bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibiotic prophylaxis and hospitalization of horses subjected to median laparotomy: gut microbiota trajectories and abundance increase ofEscherichia
Authors: Kauter Anne , Brombach Julian , Lübke-Becker Antina , Kannapin Dania , Bang Corinna , Franzenburg Sören , Stoeckle Sabita D. , Mellmann Alexander , Effelsberg Natalie , Köck Robin , Guenther Sebastian , Wieler Lothar H. , Gehlen Heidrun , Semmler Torsten , Wolf Silver A. , Walther Birgit 
Published: May 2023

AbstractHorse clinics are hotspots for the accumulation and spread of clinically relevant and zoonotic multidrug-resistant bacteria, including extended-spectrum β-lactamase producing (ESBL) Enterobacterales. Although median laparotomy in cases of acute equine colic is a frequently performed surgical intervention, knowledge about the effects of peri-operative antibiotic prophylaxis (PAP) based on a combination of penicillin and gentamicin on the gut microbiota is limited. Therefore, we collected fecal samples of horses from a non-hospitalized control group (CG) and from horses receiving either a pre-surgical single-shot (SSG) or a peri-operative 5-day (5DG) course of PAP. To assess differences between the two PAP regimens and the CG, all samples obtained at hospital admission (t0), on days three (t1) and ten (t2) after surgery, were screened for ESBL-producing Enterobacterales and subjected to 16S rRNA V1– V2 gene sequencing.We included 48 samples in the SSG (n=16 horses), 45 in the 5DG (n=15) and 20 in the CG (n=10). Two samples (6.5%) were positive for ESBL-producing Enterobacterales at t0while this rate increased to 67% at t1and decreased only slightly at t2(61%). Shannon diversity index (SDI) was used to evaluate alpha-diversity changes, revealing that horses suffering from acute colic seemed to have a compromised fecal microbiota composition (5DG, SDImeanof 5.90; SSG, SDImeanof 6.17) when compared to the CG (SDImeanof 6.53) at t0, although the difference lacked significance. Alpha-diversity decreased significantly in both PAP groups at t1, while at t2the onset of microbiome recovery was noticed. Although we did not identify a significant SDImeandifference with respect to PAP duration, the community structure (beta-diversity) was considerably restricted in samples of the 5DG at t1, most likely due to the ongoing administration of antibiotics. An increased abundance ofEnterobacteriaceae,especiallyEscherichia, was noted for both study groups at t1. Further studies are needed to reveal important factors promoting the increase and residency of ESBL-producing Enterobacterales among hospitalized horses.
The tumor microbiome as a predictor of outcomes in patients with metastatic melanoma treated with immune checkpoint inhibitors
Authors: Wheeler Caroline E. , Coleman Samuel S. , Hoyd Rebecca , Denko Louis , Chan Carlos H.F. , Churchman Michelle L. , Denko Nicholas , Dodd Rebecca D. , Eljilany Islam , Hardikar Sheetal , Husain Marium , Ikeguchi Alexandra P. , Jin Ning , Ma Qin , McCarter Martin D. , Osman Afaf E.G. , Robinson Lary A. , Singer Eric A. , Tinoco Gabriel , Ulrich Cornelia M. , Zakharia Yousef , Spakowicz Daniel , Tarhini Ahmad A. , Tan Aik Choon 
Published: May 2023

