bluuebunny/crossref_metadata_2025_split huggingface dataset:
ViralConsensus: a fast and memory-efficient tool for calling viral consensus genome sequences directly from read alignment data
Authors: Moshiri Niema 
Published: May 2023

Abstract

Motivation
In viral molecular epidemiology, reconstruction of consensus genomes from sequence data is critical for tracking mutations and variants of concern. However, as the number of samples that are sequenced grows rapidly, compute resources needed to reconstruct consensus genomes can become prohibitively large.

Results
ViralConsensus is a fast and memory-efficient tool for calling viral consensus genome sequences directly from read alignment data. ViralConsensus is orders of magnitude faster and more memory-efficient than existing methods. Further, unlike existing methods, ViralConsensus can pipe data directly from a read mapper via standard input and performs viral consensus calling on-the-fly, making it an ideal tool for viral sequencing pipelines.

Availability and implementation
ViralConsensus is freely available at https://github.com/niemasd/ViralConsensus as an open-source software project.
Efficacy and safety of dupilumab in patients with severe chronic hand eczema with inadequate response or intolerance to alitretinoin: a randomized, double-blind, placebo-controlled phase IIb proof-of-concept study
Authors: Voorberg Angelique N , Kamphuis Esmé , Christoffers Wietske A , Schuttelaar Marie L A 
Published: May 2023

Abstract

Background
Effective treatment options for patients with chronic hand eczema (CHE) are scarce. Dupilumab is licensed for the treatment of moderate-to-severe atopic dermatitis and has shown promising results for the treatment of hand eczema in other studies.

Objectives
To evaluate the efficacy and safety of dupilumab in adult patients with severe CHE (subtypes recurrent vesicular hand eczema or chronic fissured hand eczema) who have an inadequate response/intolerance to alitretinoin, or when alitretinoin is medically inadvisable.

Methods
In this 16-week, randomized, double-blind, placebo-controlled proof-of-concept phase IIb trial, patients with severe CHE were randomized 2 : 1 to dupilumab 300 mg or placebo subcutaneously every 2 weeks. Patients visited the outpatient clinic at the initiation of the study drug, and every 4 weeks until 16 weeks of treatment. The primary endpoint was the proportion of patients achieving at least a 75% improvement on the Hand Eczema Severity Index score (HECSI-75) at week 16. Adverse events were monitored during each visit. The study was registered on ClinicalTrials.gov (identifier NCT04512339).

Results
In total, 30 patients were randomized, and 29 patients received the assigned study drug (dupilumab n = 20, placebo n = 9). At week 16, more patients achieved HECSI-75 in the dupilumab group than in the placebo group {95% [95% confidence interval (CI) 73.1–99.7] vs. 33% [95% CI 9.0–69.1]}. Dupilumab also showed greater least square mean percentage change from baseline to week 16 in peak pruritus Numerical Rating Scale compared with placebo [−66.5 ± 10.7 (95% CI −88.6 to −44.5) vs. −25.3 ± 17.0 (95% CI −60.1–9.4)]. Adverse events were similar for the dupilumab and placebo groups and were mostly mild. There were no serious adverse events, nor did any of the adverse events lead to discontinuation of the study drug.

Conclusions
Dupilumab was efficacious and well tolerated. Larger studies of longer duration are needed to provide more evidence on the ­efficacy of dupilumab in CHE. Moreover, larger studies could also enable comparisons between clinical subtypes or aetiological ­diagnoses.
Whole-body cryotherapy as a treatment for chronic medical conditions?
Authors: Tabisz Hanna , Modlinska Aleksandra , Kujawski Sławomir , Słomko Joanna , Zalewski Pawel 
Published: May 2023

