bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuronal Network Dynamics in the Posterodorsal Amygdala: Shaping Reproductive Hormone Pulsatility
Authors: Nechyporenko Kateryna , Voliotis Margaritis , Li Xiao Feng , Hollings Owen , Ivanova Deyana , Walker Jamie J , O’Byrne Kevin T , Tsaneva-Atanasova Krasimira
Published: January 2024

Normal reproductive function and fertility rely on the rhythmic secretion of gonadotropin-releasing hormone (GnRH), which is driven by the hypothalamic GnRH pulse generator. A key regulator of the GnRH pulse generator is the posterodorsal subnucleus of the medial amygdala (MePD), a brain region which is involved in processing external environmental cues, including the effect of stress. However, the neuronal pathways enabling the dynamic, stress-triggered modulation of GnRH secretion remain largely unknown. Here, we employ in-silico modelling in order to explore the impact of dynamic inputs on GnRH pulse generator activity. We introduce and analyse a mathematical model representing MePD neuronal circuits composed of GABAergic and glutamatergic neuronal populations, integrating it with our GnRH pulse generator model. Our analysis dissects the influence of excitatory and inhibitory MePD projections’ outputs on the GnRH pulse generator’s activity and reveals a functionally relevant MePD glutamatergic projection to the GnRH pulse generator, which we probe with in vivo optogenetics. Our study sheds light on how MePD neuronal dynamics affect the GnRH pulse generator activity, and offers insights into stress-related dysregulation.
The chromosome-level genome of the ctenophoreMnemiopsis leidyiA. Agassiz, 1865 reveals a unique immune gene repertoire
Authors: Koutsouveli Vasiliki , Torres-Oliva Montserrat , Bayer Till , Fuß Janina , Grossschmidt Nora , Marulanda-Gomez Angela M. , Gill Diana , Schmitz Ruth A. , Pita Lucía , Reusch Thorsten B. H.
Published: January 2024

Ctenophora are basal marine metazoans, the sister group of all other animals.Mnemiopsis leidyiis one of the most successful invasive species worldwide with intense ecological and evolutionary research interest. Here, we generated a chromosome-level genome assembly ofM. leidyiwith a focus on its immune gene repertoire. The genome was 247.97 Mb, with N50 16.84 Mb, and 84.7% completeness. Its karyotype was 13 chromosomes. In this genome and that of two other ctenophores,Bolinopsis micropteraandHormiphora californensis, we detected a high number of protein domains related to potential immune receptors. Among those, proteins containing Toll/interleukin-1(TIR2) domain, NACHT domain, Scavenger Receptor Cystein-Rich (SRCR) domain, or C-type Lectin domain (CTLD) were abundant and presented unique domain architectures inM. leidyi. M. leidyiseems to lackbona fideToll like Receptors, but it does possess a repertoire of 15 TIR2-domain containing genes. Besides, we detected abona fideNOD-like receptor and 38 NACHT-domain containing genes. In order to verify the function of those domain containing genes, we exposedM. leidyito the pathogenVibrio coralliilyticus. Among the differentially expressed genes, we identified potential immune receptors, including four TIR2-domain containing genes, all of which were upregulated in response to pathogen exposure. To conclude, many common immune receptor domains, highly conserved across metazoans, are already present in Ctenophora. These domains have large expansions and unique architectures inM. leidyi, findings consistent with the basal evolutionary position of this group, but still might have conserved functions in immunity and host-microbe interaction.
A Comprehensive Evaluation of Large Language Models in Mining Gene Interactions and Pathway Knowledge
Authors: Azam Muhammad , Chen Yibo , Arowolo Micheal Olaolu , Liu Haowang , Popescu Mihail , Xu Dong
Published: January 2024

Background

Understanding complex biological pathways, including gene-gene interactions and gene regulatory networks, is critical for exploring disease mechanisms and drug development. Manual literature curation of biological pathways is useful but cannot keep up with the exponential growth of the literature. Large-scale language models (LLMs), notable for their vast parameter sizes and comprehensive training on extensive text corpora, have great potential in automated text mining of biological pathways.

Method

This study assesses the effectiveness of 21 LLMs, including both API-based models and open-source models. The evaluation focused on two key aspects: gene regulatory relations (specifically, ‘activation’, ‘inhibition’, and ‘phosphorylation’) and KEGG pathway component recognition. The performance of these models was analyzed using statistical metrics such as precision, recall, F1 scores, and the Jaccard similarity index.

