bluuebunny/crossref_metadata_2025 huggingface dataset:
An ancient transcription activator is required for the multiciliogenesis program
Authors: Jiang Haochen , Hua Mengting , Ding Mei , Hu Jiaqi , Zheng Shiqiong , Wang Hanchen , Wang Weihua , Xu Cheng , Xing Junqiao , Liu Hongni , Zhao Xue , Hu Zhangfeng
Published: December 2023

Multiciliogenesis is an evolutionarily conserved process required a unique transcriptional program. The mechanisms governing multiciliogenesis are incompletely understood. Here we show that an ancient transcription activator, Edf1, is essential for the multiciliogenesis program. Mice lacking Edf1 exhibit postnatal hydrocephalus and delayed multiciliated cells (MCCs) differentiation. Functional studies reveal that MCCs in Edf1-/-mice have defects in tissue-level polarity and reduced motility. These defects result in abnormal cerebrospinal fluid (CSF) dynamics in vivo, potentially contributing to the development of hydrocephalus. Intriguingly, we found that the expression of pivotal ciliary transcription factors was decreased in Edf1-/-mice. Collectively, our data suggest that Edf1 modulates the multiciliogenesis by regulating the transcription of important ciliary transcription factors required for ciliary gene expression.
Interferon α and β induce differential transcriptional and functional metabolic phenotypes in human monocyte-derived macrophages and blunt glycolysis in response to antigenic stimuli
Authors: Leisching Gina , Yennemadi Anjali , Gogan Karl , Keane Joseph
Published: December 2023

In the context of acute settings, the roles of type I interferons (IFNs), notably subtypes IFNα2a, 2b, and β, in modulating macrophage metabolism and contributing to host defense against viral and bacterial pathogens are well-established. However, the impact of chronic exposure to type I IFNs on macrophage metabolism, intimately linked to macrophage function, remains less understood. This study aimed to unravel the nuanced host responses induced by type I IFN cytokines, offering insights for potential therapeutic approaches in diseases associated with these cytokines.Employing a combination of transcriptional profiling and real-time functional analysis, we delineated the temporal evolution of metabolic reprogramming in response to chronic interferon exposure. Our results reveal distinct transcriptional metabolic profiles between macrophages chronically exposed to IFNα and IFNβ. Agilent Seahorse assays demonstrated that IFNβ significantly diminishes the oxygen consumption rate and glycolytic proton extrusion rate in macrophages. Conversely, IFNα2b decreased parameters of mitochondrial fitness and induced a shift towards glutamine oxidation.Assessing the ability of macrophages to induce glycolysis in response to antigenic stimuli (LPS and iH37Rv), we found that chronic exposure to all IFN subtypes limited glycolytic induction. This study addresses a critical oversight in the literature, where individual roles of IFN subtypes are frequently amalgamated and lack distinction. These findings not only provide novel insights into the divergent effects of interferon α2a, α2b, and β on macrophage metabolism but also highlight their potential implications for developing targeted therapeutic strategies. This is particularly relevant in autoimmune disorders where type I IFNs, particularly IFNα, play a central role. The observed metabolic quiescence induced by chronic IFN exposure underscores its significance in macrophage functionality and its potential contribution to the pathophysiology of autoimmune disorders and susceptibility to infection.
Observation of E-cadherin Adherens Junction Dynamics with Metal-Induced Energy Transfer Imaging and Spectroscopy
Authors: Chen Tao , Karedla Narain , Enderlein Jörg
Published: December 2023

Epithelial cadherin (E-cad) mediated cell-cell junctions play a crucial role in the establishment and maintenance of tissues and organs. In this study, we employed metal-induced energy transfer imaging and spectroscopy to investigate variations in intermembrane distance during adhesion between two model membranes adorned with E-cad. By correlating the measured intermembrane distances with the distinct E-cad junction states, as determined by their crystal structures, we probed the dynamic behavior and diversity of E-cad junctions across different binding pathways.

