bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting real-world navigation performance from a virtual navigation task in older adults
Authors: Goodroe Sarah , Fernandez Velasco Pablo , Gahnstrom Christoffer J , Wiener Jan , Coutrot Antoine , Hornberger Michael , Spiers Hugo J
Published: July 2024

Virtual reality environments presented on tablets and smartphones offer a novel way of measuring navigation skill and predicting real-world navigation problems. The extent to which such virtual tests are effective at predicting navigation in older populations remains unclear. We compared the performance of 20 older participants (54-74 years old) in wayfinding tasks in a real-world environment in London, UK, and in similar tasks designed in a mobile app-based test of navigation (Sea Hero Quest). In a previous study with young participants (18-35 years old), we were able to predict navigation performance in real-world tasks in London and Paris using this mobile app. We find that for the older cohort, virtual navigation performance predicts real-world performance for medium difficulty, but not for the easy or difficult environments. While the younger sample outperformed the older sample in the virtual task, this was not the case in the real-world task, which conflicts with the dominant view of a decline in navigation ability with age. Self-reports identifying compensatory skills and further analysis of our participants’ scores in the Montreal Cognitive Assessment and in the Navigation Strategy Questionnaire help give insights into the higher performance in the real world. Overall, our study supports the utility of using digital tests of spatial cognition in older age groups, while carefully adapting the task difficulty to the population.
PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP
Authors: Wang Jiongke , Shi Yujie , Wang Ying , Shen Yingqiang , Liu Huan , Sun Silu , Wang Yimei , Zhou Xikun , Zhou Yu , Zeng Xin , Li Jing , Chen Qianming
Published: July 2024

Proteasome activator 28γ (PA28γ) plays a critical role in malignant progression of various tumors, however, its role and regulation are not well understood. Here, using oral squamous cell carcinoma (OSCC) as main research model, we discovered that PA28γ interacted with complement 1q binding protein (C1QBP), which is dependent on the N-terminus of C1QBP rather than the known functional domain (amino acids 168-213). Notably, we found that PA28γ enhances C1QBP protein stability in OSCC. Functionally, PA28γ contributes to the malignant progression of OSCC by affecting mitochondrial morphology and oxidative phosphorylation (OXPHOS) through C1QBP in vitro and vivo. Mechanically, PA28γ upregulates the expression of optic atrophy 1 (OPA1), mitofusin 1 (MFN1), mitofusin 2 (MFN2), and the mitochondrial respiratory complex via C1QBP. Moreover, in a clinical cohort of OSCC patients, PA28γ was positively correlated with C1QBP expression and negatively correlated with prognosis. Therefore, C1QBP represents a potential therapeutic target for cancer treatment and prognosis.
Assessing the balance between excitation and inhibition in chronic pain through the aperiodic component of EEG
Authors: Gil Avila Cristina , May Elisabeth S , Bott Felix S , Tiemann Laura , Hohn Vanessa , Heitmann Henrik , Zebhauser Paul Theo , Gross Joachim , Ploner Markus
Published: July 2024

Chronic pain is a prevalent and debilitating condition whose neural mechanisms are incompletely understood. An imbalance of cerebral excitation and inhibition (E/I), particularly in the medial prefrontal cortex (mPFC), is believed to represent a crucial mechanism in the development and maintenance of chronic pain. Thus, identifying a non-invasive, scalable marker of E/I could provide valuable insights into the neural mechanisms of chronic pain and aid in developing clinically useful biomarkers. Recently, the aperiodic component of the electroencephalography (EEG) power spectrum has been proposed to represent a noninvasive proxy for E/I. We, therefore, assessed the aperiodic component in the mPFC of resting-state EEG recordings in 149 people with chronic pain and 115 healthy participants. We found robust evidence against differences in the aperiodic component in the mPFC between people with chronic pain and healthy participants, and no correlation between the aperiodic component and pain intensity. These findings were consistent across different subtypes of chronic pain and were similarly found in a whole-brain analysis. Their robustness was supported by preregistration and multiverse analyses across many different methodological choices. Together, our results suggest that the EEG aperiodic component does not differentiate between people with chronic pain and healthy individuals. These findings and the rigorous methodological approach can guide future studies investigating non-invasive, scalable markers of cerebral dysfunction in people with chronic pain and beyond.
FISH, a new tool for in situ preservation of RNA in tissues of deep-sea mobile fauna
Authors: Cueff-Gauchard V. , Aube J. , Lagadec J-R. , Bignon L. , Lafontaine J-P. , Hernandez-Avila I. , Marsaud N. , Shillito B. , Amand L. , Roussel E. G. , Cambon M-A.
Published: July 2024

