bluuebunny/crossref_metadata_2025_split huggingface dataset:
LinAliFold and CentroidLinAliFold: fast RNA consensus secondary structure prediction for aligned sequences using beam search methods
Authors: Fukunaga Tsukasa , Hamada Michiaki 
Published: October 2022

Abstract

Motivation
RNA consensus secondary structure prediction from aligned sequences is a powerful approach for improving the secondary structure prediction accuracy. However, because the computational complexities of conventional prediction tools scale with the cube of the alignment lengths, their application to long RNA sequences, such as viral RNAs or long non-coding RNAs, requires significant computational time.

Results
In this study, we developed LinAliFold and CentroidLinAliFold, fast RNA consensus secondary structure prediction tools based on minimum free energy and maximum expected accuracy principles, respectively. We achieved software acceleration using beam search methods that were successfully used for fast secondary structure prediction from a single RNA sequence. Benchmark analyses showed that LinAliFold and CentroidLinAliFold were much faster than the existing methods while preserving the prediction accuracy. As an empirical application, we predicted the consensus secondary structure of coronaviruses with approximately 30 000 nt in 5 and 79 min by LinAliFold and CentroidLinAliFold, respectively. We confirmed that the predicted consensus secondary structure of coronaviruses was consistent with the experimental results.

Availability and implementation
The source codes of LinAliFold and CentroidLinAliFold are freely available at https://github.com/fukunagatsu/LinAliFold-CentroidLinAliFold.

Supplementary information
Supplementary data are available at Bioinformatics Advances online.
LaGAT: link-aware graph attention network for drug–drug interaction prediction
Authors: Hong Yue , Luo Pengyu , Jin Shuting , Liu Xiangrong 
Published: October 2022

Abstract

Motivation
Drug–drug interaction (DDI) prediction is a challenging problem in pharmacology and clinical applications. With the increasing availability of large biomedical databases, large-scale biological knowledge graphs containing drug information have been widely used for DDI prediction. However, large knowledge graphs inevitably suffer from data noise problems, which limit the performance and interpretability of models based on the knowledge graph. Recent studies attempt to improve models by introducing inductive bias through an attention mechanism. However, they all only depend on the topology of entity nodes independently to generate fixed attention pathways, without considering the semantic diversity of entity nodes in different drug pair links. This makes it difficult for models to select more meaningful nodes to overcome data quality limitations and make more interpretable predictions.

Results
To address this issue, we propose a Link-aware Graph Attention method for DDI prediction, called LaGAT, which is able to generate different attention pathways for drug entities based on different drug pair links. For a drug pair link, the LaGAT uses the embedding representation of one of the drugs as a query vector to calculate the attention weights, thereby selecting the appropriate topological neighbor nodes to obtain the semantic information of the other drug. We separately conduct experiments on binary and multi-class classification and visualize the attention pathways generated by the model. The results prove that LaGAT can better capture semantic relationships and achieves remarkably superior performance over both the classical and state-of-the-art models on DDI prediction.

Availabilityand implementation
The source code and data are available at https://github.com/Azra3lzz/LaGAT.

Supplementary information
Supplementary data are available at Bioinformatics online.
Defining the extent of gene function using ROC curvature
Authors: Fischer Stephan , Gillis Jesse 
Published: October 2022