AbstractEmerging evidence supports the important role of the tumor microbiome in oncogenesis, cancer immune phenotype, cancer progression, and treatment outcomes in many malignancies. In this study, we investigated the metastatic melanoma tumor microbiome and potential roles in association with clinical outcomes, such as survival, in patients with metastatic disease treated with immune checkpoint inhibitors (ICIs). Baseline tumor samples were collected from 71 patients with metastatic melanoma before treatment with ICIs. Bulk RNA-seq was conducted on the formalin-fixed paraffin-embedded (FFPE) tumor samples. Durable clinical benefit (primary clinical endpoint) following ICIs was defined as overall survival ≥24 months and no change to the primary drug regimen (responders). We processed RNA-seq reads to carefully identify exogenous sequences using the {exotic}tool. The 71 patients with metastatic melanoma ranged in age from 24 to 83 years, 59% were male, and 55% survived >24 months following the initiation of ICI treatment. Exogenous taxa were identified in the tumor RNA-seq, including bacteria, fungi, and viruses. We found differences in gene expression and microbe abundances in immunotherapy responsive versus non-responsive tumors. Responders showed significant enrichment of several microbes includingFusobacterium nucleatum, and non-responders showed enrichment of fungi, as well as several bacteria. These microbes correlated with immune-related gene expression signatures. Finally, we found that models for predicting prolonged survival with immunotherapy using both microbe abundances and gene expression outperformed models using either dataset alone. Our findings warrant further investigation and potentially support therapeutic strategies to modify the tumor microbiome in order to improve treatment outcomes with ICIs.SignificanceWe analyzed the tumor microbiome and interactions with genes and pathways in metastatic melanoma treated with immunotherapy, and identified several microbes associated with immunotherapy response and immune-related gene expression signatures. Machine learning models that combined microbe abundances and gene expression outperformed models using either dataset alone in predicting immunotherapy responses.
A pancreatic cancer mouse model with human immunity
Authors: Miyamura Norio , Suzuki Kodai , Friedman Richard A. , Floratos Aristidis , Kunisada Yuki , Masuda Kazuya , Lowy Andrew M. , Tsuji Moriya , Sugahara Kazuki N. 
Published: May 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) is characterized by a tumor immune microenvironment (TIME) that promotes resistance to immunotherapy. A preclinical model system that facilitates studies of the TIME and its impact on the responsiveness of human PDAC to immunotherapies remains an unmet need. We report a novel mouse model, which develops metastatic human PDAC that becomes infiltrated by human immune cells recapitulating the TIME of human PDAC. The model may serve as a versatile platform to study the nature of human PDAC TIME and its response to various treatments.
Inferring chromosomal instability from copy number aberrations as a measure of chromosomal instability across human cancers
Authors: Taluri Sasha , Oza Vishal H. , Soelter Tabea M. , Fisher Jennifer L. , Lasseigne Brittany N. 
Published: May 2023

AbstractBackgroundCancer is a complex disease that is the second leading cause of death in the United States. Despite research efforts, the ability to manage cancer and select optimal therapeutic responses for each patient remains elusive. Chromosomal instability (CIN) is primarily a product of segregation errors wherein one or many chromosomes, in part or whole, vary in number. CIN is an enabling characteristic of cancer, contributes to tumor-cell heterogeneity, and plays a crucial role in the multistep tumorigenesis process, especially in tumor growth and initiation and in response to treatment.AimsMultiple studies have reported different metrics for analyzing copy number aberrations as surrogates of CIN from DNA copy number variation data. However, these metrics differ in how they are calculated with respect to the type of variation, the magnitude of change, and the inclusion of breakpoints. Here we compared metrics capturing CIN as either numerical aberrations, structural aberrations, or a combination of the two across 33 cancer data sets from The Cancer Genome Atlas (TCGA).Methods and resultsUsing CIN inferred by methods in the CINmetrics R package, we evaluated how six copy number CIN surrogates compared across TCGA cohorts by assessing each across tumor types, as well as how they associate with tumor stage, metastasis, and nodal involvement, and with respect to patient sex.ConclusionsWe found that the tumor type impacts how well any two given CIN metrics correlate. While we also identified overlap between metrics regarding their association with clinical characteristics and patient sex, there was not complete agreement between metrics. We identified several cases where only one CIN metric was significantly associated with a clinical characteristic or patient sex for a given tumor type. Therefore, caution should be used when describing CIN based on a given metric or comparing it to other studies.
In vivofunctional phenotypes from a computational epistatic model of evolution
Authors: Alvarez Sophia , Nartey Charisse M. , Mercado Nicholas , de la Paz Alberto , Huseinbegovic Tea , Morcos Faruck 
Published: May 2023

