bluuebunny/crossref_metadata_2025 huggingface dataset:
Exome-wide tandem repeats confer large effects on subcortical volumes in UK Biobank participants
Authors: Panoyan Mary Anne , Shi Yuxin , Abbatangelo Cristina L , Adler Nina , Moo-Choy Ashley , Parra Esteban J , Polimanti Renato , Hu Pingzhao , Wendt Frank R
Published: December 2023

The human subcortex is involved in memory and cognition. Structural and functional changes in subcortical regions is implicated in psychiatric conditions. We performed an association study of subcortical volumes using 15,941 tandem repeats (TRs) derived from whole exome sequencing (WES) data in 16,527 unrelated European ancestry participants. We identified 17 loci, most of which were associated with accumbens volume, and nine of which had fine-mapping probability supporting their causal effect on subcortical volume independent of surrounding variation. The most significant association involvedNTN1-[GCGG]Nand increased accumbens volume (β=5.93, P=8.16x10-9). Three exonic TRs had large effects on thalamus volume (LAT2-[CATC]Nβ=-949, P=3.84x10-6andSLC39A4-[CAG]Nβ=-1599, P=2.42x10-8) and pallidum volume (MCM2-[AGG]Nβ=-404.9, P=147x10-7). These genetic effects were consistent measurements of per-repeat expansion/contraction effects on organism fitness. With 3-dimensional modeling, we reinforced these effects to show that the expanded and contractedLAT2-[CATC]Nrepeat causes a frameshift mutation that prevents appropriate protein folding. These TRs also exhibited independent effects on several psychiatric symptoms, includingLAT2-[CATC]Nand the tiredness/low energy symptom of depression (β=0.340, P=0.003). These findings link genetic variation to tractable biology in the brain and relevant psychiatric symptoms. We also chart one pathway for TR prioritization in future complex trait genetic studies.
Loss of Adaptive DNA Breaks in Alzheimer’s Disease Brains
Authors: Zhang Xiaoyu , Haeri Mohammad , Swerdlow Russell H. , Wang Ning
Published: December 2023

Background

DNA breaks accumulate in Alzheimer’s disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes (IEGs). This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks (DSBs).

Objective

To characterize how AD impacts adaptive DNA breaks at nervous system genes.

Methods

We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented (ND) autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing.

Results

Although the AD brains contained 19.9 times more PAR peaks than the ND brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks (DSBs). In addition, TOP2B expression was significantly decreased in the AD brains.

Conclusion

Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.
Can structure predict function at individual level in the human connectome?
Authors: Smolders Lars , De Baene Wouter , Rutten Geert-Jan , van der Hofstad Remco , Florack Luc
Published: December 2023

Several studies predicting Functional Connectivity (FC) from Structural Connectivity (SC) at an individual level have been published in recent years, each promising increased performance and utility. We investigated three of these studies, analyzing whether the results truly represent a meaningful individual-level mapping from SC to FC. Using data from the Human Connectome Project shared accross the three studies, we constructed a predictor by averaging FC of training data and analyzed its performance in the same way. In each case, we found that this group average FC is an equivalent or better predictor of individual FC than the predictive models in terms of raw prediction performance. Furthermore, we showed that additional analyses performed by the authors of the three studies, in which they attempt to show that their predicted FC has value beyond raw prediction performance, could also be reproduced using the group average FC predictor. This makes it unclear whether any of the three methods represent a meaningful individual-level predictive model. We conclude that either the applied methods are not appropriate for the data, that the sample size is too small, or that the data itself does not contain sufficient information to learn a mapping from SC to FC e.g. due to the amount of noise in MRI measurements. We advise future individual-level studies to always explicitly report their results in comparison to the performance of the group average, and carefully demonstrate that their predictions contain meaningful individual-level information. Finally, we believe that investigating alternatives for the construction of SC and FC may improve the chances of developing a meaningful individual-level mapping from SC to FC.
Kinome focused CRISPR-Cas9 screens in African ancestry patient-derived breast cancer organoids identifies essential kinases and synergy of EGFR and FGFR1 inhibition
Authors: Rowdo Florencia P. Madorsky , Martini Rachel , Ackermann Sarah , Tang Colin , Tranquille Marvel , Irizarry Adriana , Us Ilkay , Alawa Omar , Moyer Jenna , Sigouros Michael , Nguyen John , Assaad Majd Al , Cheng Esther , Ginter Paula S. , Manohar Jyothi , Stonaker Brian , Boateng Richard , Oppong Joseph K. , Adjei Ernest K. , Awuah Baffour , Kyei Ishmael , Aitpillah Frances S. , Adinku Michael O. , Ankomah Kwasi , Osei-Bonsu Ernest B. , Gyan Kofi K. , Hoda Syed , Newman Lisa , Mosquera Juan Miguel , Sboner Andrea , Elemento Olivier , Dow Lukas E. , Davis Melissa B. , Martin M. Laura
Published: December 2023

Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapy strategies. These alterations are usually revealed via next generation sequencing of the tumor tissue. Yet, it is clear that some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. This is especially important in under-represented populations, whose mutational landscape and determinants of response to existing therapies are poorly characterized due to limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture in non-physiological conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in 3D-grown patient-derived tumor organoid (PDTO) models. We focused on identifying essential kinases that may translate to options for targeted therapies, including combination therapies. We first established a breast cancer PDTO biobank focused on underrepresented populations, including West African patients. We then performed a negative selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. We identified several previously unidentified kinase targets and showed that combination of FGFR1 and EGFR inhibitors synergizes to block organoids proliferation. Together these data demonstrate feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from under-represented cancer patients, and identify new targets for cancer therapy.
Aberrant methylation and expression of TNXB promote chondrocyte apoptosis and extracullar matrix degradation in hemophilic arthropathy via AKT signaling
Authors: Chen Jiali , Qinghe Zeng , Wang Xu , Xu Rui , Wang Weidong , Huang Yuliang , Sun Qi , Yuan Wenhua , Wang Pinger , Chen Di , Tong Peijian , Jin Hongting
Published: December 2023

Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N = 5) and osteoarthritis (N = 5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss ofTnxbinF8-/-mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss.Tnxbknockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects followingTnxbknockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.
Microglial phagocytosis of single dying oligodendrocytes is mediated by CX3CR1 but not MERTK
Authors: Olveda Genaro E. , Barasa Maryanne N. , Hill Robert A.
Published: December 2023

Oligodendrocyte death is common in aging and neurodegenerative diseases. In these conditions, single dying oligodendrocytes must be efficiently removed to allow remyelination and prevent a feed-forward degenerative cascade. Here we used a single-cell cortical demyelination model combined with longitudinal intravital imaging of dual-labeled transgenic mice to investigate the cellular dynamics underlying how brain resident microglia remove these cellular debris. Following phagocytic engagement, single microglia cleared the targeted oligodendrocyte and its myelin sheaths in one day via a precise, rapid, and stereotyped sequence. Deletion of the fractalkine receptor, CX3CR1, delayed microglia engagement with the cell soma but unexpectedly did not affect the clearance of myelin sheaths. Furthermore, and in contrast to previous reports in other demyelination models, deletion of the phosphatidylserine receptor, MERTK, did not affect oligodendrocyte or myelin sheath clearance. Thus, distinct molecular signals are used to detect, engage, and clear sub-compartments of dying oligodendrocytes to maintain tissue homeostasis.
Towards fNIRS Hyperfeedback: A Feasibility Study on Real-Time Interbrain Synchrony
Authors: Kostorz Kathrin , Nguyen Trinh , Pan Yafeng , Melinscak Filip , Steyrl David , Hu Yi , Sorger Bettina , Hoehl Stefanie , Scharnowski Frank
Published: December 2023

Social interaction is of fundamental importance to humans. Prior research has highlighted the link between interbrain synchrony and positive outcomes in human social interaction.

Neurofeedback is an established method to train one’s brain activity and might offer a possibility to increase interbrain synchrony. Consequently, it would be advantageous to determine the feasibility of creating a neurofeedback system for enhancing interbrain synchrony to benefit human interaction.

In this study, we investigated whether the most widely employed metric for interbrain synchrony, namely wavelet transform coherence, can be assessed accurately in near real-time using functional near-infrared spectroscopy (fNIRS), which is recognized for its mobility and ecological suitability for interactive research. To this end, we have undertaken a comprehensive approach encompassing simulations and a re-evaluation of two human-interaction datasets. Our findings indicate the potential for a stable near real-time measurement of wavelet transform coherence for integration durations of about one minute. This would align well with the methodology of an intermittent neurofeedback procedure.