Accessing the metabolic functioning of deep-sea animals in situ remains a technological challenge as the recovery time of samples is incompatible with the short lifespan of such molecules as mRNAs. Tools able to preserve RNA in situ exist but they are incompatible with the study of mobile fauna. Here we describe a new sampling tool, named FISH (Fixer In situ of Homogenized Substrates), implemented on a submersible and equipped with a number of new specific features to collect and preserve in situ tissue of mobile fauna. Connected to the suction pump of a submersible, FISH incorporates a sampling bowl to which two bottles of a preservative reagent are attached, a suction hose, and a support containing a motor connected to the sampling bowl by a magnetic coupling system. We used the deep-sea hydrothermal shrimpRimicaris exoculatafrom the Mid-Atlantic Ridge as a model to test the suitability of our new tool. FISH was compared to two other sampling methods, which use a metatranscriptomic approach targeting microbial communities associated with cephalothorax symbionts. RNA quality, gene assignment and taxonomic and gene function diversity showed differences between in situ and on-board preservation of tissues. Of the alternative sampling methods tested, the suction sampler was clearly not suitable for RNA-based studies, while pressurized recovery showed results closer to the sample quality obtained with FISH sampling. The FISH sampler has therefore demonstrated to be a cost-effective and reliable tool to efficiently preserve RNA recovered from deep-sea environments.
ThePlasmodiophora brassicaeeffector PbEGF1 manipulates plant immunity and regulate primary infection
Authors: Yang Hui , Xu Yushu , Zhao Yushan , Shu Yinping , Sun Xin , Du Junbo
Published: July 2024

Plasmodiophora brassicaecauses a significant global threat to cruciferous vegetables and crops. However, the current comprehensions of its pathogenic ways is still unclear. This study identified aP. brassicaeeffector, called PbEGF1, which strongly induces cell death inN. benthamiana.Notably,PbEGF1was significantly up-regulated in seedlings inoculated with highly virulentP. brassicae, indicating a pivotal role for PbEGF1 in pathogenicity. Furthermore, overexpression of PbEGF1 in hosts enhanced susceptibility toP. brassicae,and promoted elongation of root hairs, thus creating favorable conditions for root hair infection. Silencing ofPbEGF1reduced the pathogenicity ofP. brassicae. This finding confirms the significance of primary infection in host recognition and interaction withP. brassicae. To further elucidate the virulence function of PbEGF1, we identified BnNHL13 (nonrace-specific disease resistance 1/harpin-induced 1-like 13) as its target protein. SilencingBnNHL13enhanced host susceptibility toP. brassicae,and promoted root hairs elongation, indicating that down-regulation ofBnNHL13was more conducive to establishingP. brassicaeinfection. Subsequent investigation revealed that PbEGF1 has the ability to induce degradation of the BnNHL13 protein, thereby disrupting the host defense response and facilitatingP. brassicaeinfection. Our findings provide novel insights into genetic strategies for enhancing plant resistance against clubroot disease.
Protein Kinases MpkA and SepH Transduce Crosstalk Between CWI and SIN Pathways to Activate Protective Hyphal Septation Under Echinocandin Cell Wall Stress
Authors: Doan Alexander G. , Schafer Jessica E. , Douglas Casey M. , Quintanilla Matthew S. , Morse Meredith E. , Edwards Harley , Huso Walker D. , Gray Kelsey J. , Lee JungHun , Dayie Joshua K. , Harris Steven D. , Marten Mark R.
Published: July 2024

This study investigates a previously unreported stress signal transduced as crosstalk between the Cell Wall Integrity (CWI) pathway and the Septation Initiation Network (SIN). Echinocandins, which target cell wall synthesis, are widely used to treat mycoses. Their efficacy, however, is species specific; our findings suggest this is due largely to CWI-SIN crosstalk and the ability of filamentous species to fortify with septa in response to echinocandin stress. To better understand this crosstalk, we used a microscopy-based assay to measure septum density, aiming to understand the septation response to cell wall stress. The echinocandin micafungin, an inhibitor of β-(1,3)-glucan synthase, was employed to induce this stress. We observed a strong positive correlation between micafungin treatment and septum density inwild-typestrains. This finding suggests that CWI activates SIN under cell wall stress, increasing septum density to protect against cell wall failure. More detailed investigations, with targeted knockouts of CWI and SIN signaling proteins, enabled us to identify crosstalk occurring between the CWI kinase, MpkA, and the SIN kinase, SepH. This discovery, of previously unknown crosstalk between the CWI and SIN pathways, not only reshapes our understanding of fungal stress responses, but also unveils a promising new target pathway for the development of novel antifungal strategies.

IMPORTANCE

Echinocandin resistant species pose a major challenge in clinical mycology by rendering one of only four lines of treatment, notably one of the two that are well-tolerated, ineffective in treating systemic mycoses of these species. Previous studies have demonstrated that echinocandins fail against highly polarized fungi because they target only apical septal compartments. It is known that many filamentous species respond to cell wall stress with hyperseptation. In this work we show that echinocandin resistance hinges on this dynamic response, rather than on innate septation alone. We also unveil, for the first time, the signaling pathway used to deploy the hyperseptation response. By disabling this pathway, we were able to render mycelia susceptible to echinocandin stress. Hence, this work enhances our microbiological understanding of filamentous fungi and introduces a potential target to overcome echinocandin resistant species.
Chemical Induction of Longevity-Promoting Colanic Acid in the Host’s Microbiota
Authors: Hu Guo , Cooke Matthew Brandon , Wen Alice X , Yu Xin , Wang Jin , Herman Christophe , Wang Meng C.
Published: July 2024