AbstractIntroductionWhole-body cryotherapy (WBC) is a controlled exposure of the whole body to cold to gain health benefits. In recent years, data on potential applications of WBC in multiple clinical settings have emerged.Sources of dataPubMed, EBSCO and Clinical Key search using keywords including terms ‘whole body’, ‘cryotherapy’ and ‘cryostimulation’.Areas of agreementWBC could be applied as adjuvant therapy in multiple conditions involving chronic inflammation because of its potent anti-inflammatory effects. Those might include systemic inflammation as in rheumatoid arthritis. In addition, WBC could serve as adjuvant therapy for chronic inflammation in some patients with obesity.Areas of controversyWBC probably might be applied as an adjuvant treatment in patients with chronic brain disorders including mild cognitive impairment and general anxiety disorder and in patients with depressive episodes and neuroinflammation reduction as in multiple sclerosis. WBC effects in metabolic disorder treatment are yet to be determined. WBC presumably exerts pleiotropic effects and therefore might serve as adjuvant therapy in multi-systemic disorders, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).Growing pointsThe quality of studies on the effects of WBC in the clinical setting is in general low; hence, randomized controlled trials with adequate sample size and longer follow-up periods are needed.Areas are timely for developing researchFurther studies should examine the mechanism underlying the clinical efficacy of WBC. Multiple conditions might involve chronic inflammation, which in turn could be a potential target of WBC. Further research on the application of WBC in neurodegenerative disorders, neuropsychiatric disorders and ME/CFS should be conducted.
Gene expression changes reveal the impact of the space environment on the skin of International Space Station astronauts
Authors: Gu Xuefeng , Han Yuru , Shao Yue , Ma Wenhao , Shao Zeguo , Wan Guoqing , Lu Changlian , Shi Shuo , Lu Wenli 
Published: May 2023

Abstract

Background
The various types of ionizing radiation and altered gravity in the space environment present a risk to humans during space missions. Changes in the space environment lead to skin diseases, affecting the status of the aviators to fly. Therefore, it is important to explore the molecular-level changes in the skin during space missions.

Objectives
Bioinformatics analysis of gene arrays from hair follicle tissue of 10 astronauts was performed to explore changes in gene expression before, during and after space missions.

Methods
First, STEM (Short Time-series Expression Miner) software was used to identify the expression patterns of hair follicle genes of astronauts pre-, in- and postflight. Gene Ontology Enrichment Analysis was then performed to explore the gene functions within the module. Protein–protein interaction network analysis was performed on skin-related genes. The transcriptional regulatory network within the module was constructed using the TRRUST database. The circadian rhythm-related genes within the module were screened using the MSigDB (Molecular Signatures Database).

Results
Based on differential expression analysis between the two groups, there were 327 differentially expressed genes after the astronauts entered space compared with preflight, and only 54 differentially expressed genes after returning to Earth. This outcome suggests that the expression of most genes can be recovered on return to the ground, but there are a small number of genes whose expression cannot be recovered in a short period of time. Based on time series analysis, 311 genes showed increased expression on entry into space and decreased expression on return to Earth. The genes of this expression pattern were associated with skin development, keratinocyte differentiation and cornification. Ten hub genes were identified as skin-related genes within the module, as well as nine transcription factors and three circadian genes. One hundred and seventy-nine genes decreased in expression after entry into space and increased on return to Earth. By reviewing the literature, we found that four of the genes, CSCD2, HP, CXCR1 and SSTR4, are associated with skin diseases.

Conclusions
Through bioinformatics analysis, we found that the space environment affects skin keratinocyte differentiation, leading to skin barrier damage and inflammatory responses, and that this effect was decreased after return to Earth.
PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes
Authors: Swint-Kruse Liskin , Dougherty Larissa L , Page Braelyn , Wu Tiffany , O’Neil Pierce T , Prasannan Charulata B , Timmons Cody , Tang Qingling , Parente Daniel J , Sreenivasan Shwetha , Holyoak Todd , Fenton Aron W 
Published: May 2023