Our investigation lays the technical foundation for an fNIRS-based system to measure interbrain synchrony in near real-time. This advancement is crucial for the future development of a neurofeedback training system tailored to enhance interbrain synchrony to potentially benefit human interaction.
Differential interactions of the proteasome inhibitor PI31 with constitutive and immuno-20S proteasomes
Authors: Wang Jason , Kjellgren Abbey , DeMartino George N.
Published: December 2023

PI31 (ProteasomeInhibitor of31,000 Daltons) is a 20S proteasome binding protein originally identified as an in vitro inhibitor of 20S proteasome proteolytic activity. Recently reported cryo-electron microscopy structures of 20S-PI31 complexes reveal a surprising structural basis for proteasome inhibition. The natively disordered proline-rich C-terminus of PI31 enters the central chamber in the interior of the cylindrical 20S proteasome and interacts directly with the proteasome’s multiple catalytic threonine residues a manner predicted to inhibit their enzymatic function while evading its own proteolysis. Higher eukaryotes express an alternative form of 20S proteasome featuring genetically and functionally distinct catalytic subunits. This proteasome is expressed in tissues involved in immune function or in response to certain cytokines such as interferon-γ and has been termed “immuno-proteasome.” We examined the relative effects of PI31 on constitutive and immuno-20S proteasomes and show that PI31 inhibits the immuno-20S proteasome (20Si) to a significantly lesser degree than it inhibits constitutive 20S proteasome (20Sc). Unlike 20Sc, 20Si hydrolyzes the carboxyl-terminus of PI31 and this effect contributes to the reduced inhibitory activity of PI31 towards 20Si. These results demonstrate unexpected differential interactions of PI31 with 20Sc and 20Si and document their functional consequences.
Utilizing Non-Invasive Prenatal Test Sequencing Data Resource for Human Genetic Investigation
Authors: Liu Siyang , Huang Shujia , Liu Yanhong , Gu Yuqin , Lin Xingchen , Zhu Huanhuan , Liu Hankui , Xu Zhe , Cheng Shiyao , Lan Xianmei , Li Linxuan , Chen Guo-Bo , Li Hao , Xu Xun , Nielsen Rasmus , Davies Robert W , Albrechtsen Anders , Qiu Xiu , Jin Xin
Published: December 2023

Non-invasive prenatal testing (NIPT) employs ultra-low-pass sequencing of maternal plasma cell-free DNA to detect fetal trisomy. With exceptional sensitivity, specificity, and safety, NIPT has gained global adoption, exceeding ten million tests, establishing it as one of the largest human genetic resources. This resource holds immense potential for exploring population genetic variations and their correlations with phenotypes. Here, we present comprehensive methods tailored for analyzing large, low-depth NIPT genetic datasets, involving customized algorithms and software for genetic variation detection, genotype imputation, and genome-wide association analysis. Through evaluations, we demonstrate that, when integrated with appropriate probabilistic models and population-specific haplotype reference panels, accurate allele frequency estimation and high genotype imputation accuracy (0.8 to 0.9) are achievable for genetic variants with alternative allele frequencies between 0.01 and 0.05, at sequencing depths of 0.1x to 0.25x. Additionally, we attained an R-square exceeding 0.9 for estimating genetic effect sizes across various sequencing platforms. These findings establish a robust theoretical and practical foundation for leveraging NIPT data in advancing medical genetic studies, not only in realms of maternal and child health, but also for long-term health outcomes.

Highlights

Introduction of probabilistic model integration for analyzing large-scale, low-pass non-invasive prenatal test (NIPT) sequencing data

Evaluation of protocols for variant detection, genotype imputation, and genome-wide association analyses with NIPT data
WormTracer: A precise method for worm posture analysis using temporal continuity
Authors: Kuze Koyo , Tazawa Ukyo T. , Suwazono Karin , Toyoshima Yu , Iino Yuichi
Published: December 2023

This study introduces WormTracer, a novel algorithm designed to accurately quantify temporal evolution of worm postures. Unlike conventional methods that analyze individual images separately, WormTracer estimates worm centerlines within a sequence of images concurrently. This process enables the resolution of complex postures that are difficult to assess when treated as isolated images. The centerlines obtained through WormTracer exhibit higher accuracy compared to those acquired using conventional methods. By applying principal component analysis to the centerlines obtained by WormTracer, we successfully generated new eigenworms, a basic set of postures, that enables a more precise representation of worm postures than existing eigenworms.

Author summary

C. elegansis a valuable model organism for comprehensive understanding of genes, neurons and behavior. Quantification of behavior is essential for clarifying these relationships, and posture information plays a crucial role in the analyses. However, accurately quantifying the posture ofC. elegansfrom video images of worms is challenging, and while various methods have been developed to date, they have their own limitations.

