bluuebunny/crossref_metadata_2025_split huggingface dataset:
ViReMa: A Virus Recombination Mapper of Next-Generation Sequencing data characterizes diverse recombinant viral nucleic acids
Authors: Sotcheff Stephanea , Zhou Yiyang , Sun Yan , Johnson John E. , Torbett Bruce E. , Routh Andrew L 
Published: March 2022

AbstractGenetic recombination is a tremendous source of intra-host diversity in viruses and is critical for their ability to rapidly adapt to new environments or fitness challenges. While viruses are routinely characterized using high-throughput sequencing techniques, characterizing the genetic products of recombination in next-generation sequencing data remains a challenge. Viral recombination events can be highly diverse and variable in nature, including simple duplications and deletions, or more complex events such as copy/snap-back recombination, inter-virus or inter-segment recombination and insertions of host nucleic acids. Due to the variable mechanisms driving virus recombination and the different selection pressures acting on the progeny, recombination junctions rarely adhere to simple canonical sites or sequences. Furthermore, numerous different events may be present simultaneously in a viral population, yielding a complex mutational landscape. We have previously developed an algorithm called ViReMa (Virus Recombination Mapper) that bootstraps the bowtie short-read aligner to capture and annotate a wide-range of recombinant species found within virus populations. Here, we have updated ViReMa to provide an ‘error-density’ function designed to accurately detect recombination events in the longer reads now routinely generated by the Illumina platforms and provide output reports for multiple types of recombinant species using standardized formats. We demonstrate the utility and flexibility of ViReMa in different settings to report deletion events in simulated data from Flock House virus, copy-back RNA species in Sendai viruses, short duplication events in HIV, and virus to host recombination in an archaeal DNA virus.
Deep brain stimulation pulse sequences to optimally modulate frequency-specific neural activity
Authors: Farooqi Hafsa , Vitek Jerrold L. , Sanabria David Escobar 
Published: March 2022

Precise neuromodulation systems are needed to identify the role of neural oscillatory dynamics in brain function, and to advance the development of electrical stimulation therapies tailored to each patient’s signature of brain dysfunction. Low-frequency, local field potentials (LFPs) are of increasing interest for the development of these systems because they reflect the synaptic inputs to a recorded neuronal population and can be chronically recorded in humans. Here, we identified stimulation pulse sequences to optimally minimize or maximize the 2-norm of frequency-specific LFP oscillations using a generalized mathematical model of spontaneous and stimulation-evoked LFP activity, and a subject-specific model of neural dynamics in the pallidum of a Parkinson’s disease patient. We leveraged convex and mixed-integer optimization tools to identify the pulse patterns, and employed constraints on the pulse frequency and amplitude that are required to keep electrical stimulation within its safety envelope. Our analysis revealed that a combination of phase, amplitude, and frequency pulse modulation is needed to attain optimal suppression or amplification of the targeted oscillations. Phase modulation is sufficient to modulate oscillations with a constant amplitude envelope. To attain optimal modulation for oscillations with a time-varying envelope, a trade-off between frequency and amplitude pulse modulation is needed. The optimized pulse sequences identified here were invariant to changes in the dynamics of stimulation-evoked neural activity, including the damping and natural frequency or complexity (i.e., generalized vs. patient-specific model). Our results reveal the structure of pulse sequences that can be used in closed-loop brain stimulation devices to control neural activity in real-time.Significance StatementThis computational study reveals the structure of electrical pulse sequences that optimally modulate spontaneous, synaptic-related neural oscillations measured using local field potentials (LFPs). We considered constraints on the pulse amplitude and frequency, relevant to keep stimulation pulses within the safety envelope. Our mathematical analysis indicate that these optimized pulse sequences are invariant to changes in the studied neural dynamics, and a trade-off between amplitude and frequency pulse modulation is critical when the pulse amplitude is constrained. The pulse sequences identified here provide the rationale for the development of closed-loop neuromodulation systems that employ stimulation-evoked responses to control neural activity. These closed-loop systems will be key to characterize the role of neural activity in brain function and ultimately advance personalized neuromodulation devices.
A maximum-entropy model to predict 3D structural ensembles of chromatins from pairwise distances: Applications to Interphase Chromosomes and Structural Variants
Authors: Shi Guang , Thirumalai D. 
Published: March 2022

