bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination of mitomycin C and low-dose metronidazole synergistically againstClostridioides difficileinfection and recurrence prevention
Authors: Gong Jun-Jia , Huang I-Hsiu , Hung Yuan-Pin , Chen Yi-Wei , Lin Yun-Chien , Chen Jenn-Wei 
Published: October 2024

AbstractClostridioides difficileis an anaerobic, spore-forming, Gram-positive pathogen responsible for various conditions from mild diarrhea to severe toxic megacolon and potentially death. Current treatments forC. difficileinfection (CDI) rely on antibiotics like vancomycin and metronidazole (MTZ); however, the high doses required often disrupt gut microbiota, leading to a high recurrence rate. Mitomycin C (MMC), a chemotherapy drug approved by the FDA, is known for inducing phage production in lysogenic bacterial strains, effectively targeting the host bacteria. Given that 70% ofC. difficilestrains harbor prophages, this study investigates MMC’s potential to enhance antibiotic efficacy against CDI. Our in vitro experiments indicate that MMC acts synergistically with MTZ to inhibit the growth ofC. difficilestrain R20291. Furthermore, this combination decreases biofilm-resident vegetative cell resistance and reduces the MTZ concentration needed to killC. difficilein stool samples ex vivo. In a CDI mouse relapse model, in vivo results show that MMC combined with a low dose of MTZ significantly improves survival rates and reduces fecal spore counts after antibiotic treatment. Overall, these findings suggest that a low-dose combination of MMC and MTZ offers enhanced therapeutic efficacy for CDI, both in vitro and in vivo, and may provide a promising new approach for treatment.
Iron-sensitive RNA regulation by poly C binding proteins
Authors: Forbes Kwame , Goda Grant A. , Eramo Grace A. , Breen Conner , Porter Douglas F. , Khavari Paul A. , Dominguez Daniel , Aleman Maria M. 
Published: October 2024

ABSTRACTIron is essential for normal cellular function. Homeostatic responses to low iron availability have long been known to rely on posttranscriptional mechanisms. Poly C binding proteins (PCBPs) are essential RNA binding proteins that regulate alternative splicing, translation and RNA stability. They also serve as critical iron chaperones that manage intracellular iron flux. However, the impact of cellular iron levels on the PCBP-directed transcriptome has not been globally evaluated. We have found broad transcriptome changes in response to low iron availability consistent with numerous operant posttranscriptional mechanisms that sense iron. By comparing gene expression and alternative splicing directed by PCBPs to the iron-sensitive transcriptome, we found genes with iron-sensitive PCBP RNA regulation. Further, we demonstrate that cellular iron levels impact PCBP1 RNA binding. Our data show a large-scale RNA regulatory response to cellular iron levels and open the possibility for other iron-sensitive RNA binding proteins.
A hypothalamic circuit mechanism underlying the impact of stress on memory and sleep
Authors: Wiest Alyssa , Maurer John J. , Weber Franz , Chung Shinjae 
Published: October 2024

ABSTRACTStress profoundly affects sleep and memory processes. Stress impairs memory consolidation, and similarly, disruptions in sleep compromise memory functions. Yet, the neural circuits underlying stress-induced sleep and memory disturbances are still not fully understood. Here, we show that activation of CRHPVNneurons, similar to acute restraint stress, decreases sleep and impairs memory in a spatial object recognition task. Conversely, inhibiting CRHPVNneurons during stress reverses stress-induced memory deficits while slightly increasing the amount of sleep. We found that both stress and stimulation of CRHPVNneurons activate neurons in the lateral hypothalamus (LH), and that their projections to the LH are critical for mediating stress-induced memory deficits and sleep disruptions. Our results suggest a pivotal role for CRHPVNneuronal pathways in regulating the adverse effects of stress on memory and sleep, an important step towards improving sleep and ameliorating the cognitive deficits that occur in stress-related disorders.
Jamaican fruit bats’ (Artibeus jamaicensis) competence for Ebola virus but not Marburg virus is driven by intrinsic differences in viral entry and IFN-I signaling antagonism
Authors: van Tol Sarah , Port Julia R. , Fischer Robert J. , Gallogly Shane , Bushmaker Trenton , Griffin Amanda , Schulz Jonathan E. , Carmody Aaron , Myers Lara , Crowley Daniel E. , Falvo Caylee A. , Riopelle Jade C. , Wickenhagen Arthur , Clancy Chad , Lovaglio Jamie , Shaia Carl , Saturday Greg , Prado-Smith Jessica , He Yi , Lack Justin , Martens Craig , Anzick Sarah L. , Kendall Lon V. , Schountz Tony , Plowright Raina K. , Marzi Andrea , Munster Vincent J. 
Published: October 2024