AbstractComputational models of evolution are valuable for understanding the dynamics of sequence variation, to infer phylogenetic relationships or potential evolutionary pathways and for biomedical and industrial applications. Despite these benefits, few have validated their propensities to generate outputs within vivofunctionality, which would enhance their value as accurate and interpretable evolutionary algorithms. We demonstrate the power of epistasis inferred from natural protein families to evolve sequence variants in an algorithm we developed called Sequence Evolution with Epistatic Contributions. Utilizing the Hamiltonian of the joint probability of sequences in the family as fitness metric, we sampled and experimentally tested forin vivo β-lactamase activity inE. coliTEM-1 variants. These evolved proteins can have dozens of mutations dispersed across the structure while preserving sites essential for both catalysis and interactions. Remarkably, these variants retain family-like functionality while being more active than their WT predecessor. We found that depending on the inference method used to generate the epistatic constraints, different parameters simulate diverse selection strengths. Under weaker selection, local Hamiltonian fluctuations reliably predict relative changes to variant fitness, recapitulating neutral evolution. SEEC has the potential to explore the dynamics of neofunctionalization, characterize viral fitness landscapes and facilitate vaccine development.
Inhibitors of cannabinoid receptor 1 suppress the cellular entry of Lujo virus
Authors: Kimura Miyuki , Matsuoka Risa , Taniguchi Satoshi , Maruyama Junki , Paessler Slobodan , Oka Saori , Yamashita Atsushi , Fukuhara Takasuke , Matsuura Yoshiharu , Tani Hideki 
Published: May 2023

AbstractLujo virus (LUJV), which belongs to Mammarenavirus, familyarenaviridae, has emerged as pathogen causing severe hemorrhage fever with high mortality. Currently, there are no effective treatments for arenaviruses, including LUJV. Here, we screened chemical compound libraries of Food and Drug Administration (FDA)-approved drug and G protein-coupled receptor-associated drugs to identify effective antivirals against LUJV targeting cell entry using a vesicular stomatitis virus-based pseudotyped virus bearing the LUJV envelope glycoprotein (GP). Cannabinoid receptor 1 (CB1) antagonists, such as rimonabant, AM251 and AM281, have been identified as robust inhibitors of LUJV entry. The IC50of rimonabant was 0.26 and 0.53 μM in Vero and Huh7 cells, respectively. Analysis of the cell fusion activity of the LUJV GP in the presence of CB1 inhibitors revealed that these inhibitors suppressed the fusion activity of the LUJV GP. Moreover, rimonabant, AM251 and AM281 reduced the infectivity of authentic LUJVin vitro,suggesting that the antiviral activity of CB1 antagonists against LUJV is mediated, at least in part, by inhibition of the viral entry, especially, membrane fusion. These findings suggest promising candidates for developing new therapies against LUJV infections.ImportanceTo investigate antiviral drugs against Lujo virus (LUJV), we screened chemical compound libraries to identify effective antivirals against LUJV entry. CB1 antagonists were identified as robust inhibitors of LUJV entry. The cell fusion activity of LUJV GP was suppressed by CB1 inhibitors. Furthermore, CB1 antagonists reduced the infectivity of authentic LUJV. These findings suggest promising candidates for developing new therapies against LUJV infections.
Rapid intracellular acidification is a novel plant defense response countered by the brown planthopper
Authors: Jiang Yanjuan , Zhang Xiao-Ya , Li Shaoqin , Xie Yu-Cheng , Luo Xu-Mei , Yang Yongping , Pu Zhengyan , Zhang Li , Lu Jia-Bao , Huang Hai-Jian , Zhang Chuan-Xi , He Sheng Yang 
Published: May 2023