ABSTRACTThe principles that govern the organization of genomes, which are needed for a deeper understanding of how chromosomes are packaged and function in eukaryotic cells, could be deciphered if the three dimensional (3D) structures are known. Recently, single-cell imaging experiments have determined the 3D coordinates of a number of loci in a chromosome. Here, we introduce a computational method (Distance Matrix to Ensemble of Structures, DIMES), based on the maximum entropy principle, with experimental pair-wise distances between loci as constraints, to generate a unique ensemble of 3D chromatin structures. Using the ensemble of structures, we quantitatively account for the distribution of pair-wise distances, three-body co-localization and higher-order interactions. We demonstrate that the DIMES method can be applied to both small length-scale and chromosome-scale imaging data to quantify the extent of heterogeneity and fluctuations in the shapes on various length scales. We develop a perturbation method that is used in conjunction with DIMES to predict the changes in 3D structures from structural variations. Our method also reveals quantitative differences between the 3D structures inferred from Hi-C and the ones measured in imaging experiments. Finally, the physical interpretation of the parameters extracted from DIMES provides insights into the origin of phase separation between euchromatin and heterochromatin domains.
A broad and potent neutralization epitope in SARS-related coronaviruses
Authors: Yuan Meng , Zhu Xueyong , He Wan-ting , Zhou Panpan , Kaku Chengzi I. , Capozzola Tazio , Zhu Connie Y. , Yu Xinye , Liu Hejun , Yu Wenli , Hua Yuanzi , Tien Henry , Peng Linghang , Song Ge , Cottrell Christopher A. , Schief William R. , Nemazee David , Walker Laura M. , Andrabi Raiees , Burton Dennis R. , Wilson Ian A. 
Published: March 2022

AbstractMany neutralizing antibodies (nAbs) elicited to ancestral SARS-CoV-2 through natural infection and vaccination generally have reduced effectiveness to SARS-CoV-2 variants. Here we show therapeutic antibody ADG20 is able to neutralize all SARS-CoV-2 variants of concern (VOCs) including Omicron (B.1.1.529) as well as other SARS-related coronaviruses. We delineate the structural basis of this relatively escape-resistant epitope that extends from one end of the receptor binding site (RBS) into the highly conserved CR3022 site. ADG20 can then benefit from high potency through direct competition with ACE2 in the more variable RBS and interaction with the more highly conserved CR3022 site. Importantly, antibodies that are able to target this site generally neutralize all VOCs, albeit with reduced potency against Omicron. Thus, this highly conserved and vulnerable site can be exploited for design of universal vaccines and therapeutic antibodies.
Direct colorimetry of imipenem decomposition as a novel cost effective method for detecting carabapenamase producing bacteria
Authors: Kotsakis Stathis D. , Lambropoulou Anastasia , Miliotis Georgios , Tzelepi Eva , Miriagou Vivi , Tzouvelekis Leonidas S. 
Published: March 2022

AbstractIn the absence of a molecule that would collectively inhibit both metallo-β-lactamases and serine reactive carbapenemases, containment of their genes’ spreading is the main weapon currently available for confronting carbepenem resistance in hospitals. Cost effective methodologies rapidly detecting carbapenemase producing enterobacteria (CPE) would facilitate such measures. Herein a low cost CPE detection method was developed that was based on the direct colorimetry of the yellow shift caused by the accumulation of diketopiperazines – products of the acid catalyzed imipenem oligomerization – induced by carbapenemase action on dense solutions of imipenem/cilastatin. The reactions were studied by spectrophotometry in the visible spectrum using preparations of β-lactamases from the four molecular classes. The effects of various buffers on reactions containing the potent carbapenemases NDM-1 and NMC-A were monitored at 405 nm. Optimal conditions were used for the analysis of cell suspensions and the assay was evaluated using 38 selected enterobacteria including 29 CPE as well as nine carbapenemase-negative strains overexpressing other β-lactamases. The development of the yellow color was specific for carbapenemase containing enzyme preparations and the maximum intensity was achieved in acidic or un-buffered conditions in the presence of zinc. When applied on bacterial cell suspensions the assay could detect CPE with 96.7 % sensitivity and 100 % specificity with results being comparable to those obtained with the CARBA NP technique. Direct colorimetry of carbapenemase-induced imipenem decomposition required minimum reagents while exhibited high accuracy in detecting CPE. Therefore it should be considered for screening purposes after further clinical evaluation.ImportanceCurrently, spread of multi-drug resistant (MDR) carbapenemase-producing enterobacteria (CPE), mostly in the clinical setting, is among the most pressing public health problems worldwide. In order to effectively control CPE, use of reliable and affordable methods detecting carbapenemase genes or the respective β-lactamases is of vital importance. Herein we developed a novel method, based on a previously undescribed phenomenon, which can detect CPE with few reagents by direct colorimetry of bacterial suspensions and imipenem/cilastatin mixtures.
Modulation of glucose metabolism by 2-Deoxy-D-Glucose (2DG) promotes IL-17 producing human T cell subsets
Authors: Chen Xin , Kozhaya Lina , Wang Chuxi , Placek Lindsey , Karhan Ece , Unutmaz Derya 
Published: March 2022