SummaryEbola virus (EBOV) and Marburg virus (MARV) are zoonotic filoviruses that cause hemorrhagic fever in humans. Bat species in both Chiropteran suborders host filoviruses, suggesting that bats may have coevolved with this viral family. Correlative data implicate bats as natural EBOV hosts, but neither a full-length genome nor an EBOV isolate has been found in any bats sampled. Here, we modelled filovirus infection in the Jamaican fruit bat (JFB),Artibeus jamaicensis. Bats were inoculated with either EBOV or MARV through a combination of oral, intranasal, and subcutaneous routes. EBOV-infected bats supported systemic virus replication and shed infectious virus orally. In contrast, MARV replicated only transiently and was not shed.In vitro, JFB cells replicate EBOV more efficiently than MARV, and MARV infection induced innate antiviral responses that EBOV efficiently suppressed. Experiments using VSV pseudoparticles or replicating VSV expressing the EBOV or MARV glycoprotein demonstrated an advantage for EBOV entry and replication early, respectively, in JFB cells. Overall, this study describes filovirus species-specific phenotypes for both JFB and their cells.
Novel nanopore sequencing method for determining Human Papillomavirus integrations in tumors without the need for whole genome sequencing
Authors: Parida Preetiparna , Mukherjee Nivedita , Singh Agastya , Lewis Shirley , Sharan Krishna , Mallya Sandeep , Singh Ashima , Rao Mahadev , Higginson Daniel S. , Sabarinathan Radhakrishnan , Damerla Rama Rao 
Published: October 2024

ABSTRACTHuman papillomaviral (HPV) integrations into host human genome, a key event in cervical carcinogenesis, are currently mapped through laborious and expensive sequencing methodologies. We developed and validated a novel library preparation strategy for nanopore sequencing to generate long targeted reads with HPV and human chimeric sequences. Using this strategy, we validated known HPV integrations in HeLa (HPV18) and SiHa (HPV16) cell lines. We also mapped integration sites in five HPV+ cervical cancer patients, which were confirmed by whole genome and Sanger sequencing. Our nanopore-based method provides a precise and efficient strategy to capture HPV integrations crucial for understanding tumorigenesis.
The influence of downstream structured elements within mRNA on the dynamics of intersubunit rotation in ribosomes
Authors: Shebl Bassem , Pavlova Anna , Kellenberger Preston , Yu Dongmei , Menke Drew E. , Gumbart James C. , Cornish Peter V. 
Published: October 2024

AbstractProper codon/anti-codon pairing within the ribosome necessitates linearity of the transcript. Any structures formed within a messenger RNA (mRNA) must be unwound before the respective codon is interpreted. Linearity, however, is not always the norm; some intricate structures within mRNA are able to exert unique ribosome/mRNA interactions to regulate translation. Intrinsic kinetic and thermal stability in many of these structures are efficient in slowing translation causing pausing of the ribosome. Altered translation kinetics arising from atypical interactions have been shown to affect intersubunit rotation. Here, we employ single-molecule Förster Resonance Energy Transfer (smFRET), to observe changes in intersubunit rotation of the ribosome as it approaches downstream structured nucleic acid. The emergence of the hyper-rotated state is critically dependent on the distance between downstream structure and the ribosome suggesting interactions with the helicase center are allosterically coupled to intersubunit rotation. Further, molecular dynamics (MD) simulations were performed to determine ribosomal protein/mRNA interactions that may play a pivotal role in helicase activity and ultimately unwinding of downstream structure.
Deep coalescent history of the hominin lineage
Authors: Cousins Trevor , Schweiger Regev , Durbin Richard 
Published: October 2024