Our observations led to the identification of a transient intermediate state referred to as the X-dimeric state and enabled a detailed analysis of its kinetics. We discovered that the formation of the X-dimer leads to significant membrane displacement, subsequently impacting the formation of other X-dimers. These direct experimental insights into the subtle dynamics of E-cad-modified membranes and the resultant changes in intermembrane distance provide novel perspectives on the assembly of E-cad junctions between cells. This knowledge en-hances our comprehension of tissue and organ development and may serve as a foundation for the development of innovative therapeutic strategies for diseases linked to cell-cell adhesion abnormalities.

Significance Statement

In this study, we employed metal-induced energy transfer (MIET) imaging and spectroscopy to track variations in intermembrane distance during the adhesion of two membranes mediated by epithelial cadherin. Leveraging the high spatial resolution of MIET, we explored the dynamics of cadherins across various binding pathways. Furthermore, we successfully captured a transient intermediate state known as the X-dimer and revealed its ability to communicate with other X-dimers through membrane displacement. These discoveries offer valuable mechanistic insights into the dynamics of cadherin junctions.
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

Lysosomes 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

Thrombocytopenia 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

Mus 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

The 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

Autosomal 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

The 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

Stress 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

Ca2+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

Japan 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

External 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

Exposure 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 Abstract

Question

Can 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)?

Findings

In 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.

Meaning

In 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 Abstract

Aim

Current 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.

Methods

A 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.

Results

Of 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).

Conclusion

Ambulatory 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.
SARS-CoV-2 serosurvey across multiple waves of the COVID-19 pandemic in New York City between 2020-2023
Authors: Carreño Juan Manuel , Wagner Abram L. , Monahan Brian , Floda Daniel , Gonzalez-Reiche Ana S , Tcheou Johnstone , Raskin Ariel , Bielak Dominika , Singh Gagandeep , Morris Sara , Fried Miriam , Yellin Temima , Sullivan Leeba ,   PARIS study group, Sordillo Emilia Mia , Gordon Aubree , van Bakel Harm , Simon Viviana , Krammer Florian
Published: December 2023

Sero-monitoring provides context to the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and changes in population immunity following vaccine introduction. Here, we describe results of a cross-sectional hospital-based study of anti-spike seroprevalence in New York City (NYC) from February 2020 to July 2022, and a follow-up period from August 2023 to October 2023. Samples from 55,092 individuals, spanning five epidemiological waves were analyzed. Prevalence ratios (PR) were obtained using Poisson regression. Anti-spike antibody levels increased gradually over the first two waves, with a sharp increase during the 3rdwave coinciding with SARS-CoV-2 vaccination in NYC resulting in seroprevalence levels >90% by July 2022. Our data provide insights into the dynamic changes in immunity occurring in a large and diverse metropolitan community faced with a new viral pathogen and reflects the patterns of antibody responses as the pandemic transitions into an endemic stage.
Missense and Loss of Function Variants at GWAS Loci in Familial Alzheimer’s Disease
Authors: Gunasekaran Tamil Iniyan , Reyes-Dumeyer Dolly , Faber Kelley M. , Goate Alison , Boeve Brad , Cruchaga Carlos , Pericak-Vance Margaret , Haines Jonathan L. , Rosenberg Roger , Tsuang Debby , Mejia Diones Rivera , Medrano Martin , Lantigua Rafael A. , Sweet Robert A. , Bennett David A. , Wilson Robert S. , Alba Camille , Dalgard Clifton , Foroud Tatiana , Vardarajan Badri N. , Mayeux Richard
Published: December 2023

BACKGROUND

Few rare variants have been identified in genetic loci from genome wide association studies of Alzheimer’s disease (AD), limiting understanding of mechanisms and risk assessment, and genetic counseling.

METHODS

Using genome sequencing data from 197 families in The NIA Alzheimer’s Disease Family Based Study, and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study.

RESULTS

Eighty-six rare missense or loss of function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) of familiesAPOE-e4was the only variant segregating. However, in 60.3% of families neitherAPOE-e4nor missense or LoF variants were found within the GWAS loci.