SUMMARYThe brown planthopper (BPH) is the most destructive insect pest in rice. Through a stylet, BPH secrets a plethora of salivary proteins into rice phloem cells as a crucial step of infestation. However, how various salivary proteins function in rice cells to promote insect infestation is poorly understood. Among them, one of the salivary proteins is predicted to be a carbonic anhydrase (NlCA). The survival rate of theNlCA-RNA interference (RNAi) BPH insects was extremely low on rice, indicating a vital role of this salivary protein in BPH infestation. We generatedNICAtransgenic rice plants and found thatNlCAexpressed in rice plants could restore the ability ofNlCA-RNAi BPH to survive on rice. Next, we produced rice plants expressing the ratiometric pH sensor pHusion and found thatNlCA-RNAi BPH induced rapid intracellular acidification of rice cells during feeding. Further analysis revealed that bothNlCA-RNAi BPH feeding and artificial of lowering intracellular pH activated plant defense responses, and that NICA-mediated intracellular pH stabilization is linked to diminished defense responses, including reduced callose deposition at the phloem sieve plates and suppressed defense gene expression. Given the importance of pH homeostasis across the kingdoms of life, discovery of NICA-mediated intracellular pH modulation uncovered a new dimension in the interaction between plants and piecing/sucking insect pests. The crucial role of NICA for BPH infestation of rice suggests that NICA is a promising target for chemical or trans-kingdom RNAi-based inactivation for BPH control strategies in plants.HighlightsRapid intracellular acidification is a novel plant defense response.Brown planthopper delivers into rice tissues a major virulence protein, carbonic anhydrase (NlCA), critical for survival.NlCA counters intracellular acidification to suppress plant defense.Results implicate existence of pH-responsive regulators of defense responses in the rice-brown planthopper interaction.In briefThe brown planthopper (BPH) is the most devasting insect pest in rice. Jianget al. discovered that BPH secretes a salivary carbonic anhydrase (NICA) to regulate the intracellular pH of the rice cell to facilitate its feeding and survival on rice plants and that NICA-counters host intracellular pH acidification to diminished defense responses. These findings uncovered that intracellular pH homeostasis is a previously uncharacterized battleground in plant-insect interactions, but also open a door to future discovery of pH-responsive intracellular regulators of defense responses, which could add a new research dimension in the study of plant-biotic interactions.
Local contribution to the somatosensory evoked potentials in rat’s thalamus
Authors: Średniawa Władysław , Borzymowska Zuzanna , Kondrakiewicz Kacper , Jurgielewicz Paweł , Mindur Bartosz , Hottowy Paweł , Wójcik Daniel Krzysztof , Kublik Ewa 
Published: May 2023

ABSTRACTLocal Field Potential (LFP), despite its name, often reflects remote activity. Depending on the orientation and synchrony of their sources, both oscillations and more complex waves may passively spread in brain tissue over long distances and be falsely interpreted as local activity at such distant recording site. Current Source Density method was proposed to recover locally active currents from multi-site LFP recordings. Here we use a model-based kernel CSD (kCSD) to study the contribution of local and distant currents to LFP recorded with dense multichannel probes from rat thalamic nuclei and barrel cortex, activated by whisker stimulation. We show that the evoked potential wave seen in the thalamic nuclei around 7–15 ms post-stimulus has a substantial negative component reaching from cortex. This component can be analytically removed and truly local thalamic LFP, with purely thalamic contributions, can be recovered reliably using kCSD. In particular, concurrent recordings from the cortex are not essential for reliable thalamic CSD estimation. Proposed framework can be used to analyse LFP from other brain areas and has consequences for general LFP interpretation and analysis.1BRIEF SUMMARYWhile recording LFP simultaneously in multiple structures, we often see significant correlations between the observed waves. A natural question is if they are propagated passively from one structure to another or if they are simultaneously generated by different, separated sets of sources. We argue this can be answered reliably using CSD analysis. We focus on the case of thalamic and cortical recordings in the somatosensory system in response to whisker stimulation where we observe significant correlations between early thalamic and cortical responses to whisker deflection.
Mice expressing A53T / A30P mutant alpha-synuclein in dopamine neurons do not display behavioral deficits
Authors: Keomanivong Cameron , Schamp Josephine , Tabakovic Ervina , Thangavel Ramasamy , Aldridge Georgina , Pieper Andrew A. , Narayanan Nandakumar S. 
Published: May 2023

ABSTRACTAlpha-synuclein has been implicated in neurodegenerative diseases such as Parkinson’s disease and Dementia with Lewy bodies, with A53T and A30P mutations shown to be disease-causing. It has been reported that transgenic mice with tyrosine hydroxylase promotor-driven expression of A53T / A30P mutant alpha-synuclein in dopamine neurons provide a useful preclinical model of these conditions by virtue of developing dopaminergic neuronal cell death and related behavioral deficits. Here, we report a lack of replication of this finding. Despite detecting robust overexpression of A53T / A30P mutant alpha-synuclein in dopamine neurons, we observed neither cell death or related behavioral deficits in these mice. Our results demonstrate that preclinical models of synucleinopathy need careful validation in the field.
Comparative transcriptomics shows the evolutionary origin of acoustic fat bodies through a trade-off with skull muscles in toothed whales
Authors: Takeuchi Hayate , Matsuishi Takashi Fritz , Hayakawa Takashi 
Published: May 2023