Results

Our results indicated a significant disparity in model performance. Among the API-based models, ChatGPT-4 and Claude-Pro showed superior performance, with an F1 score of 0.4448 and 0.4386 for the gene regulatory relation prediction, and a Jaccard similarity index of 0.2778 and 0.2657 for the KEGG pathway prediction, respectively. Open-source models lagged their API-based counterparts, where Falcon-180b-chat and llama1-7b led with the highest performance in gene regulatory relations (F1 of 0.2787 and 0.1923, respectively) and KEGG pathway recognition (Jaccard similarity index of 0.2237 and 0. 2207, respectively).

Conclusion

LLMs are valuable in biomedical research, especially in gene network analysis and pathway mapping. However, their effectiveness varies, necessitating careful model selection. This work also provided a case study and insight into using LLMs as knowledge graphs.
Alternative translation initiation by ribosomal leaky scanning produces multiple isoforms of the Pif1 helicase
Authors: Lama-Diaz Tomas , Blanco Miguel G.
Published: January 2024

In budding yeast, the integrity of both the nuclear and mitochondrial genomes relies on dual-targeted isoforms of the conserved Pif1 helicase, generated by alternative translation initiation (ATI) ofPIF1mRNA from two consecutive AUG codons flanking a mitochondrial targeting signal. Here, we demonstrate that ribosomal leaky scanning is the specific ATI mechanism that produces not only these, but also novel, previously uncharacterized Pif1 isoforms. Both in-frame, downstream AUGs as well as near-cognate start codons contribute to the generation of these alternative isoforms. This has crucial implications for the rational design of genuine separation-of-function alleles and provides an explanation for the suboptimal behaviour of the widely employed mitochondrial- (pif1-m1) and nuclear-deficient (pif1-m2) alleles, with mutations in the first or second AUG codon, respectively. We have taken advantage of this refined model to develop improved versions of these alleles, which will serve as valuable tools to elucidate novel functions of this helicase and to disambiguate previously described genetic interactions ofPIF1in the context of nuclear and mitochondrial genome stability.
Linear-regression-based algorithms can succeed at identifying microbial functional groups despite the nonlinearity of ecological function
Authors: Zhao Yuanchen , Cordero Otto X. , Tikhonov Mikhail
Published: January 2024

Microbial communities play key roles across diverse environments. Predicting their function and dynamics is a key goal of microbial ecology, but detailed microscopic descriptions of these systems can be prohibitively complex. One approach to deal with this complexity is to resort to coarser representations. Several approaches have sought to identify useful groupings of microbial species in a data-driven way. Of these, recent work has claimed some empirical success atde novodiscovery of coarse representations predictive of a given function using methods as simple as a linear regression, against multiple groups of species or even a single such group (the EQO approach of Shanet al. [25]). This success seems puzzling, since modeling community function as a linear combination of contributions of individual species appears simplistic. However, the task of identifying a predictive coarsening of an ecosystem is distinct from the task of predicting the function well, and it is conceivable that the former could be accomplished by a simpler methodology than the latter. Here, we use the resource competition framework to design a model where the “correct” grouping to be discovered is well-defined, and use synthetic data to evaluate and compare three regression-based methods, namely, two proposed previously and one we introduce. We find that regression-based methods can recover the groupings even when the function is manifestly nonlinear; that multi-group methods offer an advantage over a single-group EQO; and crucially, that simpler (linear) methods can outperform more complex ones.

Author summary

Natural microbial communities are highly complex, making predictive modeling difficult. One appealing approach is to make their description less detailed, rendering modeling more tractable while hopefully still retaining some predictive power. The Tree of Life naturally provides one possible method for building coarser descriptions (instead of thousands of strains, we could think about hundreds of species; or dozens of families). However, it is known that useful descriptions need not be taxonomically coherent, as illustrated, for example, by the so-called functional guilds. This prompted the development of computational methods seeking to propose candidate groupings in a data-driven manner. In this computational study, we examine one class of such methods, recently proposed in the microbial context. Quantitatively testing their performance can be difficult, as the answer they “should” recover is often unknown. Here, we overcome this difficulty by testing these methods on synthetic data from a model where the ground truth is known by construction. Curiously, we demonstrate that simpler approaches, rather than suffering from this simplicity, can in fact be more robust.
Impact of maternal obesogenic diet on maternal and offspring microbiome development
Authors: Hasebe Kyoko , Kendig Michael D , Kaakoush Nadeem O , Tajaddini Aynaz , Westbrook R Frederick , Morris Margaret J
Published: January 2024

