Authors: Johnson Jordan M. , Peterlin Alek D. , Balderas Enrique , Sustarsic Elahu G. , Maschek J. Alan , Lang Marisa J. , Jara-Ramos Alejandro , Panic Vanja , Morgan Jeffrey T. , Villanueva Claudio J. , Sanchez Alejandro , Rutter Jared , Lodhi Irfan J. , Cox James E. , Fisher-Wellman Kelsey H. , Chaudhuri Dipayan , Gerhart-Hines Zachary , Funai Katsuhiko 
Published: August 2022

SUMMARYThermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of ATP synthase. Here we provide evidence that mitochondrial phosphatidylethanolamine (PE) directly regulates UCP1-dependent proton conductance across IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PSD-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.
Pharmacogenetic allele variant frequencies: An analysis of the VA’s Million Veteran Program (MVP) as a representation of the diversity in US population
Authors: Markianos K , Dong F , Gorman B , Shi Y , Dochterman D , Saxena U , Devineni P , Moser J , Muralidhar S , Ramoni R , Tsao P ,   Million Veteran Program, Pyarajan S , Przygodzki R 
Published: August 2022

AbstractWe present allele frequencies of pharmacogenomics relevant variants across multiple ancestry in a sample representative of the US population. We analyzed 658,582 individuals with genotype data and extracted pharmacogenomics relevant single nucleotide variant (SNV) alleles, human leukocyte antigens (HLA) 4-digit alleles and an important copy number variant (CNV), the full deletion/duplication of CYP2D6. We compiled distinct allele frequency tables for European, African American, Hispanic, and Asian ancestry individuals. In addition, we compiled allele frequencies based on local ancestry reconstruction in the African-American (2-way deconvolution) and Hispanic (3-way deconvolution) cohorts.
Once upon a time in Mexico: Holocene phylogeography of the spotted bat (Euderma maculatum)
Authors: Sanchez Daniel E. , Walker Faith M. , Sobek Colin J. , Lausen Cori , Chambers Carol L. 
Published: August 2022

AbstractHolocene-era range expansions are relevant to understanding how a species might respond to the warming and drying climates of today. The harsh conditions of North American deserts have phylogenetically structured desert bat communities but differences in flight capabilities are expected to affect their ability to compete, locate, and use habitat in the face of modern climate change. A highly vagile but data-deficient bat species, the spotted bat (Euderma maculatum) is thought to have expanded its range from central Mexico to western Canada during the Holocene. With specimens spanning this latitudinal extent, we coupled phylogeography (mtDNA) with ecological niche modeling (ENM) to investigate the Holocene biogeography from the rear to leading edges. The ENM and phylogeny supported a Holocene range expansion from Mexico with increased expansion throughout the intermountain west within the last 6 kya. Long-term isolation at the southern-most margin of the range suggests one or more populations were left behind as climate space contracted and are currently of unknown status. The species appears historically suited to track shifts in climate space but differences in flight behaviors between leading edge and core-range lineages suggest that range expansions could be influenced by differences in habitat quality or climate (e.g., drought). Although its vagility could facilitate the tracking of environmental change and thereby extinction avoidance, anthropogenic pressures at the core range could still threaten the ability for beneficial alleles to expand into the leading edge.
Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition
Authors: Wei Wei , Geer Mitchell J. , Guo Xinyi , Dolgalev Igor , Sanjana Neville E. , Neel Benjamin G. 
Published: August 2022

AbstractSHP2 (PTPN11) acts upstream of SOS1/2 to enable RAS activation. Allosteric inhibitors (SHP2is) stabilize SHP2 auto-inhibition, preventing activation by upstream stimuli. SHP2is block proliferation of RTK- or cycling RAS mutant-driven cancers and overcome adaptive resistance to other RAS-ERK pathway drugs. Several SHP2is are in clinical trials. To identify potential SHP2i resistance mechanisms, we performed genome-wide CRISPR/Cas9 knockout screens on two SHP2i-sensitive AML cell lines and recovered genes expected to cause resistance, including tumor suppressor (NF1, PTEN, CDKN1B) and “RASopathy” (LZTR1, RASA2) genes, and several novel targets (INPPL1, MAP4K5, epigenetic modifiers). We then screened 14 cancer lines with a focused CRISPR library targeting common “hits” from the genome-wide screens. LZTR1 deletion conferred resistance in 12/14 lines, followed by MAP4K5 (8/14), SPRED2 (6/14), STK40 (6/14), and INPPL1 (5/14). INPPL1, MAP4K5, or LZTR1 deletion reactivated ERK signaling. INPPL1-mediated sensitization to SHP2i required its NPXY motif but not its lipid phosphatase domain. MAP4K5 acted upstream of MEK via a kinase-dependent target(s), whereas LZTR1 showed cell-dependent effects on RIT and RAS stability. INPPLI, MAP4K5, or LZTR1 deletion also conferred SHP2i resistance in mice. Our results reveal multiple SHP2i resistance genes, emphasizing the need for detailed understanding of the resistance landscape to arrive at effective combinations.
Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis
Authors: Zhu Yizhou , Lee Hayan , White Shannon , Weimer Annika K. , Monte Emma , Horning Aaron , Nevins Stephanie A. , Esplin Edward D. , Paul Kristina , Krieger Gat , Shipony Zohar , Chiu Roxanne , Laquindanum Rozelle , Karathanos Thomas V. , Chua Melissa WY , Mills Meredith , Ladabaum Uri , Longacre Teri , Shen Jeanne , Jaimovich Ariel , Lipson Doron , Kundaje Anshul , Greenleaf William J. , Curtis Christina , Ford James M. , Snyder Michael P. 
Published: August 2022

AbstractAlthough 3D genome architecture can be essential for gene regulation, the biological implications of long-range chromatin interactions in disease remain elusive. In this study, we traced the early evolution and malignant transformation of colorectal cancer by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth from polyps of Familial Adenomatous Polyposis (FAP) patients. Our analysis reveals a substantial progressive loss of genome-wide cis-regulatory connectivity at early stages of malignancy, which correlates with a non-linear effect on gene regulation. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa are not correlated with elevated baseline expression, but instead tend to be up-regulated at advanced stages. Inhibition of highly connected promoters preferentially represses gene expression in colorectal cancer cells relative to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels. Overall, our study illuminates the intricate interplay between 3D genome architecture and gene regulation during early colorectal cancer progression, and provides valuable insights for potential therapeutic interventions targeting the connectivity of cis-regulatory elements.