bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurotoxic Methamphetamine Doses Alter CDCel-1 Levels and Its Interaction with Vesicular Monoamine Transporter-2 in Rat Striatum
Authors: Chauhan Heli , Carruthers Nick , Stemmer Paul , Schneider Bernard P. , Moszczynska Anna
Published: July 2024

In recent years, methamphetamine METH misuse in the US has been rapidly increasing and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including dysfunction of the neuroprotective protein parkin. However, it is not known whether parkin loss of function within striatal dopaminergic (DAergic) terminals translates into a decrease in DA storage capacity. This study examined the relationship between parkin, its substrate cell division cycle related-1 (CDCrel-1), and vesicular monoamine transporter-2 (VMAT2) in METH neurotoxicity in male Sprague Dawley rats. To also assess individual differences in response to METH’s neurotoxic effects, a large group of rats was treated with binge METH or saline and sacrificed 1h or 24h later. This study is the first to show that binge METH alters the levels and subcellular localization of CDCrel-1 and that CDCrel-1 interacts with VMAT2 and increases its levels at the plasma membrane. Furthermore, we found wide individual differences in the responses of measured indices to METH. Proteomic analysis of VMAT-2-associated proteins revealed upregulation of several proteins involved in the exocytosis/endocytosis cycle. The results suggest that at 1h after METH binge, DAergic neurons are engaged in counteracting METH-induced toxic effects, including oxidative stress- and hyperthermia-induced inhibition of synaptic vesicle cycling, with the responses varying between individual rats. Studying CDCrel-1, VMAT2, and other proteins in large groups of outbred rats can help define individual genetic and molecular differences in responses to METH neurotoxicity which, in turn, will aid treating humans suffering from METH use disorder and its neurological consequences.
Tiberius: End-to-End Deep Learning with an HMM for Gene Prediction
Authors: Gabriel Lars , Becker Felix , Hoff Katharina J. , Stanke Mario
Published: July 2024

Motivation

For more than 25 years, learning-based eukaryotic gene predictors were driven by hidden Markov models (HMMs), which were directly inputted a DNA sequence. Recently, Holst et al. demonstrated with their program Helixer that the accuracy ofab initioeukaryotic gene prediction can be improved by combining deep learning layers with a separate HMM postprocessor.

Results

We present Tiberius, a novel deep learning-basedab initiogene predictor that end-to-end integrates convolutional and long short-term memory layers with a differentiable HMM layer. Tiberius uses a custom gene prediction loss and was trained for prediction in mammalian genomes and evaluated on human and two other genomes. It significantly outperforms existingab initiomethods, achieving F1-scores of 62% at gene level for the human genome, compared to 21% for the next bestab initiomethod. Inde novomode, Tiberius predicts the exon-intron structure of two out of three human genes without error. Remarkably, even Tiberius’sab initioaccuracy matches that of BRAKER3, which uses RNA-seq data and a protein database. Tiberius’s highly parallelized model is the fastest state-of-the-art gene prediction method, processing the human genome in under 2 hours.

Availability and Implementation

https://github.com/Gaius-Augustus/Tiberius

Contact

{lars.gabriel@uni-greifswald.de,mario.stanke@uni-greifswald.de}
Downregulation of acetyl-CoA carboxylase suppresses the malignant progression of oral cancer
Authors: Jia Guodong
Published: July 2024

In this study, we aimed to investigate the specific role of the acetyl-CoA carboxylase (ACACA) gene in Oral squamous cell carcinoma (OSCC). we constructed Human Tongue Carcinoma Cell Line (SAS cell line) with low ACACA expression and evaluated changes in their cell cycle, proliferation, and metabolite levels. Furthermore, the effect of ACACA on tumor formation in vivo was determined. ACACA knockdown significantly reduced the proliferation ability of SAS cells, while also significantly increasing the number of apoptotic cells. In vivo experiments demonstrated lower tumor volume and weight in the ACACA knockdown group than those in the control group. Exploring the combined effect of ACACA knockdown and cisplatin treatment revealed a promising synergistic effect against ferroptosis signaling and downstream signaling pathways in SAS cells and in vivo. These findings suggest that targeting theACACAgene has the potential to be a novel therapeutic strategy for oral cancer treatment.
Single-cell transcriptomic profiling of the whole colony ofBotrylloides diegensis: Insights into tissue specialization and blastogenesis
Authors: Temiz Berivan , Meier Michael , Wilson Megan J.
Published: July 2024

Botrylloides diegensisis a colonial ascidian that has been the focus of developmental, evolutionary, and regeneration research. In this study, we performed single-cell RNA sequencing (scRNA-seq) of an entireB. diegensiscolony, including zooids, buds, and vascular tunics, to resolve cellular heterogeneity and identify cell and tissue markers. We identified 29 major cell clusters within the colony and usedin situhybridization to examine the spatial expression of cluster marker genes. Numerous tissue types were identified at the molecular level, including blood cells and zooid tissues such as the branchial epithelium, stomach, and endostyle. Distinct cluster markers were identified for specific regions of the stomach epithelium, highlighting the specialization of these regions and the strength of using scRNA-seq to explore their functionality. Cell trajectory projections highlighted the early appearance of progenitor clusters, whereas more differentiated zooid-related tissues appeared later in the developmental path. This study provides a valuable resource for understanding the development, tissue function, and regeneration ofB. diegensis.This demonstrates the power of scRNA-seq to define cell types and tissues in complex colonial organisms.