Microbiota-derived metabolites have emerged as key regulators of longevity. The metabolic activity of the gut microbiota, influenced by dietary components and ingested chemical compounds, profoundly impacts host fitness. While the benefits of dietary prebiotics are well-known, chemically targeting the gut microbiota to enhance host fitness remains largely unexplored. Here, we report a novel chemical approach to induce a pro-longevity bacterial metabolite in the host gut. We discovered that specificEscherichia colistrains overproduce colanic acids (CAs) when exposed to a low dose of cephaloridine, leading to an increased lifespan in hostCaenorhabditis elegans. In the mouse gut, oral administration of low-dose cephaloridine induces the transcription of the capsular biosynthesis operon responsible for CA biosynthesis in commensalE. coli, which overcomes the inhibition of CA biosynthesis above 30°C and enables its induction directly from the microbiota. Importantly, low-dose cephaloridine induces CA independently of its antibiotic properties through a previously unknown mechanism mediated by the membrane-bound histidine kinase ZraS. Our work lays the foundation for microbiota-based therapeutics through the chemical modulation of bacterial metabolism and reveals the promising potential of bacteria-targeting drugs in promoting host longevity.
The single-cell make-up of adult diffuse glioma based on the 2021 WHO classification
Authors: Alnahhas Iyad , Kayne Allison , Khan Mehak , Shi Wenyin
Published: July 2024

Introduction

Single-cell RNA sequencing (scRNA-seq) has helped to elucidate the cellular composition of cancer and its microenvironment. Recent scRNA-seq studies have highlighted the heterogeneity of glioblastoma (GBM). Moreover, single-cell GBM analyses have proposed resemblance of GBM cells to radial glia and outer radial glia supporting the hypothesis that remnants of developmental tissue get reactivated in cancer. A recent study isolated neural progenitor cells (NPCs) from developing fetal human brain (gestational week 17–19) and classified NPCs based on their expression of THY1, CD24 and EGFR. Ventricular radial glia are THY1-CD24-EGFR+ whereas outer radial glia are THY1-CD24-EGFR-. Early neuron precursors are CD24+THY1-EGFR+ and glial progenitor cells (GPCs) are THY1+EGFR+. GPCs give rise to THY1+EGFR+PDGFRA+ pre-oligodendrocyte progenitor cells. The importance of EGFR in NPCs again highlights the resemblance to glioma.

Methods

We aimed to apply the classification above in IDH mutant astrocytoma and oligodendroglioma as well as IDHwt glioblastoma samples. We used three publicly available datasets: Wang (paired 74 IDHwt primary and recurrent samples), Tirosh (6 primary oligodendroglioma samples) and Venteicher (10 primary IDH mutant astrocytoma).

Results

In IDH mutant astrocytoma, 82.63% of cells express THY1+ (mostly EGFR+PDGFRA+) and 10.76% of cells are THY1-CD24-EGFR+. In oligodendroglioma, 75% of cells are THY1+ (mostly EGFR+PDGFRA+) and 12.07% are THY1-CD24-EGFR+. In IDHwt EGFR amplified primary GBM samples, 87.5% of cells are THY1-CD24-EGFR+. This percentage drops to 70.4% in the recurrent setting. THY1-CD24-EGFR-cells increase from 9.7% to 23.1% at recurrence. In IDHwt EGFRwt primary GBM samples, 48.6% of cells are THY1-CD24-EGFR+ and 44.15% are THY1-CD24-EGFR-. In the recurrent setting, 43.26% of cells are THY1-CD24-EGFR+ and 49.58% are THY1-CD24-EGFR-.

Conclusion

IDH mutant gliomas and IDHwt glioblastoma express different progenitor cell markers. THY1 is highly expressed in IDH mutant gliomas.
Eco-evolutionary dynamics of pathogen immune-escape: deriving a population-level phylodynamic curve
Authors: Nielsen Bjarke Frost , Saad-Roy Chadi M. , Metcalf C. Jessica E. , Viboud Cécile , Grenfell Bryan T.
Published: July 2024

The phylodynamic curve [1] conceptualizes how immunity shapes the rate of viral adaptation in a non-monotonic fashion, through its opposing effects on viral abundance and the strength of selection. However, concrete and quantitative model realizations of this influential concept are rare. Here, we present an analytic, stochastic framework in which a population-scale phylodynamic curve emerges dynamically, allowing us to address questions regarding the risk and timing of emergence of viral immune escape variants. We explore how pathogen- and population-specific parameters such as strength of immunity, transmissibility and antigenic constraints affect the phylodynamic curve, leading to distinct phylodynamic curves for different pathogens. Motivated by the COVID-19 pandemic, we probe the likely effects of non-pharmaceutical interventions (NPIs), and the lifting thereof, on the risk of viral escape variant emergence. Looking ahead, the framework has the potential to become a useful tool for probing how natural immunity, as well as choices in vaccine design and distribution and the implementation of NPIs affect the evolution of common viral pathogens.
Activating FcγRs on monocytes are necessary for optimal Mayaro virus clearance
Authors: Dunagan Megan M. , Dábilla Nathânia , McNinch Colton , Brenchley Jason M. , Dolan Patrick T. , Fox Julie M.
Published: July 2024