AbstractMotivationInteractions between proteins help us understand how genes are functionally related and how they contribute to phenotypes. Experiments provide imperfect ‘ground truth’ information about a small subset of potential interactions in a specific biological context, which can then be extended to the whole genome across different contexts, such as conditions, tissues or species, through machine learning methods. However, evaluating the performance of these methods remains a critical challenge. Here, we propose to evaluate the generalizability of gene characterizations through the shape of performance curves.ResultsWe identify Functional Equivalence Classes (FECs), subsets of annotated and unannotated genes that jointly drive performance, by assessing the presence of straight lines in ROC curves built from gene-centric prediction tasks, such as function or interaction predictions. FECs are widespread across data types and methods, they can be used to evaluate the extent and context-specificity of functional annotations in a data-driven manner. For example, FECs suggest that B cell markers can be decomposed into shared primary markers (10–50 genes), and tissue-specific secondary markers (100–500 genes). In addition, FECs suggest the existence of functional modules that span a wide range of the genome, with marker sets spanning at most 5% of the genome and data-driven extensions of Gene Ontology sets spanning up to 40% of the genome. Simple to assess visually and statistically, the identification of FECs in performance curves paves the way for novel functional characterization and increased robustness in the definition of functional gene sets.Availability and implementationCode for analyses and figures is available at https://github.com/yexilein/pyroc.Supplementary informationSupplementary data are available at Bioinformatics online.
CRISPRon/off: CRISPR/Cas9 on- and off-target gRNA design
Authors: Anthon Christian , Corsi Giulia Ilaria , Gorodkin Jan 
Published: October 2022

Abstract

Summary
The effectiveness of CRISPR/Cas9-mediated genome editing experiments largely depends on the guide RNA (gRNA) used by the CRISPR/Cas9 system for target recognition and cleavage activation. Careful design is necessary to select a gRNA with high editing efficiency at the on-target site and with minimum off-target potential. Here, we present our webserver for gRNA design with a user-friendly graphical interface, which provides interoperability between our on- and off-target prediction tools, CRISPRon and CRISPRoff, for a complete and streamlined gRNA selection.

Availability and implementation
The graphical interface uses the Integrative Genomic Viewer (IGV) JavaScript plugin. The backend tools are implemented in Python and C. The CRISPRon and CRISPRoff webservers and command-line tools are freely available at https://rth.dk/resources/crispr.
Management of fracture risk in CKD—traditional and novel approaches
Authors: Haarhaus Mathias , Aaltonen Louise , Cejka Daniel , Cozzolino Mario , de Jong Renate T , D'Haese Patrick , Evenepoel Pieter , Lafage-Proust Marie-Hélène , Mazzaferro Sandro , McCloskey Eugene , Salam Syazrah , Skou Jørgensen Hanne , Vervloet Marc 
Published: October 2022

ABSTRACTThe coexistence of osteoporosis and chronic kidney disease (CKD) is an evolving healthcare challenge in the face of increasingly aging populations. Globally, accelerating fracture incidence causes disability, impaired quality of life and increased mortality. Consequently, several novel diagnostic and therapeutic tools have been introduced for treatment and prevention of fragility fractures. Despite an especially high fracture risk in CKD, these patients are commonly excluded from interventional trials and clinical guidelines. While management of fracture risk in CKD has been discussed in recent opinion-based reviews and consensus papers in the nephrology literature, many patients with CKD stages 3–5D and osteoporosis are still underdiagnosed and untreated. The current review addresses this potential treatment nihilism by discussing established and novel approaches to diagnosis and prevention of fracture risk in patients with CKD stages 3–5D. Skeletal disorders are common in CKD. A wide variety of underlying pathophysiological processes have been identified, including premature aging, chronic wasting, and disturbances in vitamin D and mineral metabolism, which may impact bone fragility beyond established osteoporosis. We discuss current and emerging concepts of CKD–mineral and bone disorders (CKD-MBD) and integrate management of osteoporosis in CKD with current recommendations for management of CKD-MBD. While many diagnostic and therapeutic approaches to osteoporosis can be applied to patients with CKD, some limitations and caveats need to be considered. Consequently, clinical trials are needed that specifically study fracture prevention strategies in patients with CKD stages 3–5D.
An IoT Privacy-Oriented selective disclosure credential system
Authors: Rasslan Mohamed , Nasreldin Mahmoud M , Aslan Heba K 
Published: October 2022