AbstractToothed whales (odontocetes) have developed acoustic fat bodies, which include forehead melon, extra-mandibular fat body and intra-mandibular fat body. These contribute to the sound transmission pathways in the unique echolocation process of toothed whales. The acoustic fat bodies of Odontocetes accumulate unusual fatty acids, making them novel traits with unique functional anatomy and chemistry. This study provides new insights into the evolutionary origin and lipid utilisation of acoustic fat bodies in harbour porpoise (Phocoena phocoena) and Pacific white-sided dolphin (Lagenorhynchus obliquidens) using comparative transcriptomics. Comprehensive gene expression analyses indicated that the acoustic fat bodies of toothed whales are composites of muscle and adipose tissues, mainly composed of intramuscular fat. The extra-mandibular fat body is a homologue of the masseter muscle. Additionally, we demonstrated that gene expression-based functional enrichments for specialised branched-chain amino acid metabolism, endocytosis, lysosomes and peroxisomes contribute to the maintenance of the unique fatty characteristics of the acoustic fat bodies of toothed whales. A trade-off occurred in the evolution of acoustic fat bodies as a result of the fatty reorganisation of head muscles involved in aquatic adaptation in toothed whales.
Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Authors: Gil-Jimenez Alberto , van Dijk Nick , Vos Joris L. , Lubeck Yoni , van Montfoort Maurits L. , Peters Dennis , Hooijberg Erik , Broeks Annegien , Zuur Charlotte L. , van Rhijn Bas , Vis Daniel J. , van der Heijden Michiel S. , Wessels Lodewyk F. A. 
Published: May 2023

AbstractImmune checkpoint inhibitors (ICI) currently achieve remarkable clinical results in urothelial cancer (UC). However, the relationship between the tumor microenvironment (TME), usually characterized by immune cell density, and response to ICI is unclear.We quantified the TME immune cell densities and spatial relationships (SRs) using the multiplex immunofluorescence data of 24 UC pre-treatment tumor resections. We described SRs by approximating the 1-NN distance distribution with a Weibull distribution and evaluated the association between TME metrics (spatial and density parameters) and ipilimumab+nivolumab response.Immune cell density did not discriminate between response groups. However, the Weibull SR metrics of CD8+T-cells or macrophages to their closest cancer cell were positively associated with response. CD8+T-cells close to B-cells were characteristic of non-response. The G- function, a threshold dependent alternative SR metric, yielded variable effect sizes and statistical power in association studies with response. We validated our SR response associations in a cohort of head and neck tumors with a comparable treatment design. Our data confirm that SRs, in contrast to density metrics, are strong biomarkers of response to ICIs, a finding with significant translational relevance.
DeepRaccess: High-speed RNA accessibility prediction using deep learning
Authors: Hara Kaisei , Iwano Natsuki , Fukunaga Tsukasa , Hamada Michiaki 
Published: May 2023

AbstractRNA accessibility is a useful RNA secondary structural feature for predicting RNA-RNA interactions and translation efficiency in prokaryotes. However, conventional accessibility calculation tools, such as Raccess, are computationally expensive and require considerable computational time to perform transcriptome-scale analyses. In this study, we developed DeepRaccess, which predicts RNA accessibility based on deep learning methods. DeepRaccess was trained to take artificial RNA sequences as input and to predict the accessibility of these sequences as calculated by Raccess. Simulation and empirical dataset analyses showed that the accessibility predicted by DeepRaccess was highly correlated with the accessibility calculated by Raccess. In addition, we confirmed that DeepRaccess can predict protein abundance inE.coliwith moderate accuracy from the sequences around the start codon. We also demonstrated that DeepRaccess achieved tens to hundreds of times software speed-up in a GPU environment. The source codes and the trained models of DeepRaccess are freely available athttps://github.com/hmdlab/DeepRaccess.