Mayaro virus (MAYV) is an emerging arbovirus. Previous studies have shown antibody Fc effector functions are critical for optimal monoclonal antibody-mediated protection against alphaviruses; however, the requirement of Fc gamma receptors (FcγRs) for protection during natural infection has not been evaluated. Here, we showed mice lacking activating FcγRs (FcRγ-/-) developed prolonged clinical disease with more virus in joint-associated tissues. Viral clearance was associated with anti-MAYV cell surface binding rather than neutralizing antibodies. Lack of Fc-FcγR engagement increased the number of monocytes through chronic timepoints. Single cell RNA sequencing showed elevated levels of pro-inflammatory monocytes in joint-associated tissue with increased MAYV RNA present in FcRγ-/-monocytes and macrophages. Transfer of FcRγ-/-monocytes into wild type animals was sufficient to increase virus in joint-associated tissue. Overall, this study suggests that engagement of antibody Fc with activating FcγRs promotes protective responses during MAYV infection and prevents monocytes from being potential targets of infection.
Distinct subcircuits within the mesolimbic dopamine system encode the salience and valence of social stimuli
Authors: Cross E. A. , Borland J.M. , Shaughnessy E.K. , Lee S.D. , Vu V. , Sambor E.A. , Huhman K. L. , Albers H. E.
Published: July 2024

The mesolimbic dopamine (DA) system (MDS) is the canonical “reward” pathway that has been studied extensively in the context of the rewarding properties of sex, food, and drugs of abuse. In contrast, very little is known about the role of the MDS in the processing of the rewarding and aversive properties of social stimuli. Social interactions can be characterized by their salience (i.e., importance) and their rewarding or aversive properties (i.e., valence). Here, we test the novel hypothesis that projections from the medial ventral tegmental area (VTA) to the nucleus accumbens (NAc)corecodes for the salience of social stimuli through the phasic release of DA in response to both rewarding and aversive social stimuli. In contrast, we hypothesize that projections from the lateral VTA to the NAcshellcodes for the rewarding properties of social stimuli by increasing the tonic release of DA and the aversive properties of social stimuli by reducing the tonic release of DA. Using DA amperometry, which monitors DA signaling with a high degree of temporal and anatomical resolution, we measured DA signaling in the NAc core or shell while rewarding and aversive social interactions were taking place. These findings, as well as additional anatomical and functional studies, provide strong support for the proposed neural circuitry underlying the response of the MDS to social stimuli. Together, these data provide a novel conceptualization of how the functional and anatomical heterogeneity within the MDS detect and distinguish between social salience, social reward, and social aversion.

Significance Statement

Social interactions of both positive and negative valence are highly salient stimuli that profoundly impact social behavior and social relationships. Although DA projections from the VTA to the NAc are involved in reward and aversion little is known about their role in the saliency and valence of social stimuli. Here, we report that DA projections from the mVTA to the NAc core signal the salience of social stimuli, whereas projections from the lVTA to the NAc shell signal valence of social stimuli. This work extends our current understanding of the role of DA in the MDS by characterizing its subcircuit connectivity and associated function in the processing of rewarding and aversive social stimuli.
Cell Storage Conditions Impact Single-Cell Proteomic Landscapes
Authors: Onat Bora , Momenzadeh Amanda , Haghani Ali , Jiang Yuming , Song Yang , Parker Sarah J. , Meyer Jesse G.
Published: July 2024

Single-cell transcriptomics (SCT) has revolutionized our understanding of cellular heterogeneity, yet the emergence of single-cell proteomics (SCP) promises a more functional view of cellular dynamics. A challenge is that not all mass spectrometry facilities can perform SCP, and not all labs have access to cell sorting equipment required for SCP, which together motivate an interest in sending bulk cell samples through the mail for sorting and SCP analysis. Shipping requires cell storage, which has an unknown impact on SCP results. This study investigates the impact of cell storage conditions on the proteomic landscape at the single-cell level utilizing a Data-Independent Acquisition (DIA) coupled with Parallel Accumulation Serial Fragmentation (diaPASEF). Three storage conditions were compared in 293T cells: (1) 37°C (control), (2) 4°C overnight, and (3) - 80°C storage followed by liquid nitrogen preservation. Either cold or frozen storage induced significant alterations in cell diameter, elongation, and proteome composition. By elucidating how cell storage conditions alter cellular morphology and proteome profiles, this study contributes foundational technical information about SCP sample preparation and data quality.
Multi-omic ADNI CSF and plasma data integration identifies distinct metabolic transitions in disease progression in Alzheimer’s Disease
Authors: Paterson Tom , Rohrs Jennifer , Hohman Timothy J. , Mapstone Mark , Levey Allan I. , Hood LeRoy ,   Alzheimer’s Disease Neuroimaging Initiative, Funk Cory C.
Published: July 2024