Summary statement

Single-cell RNA sequencing ofBotrylloides diegensisrevealed cellular heterogeneity, identified 29 major cell clusters, and provided insights into tissue specialization and blastogenesis.
Experiences of Indigenous peoples living with pelvic health conditions: A scoping review
Authors: Brown Kaeleigh , Choi Katherine , Kim Esther , Campbell Sandra M , Schulz Jane , Moffitt Pertice , Chatwood Susan
Published: July 2024

Background

Pelvic health conditions significantly impact quality of life and are prevalent in the general population. Urinary and fecal incontinence, pelvic organ prolapse, and pelvic pain are examples of pelvic health conditions. A scoping review was conducted to understand what is currently known about pelvic health conditions experienced by Indigenous populations worldwide. To date, no such review has been reported.

Methods

A scoping review methodology was used. In June 2023, a search was conducted, and then updated in February 2024, capturing both primary and grey literature. An iterative process of abstract and full text screening was conducted by two reviewers before proceeding to data extraction. Inclusion criteria focused on English publications and reports of pelvic health conditions experienced by Indigenous peoples. Data was collected in Google Sheets, and then underwent descriptive statistical analysis. Publications that provided qualitative data were analyzed using thematic analysis.

Results

A total of 203 publications were included in the analysis. Several patterns emerged regarding publication region, gender and age representation, pelvic health conditions reported, and representation of Indigenous peoples. Notable gaps were a lack of publications from China, Russia, and Nordic countries, minimal representation of gender diverse populations, few publications reporting on auto-immune and bowel conditions, and limited mention of trauma-informed and culturally safe approaches.

Conclusions

This study highlights gaps in the current literature around gender representation, bowel and auto-immune conditions, regional representation, and the use of safety frameworks, which may inform future research initiatives. It also summarizes the existing literature, which may inform clinical and health system-level decision making.
ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency
Authors: Duthoo Evi , Beyls Elien , Backers Lynn , Gudjónsson Thorkell , Huang Peiquan , Jonckheere Leander , Riemann Sebastian , Parton Bram , Du Likun , Debacker Veronique , De Bruyne Marieke , Hoste Levi , Baeyens Ans , Vral Anne , Van Braeckel Eva , Staal Jens , Mortier Geert , Kerre Tessa , Pan-Hammarström Qiang , Sørensen Claus Storgaard , Haerynck Filomeen , Claes Kathleen BM , Tavernier Simon J
Published: July 2024

ATR (Ataxia Telangiectasia and Rad3-related) kinase and its interacting protein ATRIP orchestrate the replication stress response. Two patients of independent ancestry with microcephaly, primordial dwarfism, and recurring infections were found to be homozygous for splice donor site variants ofATRIPexon 5, resulting in ATRIP deficiency. The c.829+5G>T patient exhibited autoimmune hemolytic anemia, lymphopenia, poor vaccine response, and intermittent neutropenia. Immunophenotyping revealed reduced CD16+NK cells and absent naïve T cells, mucosal-associated invariant T cells (MAITs), and invariant natural killer T cells (iNKTs). Lymphocytic defects were characterized by T cell receptor (TCR) oligoclonality, abnormal class switch recombination (CSR), and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation upon genotoxic stress. Consequently, ATRIP deficient cells inadequately regulated DNA replication, leading to chromosomal instability, compromised cell cycle control, and impaired cell viability. CRISPR-SelectTIMEconfirmed reduced cell fitness induced by both variants. This study establishes ATRIP deficiency as a monogenic cause of microcephalic primordial dwarfism, highlights ATRIP’s critical role in protecting immune cells from replication stress, and brings a renewed perspective to the canonical functions of ATRIP.
The Effects of Heart Rate Variability Biofeedback on Functional Gastrointestinal Disorders: A Scoping Review
Authors: Pereira Ashley G , Fu Lily , Xu William , Gharibans Armen A , O’Grady Greg
Published: July 2024

Functional Gastrointestinal Disorders (FGID) are a group of symptom-based disorders that occur across the alimentary tract and have a high prevalence globally in both adults and children. These symptoms are chronic and/or recurrent and often have substantial effects on quality of life. Their incidence is tied to multiple factors, including gut-brain axis imbalance, which includes autonomic dysregulation related to a relative withdrawal of vagal activity. Heart rate variability biofeedback (HRVB) is a non-invasive intervention that can influence autonomic activity and has shown benefit for diverse conditions including depression and anxiety, however the evidence of its effect has not yet been systematically assessed in FGIDs. This scoping review aimed to collate and evaluate the available literature regarding HRVB and FGIDs. We systematically searched four medical databases. Four articles met inclusion criteria for being interventional studies using HRVB in FGIDs. These were heterogeneous, including both paediatric and adult as well different subtypes of FGID. Two of the four studies demonstrated significant improvements from HRVB interventions in FGID symptoms while the other two found no significant difference. Scoping evaluation indicated this inconsistency likely reflects heterogeneous populations and study designs. Further scoping review of the broader HRVB literature also discovered that at least six weeks of HRVB is required to observe an impact on FGID symptoms and defined recommended guidance for performing future evaluations of HRVB in FGIDs. Evidence on HRVB for FGID is emergent, however HRVB appears a promising intervention when administered optimally. Further studies using best-practice techniques are required.
Systematic benchmarking demonstrates large language models have not reached the diagnostic accuracy of traditional rare-disease decision support tools
Authors: Reese Justin T , Chimirri Leonardo , Bridges Yasemin , Danis Daniel , Caufield J Harry , Wissink Kyran , McMurry Julie A , Graefe Adam SL , Casiraghi Elena , Valentini Giorgio , Jacobsen Julius OB , Haendel Melissa , Smedley Damian , Mungall Christopher J , Robinson Peter N
Published: July 2024