1AbstractCoalescent-based methods are widely used to infer population size histories, but existing analyses have limited resolution for deep time scales (>2 million years ago). Here we extend the scope of such inference by re-analysing an ancient peak seen in human and chimpanzee effective population size around 5-7 million years ago, showing that coalescent-based inference can be extended much further into the past than previously thought. This peak is consistently observed across human and chimpanzee populations, but not in gorillas or orangutans. We show that it is unlikely to be an artefact of model violations, and discuss its potential implications for understanding hominin evolutionary history, in particular the human-chimpanzee speciation.
The ribosome-associated quality control factor TCF25 imposes K48 specificity on Listerin-mediated ubiquitination of nascent chains by binding and specifically orienting the acceptor ubiquitin
Authors: Abaeva Irina S. , Bulakhov Alexander G. , Hellen Christopher U. T. , Pestova Tatyana V. 
Published: October 2024

ABSTRACTPolypeptides arising from interrupted translation undergo proteasomal degradation by the ribosome- associated quality control (RQC) pathway. The ASC-1 complex splits stalled ribosomes into 40S subunits and nascent chain-tRNA-associated 60S subunits (60S RNCs). 60S RNCs associate with NEMF that promotes recruitment of the RING-type E3 ubiquitin (Ub) ligase Listerin (Ltn1 in yeast), which ubiquitinates nascent chains. RING-type E3s mediate the transfer of Ub directly from the E2∼Ub conjugate, implying that the specificity of Ub linkage is determined by the given E2. Listerin is most efficient when it is paired with promiscuous Ube2D E2s. We previously found that TCF25 (Rqc1 in yeast) can impose K48- specificity on Listerin paired with Ube2D E2s. To determine the mechanism of TCF25’s action, we combined functional biochemical studies and AlphaFold3 modeling and now report that TCF25 specifically interacts with the RING domain of Listerin and the acceptor ubiquitin (UbA) and imposes K48-specificity by orienting UbAsuch that its K48 is directly positioned to attack the thioester bond of the Ube2D1∼Ub conjugate. We also found that TCF25 itself undergoes K48-specific ubiquitination by Listerin suggesting a mechanism for the reported upregulation of Rqc1 in the absence of Ltn1 and the observed degradation of TCF25 by the proteasomein vivo.
Single-step in vitro ribosome reconstitution mediated by two GTPase factors, EngA and ObgE
Authors: Sato Aya , Lai Weng Yu , Sakai Yusuke , Shimizu Yoshihiro 
Published: October 2024

AbstractWhen bacterial ribosomes are assembled in vitro, manipulation of incubation temperature and magnesium ion concentration have been an essential procedure, which is a crucial step for the assembly of active large subunits. The present study tackles with this issue to develop a single-step procedure, which can be performed in a physiological condition. We found that GTPase factors EngA and ObgE can complement the changes in temperature and magnesium ion concentrations. In the presence of these factors, ribosome assembly can proceed under physiological conditions, with magnesium ion concentrations below 10 mM, potassium concentrations around 100 mM, and temperatures of 37 °C. Both the ribosome assembly and translation processes were successfully integrated in the reconstituted cell-free protein synthesis system. Furthermore, we found that these GTPase factors can reassemble the ribosomes to an active state, whose structure was disrupted by EDTA chelation of magnesium ions, indicating that these two factors can reversibly induce the ribosome structure to an intact state. The findings are essential for the bottom-up construction of synthetic cells.
A Genes & Health pilot recall study of intrahepatic cholestasis of pregnancy and cholestatic liver disease
Authors: Constantinides Maria , Gafton Joseph , Garcia Ana Cristina Angel ,   Genes and Health, Dixon Peter H. , Williamson Catherine , Linton Kenneth , Finer Sarah , Gill Upkar S. , Zöllner Julia 
Published: October 2024