Age and APOE allele status are the two greatest risk factors for Alzheimer’s disease, with microglial processing, recycling of debris and cholesterol transport emerging as other key genetic determinants from AD GWAS. How risk factors contribute to neuronal loss is an unanswered question. Using the ADNI dataset, we provide evidence for distinct processes driving neurodegeneration in AD across a range of ADAS13 scores binned into quartiles (Q1-4) found in ADNI. In Q1 individuals, we see evidence of white matter hyperintensities (WMH) associated with complement and HDL proteins, independent of tau and hippocampal atrophy rates. In Q2 individuals, we see specific protein/lipid correlation networks that are associated with tau and hippocampal atrophy. Also in Q2, we see variations in enzyme levels (LPA2G7, LPCAT2) that impact phosphatidylcholine availability for cholesterol efflux onto CNS lipoproteins. Low LPA2G7 and high LPCAT are associated with lower disruption of ANLS, while high LPA2G7 and low LPCAT are associated with higher disruption. In Q3 individuals, DHA and plasmalogens appear to be protective of astrogliosis, presumably by decreasing lipid droplet size, and increasing their lipid debris flux capacity. The networks we identify in this analysis provide evidence that progressively elevated cellular cholesterol levels, likely the result of accelerating neuronal and myelin debris, are perturbing homeostatic processes, resulting in disruption of astrocyte-neuron lactate shuttle (ANLS), contributing to lipid droplet formation, and astrogliosis. Existing studies have already identified elevated cellular cholesterol as the driver of increased access of APP to β- and γ-secretase for β-amyloid production in late-onset AD. Importantly, we provide evidence that points to actionable variations in lipids associated with slower disease progression and decreased metabolic disruption and inflammation. We believe this positive feedback loop (neurodegeneration → lipid debris processing → metabolic disruption → neurodegeneration) is a key destabilizing cycle responsible for disease progression in AD, reinforcing the perspective that Alzheimer’s is fundamentally a metabolic disease. Our findings are consistent with established lipid risk factor associations. We anticipate the mechanistic insights from our analysis will advance nutritional and pharmacological interventions and slow cognitive decline.
The battle of the sexes in humans is highly polygenic
Authors: Cole Jared M. , Scott Carly B. , Johnson Mackenzie M. , Golightly Peter R. , Carlson Jedidiah , Ming Matthew J. , Harpak Arbel , Kirkpatrick Mark
Published: July 2024

Sex-differential selection (SDS), which occurs when the fitness effects of alleles differ between males and females, can have profound impacts on the maintenance of genetic variation, disease risk, and other key aspects of natural populations. Because the sexes mix their autosomal genomes each generation, quantifying SDS is not possible using conventional population genetic approaches. Here, we introduce a novel method that exploits subtle sex differences in haplotype frequencies resulting from SDS acting in the current generation. Using data from 300K individuals in the UK Biobank, we estimate the strength of SDS throughout the genome. While only a handful of loci under SDS are individually significant, we uncover polygenic signals of genome-wide SDS for both viability and fecundity. An interesting life-history tradeoff emerges: alleles that increase viability more in one sex increase fecundity more in the other sex. Lastly, we find evidence of SDS on fecundity acting on alleles affecting arm fat-free mass. Taken together, our findings connect the long-standing evidence of SDS acting on human phenotypes with its impact on the genome.

Significance statement

Selection often acts differently on females and males, as evidenced by the striking sexual dimorphism found in many taxa. As a result, alleles can have different fitness effects in each sex. Consequences can include higher levels of genetic variation and higher disease burdens in populations. This study introduces a novel method to quantify this sex-differential selection (SDS) and reveals that it acts throughout the human genome. We discovered a life history tradeoff between survival and fecundity in females and males and that SDS on fecundity acts on alleles affecting arm fat-free mass.
Comprehensive chemotyping, and the gonadal regulation, of seven kisspeptinergic neuronal populations in the mouse brain
Authors: Hernández Vito S. , Zetter Mario A. , Hernández-Pérez Oscar R. , Hernández-González Rafael , Camacho-Arroyo Ignacio , Millar Robert P. , Eiden Lee E. , Zhang Limei
Published: July 2024

Background

Kisspeptinergic signaling is well-established as crucial for regulation of reproduction, but its potential broader role in brain function is less understood. This study investigates the distribution and chemotyping of kisspeptin-expressing neurons within the mouse brain.

Methods

RNAscope singleplex, duplex and multiplexin situhybridization methods were used to assess kisspeptin mRNA (Kiss1)expression and its co-expression with other neuropeptides, excitatory and inhibitory neurotransmitter markers, and sex steroid receptors in intact and gonadectomized young adult mice.

Results

Seven distinct kisspeptin neuronal chemotypes were characterized, including within two novelKiss1-expressing groups described here for the first time: the ventral premammillary nucleus, and the nucleus of the solitary tract.Kiss1mRNA was also localized in the soma, and within the dendritic compartment, of hypothalamic neurons. AlteredKiss1expression following gonadectomy suggests a previously unappreciated role for androgen receptors in regulating kisspeptin signaling.

Conclusion

This study provides a detailed chemoanatomical map of kisspeptin-expressing neurons in the brain, highlighting their potential functional diversity. The discovery of new kisspeptin-expressing neuronal populations, and gonadectomy-induced changes inKiss1expression patterns, provide a basis for further exploration of non-endocrine roles for kisspeptin in brain function.
Knowledge and beliefs about dietary inorganic nitrate in a representative sample of adults from the United Kingdom
Authors: Griffiths Alex , Grainger Evie , Matu Jamie , Alhulaefi Shatha , Whyte Eleanor , Hayes Eleanor , Brandt Kirsten , Mathers John C. , Siervo Mario , Shannon Oliver M.
Published: July 2024

Objective

Evaluate knowledge and beliefs about dietary nitrate among United Kingdom (UK)-based adults.

Design

An online questionnaire was administered to evaluate knowledge/beliefs about dietary nitrate. Overall knowledge of dietary nitrate was quantified using a 21-point Nitrate Knowledge Index. Responses were compared between sociodemographic groups.

Setting

UK.

Participants

A nationally representative sample of three hundred adults.