Pregnancy can alter gut microbiota composition, but how an obesogenic diet impacts maternal gut microbiota, and the extent to which this influences offspring microbiome can be obscured by confounding factors. This study examined changes in gut microbiota composition across pre-pregnancy, gestation and lactation in rat dams fed either a high-fat, high-sugar Cafeteria (Caf) diet or Chow. Microbiome development was assessed in their offspring weaned onto chow. Caf diet consumption during pregnancy increased weight gain and adiposity, and compromised subsequent maternal nursing behaviour. α- and β diversity measures in Caf-fed dams showed a different trajectory across the progression of pregnancy, with no change inBacteroidetesandFirmicutesabundance compared with Chow dams. Offspring born to Caf dams exhibited greater adiposity and plasma leptin at weaning and 14 weeks of age than those born to Chow dams. Maternal Caf diet induced clear differences in β diversity in weanlings but not α diversity. SourceTracker analysis revealed similarities in the gut microbiota of Chow weanlings and maternal gut microbiota in lactation, whereas the microbiota of Caf weanlings was similar to the maternal gut microbiota during gestation. Maternal Caf diet exerted only marginal effects on gut microbiota composition in 14-week-old offspring.
Narcissus reflected: gray and white matter features joint contribution to the default mode network in predicting narcissistic personality traits
Authors: Jornkokgoud Khanitin , Baggio Teresa , Bakiaj Richard , Wongupparaj Peera , Job Remo , Grecucci Alessandro
Published: January 2024

Despite the clinical significance of narcissistic personality, its neural bases have not been clear yet, primarily due to methodological limitations of the previous studies, such as the low sample size, the use of univariate techniques and the focus on only one brain modality. In this study, we employed for the first time a combination of unsupervised and supervised machine learning methods, to identify the joint contributions of gray (GM) and white matter (WM) to narcissistic personality traits (NPT). After preprocessing, the brain scans of 135 participants were decomposed into eight independent networks of covarying GM and WM via Parallel ICA. Subsequently, stepwise regression and Random Forest were used to predict NPT. We hypothesize that a fronto-temporo parietal network mainly related to the Default Mode Network, may be involved in NPT and white matter regions related to these regions. Results demonstrated a distributed network that included GM alterations in fronto-temporal regions, the insula, and the cingulate cortex, along with WM alterations in cerebellar and thalamic regions. To assess the specificity of our findings, we also examined whether the brain network predicting narcissism could predict other personality traits (i.e., Histrionic, Paranoid, and Avoidant personalities). Notably, this network did not predict these personality traits. Additionally, a supervised machine learning model (Random Forest) was used to extract a predictive model to generalize to new cases. Results confirmed that the same network could predict new cases. These findings hold promise for advancing our understanding of personality traits and potentially uncovering brain biomarkers associated with narcissism.
Physical activity and fiber intake beneficial for muscle mass and strength preservation during aging: A Comprehensive Cross-Sectional Study in the UK Biobank cohort
Authors: Morwani-Mangnani Jordi , Rodriguez-Girondo Mar , Singh-Povel Cecile , Verlaan Sjors , Beekman Marian , Slagboom P. Eline
Published: January 2024

Background

Aging triggers intricate physiological changes, particularly in muscle mass and strength, affecting overall health and independence. Despite existing research, the broader significance of how muscle health is affected by the intricate interplay of lifestyle factors simultaneously during aging needs more exploration. This study aims to examine how nutrition, exercise, and sleep independently and differentially impact on muscle mass and strength in middle-aged men and women, facilitating future personalized recommendations for preserving muscle health.

Methods

The cross-sectional analysis of the UK Biobank involved 45,984 individuals aged 40-70. Multiple linear regression explored determinants of whole-body fat-free mass and handgrip strength, considering traditional, socio-demographics, medication use and smoking as covariates, with gender and age (younger and older than 55 years) stratifications.

Results

Higher physical activity and fiber intake beneficially affect both muscle mass and strength, especially above 55 years. Other lifestyle factors influence the two muscle parameters differently. Key determinants influencing muscle strength included higher protein intake, lower water intake, higher alcohol intake, and extended sleep duration whereas mainly higher water intake contributes to higher muscle mass.

Conclusions

Physical activity and fiber intake associate with increased muscle strength and mass which may connect gut and muscle health. Given the observed complexity of muscle health in the age and gender strata, further longitudinal research is needed to provide personalized lifestyle recommendations.
A head-mounted Tilted Reality Device for the treatment of pusher syndrome: A usability study
Authors: Wöhrstein Sofia , Bressler Michael , Röhrig Lisa , Prahm Cosima , Karnath Hans-Otto
Published: January 2024