Abstract
Personal credentials, such as passports and drivers’ licenses, can be implemented electronically using multi-show protocols. In this paper, we introduce an IoT Privacy-Oriented selective disclosure credential system, i.e. based on bilinear pairings and multilinear maps. The proposed system consists of three protocols, which allow users to be in control of their personal credentials. The Credentials Authority (CA) verifies and attests to the users credentials. Once the CA signs these credentials, the users cannot modify any of them. Moreover, the users can mask these credentials in every showing process to protect their identity from being revealed through a collusion between the CA and the verifiers. The proposed system maintains unlinkability between the issuing and showing protocols. Furthermore, it achieves unlinkability in the showing protocol such that the verifier cannot distinguish a user in two different sessions of the showing protocol. The proposed system is novel and practical in terms of introducing a new multi-show credential system that supports selective disclosure (Some credentials can be disclosed and others kept secret during the showing protocol.) The proposed system is the first that utilizes multilinear maps in the identification protocol. Making use of bilinear pairings and multilinear maps are suitable for IoT devices that have limited capabilities in terms of power consumption, key storage, and computing power. The security analysis of the proposed system is discussed using Burrows–Abadi–Needham (BAN) logic.
Genetic and epigenetic interplay allows rapid transgenerational adaptation to metal pollution in zebrafish
Authors: Pierron Fabien , Heroin Débora , Daffe Guillemine , Daramy Flore , Barré Aurélien , Bouchez Olivier , Romero-Ramirez Alicia , Gonzalez Patrice , Nikolski Macha 
Published: October 2022

Abstract
Despite still being a matter of debate, there is growing evidence that pollutant-induced epigenetic changes can be propagated across generations. Whereas such modifications could have long-lasting effects on organisms and even on population, environmentally relevant data from long-term exposure combined with follow-up through multiple generations remain scarce for non-mammalian species. We performed a transgenerational experiment comprising four successive generations of zebrafish. Only fish from the first generation were exposed to an environmentally realistic concentration of cadmium (Cd). Using a whole methylome analysis, we first identified the DNA regions that were differentially methylated in response to Cd exposure and common to fish of the first two generations. Among them, we then focused our investigations on the exon 3 (ex3) of the cep19 gene. We indeed recorded transgenerational growth disorders in Cd-exposed fish, and a mutation in this exon is known to cause morbid obesity in mammals. Its methylation level was thus determined in zebrafish from all the four generations by means of a targeted and base resolution method. We observed a transgenerational inheritance of Cd-induced DNA methylation changes up to the fourth generation. However, these changes were closely associated with genetic variations, mainly a single nucleotide polymorphism. This single nucleotide polymorphism was itself at the origin of the creation or deletion of a methylation site and deeply impacted the methylation level of neighboring methylation sites. Cd-induced epigenetic changes were associated with different mRNA transcripts and an improved condition of Cd fish. Our results emphasize a tight relationship between genetic and epigenetic mechanisms and suggest that their interplay and pre-existing diversity can allow rapid adaptation to anthropogenic environmental changes.
Integrative metabolomics and transcriptomics analyses reveal pivotal regulatory mechanisms of 1-methylcyclopropene in maintaining postharvest storage quality of ‘Fuji’ apples
Authors: Zhang Lingling , Zhang Peiyu , Gao Modi , Zhao Yi , Zhang Chunjiao , Zhu Hongliang 
Published: October 2022