Large language models (LLMs) show promise in supporting differential diagnosis, but their performance is challenging to evaluate due to the unstructured nature of their responses. To assess the current capabilities of LLMs to diagnose genetic diseases, we benchmarked these models on 5,213 case reports using the Phenopacket Schema, the Human Phenotype Ontology and Mondo disease ontology. Prompts generated from each phenopacket were sent to three generative pretrained transformer (GPT) models. The same phenopackets were used as input to a widely used diagnostic tool, Exomiser, in phenotype-only mode. The best LLM ranked the correct diagnosis first in 23.6% of cases, whereas Exomiser did so in 35.5% of cases. While the performance of LLMs for supporting differential diagnosis has been improving, it has not reached the level of commonly used traditional bioinformatics tools. Future research is needed to determine the best approach to incorporate LLMs into diagnostic pipelines.
Predicted failure of common Mpox PCR testing on a recent DRC clade I variant: Persistent genomic surveillance is critically important for accurate diagnostics
Authors: Gratalo Dawn , Morley Valerie J. , Oppenheim Ben , Philipson Casandra W. , Rush Sarah , Sureka Swati , Wolfe Mitchell I. , Simen Birgitte B.
Published: July 2024

Pathogens can rapidly evolve to evade detection via existing diagnostic testing capabilities, creating blind spots for health care and security systems. Persistent genomic surveillance of pathogens can help identify and address these gaps. Here, we present a case study of a new lineage of Monkeypox virus Clade I that emerged during an outbreak in the Democratic Republic of the Congo, in which a genomic deletion allowed the virus to evade detection by current diagnostic assays. We rapidly developed and validated an updated assay. Availability of pathogen genomic data is a critical input, and often a bottleneck, to response efforts.
Exploring Temperature Effects on Large Language Models Across Various Clinical Tasks
Authors: Patel Dhavalkumar , Timsina Prem , Raut Ganesh , Freeman Robert , levin Matthew A , Nadkarni Girish N , Glicksberg Benjamin S , Klang Eyal
Published: July 2024

Large Language Models (LLMs) are becoming integral to healthcare analytics. However, the influence of the temperature hyperparameter, which controls output randomness, remains poorly understood in clinical tasks. This study evaluates the effects of different temperature settings across various clinical tasks. We conducted a retrospective cohort study using electronic health records from the Mount Sinai Health System, collecting a random sample of 1283 patients from January to December 2023. Three LLMs (GPT-4, GPT-3.5, and Llama-3-70b) were tested at five temperature settings (0.2, 0.4, 0.6, 0.8, 1.0) for their ability to predict in-hospital mortality (binary classification), length of stay (regression), and the accuracy of medical coding (clinical reasoning). For mortality prediction, all models’ accuracies were generally stable across different temperatures. Llama-3 showed the highest accuracy, around 90%, followed by GPT-4 (80-83%) and GPT-3.5 (74-76%). Regression analysis for predicting the length of stay showed that all models performed consistently across different temperatures. In the medical coding task, performance was also stable across temperatures, with GPT-4 achieving the highest accuracy at 17% for complete code accuracy. Our study demonstrates that LLMs maintain consistent accuracy across different temperature settings for varied clinical tasks, challenging the assumption that lower temperatures are necessary for clinical reasoning.
A Specialized Reference Panel with Structural Variants Integration for Improving Genotype Imputation in Alzheimer’s Disease and Related Dementias (ADRD)
Authors: Cheng Po-Liang , Wang Hui , Dombroski Beth A , Farrell John J , Horng Iris , Chung Tingting , Tosto Giuseppe , Kunkle Brian W , Bush William S , Vardarajan Badri , Schellenberg Gerard D , Lee Wan-Ping
Published: July 2024

We developed an imputation panel for Alzheimer’s disease (AD) and related dementias (ADRD) using whole-genome sequencing (WGS) data from the Alzheimer’s Disease Sequencing Project (ADSP). Recognizing the significant associations between structural variants (SVs) and AD, and their underrepresentation in existing public reference panels, our panel uniquely integrates single nucleotide variants (SNVs), short insertions and deletions (indels), and SVs. This panel enhances the imputation of disease susceptibility, including rare AD-associated SNVs, indels, and SVs, onto genotype array data, offering a cost-effective alternative to whole-genome sequencing while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominal significant related to AD that are absent in the TOPMed-r2 panel and identified three suggestive significant (p-value < 1E-05) AD-associated SVs in the genesEXOC3L2andDMPK, were identified. These findings provide new insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.
Microvascular dysfunction induces a hyperdynamic circulation; a mathematical exploration
Authors: Popovich Ivor
Published: July 2024

Background

The discordance between the macrocirculation and microcirculation in septic shock has been recognised but never explained. I present a novel mathematical hypothesis as to how heterogenous microcirculatory flow distribution directly induces a hyperdynamic circulation and how elevated central venous pressure induces microcirculatory dysfunction.