AbstractActivation and differentiation of T cells are closely linked to their cellular metabolic programs. Glycolysis and mitochondrial metabolism are thought to be critical in modulating T cell function. Here we asked to what extent inhibition of glycolysis, using 2-Deoxy-D-Glucose (2DG), regulate activation, effector function, or differentiation of human T cell subsets. We found that glycolysis is required for T cell receptor (TCR) -mediated activation and proliferation of human naive CD4+ T cells but had less of an impact on memory subsets. CD4+ T cells cultured in the presence of 2DG displayed higher level of IL-17-secreting cells (Th17) from memory or in vitro differentiated naive regulatory T cell (Tregs) subsets. Moreover, the mucosal associated invariant T (MAIT) cell subset survived or expanded better and secreted higher IL-17 in the presence of 2DG. Remarkably, we found that the 2DG effect was reversed by mannose but not by glucose. Collectively, these findings suggest that 2DG could enrich IL-17 secreting human effector T cell subsets and their cellular functions. Our finding provides a framework to manipulate glycolytic pathways in human T cells in infectious diseases such as COVID19 and in enhancing cancer immunotherapy.
How large and diverse are field populations of fungal plant pathogens? The case of Zymoseptoria tritici
Authors: McDonald Bruce A. , Suffert Frederic , Bernasconi Alessio , Mikaberidze Alexey 
Published: March 2022

AbstractPathogen populations differ in the amount of genetic diversity they contain. Populations carrying higher genetic diversity are thought to have a greater evolutionary potential than populations carrying less diversity. We used published studies to estimate the range of values associated with two critical components of genetic diversity, the number of unique pathogen genotypes and the number of spores produced during an epidemic, for the septoria tritici blotch pathogen Zymoseptoria tritici. We found that wheat fields experiencing typical levels of infection are likely to carry between 3.2 and 14.9 million pathogen genotypes per hectare and produce at least 2.3 to 10.5 trillion pycnidiospores per hectare. Given the experimentally derived mutation rate of 3 × 10−10 substitutions per site per cell division, we estimate that between 28 and 130 million pathogen spores carrying adaptive mutations to counteract fungicides and resistant cultivars will be produced per hectare during a growing season. This suggests that most of the adaptive mutations that have been observed in Z. tritici populations can emerge through local selection from standing genetic variation that already exists within each field. The consequences of these findings for disease management strategies are discussed.
Chromatin structure influences rate and spectrum of spontaneous mutations inNeurospora crassa
Authors: Villalba de la Peña Mariana , Summanen Pauliina A. M. , Liukkonen Martta , Kronholm Ilkka 
Published: March 2022