In this study, we developed an analytical tool called WormTracer, which can obtain worm centerlines more accurately than conventional methods, even when worms assume complex postures. Using this tool, we successfully obtained new eigenworms, basis postures of a worm, that can more accurately reproduce various postures than conventional eigenworms. WormTracer and the new eigenworms will be valuable assets for future quantitative studies on worm locomotion and sensorimotor behaviors.
Evolution of apoptotic signalling pathways within lophotrochozoans
Authors: Horkan Helen R , Popgeorgiev Nikolay , Vervoort Michel , Gazave Eve , Krasovec Gabriel
Published: December 2023

Apoptosis is the main form of regulated cell death in metazoans. Apoptotic pathways are well characterised in nematode, fly and mammals, leading to a vision of the conservation of apoptotic pathways in metazoans. However, we recently showed that intrinsic apoptosis is in fact divergent among metazoans. In addition, extrinsic apoptosis is poorly studied in non-mammalian animals, making its evolution unclear. Consequently, our understanding of apoptotic signalling pathways evolution is a black-box which must be illuminated by extending research to new biological systems. Lophotrochozoans are a major clade of metazoans which, despite their considerable biological diversity and key phylogenetic position as sister group of ecdysozoans (i.e.fly, nematode), are poorly explored, especially regarding apoptosis mechanisms. Traditionally each apoptotic signalling pathway was considered to rely on a specific initiator Caspase, associated with an activator. To shed light on apoptosis evolution in animals, we explored the evolutionary history of initiator Caspases, Caspase activators and the BCL-2 family (which control mitochondrial apoptotic pathway) in lophotrochozoans using phylogenetic analysis and protein interaction predictions. We discovered a diversification of initiator Caspases in molluscs, annelids and brachiopods, and the loss of key extrinsic apoptosis components in platyhelminths, along with the emergence of a clade specific Caspase with an ankyrin pro-domain. Taken together, our data show a specific history of apoptotic actors’ evolution in lophotrochozoans, further demonstrating the appearance of distinct apoptotic signalling pathways during metazoan evolution.

Significance statement

Apoptosis, a form of programmed cell death, has been long studied in model organisms such as fly, mouse, and in humans. The restricted focus on these models has led to an overall view that the evolution of genes involved in apoptosis is highly conserved across all animals. The advent of next generation sequencing has led to a boom in the omics data available across the tree of life. Thanks to this, we explored the evolution of key genes involved in apoptosis in the clade Lophotrochozoa (i.e.molluscs, annelids, flatworms, brachiopods), one of the three large clades that make up bilaterian animals. We found a complex evolutionary history of apoptosis genes, with multiple losses, gains, divergences and redundancies, highlighting the value of exploring gene evolution and apoptotic mechanisms in Lophotrochozoans.
Sampling the Zebrafish gut Microbiota – A Genome Resolved Metagenomic Approach
Authors: Thormar Eiríkur Andri , Hansen Søren Blikdal , Jørgensen Louise von Gersdorff , Limborg Morten T.
Published: December 2023

The zebrafish is a promising model organism in the field of functional microbiota research. However, studies on the functional landscape of the zebrafish gut microbiota through shotgun based metagenomics are scarce. Thus, there is a lack of consensus regarding an appropriate sampling method that accurately represents the zebrafish gut microbiota. To address this, we sought to systematically test and evaluate four different methods of sampling the zebrafish gut microbiota: collection of feces from the tank, the whole gut, intestinal content and the application of ventral pressure to facilitate extrusion of gut material. In addition, we included water samples as an environmental control to address the potential influence of the environmental microbiota on the data interpretation. To compare these sampling methods in a context of microbiota-based studies we employed a combination of genome resolved metagenomics and 16S metabarcoding techniques. We observed differences among sample types on all levels including sampling, bioinformatic processing, metagenome co-assemblies, generation of metagenome-assembled genomes (MAGs), functional potential, MAG coverage and micro-diversity. Furthermore, our comparison to the environmental control demonstrated the potential impact of the environmental contamination on data interpretation. The findings emphasise the importance of considering the choice of sampling method. While all sample types tested are informative about the zebrafish gut microbiota, the optimal sample type depends on the specific objectives of the study.
Interspecific relationships in a suboptimal habitat, an unexpected ally for the survival of the threatened Tenerife speckled lizard (Gallotia intermedia)
Authors: Albaladejo-Robles Gonzalo , Escánez Alejandro , Perera-Castro Alicia V.
Published: December 2023

Anthropogenic-driven environmental changes are pushing species to the limits of their habitats. More often species are restricted to relic or suboptimal habitats that present the minimum requirements to sustain species populations. In this scenario of accelerated environmental change and biodiversity loss, is fundamental to understand why species can survive in such suboptimal conditions. We conduct an isotopic trophic analysis along with a behavioural experiment to show how novel ecological interactions allow an endangered species to maintain stable populations in suboptimal habitats. We show how the Tenerife speckled lizard (Gallotia intermedia), a critically endangered endemic reptile from Tenerife Island (Canary Islands), can maintain stable populations in relic habitats thanks to its interactions with the yellow-legged gull (Larus michahellis) colony. A stable isotope analysis revealed thatG. intermediarelies on marine subsidies for its diet and that the foraging area of this reptile is likely to be restricted to the limits ofL. michahellisbreeding colony. Furthermore, an antipredator behaviour analysis showed thatL. michahellisdisplayed a strong anti-predator or mobbing response against cats, one of the main threats forG. intermedia, thus potentially providing some protection to the reptiles inhabiting the seabird colony. Our results show how unusual and poorly studied biotic interactions can provide valuable resources and conditions for the conservation of a critically endangered species inhabiting a suboptimal or relict habitat.
High resolution optical spectroscopy for the evaluation of cannabidiol efficiency as a radiation therapy support of peripheral nervous system tumors
Authors: Chrabąszcz Karolina , Pogoda Katarzyna , Cieżak Klaudia , Panek Agnieszka , Kwiatek Wojciech M.
Published: December 2023

