bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lysosomal TBK1 Responds to Amino Acid Availability to Relieve Rab7-Dependent mTORC1 Inhibition
Authors: Talaia Gabriel , Bentley-DeSousa Amanda , Ferguson Shawn M. 
Published: December 2023

AbstractLysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. At lysosomes, this TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.
Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia
Authors: Zhou Ling , Ni Chengyang , Liao Ruixue , Tang Xiaoqin , Yi Taian , Ran Mei , Huang Miao , Liao Rui , Zhou Xiaogang , Qin Dalian , Wang Long , Huang Feihong , Xie Xiang , Wan Ying , Luo Jiesi , Wang Yiwei , Wu Jianming 
Published: December 2023

AbstractThrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induces the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of VLZ. The effects of Vilazodone (VLZ) on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopeniain vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.
Comparing random and timed mating of mice in the experimental paradigm
Authors: Imran M , Mohsin M , Azam T , Fatima K , Naeem MK , Ahmad W , Basri R , Naz S , Anwar M , Jabeen Q , Khurshid M. 
Published: December 2023

AbstractMus Musculushas provided scientists a well-adapted animal model for the developmental studies. There is one on one co-relation between molecular determinants such as genes between humans and mice hence making them superior model to study gene expression and to do translation research. Swiss albino mice strain of house mice was used in this study with comparisons of efficiency of pregnancies during two different strategies of mating; i.e., more traditional random/blind mating and more recent timed mating in experimental paradigms to get staged mice embryos. The workflow required for the blind mating was less labor intensive and required minimal maintenance both time and human resource and was easy to execute. On the other hand, timed mating strategy was ideal for getting staged embryos that was efficient in giving pregnancies and was ideal for less equipped labs but however required more maintenance and human resource. The results of comparisons of weight gain with pregnancies was similar in two groups where some un-pregnant mice also showed average or above average weight gain with time. The z-test analysis for difference between two proportions was employed to calculate efficiency of pregnancies in the two groups and p value was found to be 0.06 which suggested that was no significant difference between the two groups however, this might be due to small sample size that was possible in our small setting. The accurate embryonic staging was required in the experiments corresponding to the peak of neurogenesis in mice and embryos were fixed and sectioned and later studied with immunohistochemistry. The timed matings showed to be superior regarding total pregnancies and having accurate stages and is recommended in labs even if in smaller settings and prevent less animal sacrifice.
Pair-bond strength is consistent and related to partner responsiveness in a wild corvid
Authors: Hooper Rebecca , Hahn Luca G. , McIvor Guillam E. , Thornton Alex 
Published: December 2023

AbstractThe need to maintain strong social bonds is widely held to be a key driver of cognitive evolution. This assumes that the maintenance of strong bonds is a stable trait that is cognitively demanding but generates fitness benefits, and so can come under selection. However, these fundamental micro-evolutionary tenets have yet to be tested together within a single study system. Combining observational and experimental behavioural data with long-term breeding records, we tested four key assumptions in wild jackdaws (Corvus monedula), corvids whose long-term pair-bonds exemplify the putative social drivers of cognitive evolution in birds. We found support for three assumptions: (1) pair-bond strength varies across the population, (2) is consistent within pairs over time and (3) is positively associated with a measure of socio-cognitive performance. However, we did not find evidence that stronger pair-bonds lead to better fitness outcomes (prediction 4). While strongly bonded pairs were better able to adjust hatching synchrony to environmental conditions, they did not fledge more or higher quality offspring. Together, these findings provide important evidence that the maintenance of strong pair bonds is linked to socio-cognitive performance and facilitates effective coordination between partners. However, they also imply that these benefits may not be sufficient to explain how selection acts on social cognition. We argue that evaluating how animals navigate trade-offs between investing in long-term relationships versus optimising interactions in their wider social networks will be a crucial avenue for future research.
Expression Profile of Primary Microcephaly GenesCdk5rap2,Cep63and Their ParaloguesPde4dip,Ccdc67in Mouse Embryonic and Adult Tissues
Authors: Khurshid M. , Fatima K. , Azam T. 
Published: December 2023