AbstractWhile mutation rates have been extensively studied, variation in mutation rates throughout the genome is poorly understood. To understand patterns of genetic variation, it is important to understand how mutation rates vary. Chromatin modifications may be an important factor in determining variation in mutation rates in eukaryotic genomes. To study variation in mutation rates, we performed a mutation accumulation experiment in the filamentous fungusNeurospora crassa, and sequenced the genomes of the 40 MA lines that had been propagated asexually for approximately 1015 [1003, 1026] mitoses. We detected 1322 mutations in total, and observed that the mutation rate was higher in regions of low GC, in domains of H3K9 trimethylation, in centromeric regions, and in domains of H3K27 trimethylation. The rate of single nucleotide mutations in euchromatin was 2.46 [2.19, 2.77] × 10−10. In contrast, the mutation rate in H3K9me3 domains was tenfold higher: 2.43 [2.25, 2.62] × 10−9. We also observed that the spectrum of single nucleotide mutations was different between H3K9me3 and euchromatic domains. Our statistical model of mutation rate variation predicted a moderate amount of extant genetic variation, suggesting that the mutation rate is an important factor in determining levels of natural genetic variation. Furthermore, we characterized mutation rates of structural variants, complex mutations, and the effect of local sequence context on the mutation rate. Our study highlights that chromatin modifications are associated with mutation rates, and accurate evolutionary inferences should take variation in mutation rates across the genome into account.
Genome-wide analysis of PTR/POT transporters in Candida species and their functional characterization in the newly emerged pathogen Candida auris
Authors: Khatoon Rosy , Sharma Suman , Prasad Rajendra , Lynn Andrew M. , Prakash Amresh , Banerjee Atanu 
Published: March 2022

ABSTRACTThe PTR or proton-dependent oligopeptide transporter (POT) family exploits the inwardly directed proton motive force to facilitate the cellular uptake of di- and tripeptides. Interestingly, representatives from the family have shown efficacy in delivering peptide-based antifungal derivatives in certain Candida species. Given the increased incidences of fungal infections by Candida species and the associated escalating orders of resistance against frontline antifungals, peptide derivatives are attractive therapeutic options. In that direction, the identification and characterization of PTR transporters serve as an essential first step in the translation of peptide-based antifungals as next-gen therapeutics. Herein, we present a genome-wide inventory of the PTR transporters in five prominent Candida species. Our study identifies 2 PTR transporters each in C. albicans and C. dubliniensis, 1 in C. glabrata, 4 in C. parapsilosis, and 3 in C. auris. Notably, despite all representatives retaining the conserved features seen in the PTR family, there exist two distinct classes of PTR transporters that differ in terms of their sequence identities and membrane topology. Further, we also evaluated the contribution of each PTR protein of the newly emerged multidrug-resistant C. auris in di-/tripeptide uptake. Notably, deletion of the PTR transporters encoded by BNJ08_003830 and BNJ08_005124 led to a marked reduction in the transport capabilities of several tested di-/tripeptides. Besides, BNJ08_005124 deletion also resulted in increased resistance towards the peptide-nucleoside drug Nikkomycin Z, pointing towards its predominant role in the uptake mechanism. Altogether, the study provides an important template for future structure-function investigations of PTR transporters in Candida species.
Sulfur-mediated chalcogen versus hydrogen bonds in proteins: a seesaw effect in the conformational space
Authors: Adhav Vishal Annasaheb , Shelke Sanket Satish , Balanarayan P. , Saikrishnan Kayarat 
Published: March 2022

AbstractDivalent sulfur (S) form chalcogen bond (Ch-bond) via its σ–holes and hydrogen bond (H-bond) via its lone-pairs. Relevance of these interactions and their interplay for protein structure and function is unclear. Based on the analyses of the crystal structures of small organic/organometallic molecules and proteins, and their Molecular Electrostatic Surface Potential, we show that the reciprocity of the substituent-dependent strength of the σ–holes and lone-pairs correlate with the formation of either Ch-bond or H-bond. In proteins, disulfide-bonded cystine preferentially forms Ch-bond, metal-chelated cysteine forms H-bond, while methionine forms either of them with comparable frequencies. This has implications to the positioning of these residues and their role in protein structure and function. Computational analyses reveal that the S-mediated interactions stabilize protein secondary structures by mechanisms such as helix capping, protecting free β-sheet edges by negative-design, and augmenting the stability of β-turns. We find that Ch-bond can be as strong as H-bond. The study highlights the importance of S-mediated Ch-bond and H-bond for understanding protein folding and function, development of improved strategies for protein/peptide structure prediction and design, and structure-based drug discovery.
A new insight into RecA filament regulation by RecX from the analysis of conformation-specific interactions
Authors: Alekseev Aleksandr , Pobegalov Georgii , Morozova Natalia , Vedyaykin Alexey , Cherevatenko Galina , Yakimov Alexander , Baitin Dmitry , Khodorkovskii Mikhail 
Published: March 2022