Abstract
In this study, integrative metabolomics and transcriptomics analyses were conducted to investigate the effects of 1-methylcyclopropene (1-MCP) on apple fruit quality during long-term cold storage. The results showed that 1-MCP (1 μL/L) treatment could maintain fruits apparent quality (i.e. external color and firmness), inhibit the increase of rot rate and soluble solids content/titratable acidity ratio, decrease ethylene release, and respiratory intensity during cold storage, and extend shelf life. Moreover, 1-MCP had long-term effects on the accumulation of many qualities related to metabolite and gene expression in fruits. 1-MCP affected genes related to metabolism at the early stage of storage, specifically those of the glycolysis and tricarboxylic acid cycle pathways. Genes related to the degradation of sucrose, starch, and cellulose were inhibited, and some starch and cellulose synthesis genes were up-regulated by 1-MCP. Apart from ethylene synthesis and signal transduction being inhibited by 1-MCP, several enzymes (pectinesterase, pectate lyase, polygalacturonase) were involved in pectin degradation, and degradation products of the cell wall (i.e. d-galacturonic acid and d-glucuronic acid) were also strongly inhibited, further maintaining fruit firmness. Cysteine, as precursor glutathione (GSH) related to plant resistance, up-regulated the synthase gene. However, the expression of genes related to cyanoalanine synthase and amino acid utilization pathways was suppressed by 1-MCP. Collectively, 1-MCP could maintain the postharvest quality of apple fruits.
XROMM Analysis of Feeding Mechanics in Toads: Interactions of the Tongue, Hyoid, and Pectoral Girdle
Authors: Keeffe R M , Blob R W , Blackburn D C , Mayerl C J 
Published: October 2022

SynopsisDuring feeding in many terrestrial vertebrates, the tongue acts in concert with the hyoid and pectoral girdle. In frogs, these three elements are interconnected by musculature. While the feeding mechanics of the anuran tongue are well-studied, little is known of how the motions of the tongue relate to the movements of the skeleton or how buccal structures move following closure of the mouth. Although features such as the pectoral girdle and hyoid are not externally visible in frogs, their motions can be tracked in X-ray video. We used XROMM (X-ray Reconstruction of Moving Morphology) techniques to track the 3D movements of the tongue, hyoid apparatus, pectoral girdle, skull, and jaw during the feeding cycle of the cane toad, Rhinella marina. We show how the movements of these elements are integrated during tongue protrusion and prey capture, as well as during prey transport, swallowing, and recovery. Our findings suggest that the hyoid apparatus is important both for prey manipulation and swallowing. The tongue consistently stretches posterior to the skull during swallowing, often more than it stretches during protrusion to reach the prey. Feeding kinematics are similar between individuals, and the kinematics of unsuccessful strikes generally resemble those of successful strikes. Our data also provide a new perspective on the potential role of the pectoral girdle, an element with a predominant locomotor function, during feeding events. This work raises new questions about the evolution of feeding in frogs, as well as how the diversity of pectoral and buccal anatomy observed across anurans may influence feeding kinematics.
Investigating the immunomodulatory activities of omadacycline
Authors: Bryant Amy E , Stevens Dennis L 
Published: October 2022

Abstract

Background
Apart from their antimicrobial activities, some antibiotics have immunomodulatory effects on host cells, particularly monocytes. Because hyperactivation of the pro-inflammatory cytokine response contributes to acute lung injury in patients with bacterial pneumonia and other lung diseases, antimicrobial agents with immunomodulatory activity can reduce cytokine-mediated tissue injury and improve outcomes.

Objectives
Omadacycline has been recently FDA-approved for community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. The present study investigated omadacycline’s ability to modulate LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-1β), acute-phase reactants (IL-6) and anti-inflammatory cytokines (IL-4, IL-10) by human monocytes in vitro.

Methods
Isolated human monocytes from healthy consenting adults were cultured in RPMI with 1% pooled human serum. Cells were pre-exposed to omadacycline (0.5–64 μg/mL), minocycline (25, 50 or 25 μg/mL) or azithromycin (20, 40 or 80 μg/mL) for 2 h, followed by stimulation with Escherichia coli LPS for 24 h. Cytokines elaborated in the culture supernatant were quantitated by multiplex immunoassay.

Results
Omadacycline dose-dependently suppressed LPS-induced production of all cytokines tested. Only high-dose minocycline (100 μg/mL) modestly suppressed TNF-α whereas minocycline significantly increased LPS-induced IL-1β production. Lower concentrations of minocycline were also stimulatory for IFN-γ, IL-6 and IL-4. Except for suppression of IL-6, azithromycin was largely without effect.