Methods

I explore the tube law and modified Poiseuille resistance for compliant blood vessels. Using these equations a new equation is developed incorporating time constants, elastance of the vessel, unstressed volume and wave reflections that demonstrates the relationship between volume of a microcirculatory vessel and total flow through it.

Results

The relationship is demonstrated to be constant at zero until the unstressed volume is reached after which it increases exponentially. By considering n of these vessels in parallel, I demonstrate that the summed flow is minimised when flow is equally distributed among the n vessels, while it is maximised when all flow goes through one vessel alone, thereby demonstrating that heterogenous microvascular perfusion leads to increased total flow. It is shown that if conditions of wave reflection are right then a hyperdynamic circulation with high cardiac output develops. It is also demonstrated that high central venous pressure increases wave reflections and necessarily leads to microvascular perfusion heterogeneity if cardiac output is to be maintained.

Conclusions

Microvascular impairment in septic shock directly leads to a hyperdynamic circulation with high cardiac output. High central venous pressures impair the microcirculation. Decades of clinical findings can now be explained mathematically. Implications for hemodynamic therapy for septic shock are discussed.

Clinical Perspective

Research in septic shock has focussed on two main components of the circulation; the macrocirculation and microcirculation. Very discordant findings have been observed between the two, to the point that the term ‘uncoupling’ has appeared in the literature in reference to these two circulations. Thus far nobody has put forward a satisfactory physiological explanation as to the mechanism of this discordance. There is a need to understand the physiological mechanisms to guide future attempts and research into methods of resuscitating the septic patient in order to improve circulatory function.

This work provides the first theoretical mathematical groundwork as to not only how these circulations are linked, but how they directly influence one another. This sets the framework for future clinical and basic science research and helps us understand how our current resuscitation strategies may work to restore the microcirculation, and when they may start to impair it.
Prognostic Nutritional Index in Risk of Mortality Following Fulminant Myocarditis
Authors: Doi Shunichi , Ishibashi Yuki , Suzuki Norio , Miyahara Daisuke , Sato Yukio , Kuwata Shingo , Kida Keisuke , Izumo Masaki , Onoue Kenji , Kanaoka Koshiro , Saito Yoshihiko , Akashi Yoshihiro J. ,   Japanese Registry of Fulminant Myocarditis Investigators
Published: July 2024

Background

Fulminant myocarditis (FM) is an acute fatal inflammation disease, but its chronic phase is unclear. A Japanese nationwide registry evaluated the long-term mortality in FM patients using a prognostic nutritional index (PNI).

Methods and Results

The retrospective cohort study included patients with clinically suspected or histologically proven FM available for PNI. PNI was assessed on admission and at discharge. We divided patients into two groups based on PNI at discharge (PNI ≤40 or PNI >40) and analyzed the change in PNI and mortality between the groups. Of 323 patients (the median [first-third quartiles] age of this cohort was 50 [37–64] years, and 143 [44%] were female), PNI ≤40 at discharge was in 99 (31%) patients. The median PNI in all patients increased from 41 (36– 46) on admission to 43 (39–48) at discharge (P<0.0001). Patients with PNI ≤40 had a lower event-free rate of death or rehospitalization with cardiovascular causes than those with PNI >40 (log-rankP=0.0001). When the PNI at discharge, age, sex, left ventricular ejection fraction, and Barthel index were evaluated in a multivariable Cox regression analysis, PNI ≤40 had an independent association with the death or rehospitalization with cardiovascular causes (hazard ratio, 2.14 [95% confidence interval, 1.14–4.01];P=0.0289).

Conclusions

One-third of FM patients with low PNI at discharge had a higher risk of mortality than those with high PNI in the chronic phase. This study provokes clinical insight into the phenotype of chronic inflammation in FM and optimal follow-up management with low PNI.
Who Grows There? A Course-based Undergraduate Research Experience to explore the human microbiome through 16S DNA metabarcoding
Authors: Sellers Graham S , Freiheit Merideth , Winter Michael R , Joyce Domino A , Cullen Darron A , Lunt David H , Hubbard Katharine E
Published: July 2024

We describe a two week Course-based Undergraduate Research Experience (CURE) to introduce students to next-generation DNA sequencing, molecular biology methods and a bioinformatic workflow. The CURE is designed to take students with little to no technical and bioinformatic experience through key steps of the protocol through scaffolded laboratory and computational practicals. Our students extract and amplify human microbiome DNA using 16S ribosomal RNA specific primers, then construct a sequencing library for Oxford Nanopore based sequencing. They taxonomically assign the sequencing reads, and determine the ecological community composition using relevant software packages. Our students were able to successfully prepare sequencing libraries and analyse the data to produce relevant figures, demonstrating they met the learning objectives of the CURE. Students identified that they had developed higher level learning as defined by Bloom’s taxonomy, and that their confidence in practical work significantly increased as a result of doing the CURE. We share recommendations for implementation of the CURE in undergraduate curricula, and adaptations of the methods for use in schools outreach. Our CURE successfully provides training for students in genetic analysis in an enjoyable and relatively time and cost efficient manner, preparing them for future research or careers in modern molecular biology techniques.
High-yield production of recombinant human myelin oligodendrocyte glycoprotein in SHuffle bacteria without a refolding step
Authors: Wu Wesley , Gupta Sasha , Sagan Sharon A. , Moseley Carson E. , Zamvil Scott S. , Pak John E.
Published: July 2024