Pusher syndrome is a disorder of postural control after stroke. Patients show a mismatch in their perception of (almost preserved) visual and (pathologically tilted) postural verticality. In order to reduce this mismatch, we developed a novel head-mounted ‘Tilted Reality Device (TRD)’. It presents patients visual footage of their actual surroundings but tilted to one side rather than upright. We investigated its usability and possible limitations in its use for the treatment of pusher patients in two samples of healthy participants with an average age of 26.4 years and 63.9 years respectively. Individuals from both age groups showed similar levels of tolerance to prolonged exposure to the tilted visual environment for an average of 40.4 minutes while walking around in the hospital. The TRD was found to be comfortable and not frustrating whilst wearing, but somewhat challenging in terms of technical handling, particularly for older participants. At the end of the maximally tolerated exposure time participants of both groups experienced some feelings of discomfort, like dizziness or increased stomach awareness, which disappeared rapidly after terminating TRD exposure. Our TRD appears to be a practical device especially for an older population, like pusher patients. While users must be aware of the possibility of side effects, these should be balanced against the benefits of future use for rehabilitation purposes.
Sex-Based Utilization of Guideline Recommended Statin Therapy and Cardiovascular Disease Outcomes: A Primary Prevention Healthcare Network Registry
Authors: Koczo Agnes , Brickshawana Adipong , Zhu Jianhui , Thoma Floyd , Countouris Malamo , Berlacher Kathryn , Gulati Martha , Michos Erin D , Reis Steven , Mulukutla Suresh , Saeed Anum
Published: January 2024

Background

In the US, women have similar cardiovascular death rates than men. Less is known about sex differences in statin use for primary prevention and associated atherosclerotic cardiovascular disease (ASCVD) outcomes.

Methods

Statin prescriptions using electronic health records were examined in patients without ASCVD (myocardial infarction (MI), revascularization or ischemic stroke) between 2013-2019. Guideline-directed statin intensity (GDSI) at index and follow-up visits were compared among sexes across ASCVD risk groups, defined by pooled-cohort equation. Cox regression hazard ratios (HR) [95% CI] were calculated for statin use and outcomes (myocardial infarction, stroke/transient ischemic attack (TIA), and all-cause mortality) stratified by sex. Interaction terms (statin and sex) were applied.

Results

Among 282,298 patients, (mean age ∼ 50 years) 17.1% women and 19.5% men were prescribed any statin at index visit. Time to GDSI was similar between sexes, but the proportion of high-risk women on GDSI at follow-ups was lower compared to high-risk men (2-years: 27.7 vs 32.0%, and 5-years: 47.2 vs 55.2%, p<0.05). When compared to GDSI, no statin use was associated with higher risk of MI and ischemic stroke/TIA amongst both sexes. High-risk women on GDSI had a lower risk of mortality (HR=1.39 [1.22-1.59]) versus men (HR=1.67 [1.50-1.86]) of similar risk (p value interaction=0.004).

Conclusion

In a large contemporary healthcare system, there was underutilization of statins across both sexes in primary prevention. High-risk women were less likely to be initiated on GDSI compared with high-risk men. GDSI significantly improved the survival in both sexes regardless of ASCVD risk group. Future strategies to ensure continued use of GDSI, specifically among women, should be explored.
Multiple vaccine comparison in the same adults from the VITAL study reveals vaccine-specific and age-related humoral response patterns
Authors: van der Heiden Marieke , Shetty Sudarshan , Bijvank Elske , Beckers Lisa , Cevirgel Alper , van Sleen Yannick , Tcherniaeva Irina , Ollinger Thierry , Burny Wivine , van Binnendijk Rob S , van Houten Marianne A , Buisman Anne-Marie , Rots Nynke Y. , van Beek Josine , van Baarle Debbie
Published: January 2024

Vaccine responsiveness is often reduced in older adults. Yet, our lack of understanding of low vaccine responsiveness hampers the development of effective vaccination strategies to reduce the impact of infectious diseases in the ageing population.

Young-adult, middle-aged and older-adult participants of the VITAL clinical trials (n=315, age range: 28-98y), were consecutively vaccinated with a booster quadrivalent influenza (QIV) vaccine, a primary 13-valent pneumococcal-conjugate (PCV13) vaccine, and a primary series of SARS-CoV2 mRNA-1273 vaccines within the timeframe of 2 years. This unique setup allowed investigation of humoral responsiveness towards multiple vaccines within the same individuals over the entire adult age-range.

Booster QIV vaccination induced comparable H3N2 hemagglutination inhibition (HI) titers in all age groups, whereas primary PCV13 and mRNA-1273 vaccination induced lower antibody concentrations in older as compared to younger adults. The persistence of humoral responses towards the 6 months timepoint was shorter in older adults for all vaccines. Interestingly, the quantity of vaccine-induced humoral immunity within one individual differed between vaccines. Yet, a small group of mostly older male adults responded low to multiple vaccines.