AbstractBackgroundCholestatic liver disease disproportionately affects South Asians, yet they remain underrepresented in genomic studies. This recall study aimed to recall volunteers from a British South Asian genetic cohort that were considered to be at high risk of cholestatic liver disease based on their genotype or phenotype.MethodsCases were defined as participants with rare (minor allele frequency <1%) heterozygous loss of function (LoF) variants inABCB4andABCB11(genotype re-call) or with a previous intrahepatic cholestasis of pregnancy (ICP) diagnosis (ICD10 O26.6). Cases were matched 1:1 to controls. A detailed medical and family history was taken along with fasting anthropometric and transient elastography (TE) measurements and blood samples.ResultsOut of 22 eligible volunteers, 9 (41%) participated in the recall (8/9 genotype and 1/9 phenotype recall). Among the cases there were 5ABCB4LoF, 3ABCB11LoF, and 1 ICP phenotype. Of these, 6/9 (66.7%) were newly identified with a cholestatic phenotype (genotype re-call). Specifically, 3/6 (50%) had increased liver stiffness on TE with one also demonstrating abnormal liver blood tests. 2/6 (33.3%) experienced at least 2 cholestatic symptoms and an additional 1/6 (16.7%) demonstrated abnormal liver blood tests without increased liver stiffness.ConclusionThis pilot study demonstrated new evidence of cholestatic liver disease in 66.7% of volunteers, underscoring the potential of rare heterozygousABCB4/11variants as markers for identifying individuals at high risk of developing cholestatic liver disease. Consequently, individuals at higher genetic risk benefit from monitoring, personalised treatment and prevention strategies for cholestatic liver disease.Plain language summaryWe aimed to identify British South Asians at high risk of liver disease due to specific genetic factors, such as issues with bile production or liver problems during pregnancy. We invited these individuals to a clinic, where we collected their medical and family history, conducted liver blood tests, and performed a scan to check for early signs of liver scarring. We found that nearly two out of three participants had undetected liver disease. This finding suggests that genetic factors are linked to developing liver disease, highlighting the importance of early detection and monitoring for those at risk.
Oronasal mucosal melanoma is defined by two transcriptional subtypes in humans and dogs with implications for diagnosis and therapy
Authors: Blacklock Kelly L. Bowlt , Donnelly Kevin , Lu Yuting , del Pozo Jorge , Glendinning Laura , Polton Gerry , Selmic Laura , Tanis Jean-Benoir , Killick David , Parys Maciej , Morris Joanna , Breathnach Inge , Zago Stefano , Gould Sara M , Shaw Darren , Tivers Mickey , Malucelli Davide , Marques Ana , Purzycka Katarzyna , Cantatore Matteo , Mathers Marie E. , Stares Mark , Meynert Alison , Patton E. Elizabeth 
Published: October 2024

AbstractMucosal melanoma is a rare melanoma subtype associated with a poor prognosis and limited existing therapeutic interventions, in part due to a lack of actionable targets and translational animal models for pre-clinical trials. Comprehensive data on this tumour type is scarce, and existing data often overlooks the importance of the anatomical site of origin. We evaluated human and canine oronasal mucosal melanoma to determine whether the common canine disease could inform the rare human equivalent.Using a human and canine primary oronasal mucosal melanoma (OMM) cohort of treatment naive archival tissue, alongside clinicopathological data, we obtained transcriptomic immunohistochemical, and microbiome data from both species. We defined the transcriptomic landscape in both species, and linked our findings to immunohistochemical, microbiome and clinical data.Human and dog OMM stratified into two distinctive transcriptional groups which we defined using a species-independent 41-gene signature. These two subgroups are termed CTLA4-high and cMET-high, and indicate actionable targets for OMM patients. To guide clinical decision-making, we developed immunohistochemical diagnostic tools which distinguish between transcriptomic subgroups.For the first time, we find that OMM has conserved transcriptomic subtypes and biological similarity between the canine and human OMM, with significant implications for patient classification, treatment, and clinical trial design.
Research Protocol: Discrete choice modelling to understand the influence of sharing polygenic risk scores related to cardiovascular disease risk with primary care patients
Authors: Bowker-Lonnecker Lin , Dixon Padraig , Petrou Stavros , Buckell John 
Published: October 2024

AbstractIntroductionCardiovascular disease (CVD) is a leading cause of death in the UK and globally. People identified as being at high risk may receive further investigations or preventive treatment. Polygenic risk scores (PRSs) give a summary of overall underlying genetic risk, and may be used to give additional information that GPs can use alongside other information about the patient to determine which interventions, if any, would be beneficial.Methods and AnalysisTwo discrete choice experiments (DCEs) with 2000 participants recruited from the UK general adult population. The first DCE aims to determine people’s attitudes about getting their PRS in the context of cardiovascular disease, and what factors may influence this. The second DCE aims to determine how people are likely to react to this risk information, and their stated probability of undergoing further investigation or interventions for disease management. This aims to provide new, quantitative information of whether individuals’ health-related behaviour is likely to be modified by knowledge of one’s PRS. Results from the pilot study will be used to inform the design of the main study, and the analysis will use multinomial logit models. Marginal rates of substitution between attributes, and heterogeneity analysis comparing people with different demographic characteristics, will also be carried out.Ethics and DisseminationEthics approval (reference: R89898/RE001) was obtained through the Medical Sciences Interdivisional Research Ethical Committee (MS IDREC) at the University of Oxford. The results of this research will be submitted to academic journals and will be presented at conferences.
Causes of Death among Cancer Patients: Emerging Trends in the 21st Century
Authors: Wang Junpu , Liu Jie , Liu Ziyu , Zhou Zongjiang , Ousmane Diabate , Liu Liu , Peng Li , Yuan Xiaoqing 
Published: October 2024