1.1

Experimental autoimmune encephalomyelitis (EAE) is a model for central nervous system (CNS) autoimmune demyelinating diseases such as multiple sclerosis (MS) and MOG antibody-associated disease (MOGAD). Immunization with the extracellular domain of recombinant human MOG (rhMOG), which contains pathogenic antibody and T cell epitopes, induces B cell-dependent EAE for studies in mice. However, these studies have been hampered by rhMOG availability due to its insolubility when overexpressed in bacterial cells, and the requirement for inefficient denaturation and refolding. Here, we describe a new protocol for the high-yield production of soluble rhMOG in SHuffle cells, a commercially availableE. colistrain engineered to facilitate disulfide bond formation in the cytoplasm. SHuffle cells can produce a soluble fraction of rhMOG yielding >100 mg/L. Analytical size exclusion chromatography multi-angle light scattering (SEC-MALS) and differential scanning fluorimetry of purified rhMOG reveals a homogeneous monomer with a high melting temperature, indicative of a well-folded protein. Anin vitroproliferation assay establishes that purified rhMOG can be processed and recognized by T cells expressing a T cell receptor (TCR) specific for the immunodominant MOG35-55peptide epitope. Lastly, immunization of wild-type, but not B cell deficient, mice with rhMOG resulted in robust induction of EAE, indicating a B cell-dependent induction. Our SHuffle cell method greatly simplifies rhMOG production by combining the high yield and speed of bacterial cell expression with enhanced disulfide bond formation and folding, which will enable further investigation of B cell-dependent EAE and expand human research of MOG in CNS demyelinating diseases.
Parallel patterns of cognitive aging in marmosets and macaques
Authors: Vanderlip Casey R. , Jutras Megan L. , Asch Payton A. , Zhu Stephanie Y. , Lerma Monica N. , Buffalo Elizabeth A. , Glavis-Bloom Courtney
Published: July 2024

As humans age, some experience cognitive impairment while others do not. When impairment does occur, it is not expressed uniformly across cognitive domains and varies in severity across individuals. Translationally relevant model systems are critical for understanding the neurobiological drivers of this variability, which is essential to uncovering the mechanisms underlying the brain’s susceptibility to the effects of aging. As such, non-human primates are particularly important due to shared behavioral, neuroanatomical, and age-related neuropathological features with humans. For many decades, macaque monkeys have served as the primary non-human primate model for studying the neurobiology of cognitive aging. More recently, the common marmoset has emerged as an advantageous model for this work due to its short lifespan that facilitates longitudinal studies. Despite their growing popularity as a model, whether marmosets exhibit patterns of age-related cognitive impairment comparable to those observed in macaques and humans remains unexplored. To address this major limitation for the development and evaluation of the marmoset as a model of cognitive aging, we directly compared working memory ability as a function of age in macaques and marmosets on the identical working memory task. Our results demonstrate that marmosets and macaques exhibit remarkably similar age-related working memory deficits, highlighting the value of the marmoset as a model for cognitive aging research within the neuroscience community.
Smooth Muscle Cells-Expressed Bmal1 Regulates Vascular Calcification Independent of the Canonical Circadian Pathway
Authors: He Ming , Sun Yong , Huang Fengyuan , Zhu Zhehao , Velazquez-Miranda Erandi , Chong Zechen , Chen Yabing
Published: July 2024

Vascular calcification is a major cardiovascular issue that increases morbidity and mortality in diabetes patients. While dysregulation of the circadian master regulator Basic Helix-Loop-Helix ARNT-Like Protein 1 (Bmal1) in vascular smooth muscle cells (VSMC) under diabetic conditions has been suggested, its role in vascular calcification is unclear. In VSMC, Bmal1 was upregulated under high glucose treatment and in aortic tissues from a diabetic mouse model. RNA sequencing from isolated VSMC between Bmal1 deletion and wildtype mice indicated Bmal1’s pro-calcification role. Indeed, reduced levels of the osteogenic master regulator, Runt-Related Transcription Factor 2 (Runx2), were found in Bmal1 deletion VSMC under diabetic conditions. Alizarin red staining showed reduced calcification in Bmal1 deletion VSMCin vitroand vascular ringsex vivo. Furthermore, in a diabetic mouse model, SMC-Bmal1 deletion showed reduced calcium deposition in aortas. Collectively, diabetes-upregulated circadian regulator Bmal1 in VSMC contributes to vascular calcification. Maintaining normal circadian regulation may improve vascular health in diabetes.
Iron limitation differentially affects viral replication in key marine microbes
Authors: Yung Charmaine C. M. , Kelly Rachel L. , Kauffman Kathryn M. , Cunningham Brady , Zimmerman Amy , Worden Alexandra Z. , John Seth G.
Published: July 2024