DISCUSSION

AlthoughAPOE-ε4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.
Beyond Borders: Spatial Disparities in the Mortality Burden of the Covid-19 pandemic across 569 European Regions (2020-2021)
Authors: Bonnet Florian , Grigoriev Pavel , Sauerberg Markus , Alliger Ina , Mühlichen Michael , Camarda Carlo-Giovanni
Published: December 2023

This article presents a detailed analysis of the global mortality burden of the COVID-19 pandemic across 569 regions in 25 European countries. We produce age and sex-specific excess mortality and present our results using Age-Standardised Years of Life Lost (ASYLL) in 2020 and 2021, as well as the cumulative impact over the two pandemic years. Employing a robust forecasting approach that considers regional diversity and provides confidence intervals, we find notable losses in 362 regions in 2020 (440 regions in 2021). Conversely, only seven regions experienced gains in 2020 (four regions in 2021). Most importantly, we estimate that eight regions suffered losses exceeding 20 years of life per 1,000 population in 2020, whereas this number increased to 75 regions in 2021. The contiguity of the regions investigated in our study also reveals the changing geographical patterns of the pandemic. While the highest excess mortality values were concentrated in the early COVID-19 outbreak areas during the initial pandemic year, a clear East-West gradient appeared in 2021, with regions of Slovakia, Hungary, and Latvia experiencing the highest losses. This research underscores the importance of regional analyses for a nuanced comprehension of the pandemic’s impact.
Clinical, laboratory, and imaging findings of stage 3-5 chronic kidney disease patients suffering from COVID-19 in Bangladesh: a prospective cross-sectional study
Authors: Ullah Ahsan , Khanam Asia , Mondal Mina , Haque Md Rezwanul , Sumon AHM Sanjedul Haque , Khan Shakila , Hoque Mohimanul , Sumon Motiur Rahman , Rahman Mohammad Meshbahur
Published: December 2023

Background

Chronic kidney disease (CKD) patients were susceptible to morbidity and mortality once they affected by COVID-19. These patients were more likely to develop severe disease, requiring dialysis, admission to intensive care unit. The aim of this study was to evaluate the presentations and outcomes of COVID-19 in stage 3-5 CKD patients not on dialysis.

Methods

This prospective observational study was conducted in the COVID-19 unit, at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from September 2020 to August 2021. Hospitalized RT-PCR positive COVID-19 patients with pre-existing CKD having eGFR <60 ml/min/1.73 m2but not yet on dialysis were enrolled. Clinical and laboratory parameters were recorded. Outcomes were observed till discharge from the hospital and followed up after 3 months of survived patients.

Results

Out of 109 patients, the mean age was 58.1(SD: ±15.4) years where 61.5% were male. Common co-morbid conditions were hypertension (89.0%), diabetes mellitus (58.7%) and ischemic heart disease (24.8%). Fever, cough, shortness of breath and fatigue were common presenting features. Most of the patients had moderate (41.3%) and severe (41.3%) COVID-19. Sixty-six patients (60.6%) developed AKI on CKD. Twenty patients (30.3%) required dialysis. Death occurred in 16 patients (14.7%) and 12 patient’s (11%) required ICU admission and 6 patients (9.1%) achieved baseline renal function at discharge. We identified risk factors like low haemoglobin, lymphopenia, high CRP, high procalcitonin, high LDH and low SpO2in patients who did not survive. Seventy-six patients were followed up at 3rd month where 17 patients were lost. Ten patients (27.0%) achieved baseline renal function who had persistent AKI at discharge and 34 patients (87.1%) remained stable who had stable renal function at discharge.

Conclusion

The stage 3-5 chronic kidney patients with COVID-19 are vulnerable to severe to critical morbidity and mortality with higher incidence of AKI which demands a special attention to this group of patients.
Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors
Authors: Ray Christina MP , Yang Huilin , Spangler Jamie B , Mac Gabhann Feilim
Published: December 2023

The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design.
An evolutionary optimum amid moderate heritability in prokaryotic cell size
Authors: Secaira-Morocho Henry , Chede Abhinav , Gonzalez-de-Salceda Luis , Garcia-Pichel Ferran , Zhu Qiyun
Published: December 2023