AbstractMost studies examining the causes of cancer-related deaths have primarily focused on specific cancer types, often neglecting the evolving spectrum of death causes among cancer patients in the 21st century. This study, utilizing data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, analyzed the causes of death in patients diagnosed with 36 types of cancer between 2000 and 2021. By categorizing these causes into deaths from index cancers, non-index cancers, and non-cancer causes, this study provides a comprehensive analysis of cause-of-death patterns and emerging trends, stratified by year of death, age at diagnosis, and survival duration. The findings reveal that while relative mortality rates from index cancers remain elevated for brain, pancreatic, and gallbladder cancers, significant declines were observed for lung, liver, nasopharyngeal, and esophageal cancers, as well as multiple myeloma cancers, reflecting advancements in cancer treatment. Besides, relative mortality rates from non-index cancers surpassed those from index cancers in oral cavity, oropharyngeal, vaginal, and small intestine cancers, indicating a potential benefit from enhanced surveillance and early detection of non-index cancers in these patient populations. Importantly, non-cancer-related causes of death, such as heart disease, chronic liver disease and cirrhosis, also emerged as prominent contributors to mortality among cancer patients. The results of this study offer critical and current data to inform public health policy, optimize healthcare resource allocation, and facilitate international collaboration in cancer research and control. Meanwhile, this study is of great reference value for developing countries to formulate medium– and long-term public health policies.
Prevalence of gastrointestinal symptoms is higher close to the sea: evidence from coastal Bangladesh
Authors: Fardousi Ammatul , Novak Masuma , Sagar Sharoardy , Chowdhury Srizan , Haque Rehnuma , Rahman Habibur , Kabir Iqbal , Hanifi Manzoor Ahmed 
Published: October 2024

AbstractBackgroundSea level rise, heavy rainfall, flooding, and temperature changes due to climate change contribute to the spread of enteric infections, disrupting normal intestinal functions and leading to gastrointestinal (GI) symptoms such as nausea, vomiting, and diarrhea etc. Coastal regions of Bangladesh are projected to be highly vulnerable to diarrheal diseases and cholera outbreaks by 2050. However, there is limited research on how coastal proximity affects GI health. Thus, we aimed to examine the association between GI symptoms and geographic distance from the sea in a coastal area of Bangladesh.Materials and methodsThis study was conducted in the Chakaria Health and Demographic Surveillance System area of icddr,b which is running since 1999. A total of 61,295 household members were interviewed between 2012 and 2016. GI symptoms were chosen as the primary outcome measure of this study. We employed chi-square tests and logistic regression analysis model.ResultOverall, 7% reported experiencing one or more GI symptoms in the previous two weeks. Diarrhea was the most prevalent symptom (35%), followed by heartburn (22%) and abdominal pain (18%). Prevalence was significantly higher among females (8%, p<0.05), older adults (13%, p<0.05), and individuals from lower socioeconomic backgrounds (8%, p<0.05). Seasonal variation was observed, with the highest prevalence in summer (9%, p<0.05) and the lowest in winter (5%, p<0.05). Additionally, participants living within 15 kilometers (aOR: 1.35, 95% CI: 1.24-1.46) and 15-20 kilometers (aOR: 1.23, 95% CI: 1.10-1.38) of the sea had a higher risk of GI symptoms compared to those residing more than 20 kilometers away, after adjusting for other covariates.ConclusionOur finding demonstrates that individuals residing near the coast have a higher prevalence of GI symptoms. This evidence suggests the need for targeted public health strategies to improve GI health in climate vulnerable coastal populations. Also, further research is needed to determine the causal effect as well as the underlying biological mechanisms of GI symptoms in these population.