This study aids the identification of risk groups for low vaccine responsiveness and guides the design of more targeted vaccination strategies for the ageing population.
Application of polygenic scores to a deeply phenotyped sample enriched for substance use disorders reveals extensive pleiotropy with psychiatric and medical traits
Authors: Hartwell Emily E. , Jinwala Zeal , Milone Jackson , Ramirez Sarah , Gelernter Joel , Kranzler Henry R. , Kember Rachel L.
Published: January 2024

Co-occurring psychiatric, medical, and substance use disorders (SUDs) are common, but the complex pathways leading to such comorbidities are poorly understood. A greater understanding of genetic influences on this phenomenon could inform precision medicine efforts. We used the Yale-Penn dataset, a cross-sectional sample enriched for individuals with SUDs, to examine pleiotropic effects of genetic liability for psychiatric and medical traits. Participants completed an in-depth interview that provides information on demographics, environment, medical illnesses, and psychiatric and SUDs. Polygenic scores (PGS) for psychiatric disorders and medical traits were calculated in European-ancestry (EUR; n=5,691) participants and, when discovery datasets were available, for African-ancestry (AFR; n=4,918) participants. Phenome-wide association studies (PheWAS) were then conducted. In AFR participants, the only PGS with significant associations was bipolar disorder (BD), all of which were with substance use phenotypes. In EUR participants, PGS for major depressive disorder (MDD), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), schizophrenia (SCZ), body mass index (BMI), coronary artery disease (CAD), and type 2 diabetes (T2D) all showed significant associations, the majority of which were with phenotypes in the substance use categories. For instance, PGSMDDwas associated with over 200 phenotypes, 15 of which were depression-related (e.g., depression criterion count), 55 of which were other psychiatric phenotypes, and 126 of which were substance use phenotypes; and PGSBMIwas associated with 138 phenotypes, 105 of which were substance related. Genetic liability for psychiatric and medical traits is associated with numerous phenotypes across multiple categories, indicative of the broad genetic liability of these traits.
Constipation is associated with an increased risk of major adverse cardiac events in a UK population
Authors: Zheng Tenghao , Camargo Tavares Leticia , D’Amato Mauro , Marques Francine Z.
Published: January 2024

Background

Traditional cardiovascular risk factors, including hypertension, only explain part of major adverse cardiac events (MACE). Understanding what other risk factors contribute to MACE is essential for prevention. Constipation shares common risk factors with hypertension and is associated with an increased risk of several cardiovascular diseases. We hypothesised that constipation is an under-appreciated risk factor for MACE.

Methods

We used the population healthcare and genomic data in the UK Biobank (UKBB) (n=408,354) to study the contribution of constipation (ICD-10 K59.0) to the risk of MACE, defined by any episode of acute coronary syndrome (ACS), ischemic stroke and heart failure (HF). Analyses were controlled for traditional cardiovascular risk factors. We also assessed genetic correlations (rg) between constipation and MACE.

Results

Constipation cases (N=23,814) exhibited significantly higher risk of MACE compared to those with normal bowel habits (OR=2.15, P<1.00×10-300). Constipation was also significantly associated with individual MACE subgroups, in order: HF (OR=2.72, P<1.00×10-300), ischemic stroke (OR=2.36, P=2.02×10-230), and ACS (OR=1.62, P=5.82×10-113). In comparison with constipation-free hypertensive patients, hypertensive patients with constipation showed significantly higher odds of MACE (OR=1.68, P=1.05×10-136) and a 34% increased risk of death (P=2.3×10-50) after adjustment for medications that affect gut motility and other traditional cardiovascular risk factors. Finally, we detected positive genetic correlations between constipation and MACE subgroups ACS (rg=0.27, P=2.12×10-6), ischemic stroke (rg=0.23, P=0.011), and HF (rg=0.21, P=0.0062).

Conclusion

We identified constipation as a potential risk factor independently associated with higher MACE prevalence. These findings warrant further studies on their causal relationship and identification of pathophysiological mechanisms.
PRIMARY CENTRAL NERVOUS SYSTEM VASCULITIS WITH INTRACRANIAL ANEURYSM
Authors: Salvarani Carlo , Brown Robert D. , Christianson Teresa J. H. , Huston John , Giannini Caterina , Hunder Gene G.
Published: January 2024

Background

Unruptured intracranial aneurysms (UIAs) are rarely reported in primary central nervous system vasculitis (PCNSV). In this study we described the clinical findings, response to therapy, and outcomes of UIA in a large cohort of PCNSV patients.