An increasing number of scientific papers discuss the promising therapeutic potential of cannabidiol (CBD) not only for the treatment of cancer, but also for asthma and neurodegenerative disorders. This happens mainly due to its proven anticancer, anti-inflammatory, and antioxidant properties. In the field of cancer research, the use of CBD has already been investigated on malignant tumors of the central nervous system, like gliomas. So far, CBD has not yet been explored in the therapy of peripheral nervous system (PNS) tumors. Peripheral nerves reside outside the central nervous system, therefore peripheral nerve tumors can occur anywhere in the body. When the tumor develops within large blood vessels, spinal nerves or involves more than one peripheral nerve, radiotherapy is recommended. Due to high doses of ionizing radiation, complications such as dizziness, damage to adjacent nerves, or malignancy of the lesion may occur. Therefore, it is important to develop a treatment scheme that efficiently reduces tumor volume while maintaining the normal functions of the surrounding cells and decrease the side effects. Herein, we proposed to combine hyperspectral imaging using Raman and FTIR spectroscopy and AFM-IR technique as a novel approach to monitor the therapeutic efficacy of CBD. Performed studies reviled the dual effect of CBD, that protects normal cells from ionizing radiation and increases its toxicity in cancer cells.
Predicting Anorexia Nervosa and Autistic Characteristics in Individuals with Anorexia Nervosa from Resting State Cyclic Connectivity
Authors: Halls Daniel , Leppanen Jenni , Williams Steve , Tchanturia Kate
Published: December 2023

Background

Resting state functional Magnetic Resonance Imaging (rsfMRI) differences have been reported in individuals with anorexia nervosa (AN). However, methodological issues limit inferences, the dynamic cyclic nature of the resting state signal has not been explored, neither has the association with known elevated autistic characteristics.

Methods

92 participants, 65 Individuals with AN and 27 controls underwent rsfMRI. Cyclic analysis was conducted to obtain pairwise relationships between regions. Classification of group and regression to predict autistic characteristics within the AN group was conducted, with model weights being explored to ascertain the most predictive pairwise relationships.

Results

Pairwise relationships in the temporal, dorsal and ventral attention networks were most predictive of group. The anterior intraparietal sulcus, salience, dorsal attention, auditory dorsal posterior cingulate cortex, and ventral attention networks were most predictive of autistic characteristics.

Discussion

Several distinct pairwise relationships predicting group and autistic characteristics were found, however, the global disruption of the temporal ordering of the cyclic wave, and variation in temporal ordering across resting state scan are also a neurophenotype in individuals with AN and the relationship to autistic characteristics. Characteristics associated with AN and autism are also predicted by distinct neural regions.
Modeling Sex Differences in the Effects of Diuretics in Renal Epithelial Transport during Angiotensin II-induced Hypertension
Authors: Zheng Kaixin , Layton Anita T.
Published: December 2023

Chronic angiotensin II (AngII) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females, perhaps unexpectedly, given the rodent kidney, which plays a key role in blood pressure regulation, exhibit marked sex differences. Those sex differences include morphology, hemodynamics, and, under healthy (undrugged) conditions, solute and electrolyte transporter abundance. Notably, compared to the male rat nephron, the female rat nephron exhibits lower Na+/H+exchanger 3 (NHE3) activity along the proximal tubule, but higher Na+transporter activities along the distal segments. AngII infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+transport capacity downstream, to different extents in the two sexes. The goals of this study are (i) to understand how the sexually dimorphic responses differentially impact segmental electrolyte transport following a 14- day AngII infusion, and (ii) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. To achieve those goals, we developed sex-specific computational models of renal epithelial transport of electrolytes and water. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with a stronger effect in males. Due to the downstream shift of Na+transport load in hypertension, all three diuretic classes are predicted to induce stronger natriuretic and diuretic effects under hypertension compared to normotension, especially in females.

