bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive Survey of Conserved RNA Secondary Structures in Full-Genome Alignment of Hepatitis C Virus
Authors: Triebel Sandra , Lamkiewicz Kevin , Ontiveros Nancy , Sweeney Blake , Stadler Peter F. , Petrov Anton I. , Niepmann Michael , Marz Manja 
Published: November 2023

AbstractHepatitis C virus (HCV) is a plus-stranded RNA virus that often chronically infects liver hepatocytes and causes liver cirrhosis and cancer. These viruses replicate their genomes employing error-prone replicases. Thereby, they routinely generate a large “cloud” of RNA genomes which - by trial and error - comprehensively explore the sequence space available for functional RNA genomes that maintain the ability for efficient replication and immune escape. In this context, it is important to identify which RNA secondary structures in the sequence space of the HCV genome are conserved, likely due to functional requirements.Here, we provide the first genome-wide multiple sequence alignment (MSA) with the prediction of RNA secondary structures throughout all representative full-length HCV genomes. We selected 57 representative genomes by clustering all complete HCV genomes from the BV-BRC database based on k-mer distributions and dimension reduction and adding RefSeq sequences. We include annotations of previously recognized features for easy comparison to other studies.Our results indicate that mainly the core coding region, the C-terminal NS5A region, and the NS5B region contain secondary structure elements that are conserved beyond coding sequence requirements, indicating functionality on the RNA level. In contrast, the genome regions in between contain less highly conserved structures. The results provide a complete description of all conserved RNA secondary structures and make clear that functionally important RNA secondary structures are present in certain HCV genome regions but are largely absent from other regions. Full-genome alignments of all branches ofHepacivirus Care provided in the supplement.
Simultaneous Profiling of Chromatin Accessibility and DNA Methylation in Complete Plant Genomes Using Long-Read Sequencing
Authors: Leduque Basile , Edera Alejandro , Vitte Clementine , Quadrana Leandro 
Published: November 2023

ABSTRACTEpigenetic regulations, including chromatin accessibility, nucleosome positioning, and DNA methylation intricately shape genome function. However, current chromatin profiling techniques relying on short-read sequencing technologies fail to characterise highly repetitive genomic regions and cannot detect multiple chromatin features simultaneously. Here, we performed Simultaneous Accessibility and DNA Methylation Sequencing (SAM-seq) of purified plant nuclei. Thanks to the use of long-read nanopore sequencing, SAM-seq enables high-resolution profiling of m6A-tagged chromatin accessibility together with endogenous cytosine methylation in plants. Analysis of naked genomic DNA revealed significant sequence preference biases of m6A-MTases, controllable through a normalisation step. By applying SAM-seq to Arabidopsis and maize nuclei we obtained fine-grained accessibility and DNA methylation landscapes genome-wide. We uncovered crosstalk between chromatin accessibility and DNA methylation within nucleosomes of genes, TEs, and centromeric repeats. SAM-seq also detects DNA footprints over cis-regulatory regions. Furthermore, using the single-molecule information provided by SAM-seq we identified extensive cellular heterogeneity at chromatin domains with antagonistic chromatin marks, suggesting that bivalency reflects cell-specific regulations. SAM-seq is a powerful approach to simultaneously study multiple epigenetic features over unique and repetitive sequences, opening new opportunities for the investigation of epigenetic mechanisms.
Quantification of water exchange across the blood-brain barrier using non-contrast MR fingerprinting
Authors: Thomson Emma L. , Powell Elizabeth , Wheeler-Kingshott Claudia A. M. Gandini , Parker Geoff J. M. 
Published: November 2023