Methods

We retrospectively studied 216 consecutive patients with PCNSV, selected by predetermined diagnostic criteria, who were seen during a 40-year period. UIAs were identified on cerebral angiography. The clinical, laboratory, radiologic and pathologic findings, management, and outcomes of patients with UIA were described and compared with those without UIA.

Results

12/216 (5.5%) PCNSV patients had at least one UIA. In the only positive patient biopsy showed necrotizing vasculitis. Eleven patients had evidence of UIA on angiogram at diagnosis. One patient developed an aneurysm during the follow-up associated with a worsening of vasculitic radiological findings. The most common presenting symptom for PCNSV in the setting of UIA was headache (67%), followed by persistent neurologic deficit or stroke (50%). Most patients with UIA presented with multiple cerebral infarcts on MRI (67%), one patient had subarachnoid hemorrhage, and one left parieto-occipital intracerebral hematoma, both unrelated to the aneurysm. Black blood imaging was performed in 4 patients and 2 showed segmental circumferential mural enhancement involving multiple vessels. Two patients had 2 UIAs, while the other 10 had 1. The most frequent UIA location was internal carotid artery (50%), followed by anterior cerebral artery (21%). Ten of the UIAs were < 5 mm in diameter, and 3 were 5-7 mm in diameter; the size was not available for one. All UIAs were unchanged in size and configuration during follow-up and no new aneurysms were detected. Compared to the 204 patients with PCNSV without a UIA, no significant clinical differences were observed, except for a reduced disability at last follow-up (p = 0.038).

Conclusions

UIAs uncommonly occur in PCNSV.
TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes
Authors: Zeng Yi , Lovchykova Anastasiia , Akiyama Tetsuya , Liu Chang , Guo Caiwei , Jawahar Vidhya Maheswari , Sianto Odilia , Calliari Anna , Prudencio Mercedes , Dickson Dennis W. , Petrucelli Leonard , Gitler Aaron D.
Published: January 2024

In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g.,ELP1, NEFL,andTMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.
An evolutionary-conserved VPS34-PIKfyve-TRPML1-Myosin II axis regulates the speed of amoeboid cell migration
Authors: Dehio Philippe , Michard Céline , Yam-Puc Juan Carlos , Martí i Líndez Adrià-Arnau , Fabre Lucien , Schaefer Thorsten , Wymann Matthias P. , Okkenhaug Klaus , Soldati Thierry , Mehling Matthias , Hess Christoph
Published: January 2024

Amoeboid cell migration is key to efficient T cell immunity. Spatial polarization of organelles within cells, including endo-lysosomes, is a prerequisite of migration. However, how ultrastructural polarization is linked to the signaling requirements governing T cell migration, remains unknown. Here we show that signaling molecules generated by endo-lysosome-localized kinases regulate velocity of amoeboid migration. Specifically, imaging of T cells identified accumulation of endo-lysosomes decorated with the lipid kinases VPS34–PIKfyve at the uropod of polarized cells. Activity of VPS34 and PIKfyve regulated speed, but not directedness, of migrating T cells. Mechanistically, PI(3,5)P2generated by the sequential action of VPS34 and PIKfyve mediated Ca2+efflux from lysosomes via the mucolipin TRP cation channel 1 (TRPML1), thus controlling activity of myosin IIA and hence the generation of propulsive force through retrograde actin flow. The VPS34–PIKfyve kinases also regulated velocity of myeloid cells, as well as of the amoebaDictyostelium discoideum– establishing the axis as an evolutionary conservedspeed control systemof amoeboid cell migration.

Graphical Abstract

The VPS34–PIKfyve axis is active on endo-lysosomes at the uropod of migrating T cells.

VPS34 and PIKfyve promote myosin IIA activation and retrograde action flow.

Amoeboid cell migration speed is controlled by VPS34 and PIKfyve via TRPML1.

Regulation of amoeboid migration speed is a conserved function of the VPS34–PIKfyve axis.
Conditional knockout ofShank3in the ventral CA1 by quantitativein vivogenome-editing impairs social memory
Authors: Chung Myung , Imanaka Katsutoshi , Huang Ziyan , Watarai Akiyuki , Wang Mu-Yun , Tao Kentaro , Ejima Hirotaka , Aida Tomomi , Feng Guoping , Okuyama Teruhiro
Published: January 2024

Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral CA1 (vCA1) neurons possess social memory engram and that the neurophysiological representation of social memory in the vCA1 neurons is disrupted in ASD-associatedShank3knockout mice. However, whether the dysfunction of Shank3 in vCA1 causes the social memory impairment observed in ASD remains unclear. In this study, we found that vCA1-specificShank3conditional knockout (cKO) by the adeno-associated virus (AAV)- or specialized extracellular vesicle (EV)-mediatedin vivogene editing was sufficient to recapitulate the social memory impairment in male mice. Furthermore, the utilization of EV-mediatedShank3-cKO allowed us to quantitatively examine the role of Shank3 in social memory. Our results suggested that there is a certain threshold for the proportion ofShank3-cKO neurons required for social memory disruption. Thus, our study provides insight into the population coding of social memory in vCA1, as well as the pathological mechanisms underlying social memory impairment in ASD.
Glycolysis–Wnt signaling axis tunes developmental timing of embryo segmentation
Authors: Miyazawa Hidenobu , Rada Jona , Sanchez Paul Gerald Layague , Esposito Emilia , Bunina Daria , Girardot Charles , Zaugg Judith , Aulehla Alexander
Published: January 2024

The question of how metabolism impacts development is seeing a renaissance [1, 2]. How metabolism exerts instructive signaling functions is one of the central issues that need to be resolved. We tackled this question in the context of mouse embryonic axis segmentation. Previous studies have shown that changes in central carbon metabolism impact Wnt signaling [3–6] and the period of the segmentation clock [7], which controls the timing of axis segmentation. Here, we reveal that glycolysis tunes the segmentation clock period in an anti-correlated manner: higher glycolytic flux slows down the clock, and vice versa. Transcriptome and gene regulatory network analyses identified Wnt signaling and specifically the transcription factor Tcf7l2, previously associated with increased risk for diabetes [8, 9], as potential mechanisms underlying flux-dependent control of the clock period. Critically, we show that deletion of the Wnt antagonist Dkk1 rescued the slow segmentation clock phenotype caused by increased glycolysis, demonstrating that glycolysis instructs Wnt signaling to control the clock period. In addition, we demonstrate metabolic entrainment of the segmentation clock: periodic changes in the levels of glucose or glycolytic sentinel metabolite fructose 1,6-bisphosphate (FBP) synchronize signaling oscillations. Notably, periodic FBP pulses first entrained Wnt signaling oscillations and subsequently Notch signaling oscillations. We hence conclude that metabolic entrainment has an immediate, specific effect on Wnt signaling. Combined, our work identifies a glycolysis-FBP-Wnt signaling axis that tunes developmental timing, highlighting the instructive signaling role of metabolism in embryonic development.
Concurrent processing of the prosodic hierarchy is supported by cortical entrainment and phase-amplitude coupling
Authors: Oderbolz Chantal , Sauppe Sebastian , Meyer Martin
Published: January 2024

Models of phonology posit a hierarchy of prosodic units that are relatively independent from syntactic structure, requiring its own parsing. Surprisingly, it remains unexplored how this prosodic hierarchy is represented in the brain. We investigated this foundational question by means of an EEG study. Thirty young adults listened to German sentences containing manipulations at different levels of the prosodic hierarchy. Evaluating speech-to-brain cortical entrainment and phase-amplitude coupling revealed that prosody’s hierarchical structure is maintained at the neural level. The faithfulness of this tracking varied as a function of the hierarchy’s degree of intactness as well as systematic inter-individual differences in audio-motor synchronization. The results underscore the role of complex oscillatory mechanisms in configuring the continuous and hierarchical nature of the speech signal and firmly situate prosody as a structure indispensable from theoretical perspectives on spoken language comprehension in the brain.
Exploring functional connectivity in clinical and data-driven groups of preterm and term adults
Authors: Hadaya Laila , Váša František , Dimitrakopoulou Konstantina , Saqi Mansoor , Shergill Sukhwinder S , Edwards David A , Batalle Dafnis , Leech Robert , Nosarti Chiara
Published: January 2024

Background

Adults born very preterm (i.e., at <33 weeks’ gestation) are more susceptible to long-lasting structural and functional brain alterations and cognitive and socio-emotional difficulties, compared to full-term controls. However, behavioural heterogeneity within very preterm and full-term individuals makes it challenging to find biomarkers of specific outcomes. To address these questions, we parsed brain-behaviour heterogeneity in participants subdivided according to their clinical birth status (very preterm vs full-term) and/or data-driven behavioural phenotype (regardless of birth status).

Methods

The Network Based Statistic approach was used to identify topological components of resting state functional connectivity differentiating between i) 116 very preterm and 83 full-term adults (43% and 57% female, respectively), and ii) data-driven behavioural subgroups identified using consensus clustering (n= 156, 46% female). Age, sex, socio-economic status, and in-scanner head motion were used as confounders in all analyses. Post-hoc two-way group interactions between clinical birth status and behavioural data-driven subgrouping classification labels explored whether functional connectivity differences between very preterm and full-term adults varied according to distinct behavioural outcomes.