Viral lysis accounts for much of microbial mortality in the ocean, and iron (Fe) is a critical micronutrient that can limit phytoplankton growth, yet interactions between Fe-nutrition and viral lysis are not well known. Here, we present viral infection dynamics under Fe-limited and Fe-replete conditions for three distinct marine microbes, the photosynthetic picoeukaryoteOstreococcus lucimarinus, the cyanobacteriumSynechococcus, and two strains of the heterotrophic bacteriumVibrio. Iron limitation ofOstreococcusresulted in slowed growth, and a corresponding decrease in viral burst sizes was observed; this is similar to results from studies of larger eukaryotic phytoplankton (Slagter et al. 2016; Kranzler et al. 2021), where reduced viral replication under Fe-limitation is attributed to the viral reliance on host metabolism and replication machinery. For one strain ofVibrio, Fe-limitation similarly impacted viral dynamics, increasing the latent period before infected cells burst to release new virus, and reducing the number of infective viral particles released upon viral lysis. Unexpectedly, for another strain ofVibrio, Fe-limitation had no discernible effect on viral replication. Furthermore, dynamics of threeSynechococcuscyanophages was not affected by Fe-limitation of the host, either in terms of latent period or burst size. The results illuminate the extraordinary ability of some marine viruses, particularly cyanophages, to highjack host metabolism to produce new viral particles, even when host growth is compromised. This has implications for marine ecology and carbon cycling in Fe-limited regions of the global ocean.
Characterizing the heterogeneity of neurodegenerative diseases through EEG normative modeling
Authors: Tabbal Judie , Ebadi Aida , Mheich Ahmad , Kabbara Aya , Güntekin Bahar , Yener Görsev , Paban Veronique , Gschwandtner Ute , Fuhr Peter , Verin Marc , Babiloni Claudio , Allouch Sahar , Hassan Mahmoud
Published: July 2024

Neurodegenerative diseases such as Parkinson’s (PD) and Alzheimer’s (AD) exhibit considerable heterogeneity of functional brain features within patient populations, complicating diagnosis, treatment, prognosis, and drug discovery. Here, we use electroencephalography (EEG) and normative modeling to investigate neurophysiological oscillatory mechanisms underpinning this heterogeneity. To this aim, we use resting-state EEG activity collected by 14 clinical units, in healthy older persons (n=499) and patients with PD (n=237) and AD (n=197), aged over 40 years old. Spectral and source connectivity analyses of EEG activity provided EEG features for normative modeling and deviation measures in the PD and AD patients. Normative models confirmed significant deviations of the EEG features in PD and AD patients over population norms, characterized by high heterogeneity and frequency-dependence. The percentage of patients with at least one deviating EEG feature was ∼30% for spectral measures and ∼80% for functional source connectivity. Notably, the spatial overlap of the deviant EEG features did not exceed 60% for spectral analysis and 25% for functional source connectivity analysis. Furthermore, the patient-specific deviations were correlated with relevant clinical measures, such as the UPDRS for PD (⍴=0.24,p=0.025) and the MMSE for AD (⍴=-0.26,p=0.01), indicating that greater deviations from normative EEG features are associated with worsening score values. These results suggest that the deviation percentage from EEG norms may enrich clinical assessment in PD and AD patients at individual levels in the framework of Precision Neurology.
The role of methylation and structural variants in shaping the recombination landscape of barley
Authors: Casale Federico , Arlt Christopher , Kühl Marius , Li Jinquan , Engelhorn Julia , Hartwig Thomas , Stich Benjamin
Published: July 2024

Meiotic recombination is not only a key mechanism for sexual adaptation in eukaryotes but crucial for the accumulation of beneficial alleles in breeding populations. The effective manipulation of recombination requires, however, a better understanding of the mechanisms regulating the rate and distribution of recombination events in genomes. Here, we identified the genomic features that best explain the recombination variation among a diverse set of segregating populations of barley at a resolution of 1 Mbp and investigated how methylation and structural variants determine recombination hotspots and coldspots at a high-resolution of 10 kb. Hotspots were found to be in proximity to genes and the genetic effects not assigned to methylation were found to be the most important factor explaining differences in recombination rates among populations along with the methylation and the parental sequence divergence. Interestingly, the inheritance of a highly-methylated genomic fragment from one parent only was enough to generate a coldspot, but both parents must be equally low methylated at a genomic segment to allow a hotspot. The parental sequence divergence was shown to have a sigmoidal correlation with recombination indicating an upper limit of mismatch among homologous chromosomes for CO formation. Structural variants (SVs) were shown to suppress COs, and their type and size were not found to influence that effect. Methylation and SVs act jointly determining the location of coldspots in barley and the weight of their relative effect depends on the genomic region. Our findings suggest that recombination in barley is highly predictable, occurring mostly in multiple short sections located in the proximity to genes and being modulated by local levels of methylation and SV load.
STK19 drives Transcription-Coupled Repair by stimulating repair complex stability, Pol II ubiquitylation and TFIIH recruitment
Authors: Ramadhin Anisha R. , Lee Shun-Hsiao , Zhou Di , Salmazo Anita , Gonzalo-Hansen Camila , van Sluis Marjolein , Blom Cindy M.A. , Janssens Roel C. , Raams Anja , Dekkers Dick , Bezstarosti K , Slade Dea , Vermeulen Wim , Pines Alex , Demmers Jeroen A.A. , Bernecky Carrie , Sixma Titia K. , Marteijn Jurgen A.
Published: July 2024