PurposeA method is proposed to quantify cerebral blood volume (vb) and intravascular water residence time (τb) using magnetic resonance fingerprinting (MRF), applied using a spoiled gradient echo sequence, without the need for contrast agent.MethodsAn in silico study optimised an acquisition protocol to maximise the sensitivity of the measurement tovbandτbchanges. Its accuracy in the presence of variations inT1,t,T1,b, andB1was evaluated. The optimised protocol (scan time of 19 minutes) was then tested in a exploratory healthy volunteer study (10 volunteers, mean age 24 ± 3, 6 male) at 3 T with a repeat scan taken after repositioning to allow estimation of repeatability.ResultsSimulations show that assuming literature values forT1,bandT1,t, no variation inB1, while fitting onlyvbandτb, leads to large errors in quantification ofvbandτb, regardless of noise levels. However, simulations also show that matchingandτb, simultaneously is feasible at clinically achievable noise levels. Across the healthy volunteers, all parameter quantifications fell within the expected literature range. In addition, the maps show good agreement between hemispheres suggesting physiologically relevant information is being extracted. Expected differences between white and grey matterT1,t(p<0.0001) andvb(p<0.0001) are observed,T1,bandτbshow no significant differences, p=0.4 and p=0.6 repectively. Good repeatability was seen between repeat scans: mean ICC ofT1,t: 0.91,T1,b: 0.58,vb: 0.90, andvτb: 0.96.ConclusionWe demonstrate that regional simultaneous quantification ofvb,τb,T1,b,T1,t, andB1using MRF is feasible in vivo.
Pain persists in mice lacking both Substance P and CGRPα signaling
Authors: MacDonald Donald Iain , Jayabalan Monessha , Seaman Jonathan , Balaji Rakshita , Nickolls Alec , Chesler Alexander 
Published: November 2023

SummaryThe neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides and their receptors are expressed at high levels in pain-responsive neurons from the periphery to the brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve pain in clinical trials. Since Substance P and CGRPα are extensively co-expressed we hypothesized that their simultaneous inhibition would be required for effective analgesia. We therefore generated Tac1 and Calca double knockout (DKO) mice and assessed their behavior using a wide range of pain-relevant assays. As expected, Substance P and CGRPα peptides were undetectable throughout the nervous system of DKO mice. To our surprise, these animals displayed largely intact responses to mechanical, thermal, chemical, and visceral pain stimuli, as well as itch. Moreover, chronic inflammatory pain and neurogenic inflammation were unaffected by loss of the two peptides. Finally, neuropathic pain evoked by nerve injury or chemotherapy treatment was also preserved in peptide-deficient mice. Thus, our results demonstrate that even in combination, Substance P and CGRPα are not required for the transmission of acute and chronic pain.
Time-restricted feeding ameliorates MCDD-induced steatohepatitis in mice
Authors: Jung Ik-Rak , Ahima Rexford S. , Kim Sangwon F. 
Published: November 2023

AbstractNon-Alcoholic Steatohepatitis (NASH) is an inflammatory form of Non-Alcoholic Fatty Liver Disease (NAFLD), closely associated with disease progression, cirrhosis, liver failure, and hepatocellular carcinoma. Time-restricted feeding (TRF) has been shown to decrease body weight and adiposity and improve metabolic outcomes, however, the effect of TRF on NASH has not yet been fully understood. We had previously reported that inositol polyphosphate multikinase (IPMK) mediates hepatic insulin signaling. Importantly, we have found that TRF increases hepatic IPMK levels. Therefore, we investigated whether there is a causal link between TRF and IPMK in a mouse model of NASH, i.e., methionine and choline deficient diet (MCDD)-induced steatohepatitis. Here, we show that TRF alleviated markers of NASH, i.e., reduced hepatic steatosis, liver triglycerides (TG), serum alanine transaminase (ALT) and aspartate aminotransferase (AST), inflammation and fibrosis in MCDD mice. Interestingly, MCDD led to a significant reduction in IPMK levels, and the deletion of hepatic IPMK exacerbates the NASH phenotype induced by MCDD, accompanied by increased gene expression of pro-inflammatory chemokines. Conversely, TRF restored IPMK levels and significantly reduced gene expression of proinflammatory cytokines and chemokines. Our results demonstrate that TRF attenuates MCDD-induced NASH via IPMK-mediated changes in hepatic steatosis and inflammation.
De novo lipogenesis pathway is a vulnerability in IDH1 mutant glioma
Authors: Elahi Lubayna S , Condro Michael C , Kawaguchi Riki , Qin Yue , Alvarado Alvaro G. , Gruender Brandon , Qi Haocheng , Li Tie , Lai Albert , Castro Maria G. , Lowenstein Pedro R. , Garrett Matthew C , Kornblum Harley I. 
Published: November 2023