Results

Only 19% of participants had heard of dietary nitrate prior to completing the questionnaire. Most participants (∼70%) were unsure about the effects of dietary nitrate on health parameters (e.g., blood pressure, cognitive function, cancer risk) or exercise performance. Most participants were unsure of the average population intake (78%) and acceptable daily intake (ADI) (83%) of nitrate. Knowledge of dietary sources of nitrate was generally low, with only ∼30% of participants correctly identifying foods with higher/lower nitrate contents. Almost none of the participants had deliberately purchased, or avoided purchasing, a food based around its nitrate content. Nitrate Knowledge Index scores were generally low (median[IQR]: 5[8]), but were significantly higher in individuals who were currently employed vs. unemployed (median[IQR]: 5[7]vs.4[7];p<0.001), in those with previous nutritional education vs. no nutritional education (median[IQR]: 6[7]vs.4[8];p=0.012), and in individuals who had heard of nitrate prior to completing the questionnaire vs. those who had not (median [IQR]: 9[8]vs.4 [7];p<0.001).

Conclusions

This study demonstrates low knowledge around dietary nitrate in UK-based adults. Greater education around dietary nitrate may be valuable to help individuals make more informed decisions about their consumption of this compound.
Markers of Biological Brain Aging Mediate Effects of Vascular Risk Factors on Cognitive and Motor Functions: A Multivariate Imaging Analysis of 40,579 Individuals
Authors: Petersen Marvin , Link Moritz A. , Mayer Carola , Nägele Felix L. , Schell Maximilian , Fiehler Jens , Gallinat Jürgen , Kühn Simone , Twerenbold Raphael , Omidvarnia Amir , Hoffstaedter Felix , Patil Kaustubh R. , Eickhoff Simon B. , Thomalla Götz , Cheng Bastian
Published: July 2024

The increasing global life expectancy brings forth challenges associated with age-related cognitive and motor declines. To better understand underlying mechanisms, we investigated the connection between markers of biological brain aging based on magnetic resonance imaging (MRI), cognitive and motor performance, as well as modifiable vascular risk factors, using a large-scale neuroimaging analysis in 40,579 individuals of the population-based UK Biobank and Hamburg City Health Study. Employing partial least squares correlation analysis (PLS), we investigated multivariate associative effects between three imaging markers of biological brain aging – relative brain age, white matter hyperintensities of presumed vascular origin, and peak-width of skeletonized mean diffusivity – and multi-domain cognitive test performances and motor test results. The PLS identified a latent dimension linking higher markers of biological brain aging to poorer cognitive and motor performances, accounting for 94.7% of shared variance. Furthermore, a mediation analysis revealed that biological brain aging mediated the relationship of vascular risk factors — including hypertension, glucose, obesity, and smoking — to cognitive and motor function. These results were replicable in both cohorts. By integrating multi-domain data with a comprehensive methodological approach, our study contributes evidence of a direct association between vascular health, biological brain aging, and functional cognitive as well as motor performance, emphasizing the need for early and targeted preventive strategies to maintain cognitive and motor independence in aging populations.
Host trees partially explain the complex bacterial communities of two threatened saproxylic beetles
Authors: Kolasa Michał , Krovi Rama Sarvani , Plewa Radosław , Jaworski Tomasz , Kadej Marcin , Smolis Adrian , Gutowski Jerzy M. , Sućko Krzysztof , Ruta Rafał , Olbrycht Tomasz , Saluk Sergey , Oczkowicz Maria , Kajtoch Łukasz
Published: July 2024

Microorganisms are integral to ecosystem functioning and host adaptation, yet the understanding of microbiomes in diverse beetle taxa remains limited. We conducted a comprehensive study to investigate the microbial composition of two red flat bark beetle species,Cucujus haematodesandC. cinnaberinus, and assessed the influence of host taxonomic relatedness and host tree species on their microbiomes. Moreover, we summarize the available data on the microbiome of saproxylic beetles as a reference. We sampled 67 larvae of twoCucujustaxa taken from eleven host tree species. 16S rRNA V4 fragment sequencing revealed distinct microbial communities associated with eachCucujusspecies, with host tree species significantly influencing microbiome composition. Alpha and beta diversity metrics indicated significant differences between microbial communities in both, beetle and host tree species. Principal Component Analysis indicated distinct clustering based on host tree species but not for beetle species. This overlap could be attributed to the similar ecology of bothCucujusspecies. The detection of various bacteria, among which some have already been reported in saproxylophagous beetles, suggests that the red flat bark beetles ingest the bacteria via foraging on other wood-dwelling invertebrates. Our findings show the complex interplay between host taxonomy, microhabitat, and microbial composition inCucujus, providing insights into their ecological roles and conservation implications. This research helps to fill the gap in understanding the microbial dynamics of saproxylic beetles, sheds light on factors shaping their microbiomes, and highlights the importance of considering both host species and environmental conditions when studying insect-microbe interactions in forest ecosystems.
A systematic targeted genetic screen identifies proteins involved in cytoadherence of the malaria parasiteP. falciparum
Authors: Küster Nina , Roling Lena , Ouayoue Ardin , Steeg Katharina , Przyborski Jude M
Published: July 2024