Abstract
Interpreting changes in patient genomes, understanding how viruses evolve and engineering novel protein function all depend on accurately predicting the functional outcomes that arise from amino acid substitutions. To that end, the development of first-generation prediction algorithms was guided by historic experimental datasets. However, these datasets were heavily biased toward substitutions at positions that have not changed much throughout evolution (i.e. conserved). Although newer datasets include substitutions at positions that span a range of evolutionary conservation scores, these data are largely derived from assays that agglomerate multiple aspects of function. To facilitate predictions from the foundational chemical properties of proteins, large substitution databases with biochemical characterizations of function are needed. We report here a database derived from mutational, biochemical, bioinformatic, structural, pathological and computational studies of a highly studied protein family—pyruvate kinase (PYK). A centerpiece of this database is the biochemical characterization—including quantitative evaluation of allosteric regulation—of the changes that accompany substitutions at positions that sample the full conservation range observed in the PYK family. We have used these data to facilitate critical advances in the foundational studies of allosteric regulation and protein evolution and as rigorous benchmarks for testing protein predictions. We trust that the collected dataset will be useful for the broader scientific community in the further development of prediction algorithms.
Database URL https://github.com/djparente/PYK-DB
Complex cross-incompatibility in morning glories is consistent with a role for mating system in plant speciation
Authors: Rifkin Joanna L , Ostevik Kate L , Rausher Mark D 
Published: May 2023

Abstract
Reproductive isolation between selfing and outcrossing species can arise through diverse mechanisms, some of which are directly associated with differences in mating system. We dissected cross-incompatibility between the highly selfing morning glory Ipomoea lacunosa and its mixed-mating sister species Ipomoea cordatotriloba. We found that cross-incompatibility is complex, with contributions acting both before and after fertilization. We then investigated whether the transition in mating system may have facilitated the evolution of these reproductive barrier components through mismatched floral morphology, differences in reproductive context, or both. We found evidence that morphological mismatch likely contributes to reproductive isolation in at least one cross-direction and that other pollen–pistil interactions are present. We also identified hybrid seed inviability consistent with the predictions of the weak-inbreeder, strong-outbreeder hypotheses, suggesting endosperm misregulation plays an important role in cross-incompatibility. In contrast, we did not find evidence consistent with the prezygotic weak-inbreeder, strong-outbreeder hypothesis. Our study highlights the complexity of reproductive isolation between outcrossing and selfing species and the extent to which evolutionary consequences of mating system transitions can facilitate speciation.
Local signaling enhances output specificity of bacterial c-di-GMP signaling networks
Authors: Junkermeier Eike H , Hengge Regine 
Published: May 2023

Abstract
For many years the surprising multiplicity, signal input diversity, and output specificity of c-di-GMP signaling proteins has intrigued researchers studying bacterial second messengers. How can several signaling pathways act in parallel to produce specific outputs despite relying on the same diffusible second messenger maintained at a certain global cellular concentration? Such high specificity and flexibility arise from combining modes of local and global c-di-GMP signaling in complex signaling networks. Local c-di-GMP signaling can be experimentally shown by three criteria being met: (i) highly specific knockout phenotypes for particular c-di-GMP-related enzymes, (ii) actual cellular c-di-GMP levels that remain unchanged by such mutations and/or below the Kd’s of the relevant c-di-GMP-binding effectors, and (iii) direct interactions between the signaling proteins involved. Here, we discuss the rationale behind these criteria and present well-studied examples of local c-di-GMP signaling in Escherichia coli and Pseudomonas. Relatively simple systems just colocalize a local source and/or a local sink for c-di-GMP, i.e. a diguanylate cyclase (DGC) and/or a specific phosphodiesterase (PDE), respectively, with a c-di-GMP-binding effector/target system. More complex systems also make use of regulatory protein interactions, e.g. when a “trigger PDE” responds to locally provided c-di-GMP, and thereby serves as a c-di-GMP-sensing effector that directly controls a target’s activity, or when a c-di-GMP-binding effector recruits and directly activates its own “private” DGC. Finally, we provide an outlook into how cells can combine local and global signaling modes of c-di-GMP and possibly integrate those into other signaling nucleotides networks.
MHC Architecture in Amphibians—Ancestral Reconstruction, Gene Rearrangements, and Duplication Patterns
Authors: He Ke , Babik Wiesław , Majda Mateusz , Minias Piotr 
Published: May 2023