AbstractAutosomal recessive primary microcephaly (MCPH) is characterized by the prenatal reduction in the human brain growth, without any change in the cerebral architecture. MCPH can result from the bi-allelic mutations in at least thirty genes and still counting on. MCPH genes majorly code for a centrosomal protein subset, cell cycle proteins, nuclear proteins and cytoskeletal proteins. Centrosomal subset is the most highly characterized subset of MCPH proteins.Cep63andCdk5rap2with their paraloguesCcdc67andPde4dipplay important role for the normal assembly of spindles and in DNA damage response. They regulate neuroepithelial cell division in the developing brain, so decrease in centrosome number results in genomic instability. Study presented in this manuscript was aimed to identify the tissue specific expression of genes with their paralogues (Cep63andCcdc67) and (Cdk5rap2andPde4dip) in developing and adult normal mice tissue cells. For this purpose we successfully generated timed pregnant mice at the peak of neurogenesis and 36 samples were screened for the expression of these genes and their paralogues. RNA was extracted from the mice tissues using trizol reagent. Extracted RNA was reverse transcribed and cDNA was subjected to PCR amplification using gene specific primers, generated by using primer3 at the intron-exon junction to avoid the genomic interference. One house keeping gene β-actin was used as a positive control. This study reveals thatCep63 and Ccdc67paralogues are playing a suggestive collective role in the mice development as shown by multiple length bands.Cdk5rap2an MCPH gene and its paraloguePde4dipband suggested that maybe they might have redundant roles in body organs apart from the brain. These proteins have tissue-specific expression in all studied tissues from the developing and adult mice. We identified multiple bands in the different samples of all four genes which might reflect towards multiple transcript variants.
Characterization of β-lactamase and virulence genes inPseudomonas aeruginosaisolated from clinical, environmental and poultry sources in Bangladesh
Authors: Islam Raihana , Ferdous Farhana Binte , Hoque M. Nazmul , Asif Nowshad Atique , Rana Md. Liton , Siddique Mahbubul Pratik , Rahman Md. Tanvir 
Published: December 2023

AbstractThe emergence and spread of multidrug-resistant pathogens likePseudomonas aeruginosaare major concerns for public health worldwide. This study aimed to investigate the prevalence of circulatingP. aeruginosaisolated from clinical, environmental and poultry sources in Bangladesh, their antibiotic susceptibility, β-lactamase and virulence gene profiling using standard molecular and microbiology techniques. We collected 110 samples from five different locations,viz., BAU residential area (BAURA; n=15), BAU Healthcare Center (BAUHCC; n = 20), BAU Veterinary Teaching Hospital (BAUVTH; n=22), Poultry Market (PM; n=30) and Mymensingh Medical College Hospital (MCCH; n=23). After overnight enrichment in nutrient broth, 89 probablePseudomonasisolates (80.90%) were screened through selective culture, gram-staining and biochemical tests. Using genus- and species-specific PCR, we confirmed 22 isolates (20.0%) asP. aeruginosafrom these samples. Antibiogram profiling revealed that 100.0%P. aeruginosaisolates (n = 22) were multidrug-resistant isolates, showing resistance against Doripenem, Penicillin, Ceftazidime, Cefepime, and Imipenem. Furthermore, resistance to aztreonam was observed in 95.45% isolates. However,P. aeruginosaisolates showed a varying degree of sensitivity against Amikacin, Gentamicin, and Ciprofloxacin. TheblaTEMgene was detected in 86.0% isolates, whileblaCMY,blaSHVandblaOXA,were detected in 27.0%, 18.0% and 5.0% of theP. aeruginosaisolates, respectively. ThealgDgene was detected in 32.0% isolates, whereaslasBandexoAgenes were identified in 9.0% and 5.0%P. aeruginosaisolates. However, none of theP. aeruginosaisolates harboredexoSgene. Thus, this study provides novel and important data on the resistance and virulence ofP. aeruginosacurrently circulating in clinical, environmental and poultry environment of Bangladesh. These data provide important insights into the emergence of β-lactamase resistance inP. aeruginosa, highlighting its usefulness in the treatment and control ofP. aeruginosainfections in both humans and animals.
Transgenerational effects of early life stress on the fecal microbiota in mice
Authors: Otaru Nize , Kourouma Lola , Pugin Benoit , Constancias Florentin , Braegger Christian , Mansuy Isabelle M. , Lacroix Christophe 
Published: December 2023

AbstractStress in early life can affect the progeny and increase the risk to develop psychiatric and cardiometabolic diseases across generations. The cross-generational effects of early life stress have been modeled in mice and demonstrated to be associated with epigenetic factors in the germline. While stress is known to affect gut microbial features, whether its effects can persist across life and be passed to the progeny is not well defined. Here we show that early postnatal stress in mice shifts the fecal microbial composition (binary Jaccard index) throughout life. Further effects on fecal microbial composition and structure (weighted Jaccard index) are detected in the progeny across two generations. These effects are not accompanied by changes in bacterial metabolites and related predicted metabolic pathways in any generation. These results suggest that changes in the fecal microbial community induced by early life traumatic stress can be perpetuated from exposed parent to the offspring.
Architecture of Ca2+tunneling, a basic Ca2+signaling modality important for secretion
Authors: Courjaret Raphael J. , Wagner Larry E. , Ammouri Rahaf R. , Assaf Lama , Yu Fang , Fisher Melanie , Terasaki Mark , Yule David I. , Machaca Khaled 
Published: December 2023