We investigated the distribution and evolution of prokaryotic cell size based on a compilation of 5380 species. Size spans four orders of magnitude, from 100 nm (Mycoplasma) to more than 1 cm (Thiomargarita), however most species congregate heavily around the mean. The distribution approximates but is distinct from log-normality. Comparative phylogenetics suggested that size is heritable, yet the phylogenetic signal is moderate, and the degree of heritability is independent of taxonomic scale (i.e. fractal). Evolutionary modeling indicated the presence of an optimal cell size, corresponding to a coccus 0.70 µm in diameter, to which most species gravitate. Analyses of 1361 species with sequenced genomes showed that genomic traits contribute to size evolution moderately and synergistically. In light of our results, scaling theory, and empirical evidence, we discuss potential drivers that may expand or shrink cells around the optimum and propose a stability landscape model for prokaryotic cell size.
Emotion Dynamics in Reciprocity: Deciphering the Role of Prosocial Emotions in Social Decision-making
Authors: Kim Jaewon , Bong Su Hyun , Yoon Dayoung , Jeong Bumseok
Published: December 2023

To date, the relevance of prosocial emotions in social decisions based on reciprocity remains poorly understood. Expected and experienced emotions in interoceptive-social dimension, expected offers, and actual acceptance were measured in 476 participants during an ultimatum game consisting of fair, moderate, and unfair offers. We investigated whether participants adjust social decisions according to prediction errors on prosocial emotions and reciprocity. Participants’ acceptance trajectories were explained by prediction errors in dominance, valence, and reward. Participants were categorized into 4 distinct subgroups based on their patterns of reward expectation, acceptance, and emotional experiences before and after the offer. Furthermore, the relationships between prosocial emotions, social decisions, and reciprocity varied across these subgroups. This study’s measurement and analysis of multidimensional trajectories across four affect dimensions reveal that social decisions are influenced by the responder’s perception of partner’s reciprocity, as well as by the subsequent prediction error of basic and prosocial emotion.
Atlas of telomeric repeat diversity inArabidopsis thaliana
Authors: Tao Yueqi , Xian Wenfei , Rabanal Fernando , Movilli Andrea , Lanz Christa , Shirsekar Gautam , Weigel Detlef
Published: December 2023

Telomeric repeat arrays at the ends of chromosomes are highly dynamic but their repetitive nature and technological limitations have made it difficult to assess the variation in genome diversity surveys. Here we present a comprehensive characterization of the sequence variation immediately adjacent to the canonical telomeric repeat arrays at the very ends of chromosomes in 49 genetically diverseArabidopsis thalianaaccessions. We reveal several types of distinct telomeric repeat units and identify evolutionary processes such as local homogenization and higher-order repeat formation that shape diversity of chromosome ends. The identification of segmental duplications and at least one recombination event suggests a plausible history of telomerase-independent maintenance generation. By comparing largely isogenic samples, we are able to determine variant telomeric repeat number variation at both the germline and somatic levels. Analysis of haplotype structure uncovers chromosome end-specific as well as genetic group-specific patterns in telomeric repeat diversity and provides evidence for linkage disequilibrium between repeat arrays and their adjacent non-coding regions. Together, our findings illustrate the fine-scale telomeric repeat spectrum inA. thaliana, expanding our knowledge of the evolution of chromosome ends.
The genome of the rayed Mediterranean limpetPatella caerulea(Linnaeus, 1758)
Authors: Halstead-Nussloch Gwyneth , Signorini Silvia Giorgia , Giulio Marco , Crocetta Fabio , Munari Marco , Torre Camilla Della , Weber Alexandra Anh-Thu
Published: December 2023

Patella caerulea(Linnaeus, 1758) is a molluscan limpet species of the class Gastropoda. Endemic to the Mediterranean Sea, it is considered to be a keystone species in tidal and subtidal habitats due to its primary role in structuring and regulating the ecological balance of these habitats. It is currently being used as a bioindicator to assess the environmental quality of coastal marine waters and as a model species to understand adaptation to ocean acidification. Here we provide a high-quality reference genome assembly and annotation forPatella caerulea. We used a single specimen collected in the field to generate ∼30 Gb of PacBio HiFi data. The final assembly is 749.8 Mb large and contains 62 contigs, including the mitochondrial genome (14,938 bp). With an N50 of 48.8 Mb and 98% of the assembly contained in the 18 largest contigs, this assembly is near chromosome-scale. BUSCO scores were high (Mollusca: 87.8% complete; Metazoa: 97.2% complete) and similar to metrics observed for other chromosome-levelPatellagenomes, highlighting a possible bias in the Mollusca database for Patellids. We generated transcriptomic Illumina data from a second individual collected at the same locality, and used it together with protein evidence to annotate the genome. 23,938 protein coding gene models were found. By comparing this annotation with other publishedPatellaannotations, we found that the distribution and median values of exon and gene lengths was comparable to otherPatellaspecies despite different annotation approaches. The present high-qualityPatella caeruleareference genome is an important resource for future ecological and evolutionary studies.