Conclusions
Omadacycline has unique and broad immunomodulatory properties. Such activity supports its use in settings where hyperactivation of the immune response contributes to tissue injury and poor outcomes, especially at sites where pro-inflammatory M-type 1 macrophages dominate the cellular immune response.
In vivo pharmacokinetics and pharmacodynamics of ceftibuten/ledaborbactam, a novel oral β-lactam/β-lactamase inhibitor combination
Authors: Fratoni Andrew J , Avery Lindsay M , Nicolau David P , Asempa Tomefa E 
Published: October 2022

Abstract

Objectives
Oral β-lactam treatment options for MDR Enterobacterales are lacking. Ledaborbactam (formerly VNRX-5236) is a novel orally bioavailable β-lactamase inhibitor that restores ceftibuten activity against Ambler Class A-, C- and D-producing Enterobacterales. We assessed the ledaborbactam exposure needed to produce bacteriostasis against ceftibuten-resistant Enterobacterales in the presence of humanized ceftibuten exposures in the neutropenic murine thigh infection model.

Methods
Twelve ceftibuten-resistant clinical isolates (six Klebsiella pneumoniae, five Escherichia coli and one Enterobacter cloacae) were utilized. Ceftibuten/ledaborbactam MICs ranged from 0.12 to 2 mg/L (ledaborbactam fixed at 4 mg/L). A ceftibuten murine dosing regimen mimicking ceftibuten 600 mg q12h human exposure was developed and administered alone and in combination with escalating exposures of ledaborbactam. The log10 cfu/thigh change at 24 h relative to 0 h controls was plotted against ledaborbactam fAUC0–24/MIC and the Hill equation was used to determine exposures associated with bacteriostasis.

Results
The mean ± SD 0 h bacterial burden was 5.96 ± 0.24 log10 cfu/thigh. Robust growth (3.12 ± 0.93 log10 cfu/thigh) was achieved in untreated control mice. Growth of 2.51 ± 1.09 log10 cfu/thigh was observed after administration of humanized ceftibuten monotherapy. Individual isolate exposure–response relationships were strong (mean ± SD R2 = 0.82 ± 0.15). The median ledaborbactam fAUC0–24/MIC associated with stasis was 3.59 among individual isolates and 6.92 in the composite model.

Conclusions
Ledaborbactam fAUC0–24/MIC exposures for stasis were quantified with a ceftibuten human-simulated regimen against β-lactamase-producing Enterobacterales. This study supports the continued development of oral ceftibuten/ledaborbactam etzadroxil (formerly ceftibuten/VNRX-7145).
16 An Overview of the AVMA Working Group on the Psychological Impacts of Humane Endings and Related Guidance Documents
Authors: Kollias Nathaniel S 
Published: October 2022

Abstract
The psychological impacts of humane endings on veterinarians, animal health and production personnel, and support staff are a growing concern within the veterinary community. The COVID-19 pandemic has further highlighted the need for resources, understanding, and compassion for our colleagues involved in the care and wellbeing of animals. Whether humane endings activities are related to euthanasia of individual animals, slaughter of animals for human consumption, or rare emergency situations warranting depopulation of a large group of animals, the veterinarian plays an important role in these determinations. The AVMA has led and continues to lead in providing guidance on humane endings including their three documents: AVMA Guidelines for the Euthanasia of Animals, AVMA Guidelines for the Humane Slaughter of Animals, and AVMA Guidelines for the Depopulation of Animals. Recently, the AVMA formed a working group on the psychological impacts of humane endings to address the needs of veterinarians and other animal health professionals. This working group has reviewed the existing literature to lay the foundation and rationale for improved preparation, development of mental health resources, and to offer recommendations on pragmatic ways to support and prepare veterinary professionals impacted by depopulation events. While there are mental health challenges shared by those involved in euthanasia, slaughter, and depopulation, there are some stressors specific to depopulation, and it is those that this group is addressing first.