New and Noteworthy

Sex differences in the prevalence of hypertension are found in humans and animal models. The kidney, which plays an important role in blood pressure regulation, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport. Simulations results also explain sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics.
Fatty Acid Metabolism and The Oxidative Stress Response Support Bacterial Predation
Authors: Jain Rikesh , Le Nguyen-Hung , Bertaux Lionel , Baudry Jean , Bibette Jérôme , Denis Yann , Habermann Bianca H. , Mignot Tâm
Published: December 2023

Despite growing awareness of their importance in soil ecology, the genetic and physiological traits of bacterial predators are still relatively poorly understood. In the course of aMyxococcus xanthuspredator evolution experiment, we discovered a class of genotypes leading to enhanced predation against diverse species. RNA-seq analysis demonstrated that this phenotype is linked to the constitutive activation of a predation-specific program. Functional analysis of the mutations accumulated across the evolutionary time in a two- component system and Acyl-CoA-manipulating enzymes revealed the critical roles of fatty acid metabolism and antioxidant gene induction. The former likely adapts the predator to metabolites derived from the prey while the latter protects predatory cells from reactive oxygen species (ROS) generated by prey cells under stress and released upon lysis during predation. These findings reveal interesting parallels between bacterial predator-prey dynamics and pathogen-host cell interactions.

Significance Statement

This study illuminates the largely unexplored genetic and metabolic strategies used by bacterial predators in soil ecosystems. Through experimental evolution inMyxococcus xanthus, we discovered that more efficient predators accumulate mutations that activate a genetic program for predation. This program simultaneously triggers a metabolic shift favoring fatty acid degradation for energy production and upregulates antioxidant gene expression, enhancing protection against reactive oxygen species generated during prey cell lysis. This adaptive mechanism proves advantageous across a wide range of prey species, suggesting that metabolic adaptation plays a crucial role in the evolutionary trajectory of bacterial predators within their natural ecological niche.
Restoring Protein Glycosylation with GlycoShape
Authors: Ives Callum M , Singh Ojas , D’Andrea Silvia , Fogarty Carl A , Harbison Aoife M , Satheesan Akash , Tropea Beatrice , Fadda Elisa
Published: December 2023

During the past few years, we have been witnessing a revolution in structural biology. Leveraging on technological and computational advances, scientists can now resolve biomolecular structures at the atomistic level of detail by cryogenic electron microscopy (cryo-EM) and predict 3D structures from sequence alone by machine learning (ML). One technique often supports the other to provide the view of atoms in molecules required to capture the function of molecular machines. An example of the extraordinary impact of these advances on scientific discovery and on public health is given by how structural information supported the rapid development of COVID-19 vaccines based on the SARS-CoV-2 spike (S) glycoprotein. Yet, none of these new technologies can capture the details of the dense coat of glycans covering S, which is responsible for its natural, biologically active structure and function and ultimately for viral evasion. Indeed, glycosylation, the most abundant post-translational modification of proteins, is largely invisible through experimental structural biology and in turn it cannot be reproduced by ML, because of the lack of data to learn from. Molecular simulations through high-performance computing (HPC) can fill this crucial information gap, yet the computational resources, the users’ skills and the long timescales involved limit applications of molecular modelling to single study cases. To broaden access to structural information on glycans, here we introduce GlycoShape (https://glycoshape.org) an open access (OA) glycan structure database and toolbox designed to restore glycoproteins to their native functional form by supplementing the structural information available on proteins in public repositories, such as the RCSB PDB (www.rcsb.org) and AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk/), with the missing glycans derived from over 1 ms of cumulative sampling from molecular dynamics (MD) simulations. The GlycoShape Glycan Database (GDB) currently counts over 435 unique glycans principally covering the human glycome and with additional structures, fragments, and epitopes from other eukaryotic and prokaryotic organisms. The GDB feeds into Re-Glyco, a bespoke algorithm in GlycoShape designed to rapidly restore the natural glycosylation to protein 3D structures and to predictN-glycosylation occupancy, where unknown. Ultimately, integration of GlycoShape with other OA protein structure databases can provide a step-change in scientific discovery, from the structural and functional characterization of the active form of biomolecules, all the way down to pharmacological applications and drug discovery.
Polymorphism-aware models in RevBayes: Species trees, disentangling Balancing Selection and CG-biased gene conversion
Authors: Braichenko Svitlana , Borges Rui , Kosiol Carolin
Published: December 2023