Abstract
The hypervariable major histocompatibility complex (MHC) is a crucial component of vertebrate adaptive immunity, but large-scale studies on MHC macroevolution in nonmodel vertebrates have long been constrained by methodological limitations. Here, we used rapidly accumulating genomic data to reconstruct macroevolution of the MHC region in amphibians. We retrieved contigs containing the MHC region from genome assemblies of 32 amphibian species and examined major structural rearrangements, duplication patterns, and gene structure across the amphibian phylogeny. Based on the few available caecilian and urodele genomes, we showed that the structure of ancestral MHC region in amphibians was probably relatively simple and compact, with a close physical linkage between MHC-I and MHC-II regions. This ancestral MHC architecture was generally conserved in anurans, although the evolution of class I subregion proceeded toward more extensive duplication and rapid expansion of gene copy number, providing evidence for dynamic evolutionary trajectories. Although, in anurans, we recorded tandems of duplicated MHC-I genes outside the core subregion, our phylogenetic analyses of MHC-I sequences provided little support for an expansion of nonclassical MHC-Ib genes across amphibian families. Finally, we found that intronic regions of amphibian classical MHC genes were much longer when compared with other tetrapod lineages (birds and mammals), which could partly be driven by the expansion of genome size. Our study reveals novel evolutionary patterns of the MHC region in amphibians and provides a comprehensive framework for further studies on the MHC macroevolution across vertebrates.
Human Gene Age Dating Reveals an Early and Rapid Evolutionary Construction of the Adaptive Immune System
Authors: Zhang Li , Park Jonathan J , Dong Matthew B , Arsala Deanna , Xia Shengqian , Chen Jianhai , Sosa Dylan , Atlas Jared E , Long Manyuan , Chen Sidi 
Published: May 2023

Abstract
T cells are a type of white blood cell that play a critical role in the immune response against foreign pathogens through a process called T cell adaptive immunity (TCAI). However, the evolution of the genes and nucleotide sequences involved in TCAI is not well understood. To investigate this, we performed comparative studies of gene annotations and genome assemblies of 28 vertebrate species and identified sets of human genes that are involved in TCAI, carcinogenesis, and aging. We found that these gene sets share interaction pathways, which may have contributed to the evolution of longevity in the vertebrate lineage leading to humans. Our human gene age dating analyses revealed that there was rapid origination of genes with TCAI-related functions prior to the Cretaceous eutherian radiation and these new genes mainly encode negative regulators. We identified no new TCAI-related genes after the divergence of placental mammals, but we did detect an extensive number of amino acid substitutions under strong positive selection in recently evolved human immunity genes suggesting they are coevolving with adaptive immunity. More specifically, we observed that antigen processing and presentation and checkpoint genes are significantly enriched among new genes evolving under positive selection. These observations reveal evolutionary processes of TCAI that were associated with rapid gene duplication in the early stages of vertebrates and subsequent sequence changes in TCAI-related genes. The analysis of vertebrate genomes provides evidence that a "big bang" of adaptive immune genes occurred 300-500 million years ago. These processes together suggest an early genetic construction of the vertebrate immune system and subsequent molecular adaptation to diverse antigens.
Genome-wide maps of UVA and UVB mutagenesis in yeast reveal distinct causative lesions and mutational strand asymmetries
Authors: Laughery Marian F , Plummer Dalton A , Wilson Hannah E , Vandenberg Brittany N , Mitchell Debra , Mieczkowski Piotr A , Roberts Steven A , Wyrick John J 
Published: May 2023