ABSTRACTCa2+tunneling is a signaling modality that requires both Store-operated Ca2+entry (SOCE) and Ca2+release from the endoplasmic reticulum (ER). Tunneling expands the SOCE microdomain at ER-plasma membrane (PM) contact sites (ERPMCS) through Ca2+uptake by the sarco/endoplasmic reticulum Ca2+ATPase (SERCA) into the ER lumen where it diffuses and is released via open inositol trisphosphate (IP3) receptors (IP3Rs). In this study using high resolution imaging, we outline the spatial remodeling of the Ca2+tunneling machinery (IP3R1; SERCA; PMCA; and Ano1 as an effector) relative to STIM1 in response to store depletion. We show that store depletion leads to redistribution of these Ca2+signaling modulators to distinct subdomains laterally at the PM and axially within the cortical ER. To functionally define the role of Ca2+tunneling, we engineered a Ca2+tunneling attenuator (CaTAr) that blocks tunneling without affecting Ca2+release or SOCE. CaTAr inhibits Cl−secretion in sweat gland cells. Viral mediated expression of CaTAr in the mouse reduces sweating, showing that Ca2+tunneling is important physiologically. Collectively our findings outline the architecture of the Ca2+tunneling machinery and show that it is a fundamental physiological pertinent Ca2+signaling modality.
Nationwide genome surveillance of carbapenem-resistantPseudomonas aeruginosain Japan
Authors: Yano Hirokazu , Hayashi Wataru , Kawakami Sayoko , Aoki Sadao , Anzai Eiko , Zuo Hui , Kitamura Norikazu , Hirabayashi Aki , Kajihara Toshiki , Kayama Shizuo , Sugawara Yo , Yahara Koji , Sugai Motoyuki 
Published: December 2023

ABSTRACTJapan is a country with an approximate 10 % prevalence rate of carbapenem-resistantPseudomonas aeruginosa(CRPA). Currently, a comprehensive overview of the genotype and phenotype patterns of CRPA in Japan is lacking. Herein, we conducted genome sequencing and quantitative antimicrobial susceptibility testing for 382 meropenem-resistant CRPA isolates that were collected from 78 hospitals across Japan from 2019 to 2020. CRPA exhibited susceptibility rates of 52.9%, 26.4%, and 88.0% against piperacillin-tazobactam, ciprofloxacin, and amikacin, respectively, whereas 27.7% of CRPA isolates were classified as difficult-to-treat resistanceP. aeruginosa. Of the 148 sequence types detected, ST274 (9.7%) was predominant, followed by ST235 (7.6%). The proportion of urine isolates in ST235 was higher than that in other STs (P= 0.0056, chi-square test). Only 4.1% of CRPA isolates carried the carbapenemase genes:blaGES(2) andblaIMP(13). One ST235 isolate carried the novelblaIMPvariantblaIMP-98in the chromosome. Regarding chromosomal mutations, 87.1% of CRPA isolates possessed inactivating or other resistance mutations inoprD, and 28.8% showed mutations in the regulatory genes (mexR, nalC, andnalD) for the MexAB-OprM effux pump. Additionally, 4.7% of CRPA isolates carried a resistance mutation in the PBP3-encoding geneftsI. The findings from this study and other surveillance studies collectively demonstrate that CRPA exhibits marked genetic diversity and that its multidrug resistance in Japan is less prevailed than in other regions. This study contributes a valuable dataset that addresses a gap in genotype/phenotype information regarding CRPA in the Asia–Pacific region, where the epidemiological background markedly differs between regions.
First animal source metagenome assembly ofLawsonella clevelandensisfrom canine external otitis
Authors: Tóth Adrienn Gréta , Solymosi Norbert , Tenk Miklós , Káldy Zsófia , Németh Tibor 
Published: December 2023

ABSTRACTExternal otitis is one of the most common conditions in dogs to be presented to the veterinarian. Moreover, the disorder is often difficult to manage. The range and role of microorganisms involved in the pathogenesis are currently not fully understood. Therefore, the condition has been studied using third-generation sequencing (Oxford Nanopore Technology) to gain a more complete picture of the pathogens involved. Throughout the metagenome assembly of a sample harvested from the ear canal of an 11-year-old female Yorkshire terrier suffering from chronic external otitis, a genome ofLawsonella clevelandensiswas compiled. To our knowledge, this result is the first of its type of animal origin. The outcome of the assembly (CP140010) is a single circular chromosome with a length of 1,878,509 bp, and 1,826 predicted protein-coding genes. No open reading frames associated with antimicrobial resistance could have been identified.
Transcriptional shut-off of MAP kinase signaling enables pluripotency maintenance during diapause
Authors: Zhang Tuo , Marina Ryan J. , Prinjha Rab , Adelman Karen , Tarakhovsky Alexander 
Published: December 2023