The role of balancing selection is a long-standing evolutionary puzzle. Balancing selection is a crucial evolutionary process that maintains genetic variation (polymorphism) over extended periods of time; however, detecting it poses a significant challenge. Building upon the polymorphismaware phylogenetic models (PoMos) framework rooted in the Moran model, we introduce Po-MoBalance model. This novel approach is designed to disentangle the interplay of mutation, genetic drift, directional selection (GC-biased gene conversion), along with the previously unexplored balancing selection pressures on ultra-long timescales comparable with species divergence times by analysing multi-individual genomic and phylogenetic divergence data. Implemented in the open-source RevBayes Bayesian framework, PoMoBalance offers a versatile tool for inferring phylogenetic trees as well as quantifying various selective pressures. The novel aspect of our approach in studying balancing selection lies in PoMos’ ability to account for ancestral polymorphisms and incorporate parameters that measure frequency-dependent selection, allowing us to determine the strength of the effect and exact frequencies under selection. We implemented validation tests and assessed the model on the data simulated with SLiM and a custom Moran model simulator. Real sequence analysis ofDrosophilapopulations reveals insights into the evolutionary dynamics of regions subject to frequency-dependent balancing selection, particularly in the context of sex-limited colour dimorphism inDrosophila erecta.
Evaluation of phenotypic and genotypic methods for the identification and characterisation of bacterial isolates recovered from catheter-associated urinary tract infections
Authors: Varney Adam M. , Mannix-Fisher Eden , Thomas Jonathan C. , McLean Samantha
Published: December 2023

Purpose

Urinary tract infections are the most common type of hospital-acquired infection, up to 80% of which are associated with catheterisation. The present study evaluates phenotypic and genomic characterisation of a panel of catheter associated urinary tract infection isolates from a UK hospital.

Methods

Strains were identified and characterised utilising a range of phenotypic and genomic techniques to understand where methodologies agree. The effect of medium composition on growth and biofilm formation phenotype was also determined to evidence the importance of assay design in characterisation of bacterial isolates.

Results

No consensus was observed for any of the CAUTI isolates across five identification methods, including biochemical testing, MALDI and sequencing technologies. Comparison of EUCAST antimicrobial susceptibility testing and genotypic data for antibiotic resistance showed high concordance where strains were phenotypically resistant to multiple antibiotic classes, however discordance increased for strains that were phenotypically sensitive to range of antibiotics. Phenotypic analysis of bacterial pathogens often relies on the use of rich laboratory media; however, we observed significant differences in growth rate and biofilm formation within a range of media, with a trend towards comparatively low planktonic growth and significant biofilm biomass formation in artificial urine.

Conclusion

This study emphasises potential pitfalls of relying on a single method of species identification, with only whole genome sequencing providing accurate identification of isolates to species level. Furthermore, it highlights the continuing importance of utilising phenotypic methods to understand antibiotic resistance within clinical settings and of utilising clinically relevant conditions for pathogen characterisation.
Modulating social learning-induced evaluation updating during human sleep
Authors: Chen Danni , Xia Tao , Yao Ziqing , Zhang Lingqi , Hu Xiaoqing
Published: December 2023

People often change their evaluations upon learning about their peers’ evaluations, i.e., social learning. Given sleep’s vital role in consolidating daytime experiences, sleep may facilitate social learning and thereby further changing people’s evaluations. Combining a social learning task and the sleep-based targeted memory reactivation technique, we asked whether social learning-induced evaluation changes can be modulated during sleep. After participants indicated their initial evaluation for snacks, they learned about their peers’ evaluation while hearing the snacks’ spoken names. During the post-learning non-rapid-eye-movement sleep, we re-played half of the snack names (i.e., cued snack) to reactivate the associated peers’ evaluations. Upon waking up, we found that the social learning-induced evaluation changes further enlarged for both cued and uncued snacks. Examining sleep electroencephalogram (EEG) activity revealed that cue-elicited delta-theta EEG power and the overnight N2 sleep spindle density predicted post-sleep evaluation changes for cued but not for uncued snacks. Our findings suggested that sleep-mediated memory reactivation processes could strengthen social learning-induced evaluation changes.
An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism
Authors: Cai Ling , Vu Hieu S , Gu Wen , Chen Hongli , Franklin Jordan , Haidar Lea Abou , Wu Zheng , Pan Chunxiao , Cai Feng , Nguyen Phong , Ko Bookyung , Yang Chendong , Zacharias Lauren G. , Sudderth Jessica , Montgomery Sarah , Uhles Crescenda , Fisher Heather , Hudnall Julianna , Hornbuckle Callie , Quinn Christine , Michel Donnice , Umaña Luis , Scheuerle Angela , McNutt Markey C. , Gotway Garrett K. , Afroze Bushra , Ni Min , DeBerardinis Ralph
Published: December 2023