Immediately after invading their chosen host cell, the mature human erythrocyte, malaria parasites begin to export an array of proteins to this compartment, where they initiate processes that are prerequisite for parasite survival and propagation, including nutrient import and immune evasion. One consequence of these activities is the emergence of novel adhesive phenotypes that can lead directly to pathology in the human host. To identify parasite proteins involved in this process we used modern genetic tools to target genes encoding 15 exported parasite proteins, selected by anin-silicoworkflow. This resulted in 4 genetically modified parasite lines that were then characterised in detail. Of these lines, 3 could be shown to have aberrations in adhesion, and of these 1 appears to have a block in the transport and/or correct folding of the major surface adhesin PfEMP1 (Plasmodium falciparumerythrocyte membrane protein 1). Our data expand the known factors involved in this important process, and once again highlight the complexity of this phenomenon.
Nuclear FAK aggravates CD8+T cell exhaustion via the SP1-IL-6 axis in colorectal cancer
Authors: Kong Hao , Wu Xiangji , Yang Qingxin , Wu Chunwei , Yu Xin , Yang Jie , Xie Dai , Dai Yu , Chen Lang , Ma Panpan , Dai Siqi , Huang Libin , Chen Chong , Mi Peng , Peng Yong , Shi Hubing , Zhang Dunfang , Ke Nengwen , Zhou Zongguang , Cao Dan , Hu Bing , Wang Ping , Chen Lu , Liu Yun-Hua , Jiang Hong
Published: July 2024

Although immune checkpoint blockade (ICB) therapy has shown promise in colorectal cancer patients with high microsatellite instability (MSI-H), response rates remain low for the majority of patients. Key challenges include the exhaustion of CD8+T cells and the presence of immunosuppressive cells within the tumor microenvironment. By integrating digital spatial profiling and scRNA sequencing, we found that the tumor-intrinsic activation of focal adhesion kinase (FAK) was strongly correlated with the heterogeneity and exhaustion of CD8+T cells within the spatial context of the tumor microenvironment and correlated with patient survival. Pharmacological inhibition or genetic loss of FAK enhanced antitumor immune responses and synergistically potentiated αPD-1 and αTIM-3 immunotherapy by augmenting CD8+T cell cytotoxicity and restoring exhaustion in preclinical models of colorectal cancer. Mechanistically, nuclear FAK was found to regulate SP1/IL-6-mediated T cell exhaustion and the transcription of proinflammatory cytokines/chemokines. These findings underscore FAK’s pivotal role in CD8+T cell exhaustion within the immunosuppressive tumor microenvironment, suggesting that FAK is a promising target for advancing cancer immunotherapy.
Microscale Spatial Dysbiosis in Oral biofilms Associated with Disease
Authors: Grodner Benjamin , Wu David T. , Hahm Sumin , Takayasu Lena , Wen Natalie , Kim David M. , Chen Chia-Yu , De Vlaminck Iwijn
Published: July 2024

Microbiome dysbiosis has largely been defined using compositional analysis of metagenomic sequencing data; however, differences in the spatial arrangement of bacteria between healthy and diseased microbiomes remain largely unexplored. In this study, we measured the spatial arrangement of bacteria in dental implant biofilms from patients with healthy implants, peri-implant mucositis, or peri-implantitis, an oral microbiome-associated inflammatory disease. We discovered that peri-implant biofilms from patients with mild forms of the disease were characterized by large single-genus patches of bacteria, while biofilms from healthy sites were more complex, mixed structures. Based on these findings, we propose a model of peri-implant dysbiosis where changes in biofilm spatial architecture allow the colonization of new community members. This model indicates that spatial structure could be used as a potential biomarker for community stability and has implications in diagnosis and treatment of peri-implant diseases. These results enhance our understanding of peri-implant disease pathogenesis and may be broadly relevant for spatially structured microbiomes.
Contrasting defense strategies of oligotrophs and copiotrophs revealed by single-cell-resolved virus–host pairing of freshwater bacteria
Authors: Okazaki Yusuke , Nishikawa Yohei , Wagatsuma Ryota , Takeyama Haruko , Nakano Shin-ichi
Published: July 2024

The ecological importance of virus–host interactions is unclear due to the limited ability of metagenomics to resolve virus–host pairs and the infection state of individual cells. We addressed these problems using single-cell genomics combined with published metagenomic data on lake bacterioplankton. We obtained 862 medium- to high-quality single-cell amplified genomes (SAGs) from two water layers and two seasons in Lake Biwa, Japan. We assembled 176 viral (dsDNA phage) contigs in the SAGs, and identified novel virus–host pairs including the discovery of viruses infecting CL500-11, the dominant bacterioplankton lineage in deep freshwater lakes worldwide. A virus was detected in 133 (15.4%) SAGs through read mapping analysis. The viral detection rate showed little variation among samples (12.1–18.1%) but significant variation in host taxonomy (4.2–65.3%), with copiotrophs showing higher values than oligotrophs. The high infection rates of copiotrophs were achieved by collective infection by diverse viruses, suggesting weak density-dependent virus–host selections, presumably because of their non-persistent interactions with viruses due to their fluctuating abundance. In contrast, the low infection rates of oligotrophs supported the idea that their co-dominance with viruses is achieved by genomic microdiversification that diversifies the virus–host specificity, sustained by their large population size and persistent density-dependent fluctuating selection. Overall, we demonstrated that virus–host interactions are highly diverse within and between host lineages, which was overlooked by metagenomics analysis, as exemplified by the CL500-11 virus, which showed extremely high read coverages in cellular and virion metagenomes, but infected < 1% of host cells.