AbstractExposure of unicellular or multicellular organisms to adverse environmental conditions, including nutrient deprivation, may induce a state of suspended animation or diapause. The diapause minimizes the organism’s reliance on external energy sources and ensures survival. Among different forms of diapause, embryonic diapause, caused by a limited supply of nutrients to the growing embryos, is particularly challenging for the organism. Diapause embryos stop developing at the peak of pluripotent cell differentiation and maintain this undifferentiated yet entirely vital state despite the overall reduction in anabolic processes and genome-wide transcriptional repression. Using ES cells commonly employed to study the mechanism of embryonic diapause, we solve the paradox of the cell maintenance in an undifferentiated ES cell state during diapause. We find that broad transcriptional repression by long-term inhibition of the bromodomain and extra-terminal (BET) proteins causes diapause. These diapause ES cells upregulate a functionally linked group of genes encoding negative regulators of MAP kinase signaling (NRMKS), which play a crucial role in ES cell differentiation. We find that elevated NRMKS expression is a hallmark of the diapause cells and cells exposed to diapause-inducing conditions, including mTOR inhibition, and is required for the maintenance of ES cell pluripotency during diapause. Mechanistically, exposure of ES cells to diapause-inducing conditions leads to rapid decline of the Capicua transcriptional repressor (CIC) at the NRMKS gene promoters, followed by transcriptional upregulation of NRMKS genes. The mTOR and BET-dependent transcriptional switch supporting the undifferentiated state of the diapause ES cells suggests a broader usage of this mechanism in maintaining the undifferentiated state of metabolically dormant stem- or stem-like cells in different tissues.
Artificial intelligence for ventricular arrhythmia capability using ambulatory electrocardiograms
Authors: Barker Joseph , Li Xin , Kotb Ahmed , Mavilakandy Akash , Antoun Ibrahim , Thaitirarot Chokanan , Koev Ivelin , Man Sharon , Schlindwein Fernando S , Dhutia Harshil , Chin Shui Hao , Tyukin Ivan , Nicolson William B , Ng G Andre 
Published: December 2023

Lay AbstractQuestionCan artificial intelligence (AI) be used to predict if a person is at risk of a lethal heart rhythm, based solely on an electrocardiogram (an electrical heart tracing)?FindingsIn a study of 270 adults (of which 159 had lethal arrhythmias), the AI was correct in 4 out of every 5 cases. If the AI said a person was at risk, the risk of lethal event was three times higher than normal adults.MeaningIn this study, the AI performed better than current medical guidelines. The AI was able accurately determine the risk of lethal arrhythmia from standard heart tracings over a year away which is a conceptual shift in what an AI model can see and predict. This method shows promise in better allocating implantable shock box pacemakers (ICDs) that saves lives.Scientific AbstractAimCurrent clinical practice guidelines for implantable cardioverter defibrillators (ICDs) are insufficiently accurate for ventricular arrhythmia (VA) risk stratification leading to significant morbidity and mortality. Artificial intelligence offers novel risk stratification lens through which VA capability can be determined from electrocardiogram in normal sinus rhythm. The aim was to develop and test a deep neural network for VA risk stratification using routinely collected ambulatory electrocardiograms.MethodsA multicentre case-control study was undertaken to assess VA-ResNet-50, our open source ResNet-50 based deep neural network. VA-ResNet-50 was designed to read pyramid samples of 3-lead 24-hour ambulatory electrocardiograms to decide if a heart is capable of VA based on the electrocardiogram alone. Consecutive adults with VA from East Midlands, UK, who had ambulatory electrocardiograms as part of their NHS care between 2014 and 2022 were recruited and compared to all comer ambulatory electrocardiograms without VA.ResultsOf 270 patients, 159 heterogeneous patients had a composite VA outcome. The mean time difference between the electrocardiogram and VA was 1.6 years (⅓ ambulatory electrocardiogram before VA). The deep neural network was able to classify electrocardiograms for VA capability with an accuracy of 0.76 (CI 95% 0.66 - 0.87), F1 score of 0.79 (0.67 - 0.90), AUC of 0.8 (0.67 - 0.91) and RR of 2.87 (1.41 - 5.81).ConclusionAmbulatory electrocardiograms confer risk signals for VA risk stratification when analysed using VA-ResNet-50.Pyramid samplingfrom the ambulatory electrocardiograms is hypothesised to capture autonomic activity. We encourage groups to build on this open-source model.