Abstract
Ultraviolet (UV) light primarily causes C &gt; T substitutions in lesion-forming dipyrimidine sequences. However, many of the key driver mutations in melanoma do not fit this canonical UV signature, but are instead caused by T &gt; A, T &gt; C, or C &gt; A substitutions. To what extent exposure to the UVB or UVA spectrum of sunlight can induce these noncanonical mutation classes, and the molecular mechanism involved is unclear. Here, we repeatedly exposed wild-type or repair-deficient yeast (Saccharomyces cerevisiae) to UVB or UVA light and characterized the resulting mutations by whole genome sequencing. Our data indicate that UVB induces C &gt; T and T &gt; C substitutions in dipyrimidines, and T &gt; A substitutions that are often associated with thymine–adenine (TA) sequences. All of these mutation classes are induced in nucleotide excision repair–deficient cells and show transcriptional strand asymmetry, suggesting they are caused by helix-distorting UV photoproducts. In contrast, UVA exposure induces orders of magnitude fewer mutations with a distinct mutation spectrum. UVA-induced mutations are elevated in Ogg1-deficient cells, and the resulting spectrum consists almost entirely of C &gt; A/G &gt; T mutations, indicating they are likely derived from oxidative guanine lesions. These mutations show replication asymmetry, with elevated G &gt; T mutations on the leading strand, suggesting there is a strand bias in the removal or bypass of guanine lesions during replication. Finally, we develop a mutation reporter to show that UVA induces a G &gt; T reversion mutation in yeast that mimics the oncogenic NRAS Q61K mutation in melanoma. Taken together, these findings indicate that UVA and UVB exposure can induce many of the noncanonical mutation classes that cause driver mutations in melanoma.
Detecting directional and non-directional epistasis in bi-parental populations using genomic data
Authors: Rio Simon , Charcosset Alain , Moreau Laurence , Mary-Huard Tristan 
Published: May 2023

Abstract
Epistasis, commonly defined as interaction effects between alleles of different loci, is an important genetic component of the variation of phenotypic traits in natural and breeding populations. In addition to its impact on variance, epistasis can also affect the expected performance of a population and is then referred to as directional epistasis. Before the advent of genomic data, the existence of epistasis (both directional and non-directional) was investigated based on complex and expensive mating schemes involving several generations evaluated for a trait of interest. In this study, we propose a methodology to detect the presence of epistasis based on simple inbred biparental populations, both genotyped and phenotyped, ideally along with their parents. Thanks to genomic data, parental proportions as well as shared parental proportions between inbred individuals can be estimated. They allow the evaluation of epistasis through a test of the expected performance for directional epistasis or the variance of genetic values. This methodology was applied to two large multiparental populations, i.e. the American maize and soybean nested association mapping populations, evaluated for different traits. Results showed significant epistasis, especially for the test of directional epistasis, e.g. the increase in anthesis to silking interval observed in most maize inbred progenies or the decrease in grain yield observed in several soybean inbred progenies. In general, the effects detected suggested that shuffling allelic associations of both elite parents had a detrimental effect on the performance of their progeny. This methodology is implemented in the EpiTest R-package and can be applied to any bi/multiparental inbred population evaluated for a trait of interest.
Frailty, an Independent Risk Factor in Progression Trajectory of Cardiometabolic Multimorbidity: A Prospective Study of UK Biobank
Authors: Ma Tianqi , He Lingfang , Luo Yi , Fu Dihan , Huang Jiaqi , Zhang Guogang , Cheng Xunjie , Bai Yongping 
Published: May 2023

Abstract

Background
Although frailty was associated with cardiometabolic diseases (CMDs, including coronary heart disease, stroke, and diabetes here), there was no systematic analyses estimating its role in incidence, progression, and prognosis of cardiometabolic multimorbidity (CMM).

Methods
We included 351 205 participants without CMDs at baseline in UK Biobank. Occurrences of first CMD, CMM, and death were recorded. We used multistate models to assess transition-specific role of baseline frailty measured by frailty phenotype and frailty index in CMM progression trajectory from no disease to single CMD, CMM, and death. Association between changes in frailty and outcomes was investigated among 17 264 participants.

Results
Among 351 205 participants (44.0% male, mean age 56.55 years), 8 190 (2.3%) had frail phenotype, and 13 615 (3.9%) were moderate/severe frail according to the frailty index. During median follow-up of 13.11 years, 41 558 participants experienced ≥1 CMD, 4 952 had CMM, and 20 670 died. In multistate models, frail phenotype-related hazard ratios were 1.94 and 2.69 for transitions from no CMD to single disease and death, 1.63 and 1.67 for transitions from single CMD to CMM and death, and 1.57 for transitions from CMM to death (all p &lt; .001). Consistent results were observed for frailty index. Improvement of frailty reduced the risk of CMD progression and death.

Conclusions
Frailty is an independent risk factor for all transitions of CMM progression trajectory. Frailty-targeted management is a potential strategy for primary and secondary prevention of CMM beyond chronological age.