Significance statement

Virus–host interactions are among the most significant driving forces of microbial biogeochemical cycles and genomic diversification. Unlike experimental conditions, bacterial cells in the natural environment are not uniformly infected by a single virus, but interact with diverse viruses under heterogeneous eco-physiological and genetic conditions. The specificity and heterogeneity of infection are the keys to understanding complex virus–host interactions and the mechanisms behind their co-existence. However, these interactions remain unclear due to the limitations of conventional metagenomic approaches. We addressed this issue by detecting viral signals from single-cell-amplified genomes of lake bacterial communities. The results revealed novel virus–host pairs and their infection rates, suggesting that viral defense strategies differ among host lineages, reflecting their ecological characteristics.
Investigation of a Novel Mouse Model of Prader-Willi Syndrome with Invalidation ofNecdinandMagel2
Authors: Barelle Pierre-Yves , Sicardi Alicia , Schaller Fabienne , Buron Julie , Becquet Denis , Omnes Felix , Watrin Françoise , Santos Catarina , Menuet Clément , François-Bellan Anne-Marie , Caron Emilie , Klucznik Jessica , Prevot Vincent , Bouret Sebastien G , Muscatelli Françoise
Published: July 2024

Prader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of seven contiguous paternally expressed genes. Mouse models with inactivation of all PWS genes are lethal. Knockout (KO) mouse models for each candidate gene were generated, but they lack the functional interactions between PWS genes. Here, we revealed an interplay betweenNecdinandMagel2“PWS” genes and generated a novel mouse model (named “Madin”) with a deletion including both genes. A subset ofMadinKO mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood.MadinKO mice had a lower body weight before weaning, persisting after weaning in males only, with reduced fat mass and improved glucose tolerance. Delayed sexual maturation and altered timing of puberty onset were observed in mutant mice. AdultMadinKO mice displayed increased ventilation and a persistent increase in apneas following a hypercapnic challenge. Transcriptomics analyses revealed a dysregulation of key circadian genes and alterations of genes associated with axonal function that were also found in the hypothalamus of patients with PWS. At neuroanatomical levels, we report an impaired maturation of oxytocin neurons and a disrupted development of melanocortin circuits. Together, these data indicate that theMadinKO mouse is a reliable and more genetically relevant model for the study of PWS.
Unraveling the Role of Ctla-4 in Intestinal Immune Homeostasis: Insights from a novel Zebrafish Model of Inflammatory Bowel Disease
Authors: Qin Lulu , Hu Chongbin , Zhao Qiong , Wang Yong , Fan Dongdong , Lin Aifu , Xiang Lixin , Chen Ye , Shao Jianzhong
Published: July 2024

Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 homolog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient (ctla-4−/−) zebrafish line. These mutant zebrafish exhibited reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, our findings demonstrate the pivotal role of Ctla-4 in maintaining intestinal homeostasis. Additionally, they offer substantial evidence linking CTLA-4 to IBD and establish a novel zebrafish model for investigating both the pathogenesis and potential treatments.
A whole-body atlas of non-graded BMP signaling activity in a sea anemone
Authors: Knabl Paul , Mörsdorf David , Genikhovich Grigory
Published: July 2024

BMP signaling is responsible for the second body axis patterning in Bilateria and in the bilaterally symmetric members of the bilaterian sister clade Cnidaria – corals and sea anemones. However, medusozoan cnidarians (jellyfish, hydroids) are radially symmetric, and yet their genomes contain BMP signaling components. This evolutionary conservation suggests that BMP signaling must have other functions not related to axial patterning, which keeps BMP signaling components under selective pressure. To find out what these functions might be, we generated a detailed whole-body atlas of BMP activity in the sea anemoneNematostella. In the adult polyp, we discover an unexpected diversity of domains with BMP signaling activity, which is especially prominent in the head, as well as across the neuro-muscular and reproductive parts of the gastrodermis. In accordance, analysis of two medusozoan species, the true jellyfishAureliaand the box jellyfishTripedalia,revealed similarly broad and diverse BMP activity, supporting the versatile nature of the BMP pathway across anthozoan and medusozoan Cnidaria.
Tunnel transport problem for open multilayer nitride nanostructures with an applied constant magnetic field and time-dependent potential: An exact solution
Authors: Boyko Igor , Petryk Mykaylo , Lebovka Nikolai
Published: July 2024

A quantum mechanical theory for description of electronic quasistationary states in two-dimensional (2D) layered semiconductor nanostructure was developed. A constant external magnetic field B was directed along semiconductor layers. The presence of internal electric fields F originated from the potential barriers and wells in semiconductor layers was taken into account. The vector of F was directed perpendicularly to semiconductor layers. The interaction of tunneled electrons with a time-dependent electromagnetic fields was analyzed in detail. An approach to obtain an exact solution to the problem based on a combination of the Lewis-Riesenfeld method for complete Schrödinger equation and scattering theory was developed. Application of the scattering theory in combination with the -matrix and transfer-matrix methods allowed us to calculate the electron quasistationary spectra. Effects of magnetic field on the resonant energy and width of electronic quasistationary states as well as on the electronic conductivity were also discussed.

Published by the American Physical Society
2024