AbstractHistone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-epileptic and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild type tumors. Surprisingly, genes upregulated by VPA showed no change in chromatin accessibility at the promoter, but there was a correlation between VPA downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decrease in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA targeted a key lipogenic gene, fatty acid synthase (FASN), via inhibition of the mTOR pathway and both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find HDACs are involved in the regulation of lipogenic genes and in particular HDAC6 is important for regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in a IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic option in IDH1 mutant gliomas.
Well-tempered metadynamics calculations of free energy surfaces of benzothiadiazine derivatives in aqueous solution
Authors: Hu Zheyao , Marti Jordi 
Published: November 2023

ABSTRACTKRAS oncogenes are the largest family of mutated RAS isoforms, participating in about 30% of all cancers. Due to their paramount medical importance, enormous effort is being devoted to the development of inhibitors using clinical tests, wet-lab experiments and drug design, being this a preliminary step in the process of creating new drugs, prior to synthesis and clinical testing. One central aspect in the development of new drugs is the characterization of all species that can be used for treatment. In this aim we propose a computational framework based on combined all-atom molecular dynamics and metadynamics simulations in order to accurately access the most stable conformational variants for several derivatives of a recently proposed small-molecule, called DBD15-21-22. Free energy calculations are essential to unveil mechanisms at the atomic scale like binding affinities or dynamics of stable states. Considering specific atom-atom distances and torsional angles as reliable reaction coordinates we have obtained free-energy landscapes by well-tempered metadynamics simulations, revealing local and global minima of the free-energy hypersurface. We have observed that a variety of stable states together with transitions states are clearly detected depending on the particular species, leading to predictions on the behaviour of such compounds in ionic aqueous solution.
Metabolic and imaging phenotypes associated withRB1loss in castrate resistant prostate cancer
Authors: Ahmad Fahim , White Margaret , Yamamoto Kazutoshi , Crooks Daniel R. , Agarwal Supreet , Yang Ye , Capaldo Brian , Raj Sonam , Alilin Aian Neil , Ton Anita , Adler Stephen , Seidel Jurgen , Olkowski Colleen , Cherukuri Murali Krishna , Choyke Peter L , Kelly Kathleen , Brender Jeffrey R. 
Published: November 2023

PurposeAdvanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but the majority of patients eventually develop resistance and progress to castrate resistant prostate cancer (CRPC). Loss ofRB1in CRPC tumors is correlated with rapid progression and poor patient survival, and in combination withTP53loss, predisposes to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressing CRPC is clinically associated with higher18FDG-PET SUVmaxvalues, it is unknown whether inactivation ofRB1and/orTP53is a driver of increased glucose import.Experimental DesignA cohort of patient-derived xenograft (PDX)-derived CRPC organoids was screened to assess18FDG uptake in ARPC and NEPC, considering the influence of RB1 and TP53 status. Experimental loss ofRB1and/orTP53was induced in an androgen sensitive and a castrate resistant model, and metabolic changes were evaluated using18FDG-PET,13C-hyperpolarized magnetic resonance spectroscopy, Seahorse, andex vivoNMR.ResultsKnockdown of eitherRB1orTP53increased glycolysis and TCA cycle intermediates, while knockdown of both created a new phenotype where glucose was diverted to the pentose phosphate pathway and into glycogen synthesis. These large-scale metabolic changes were not reflected in18FDG uptake, which was not increased upon knockdown of either gene.13C-hyperpolarized magnetic resonance spectroscopy, on the other hand, showed significant differences in lactate dehydrogenase flux upon loss ofRB1. The metabolic heterogeneity revealed here suggests a multimodal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment.
The anti-B7-H3 blocking antibody MJ18 does not recognize B7-H3 in murine tumor models
Authors: Nammor Talah , Frizzell Jenna , Lavoie Roxane R. , Lucien Fabrice 
Published: November 2023