DNA damage forms a major obstacle for gene transcription by RNA polymerase II (Pol II). Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates transcription-blocking lesions (TBLs), thereby safeguarding accurate transcription, preserving correct cellular function and counteracting aging. TC-NER initiation involves the recognition of lesion-stalled Pol II by CSB, which recruits the CRL4CSAE3 ubiquitin ligase complex and UVSSA. TBL-induced ubiquitylation of Pol II at lysine 1268 of the RPB1 subunit by CRL4CSAserves as a critical TC-NER checkpoint, governing Pol II stability and initiating TBL excision by TFIIH recruitment. However, the precise regulatory mechanisms of the CRL4CSAE3 ligase activity and TFIIH recruitment remain elusive. Here, we reveal Inactive Serine/Threonine Kinase 19 (STK19) as a novel TC-NER factor, that is essential for correct TBL removal repair and subsequent transcription restart. Cryo-EM studies demonstrate that STK19 is an integral part of the Pol II-TC-NER complex, bridging CSA with UVSSA, RPB1 and downstream DNA. Live-cell imaging and interaction studies show that STK19 stimulates TC-NER complex stability and CRL4CSAactivity, resulting in efficient Pol II ubiquitylation and correct UVSSA and TFIIH binding. These findings underscore the crucial role of STK19 as a core component of the TC-NER machinery and its key involvement in the cellular responses to DNA damage that interfere with transcription.
Super-resolution imaging of proteins inside live mammalian cells with mLIVE-PAINT
Authors: Bhaskar Haresh , Gidden Zoe , Virdi Gurvir , Kleinjan Dirk-Jan , Rosser Susan J. , Gandhi Sonia , Regan Lynne , Horrocks Mathew H.
Published: July 2024

Super-resolution microscopy has revolutionized biological imaging, enabling the visualization of structures at the nanometer length scale. Its application in live cells, however, has remained challenging. To address this, we adapted LIVE-PAINT, an approach we established in yeast, for application in live mammalian cells. Using the 101A/101B coiled-coil peptide pair as a peptide-based targeting system, we successfully demonstrate the super-resolution imaging of two distinct proteins in mammalian cells, one localized in the nucleus, and the second in the cytoplasm. This study highlights the versatility of LIVE-PAINT, suggesting its potential for live-cell super-resolution imaging across a range of protein targets in mammalian cells. We name the mammalian cell version of our original method mLIVE-PAINT.
Binocular processing facilitates escape behavior through multiple pathways to the superior colliculus
Authors: Broersen Robin , Thompson Genevieve , Thomas Felix , Stuart Greg J.
Published: July 2024

The superior colliculus (SC) is the main brain region regulating innate defensive behaviors to visual threat. Yet, how the SC integrates binocular visual information and to what extent binocular vision drives defensive behaviors is unknown. Here, we show that binocular vision facilitates visually-evoked escape behavior. Furthermore, we find that SC neurons respond to binocular visual input with diverse synaptic and spiking responses, and summate visual inputs largely sublinearly. Using pathway-specific optogenetic silencing we find that contralateral and ipsilateral visual information is carried to binocular SC neurons through retinal, interhemispheric and corticotectal pathways. These pathways carry binocular visual input to the SC in a layer-specific manner, with superficial layers receiving visual information through retinal input, whereas intermediate and deep layers rely on interhemispheric and corticotectal pathways. Together, our data shed light on the cellular and circuit mechanisms underlying binocular visual processing in the SC and its role in escape behavior.
Variation in the fitness impact of translationally optimal codons among animals
Authors: Bénitìere Florian , Lefébure Tristan , Duret Laurent
Published: July 2024

Early studies in invertebrate model organisms (fruit flies, nematodes) showed that their synonymous codon usage is under selective pressure to optimize translation efficiency in highly expressed genes (a process called translational selection). In contrast, mammals show little evidence of selection for translationally optimal codons. To understand this difference, we examined the use of synonymous codons in 223 metazoan species, covering a wide range of animal clades. For each species, we predicted the set of optimal codons based on the pool of tRNA genes present in its genome, and we analyzed how the frequency of optimal codons correlates with gene expression to quantify the intensity of translational selection (S). Surprisingly, few metazoans show clear signs of translational selection. As predicted by the nearly neutral theory, the highest values ofSare observed in species with large effective population sizes (Ne). Overall, however,Neappears to be a poor predictor of the intensity of translational selection, suggesting important differences in the fitness effect of synonymous codon usage across taxa. We propose that the few animal taxa that are clearly affected by translational selection correspond to organisms with strong constraints for a very rapid growth rate.
Gut and oral microbial community characterization from women with breast cancer, women with ductal carcinoma in situ, and healthy women reveals differences in gut but not oral microbiota
Authors: McCune Emma , Sharma Anukriti , Johnson Breanna , O’Meara Tess , Theiner Sarah , Campos Maribel , Heditsian Diane , Brain Susie , Gilbert Jack A. , Esserman Laura , Campbell Michael J.
Published: July 2024

This study characterized and compared the fecal and oral microbiota from women with early-stage breast cancer (BC), women with ductal carcinoma in situ (DCIS), and healthy women. Fecal and oral samples were collected from newly diagnosed patients prior to any therapy and characterized using 16S rRNA sequencing. Measures of gut microbial alpha diversity were significantly lower in the BC versus healthy cohort. Beta diversity differed significantly between the BC or DCIS and healthy groups and several differentially abundant taxa were identified. Clustering (non-negative matrix factorization) of the gut microbiota identified 5 bacterial guilds dominated by eitherPrevotella, Enterobacteriaceae,Akkermansia, Clostridiales, orBacteroides. TheBacteroidesand Enterobacteriaceae guilds were significantly more abundant in the BC cohort compared to healthy controls whereas the Clostridiales guild was more abundant in the healthy group. Finally, prediction of functional pathways identified 23 pathways that differed between the BC and healthy gut microbiota including lipopolysaccharide biosynthesis, glycan biosynthesis and metabolism, lipid metabolism, and sphingolipid metabolism. In contrast to the gut microbiomes, there were no significant differences in alpha or beta diversity in the oral microbiomes and very few differentially abundant taxa were observed. NMF analysis of the oral microbiota samples identified 7 guilds dominated byVeillonella,Prevotella, Gemellaceae,Haemophilus,Neisseria,Propionibacterium, andStreptococcus,however, none of these guilds were differentially associated with the different cohorts. Our results suggest that alterations in the gut microbiota, but not oral microbiota, may provide the basis for interventions targeting the gut microbiome to improve treatment outcomes and long-term prognosis.