AbstractRecA protein mediates homologous recombination repair in bacteria through assembly of long helical filaments on single-stranded DNA (ssDNA) in an ATP dependent manner. RecX, an important negative regulator of RecA, is known to inhibit RecA activity by stimulating the disassembly of RecA nucleoprotein filaments. Here we use a single-molecule approach to address the regulation of (E. coli) RecA-ssDNA filaments by RecX (E. coli) within the framework of distinct conformational states of RecA-ssDNA filament. Our findings revealed that RecX effectively binds the inactive conformation of RecA-ssDNA filaments and slows down the transition to the active state. Results of this work provide new mechanistic insights into the RecX-RecA interactions and highlight the importance of conformational transitions of RecA filaments as an additional level of regulation of its biological activity.
A consensus protocol for the recovery of mercury methylation genes from metagenomes
Authors: Capo Eric , Peterson Benjamin D. , Kim Minjae , Jones Daniel S. , Acinas Silvia G. , Amyot Marc , Bertilsson Stefan , Björn Erik , Buck Moritz , Cosio Claudia , Elias Dwayne , Gilmour Cynthia , Goñi Urriza Maria Soledad , Gu Baohua , Lin Heyu , Liu Yu-Rong , McMahon Katherine , Moreau John W. , Pinhassi Jarone , Podar Mircea , Puente-Sánchez Fernando , Sánchez Pablo , Storck Veronika , Tada Yuya , Vigneron Adrien , Walsh David , Vandewalle-Capo Marine , Bravo Andrea G. , Gionfriddo Caitlin 
Published: March 2022

AbstractMercury methylation genes (hgcAB) mediate the formation of the toxic methylmercury and have been identified from diverse environments, including freshwater and marine ecosystems, Arctic permafrost, forest and paddy soils, coal-ash amended sediments, chlor-alkali plants discharges and geothermal springs. Here we present the first attempt at a standardized protocol for the detection, identification and quantification of hgc genes from metagenomes. Our Hg-MATE (Hg-cycling Microorganisms in Aquatic and Terrestrial Ecosystems) database, a catalogue of hgc genes, provides the most accurate information to date on the taxonomic identity and functional/metabolic attributes of microorganisms responsible for Hg methylation in the environment. Furthermore, we introduce “marky-coco”, a ready-to-use bioinformatic pipeline based on de novo single-metagenome assembly, for easy and accurate characterization of hgc genes from environmental samples. We compared the recovery of hgc genes from environmental metagenomes using the marky-coco pipeline with an approach based on co-assembly of multiple metagenomes. Our data show similar efficiency in both approaches for most environments except those with high diversity (i.e., paddy soils) for which a co-assembly approach was preferred. Finally, we discuss the definition of true hgc genes and methods to normalize hgc gene counts from metagenomes.
Impact of foreign and domestic ETFs on the volatility and pricing-efficiency of constituents during turbulent and tranquil times: Indian evidence
Authors: Tripathi Vanita , Sethi Aakanksha 
Published: March 2022

PurposeThe purpose of this study is to ascertain how foreign and domestic Exchange Traded Funds (ETFs) investing in Indian equities affect their return volatility and pricing efficiency. Further, we investigate how the difference in market timings affect the impact of ETFs on their constituents. Lastly, we examine how these effects vary during tranquil and turmoil periods in the ETF markets.Design/methodology/approachThe study is based on quarterly data for stocks comprising the CNX Nifty 50 Index from 2009Q1 to 2019Q3. The data on holdings of 45 domestic and 196 foreign ETFs in the sample stocks were obtained from Thomson Reuters' Eikon. The paper employs a panel-regression methodology with stock and time fixed effects and robust standard errors.FindingsForeign ETFs from North America and the Asia Pacific largely have an adverse impact on stocks' return volatility. In times of turmoil, stocks with higher coverage of European, North American and Domestic funds are susceptible to volatility shocks emanating from these regions. European and Asia Pacific ETFs are associated with improved price discovery while North American funds impound a mean-reverting component in stock prices. However, in turbulent markets, both positive and negative impacts of ETFs on pricing efficiency coexist.Originality/valueTo the best of the authors' knowledge, this is the first study that examines the impact of domestic as well as foreign ETFs on the equities of an emerging market. Furthermore, the study is unique as we investigate how the effects of ETFs vary in turbulent and tranquil markets. Moreover, the paper examines the role of asynchronous market timings in determining the ETF impact. The paper adds to the growing literature on the unintended consequences of index-linked products.