Metabolomic profiling is instrumental in understanding the systemic and cellular impact of inborn errors of metabolism (IEMs), monogenic disorders caused by pathogenic genomic variants in genes involved in metabolism. This study encompasses untargeted metabolomics analysis of plasma from 474 individuals and fibroblasts from 67 subjects, incorporating healthy controls, patients with 65 different monogenic diseases, and numerous undiagnosed cases. We introduce a web application designed for the in-depth exploration of this extensive metabolomics database. The application offers a user-friendly interface for data review, download, and detailed analysis of metabolic deviations linked to IEMs at the level of individual patients or groups of patients with the same diagnosis. It also provides interactive tools for investigating metabolic relationships and offers comparative analyses of plasma and fibroblast profiles. This tool emphasizes the metabolic interplay within and across biological matrices, enriching our understanding of metabolic regulation in health and disease. As a resource, the application provides broad utility in research, offering novel insights into metabolic pathways and their alterations in various disorders.
Distinct TORC1 signalling branches regulate Adc17 proteasome assembly chaperone expression
Authors: Williams Thomas D. , Dublanska Sylwia M. , Bergquist Rebecka , Rousseau Adrien
Published: December 2023

When stressed, cells need to adapt their proteome to maintain protein homeostasis. This requires increased proteasome assembly. Increased proteasome assembly is dependent on increased proteasome assembly chaperone expression. InS. cerevisiae, inhibition of the growth-promoting kinase complex TORC1 causes increased proteasome assembly chaperone expression. This is dependent upon activation of the MAPKinase Mpk1 and relocalisation of assembly chaperone mRNA to patches of dense actin. We show here that TORC1 inhibition alters cell wall properties to induce these changes by activating the Cell Wall Integrity pathway through the Wsc1, Wsc3, and Wsc4 sensor proteins. We demonstrate that in isolation these signals are insufficient to drive protein expression. We identify that the TORC1-activated S6Kinase Sch9 must be inhibited as well. This work expands our knowledge on the signalling pathways which regulate proteasome assembly chaperone expression.

TORC1-regulated proteasome assembly chaperone expression is necessary for proteasome assembly and proteostasis. We identify Cell Wall Integrity and Sch9 signalling as mechanisms controlling this.
Differentiation SELEX approach identifies RNA aptamers with different specificities for HIV-1 capsid assembly forms
Authors: Gruenke Paige R. , Mayer Miles D. , Aneja Rachna , Song Zhenwei , Burke Donald H. , Heng Xiao , Lange Margaret J.
Published: December 2023

The HIV-1 capsid protein (CA) assumes distinct assembly forms during replication, each presenting unique, solvent-accessible surfaces that facilitate multifaceted functions and host factor interactions. However, contributions of individual CA assemblies remain unclear, as the evaluation of CA in cells presents several technical challenges. To address this need, we sought to identify CA assembly form-specific aptamers. Aptamer subsets with different specificities emerged from within a highly converged, pre-enriched aptamer library previously selected to bind the CA hexamer lattice. Subsets were either highly specific for CA lattice or bound both CA lattice and CA hexamer. We further evaluated four representatives to reveal aptamer structural features required for binding, highlighting interesting features and challenges in aptamer structure determination. Importantly, our aptamers bind biologically relevant forms of CA and we demonstrate aptamer-mediated affinity purification of CA from cell lysates without virus or host modification. Thus, we have identified CA assembly form-specific aptamers that represent exciting new tools for the study of CA.
Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase (MDH2)
Authors: Noble Michelle , Chatterjee Aindrila , Sekaran Thileepan , Schwarzl Thomas , Hentze Matthias W.
Published: December 2023

Several enzymes of intermediary metabolism have been identified to bind RNA in cells, with potential consequences for the bound RNAs and/or the enzyme. In this study, we investigate the RNA-binding activity of the mitochondrial enzyme malate dehydrogenase 2 (MDH2), which functions in the tricarboxylic acid (TCA) cycle and the malate-aspartate shuttle. We confirmedin celluloRNA-binding of MDH2 using orthogonal biochemical assays and performed enhanced crosslinking and immunoprecipitation (eCLIP) to identify the cellular RNAs associated with endogenous MDH2. Surprisingly, MDH2 preferentially binds cytosolic over mitochondrial RNAs, although the latter are abundant in the milieu of the mature protein. Subcellular fractionation followed by RNA-binding assays revealed that MDH2-RNA interactions occur predominantly outside of mitochondria. We also found that a cytosolically-retained N-terminal deletion mutant of MDH2 is competent to bind RNA, indicating that mitochondrial targeting is dispensable for MDH2-RNA interactions. MDH2 RNA binding increased when cellular NAD+levels (MDH2’s co-factor) was pharmacologically diminished, suggesting that the metabolic state of cells affects RNA binding. Taken together, our data implicate an as yet unidentified function of MDH2 binding RNA in the cytosol.