IMPORTANCE

Emerging evidence suggests that the gut microbiota may play a role in breast cancer. Few studies have evaluated both the gut and oral microbiomes in women with breast cancer (BC) and none have characterized these microbiomes in women with ductal carcinoma in situ (DCIS). We surveyed the gut and oral microbiomes from women with BC or DCIS and healthy women and identified compositional and functional features of the gut microbiota that differed between these cohorts. In contrast, very few differential features were identified in the oral microbiota. These findings suggest that the oral microbiome is unlikely to be an effective risk marker for DCIS or breast cancer compared to the gut microbiome. Understanding the role of gut bacteria in BC and DCIS may open up new opportunities for the development of novel markers for early detection (or markers of susceptibility) as well as new strategies for prevention and/or treatment.
Experimentally induced pain and paresthesia respond differently to parameter changes of cuff-based compression in pain-free young individuals
Authors: Skalski Jacek , Swoboda Sylwia , Szikszay Tibor M. , Wodarski Piotr , Bieniek Andrzej , Luedtke Kerstin , Adamczyk Wacław M.
Published: July 2024

Neuropathic pain is a significant therapeutic challenge due to the co-occurrence with other neurological symptoms such as paresthesia. Human-based models such as cuff algometry can enhance our understanding of pain-paresthesia relationships. This experiment aimed to characterize (psychophysically) pain and paresthesia evoked by stimuli of different temporal and intensity parameters and to demonstrate the reliability of experimental induction of these two symptoms using cuff algometry. Forty participants, aged 18-35, were exposed to mechanical pressure stimuli at three intensities (100, 150, 200 mmHg) and three durations (90, 120, 150s). Skin Conductance (SC) was continuously monitored, and participants rated pain and paresthesia in real-time using a computerized visual analog scale. The General Linear Model analysis revealed significant differences in paresthesia across all durations (p<0.01), but not all intensities, as paresthesia did not increase from 150 to 200 mmHg (p>0.05). Conversely, pain responses showed significant differences across all pressure intensities (p<0.05) but not durations, as pain did not increase from 90 to 120 and from 120 to 150s (p>0.05). No interaction effects were found for either symptom. SC analysis showed no significant main or interaction effects. Intraclass correlation coefficients (ICCs) indicated moderate to good reliability for pain and paresthesia induction across different durations and intensities (ICC: 0.52-0.90), while SC showed poor to moderate reliability (ICC: 0.21-0.73). In conclusion, computerized cuff algometry seems to be an effective and reliable method for simultaneously inducing and assessing pain and paresthesia, revealing that these symptoms follow different patterns based on pressure duration and intensity.
A new trait in a well-studied ant: low aggression between workers fromLasius niger(Hymenoptera, Formicidae) nest complexes
Authors: Stukalyuk Stanislav
Published: July 2024

The formicine antLasius nigeris one of the most abundant and most intensively studied Palaearctic ant species and was believed so far to form exclusively monogynous colonies, to spread via single-queen dispersal and to found claustrally. Two closely neighboring nest complexes ofLasius nigerwere observed in an abandoned field near Kyiv / Ukraine in 2017-2020. Nest complex A includes 14650 mounds on an area of 11.8 ha and nest complex B 15600 mounds on 13.3 ha. The nests within the nest complexes are connected via a developed trail network. Aggression tests revealed a low level of aggression between workers from different zones of the same nest complex but increased aggression in confrontations of nest complex workers with workers from a remote monodomous population. Reduced aggression between workers facilitate the integrity of the nest complex and its rapid growth.
Unveiling the
a0(1710)
nature in the process
J/ψ→K¯0K+ρ−
Authors: Ding Yan , Wang En , Li De-Min , Geng Li-Sheng , Xie Ju-Jun
Published: July 2024

We have investigated the process J/ψ→K¯0K+ρ− by taking into account the S-wave K*K¯*, ρω, and ρϕ final-state interactions, where the scalar meson

a

0

(

1710

)

is generated. In addition, we also take into account the contributions from the scalar a0(980)(→K¯0K+) and the intermediate resonances K1(1270)−(→K¯0ρ−) and K1(1270)0(→K+ρ−). Our results show that, in the K¯0K+ invariant mass distribution, a clear peak structure around 1.8 GeV appears, which could be associated with the scalar a0(1710), however, no significant structure of the a0(980) is observed. On the other hand, one can find clear peaks of the K1(1270) in the K¯0ρ− and K+ρ− invariant mass distributions. The future precise measurement of this process by the BESIII and Belle II Collaborations and the planned Super Tau-Charm Facility in the future could shed light on the nature of a0(1710).

Published by the American Physical Society
2024