AbstractThe immune checkpoint molecule B7-H3 is regarded as one of the most promising therapeutic targets for the treatment of human cancers. B7-H3 is highly expressed in many cancers and its expression has been associated to impaired antitumor immunity and poor patient prognosis. In immunocompetent mouse tumor models, genetic deletion of B7-H3 in tumor cells enhances antitumor immune response leading to tumor shrinkage. The underlying mechanisms of B7-H3 inhibitory function remain largely uncharacterized and the identity of potential cognate(s) receptor(s) of B7-H3 is still to be defined. To better understand B7-H3 functionin vivo, several studies have employed MJ18, a monoclonal antibody reported to bind murine B7-H3 and blocks its immune-inhibitory function. In this brief research report, we show that 1) MJ18 does not bind B7-H3, 2) MJ18 binds the Fc receptor FcγRIIB on surface of murine splenocytes, and 3) MJ18 does not induce tumor regression in a mouse model responsive to B7-H3 knockout. Given the high profile of B7-H3 as therapeutic target for human cancers, our work emphasizes that murine B7-H3 studies using the MJ18 antibody should be interpreted with caution. Finally, we hope that our study will motivate the scientific community to establish much-needed validated research tools to study B7-H3 biology in mouse models.
Use of dye sensitizers for increased photoacoustic mechanosensation
Authors: Rafeedi Tarek , Becerra Laura , Root Nicholas , Qi Baiyan , Fu Lei , Esparza Guillermo , Qie Yi , Sasi Lekshmi , Rouw Romke , Jokerst Jesse , Lipomi Darren 
Published: November 2023

AbstractThe photoacoustic effect refers to the generation of pressure waves in matter stimulated by light[1]. In the context of radiology (i.e., photoacoustic imaging) waves generated by pulsed laser light are detected by an ultrasound transducer[2–4]. It has been shown that photoacoustic waves produce a mechanical, tactile sensation in humans on bare skin[5]. In a series of psychophysical experiments, performed with both medical grade and off-the-shelf pulsed light systems, participants could detect, categorically describe, and discern the direction of travel of pulsed optical stimuli with the use of a dye as an optical absorber on the skin. To a large extent, the sensations were perceived as localized vibration on the glabrous surface of the fingers, when sensitized with the thin film of dye. This form of sensory stimulation demonstrates an enhanced non-contact, non-optogenetic, in situ activation of the mechanosensory system. This modality of sensation may provide a tool that leads to new insights in psychology, neuroscience, mechanobiology, and the health sciences. Finally, it has many advantageous characteristics for human interaction with artificial environments, as optical signals can be projected onto the skin across distances.
Comprehensive mapping of sensory and sympathetic innervation of the developing kidney
Authors: N’Guetta Pierre-Emmanuel Y. , McLarnon Sarah R. , Tassou Adrien , Geron Matan , Shirvan Sepenta , Hill Rose Z. , Scherrer Grégory , O’Brien Lori L. 
Published: November 2023

AbstractThe kidney functions as a finely tuned sensor to balance body fluid composition and filter out waste through complex coordinated mechanisms. This versatility requires tight neural control, with innervating efferent nerves playing a crucial role in regulating blood flow, glomerular filtration rate, water and sodium reabsorption, and renin release. In turn sensory afferents provide feedback to the central nervous system for the modulation of cardiovascular function. However, the cells targeted by sensory afferents and the physiological sensing mechanisms remain poorly characterized. Moreover, how the kidney is innervated during development to establish these functions remains elusive. Here, we utilized a combination of light-sheet and confocal microscopy to generate anatomical maps of kidney sensory and sympathetic nerves throughout development and resolve the establishment of functional crosstalk. Our analyses revealed that kidney innervation initiates at embryonic day (E)13.5 as the nerves associate with vascular smooth muscle cells and follow arterial differentiation. By E17.5 axonal projections associate with kidney structures such as glomeruli and tubules and the network continues to expand postnatally. These nerves are synapsin I-positive, highlighting ongoing axonogenesis and the potential for functional crosstalk. We show that sensory and sympathetic nerves innervate the kidney concomitantly and classify the sensory fibers as calcitonin gene related peptide (CGRP)+, substance P+, TRPV1+, and PIEZO2+, establishing the presence of PIEZO2 mechanosensory fibers in the kidney. Using retrograde tracing, we identified the primary dorsal root ganglia, T10-L2, from which PIEZO2+sensory afferents project to the kidney. Taken together our findings elucidate the temporality of kidney innervation and resolve the identity of kidney sympathetic and sensory nerves.
A novel antagonist of the CCL5/CCR5 axis suppresses the tumor growth and metastasis of triple-negative breast cancer by CCR5-YAP1 regulation
Authors: Chen Ling , Xu Guiying , Song Xiaoxu , Zhang Lianbo , Chen Chuyu , Xiang Gang , Wang Shuxuan , Zhang Zijian , Wu Fang , Yang Xuanming , Zhang Lei , Ma Xiaojing , Yu Jing 
Published: November 2023

AbstractTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with a high mortality rate, and few effective therapeutic strategies are available. CCL5/CCR5 is an appealing immunotherapeutic target for TNBC. However, its signaling mechanism is poorly understood and its direct antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a more selective and potent antagonist than the known CCR5 antagonist maraviroc. Without photodynamic therapy, verteporfin demonstrated significant inhibition on TNBC tumor growth through immune regulation, remarkable suppression of lung metastasis by cell-intrinsic mechanism, and a significant extension of overall survivalin vivo. Mechanistically, CCR5 was found to be essential for expression of the key hippo effector YAP1. It promotedYAP1transcription via HIF-1α and exerted further control over the migration of CD8+T, NK, and MDSC immune cells through chemokines CXCL16 and CXCL8 which were identified from RNA-seq. Moreover, the CCR5-YAP1 axis played a vital role in promoting metastasis by modulating β-catenin and core epithelial-mesenchymal transition transcription factors ZEB1 and ZEB2. It is noteworthy that the regulatory relationship between CCR5 and YAP1 was observed across various BC subtypes, TNBC patients, and showed potential relevance in fifteen additional cancer types. Overall, this study introduced an easy-to-use HTS assay that streamlines the discovery of CCL5/CCR5 axis antagonists. Verteporfin was identified as a specific molecular probe of this axis with great potentials as a therapeutic agent for treating sixteen malignant diseases characterized by heightened CCR5 and YAP1 levels.
Refining the taxonomy of the orderHyphomicrobiales(Rhizobiales) based on whole genome comparisons of over 130 genus type strains
Authors: diCenzo George C. , Yang Yuqi , Young J. Peter W. , Kuzmanović Nemanja 
Published: November 2023

ABSTRACTThe alphaproteobacterial orderHyphomicrobialesconsists of 38 families comprising 155 validly published genera as of June 2023. The orderHyphomicrobialeswas first described in 1957 and underwent important revisions in 2020. However, several inconsistencies in the taxonomy of this order remain, and there is a need for a consistent framework for defining families within the order. We propose a common genome-based framework for defining families within the orderHyphomicrobiales, suggesting that families represent monophyletic groups in core-genome phylogenies that share pairwise average amino acid identity values above ∼75% when calculated from a core set of 59 proteins. Applying this framework, we propose the formation of four new families and to reassign the generaSalaquimonas,Rhodoblastus, andRhodoligotrophosintoSalaquimonadaceaefam. nov.,Rhodoblastaceaefam. nov., andRhodoligotrophaceaefam. nov., respectively, and the generaAlbibacter,Chenggangzhangella,Hansschlegelia, andMethylopilaintoMethylopilaceaefam. nov.. We further propose to unify the familiesBartonellaceae,Brucellaceae,Phyllobacteriaceae, andNotoacmeibacteraceaeasBartonellaceae; the familiesSegnochrobactraceaeandPseudoxanthobacteraceaeasSegnochrobactraceae; the familiesLichenihabitantaceaeandLichenibacteriaceaeasLichenihabitantaceae; and the familiesBreoghaniaceaeandStappiaceaeasStappiaceae. Lastly, we propose to reassign several genera to existing families. Specifically, we propose to reassign the genusPseudohoefleato the familyRhizobiaceae; the generaOricola,Roseitalea, andOceaniradiusto the familyAhrensiaceae; the genusLimoniibacterto the emended familyBartonellaceae; the genusFaunimonasto the familyAfifellaceae; and the genusPseudochelatococcusto the familyChelatococcaceae. Our data also support the recent proposal to reassign the genusProsthecomicrobiumto the familyKaistiaceae.