Significance

Reference genomes are essential resources for biodiversity conservation and management.Patella caerulea(Linnaeus, 1758) is a gastropod species occurring in the Mediterranean Sea that is currently used as a model to understand the impact of pollution and ocean acidification on marine biodiversity. Here we present a high-quality reference genome ofP. caerulea, that almost reaches chromosome-level contiguity. We further provide a high-quality genome annotation supported by transcriptomic evidence. This reference genome will be of interest for researchers working on the ecology and evolution of marine biodiversity. All data is available on the public database NCBI for future use by researchers.
HLA-EpiCheck : A B-cell epitope prediction tool for HLA proteins using molecular dynamics simulation data
Authors: Amaya-Ramirez Diego , Devriese Magali , Lhotte Romain , Usureau Cedric , Smail-Tabbone Malika , Taupin Jean-Luc , Devignes Marie-Dominique
Published: December 2023

1

The Human Leukocyte Antigen (HLA) system is the main cause of organ transplant loss through the recognition of HLA proteins by Donor-Specific Antibodies (DSA). Therefore, the identification of potentially immunogenic epitopes is a key task to refine organ allocation and then to improve the survival of transplanted organs. Here, we present HLA-EpiCheck, a machine learning predictor for B-cell epitopes on HLA proteins that leverages an unprecedented dataset of high-quality molecular dynamics simulations of 207 HLA proteins. Candidate epitopes are represented as surface patches centered on solvent-accessible residues and described by a set of 18 descriptors. The descriptors include both static and dynamic properties, such as hydrophobicity, electrostatic charges, relative solvent-accessible surface area and side-chain flexibility. The HLA-EpiCheck was trained using an Extra Trees ensemble learning method and was compared to DiscoTope-3.0, a state-of-the-art B-cell epitope predictor. HLA-EpiCheck largely outperformed DiscoTope-3.0 in the task of predicting HLA epitopes. HLA-EpiCheck was also used to assess the epitope status of a subset of non-confirmed eplets. The predictions were compared to experimental data and a notable consistency was found. These results suggest that HLA-EpiCheck could be used to better define HLA matching between donor and recipient to reducede novoDSA formation and graft rejection.
Nanobodies as novel tools to monitor the mitochondrial fission factor Drp1
Authors: Froehlich Theresa , Jenner Andreas , Cavarischia-Rega Claudia , Fagbadebo Funmilayo O. , Lurz Yannic , Frecot Desiree I. , Kaiser Philipp D. , Nueske Stefan , Scholz Armin , Schäffer Erik , Garcia-Saez Ana J. , Macek Boris , Rothbauer Ulrich
Published: December 2023

In cells, mitochondria undergo constant fusion and fission. An essential factor for fission is the mammalian dynamin-related protein 1 (Drp1). Dysregulation of Drp1 has been linked to neurodegenerative diseases including Parkinson’s as well as cardiovascular diseases and cancer. Here, we developed nanobodies (Nbs) for proteomics, advanced microscopy and live cell imaging of Drp1. To specifically enrich endogenous Drp1 with interacting proteins for proteomics, we functionalized high-affinity Nbs as capture matrices. Furthermore, we detected Drp1 by bivalent Nbs combined with site-directed fluorophore labelling in super-resolution STORM microscopy. For real-time imaging of Drp1, we intracellularly expressed fluorescently labelled Nbs, so-called chromobodies (Cbs). To improve the signal-to-noise ratio, we further converted Cbs into a “turnover-accelerated” format. With these imaging probes, we visualized the dynamics of endogenous Drp1 upon compound-induced mitochondrial fission in living cells. Considering the wide range of research applications, the presented Nb toolset will open up new possibilities for advanced functional studies of Drp1 in disease-relevant models.