Results

Very preterm compared to full-term adults had poorer scores in selective measures of cognitive and socio-emotional processing and displayed complex patterns of hyper- and hypo-connectivity in subsections of the default mode, visual, and ventral attention networks. Stratifying the study participants in terms of their behavioural profiles (irrespective of birth status), identified two data-driven subgroups: An “At-risk”subgroup, characterised by increased cognitive, mental health, and socio-emotional difficulties, displaying hypo-connectivity anchored in frontal opercular and insular regions, relative to a“Resilient”subgroup with more favourable outcomes. No significant interaction was noted between clinical birth status and behavioural data-driven subgrouping classification labels in terms of functional connectivity.

Conclusions

Functional connectivity differentiating between very preterm and full-term adults was dissimilar to functional connectivity differentiating between the data-driven behavioural subgroups. We speculate that functional connectivity alterations observed in very preterm relative to full-term adults may confer both risk and resilience to developing behavioural sequelae associated with very preterm birth, while the localised functional connectivity alterations seen in the “At-risk”subgroup relative to the “Resilient” subgroup may underlie less favourable behavioural outcomes in adulthood, irrespective of birth status.
Condensin-mediated restriction of retrotransposable elements facilitates brain development inDrosophila melanogaster
Authors: Crawford Bert I. , Talley Mary Jo , Russman Joshua , Riddle James , Torres Sabrina , Williams Troy , Longworth Michelle S.
Published: January 2024

Neural stem and progenitor cell (NSPC) maintenance are essential for ensuring that organisms are born with proper brain volumes and head sizes. Microcephaly is a disorder in which babies are born with significantly smaller head sizes and cortical volumes. Mutations in subunits of the DNA organizing complexes, condensins have been identified in microcephaly patients. However the molecular mechanisms by which condensin insufficiency causes microcephaly remain elusive. We previously identified conserved roles for condensins in repression of retrotransposable elements (RTEs). Here, we show that condensin subunit knockdown in NSPCs of theDrosophilalarval central brain increases RTE expression and mobility which causes cell death, and significantly decreases adult head sizes and brain volumes. These findings suggest that unrestricted RTE expression and activity may lead to improper brain development in condensin insufficient organisms, and lay the foundation for future exploration of causative roles for RTEs in other microcephaly models.
Contrasting contribution of embryo- and postnatally-derived brain-resident macrophages in sustaining sleep-wake circuitry
Authors: Seifinejad Ali , Bandarabadi Mojtaba , Haddar Meriem , Wundt Saskia , Tafti Mehdi , Vassalli Anne , Khani Abbas , Monaco Gianni
Published: January 2024

Sleep is a complex behavior regulated by various brain cell types. However, the roles of brain-resident macrophages, including microglia and CNS-associated macrophages (CAMs), particularly those derived postnatally, in sleep regulation remain poorly understood. Here, we investigated the effects of natural (embryo-derived) and repopulated (postnatally derived) brain-resident macrophages on the regulation of vigilance states. We found that depletion in embryonically-derived brain macrophages caused increased sleep in the active period, but reduced its quality, reflected in reduced power of brain sleep oscillations. This was observed both for the Non-REM and REM sleep stages. Subsequent repopulation by postnatal brain macrophages unexpectedly failed to reestablish normal sleep-wake patterns and additionally induced sleep fragmentation. Furthermore, brain macrophage depletion caused excitatory-inhibitory synaptic imbalance, which was resistant to repopulation, and led to increased inhibitory synapses. At the metabolite level, the distinct metabolite profile induced by brain macrophage depletion largely returned to normal after repopulation. Our findings suggest a so far largely unknown interaction between brain-resident macrophages and sleep and emphasizes striking functional differences between embryonic and postnatally-derived brain macrophages, paving the way to future exploration of the role of brain macrophages of different origin in sleep disorders and synaptic connectivity.
When the tap runs dry: The multi-tissue gene expression and physiological responses of water deprivedPeromyscus eremicus
Authors: Blumstein Danielle M. , MacManes Matthew D.
Published: January 2024

The harsh and dry conditions of desert environments have resulted in genomic adaptations, allowing for desert organisms to withstand prolonged drought, extreme temperatures, and limited food resources. Here, we present a comprehensive exploration of gene expression across five tissues (kidney, liver, lung, gastrointestinal tract, and hypothalamus) and 19 phenotypic measurements to explore the whole-organism physiological and genomic response to water deprivation in the desert-adapted cactus mouse (Peromyscus eremicus). The findings encompass the identification of differentially expressed genes and correlative analysis between phenotypes and gene expression patterns across multiple tissues. Specifically, we found robust activation of the vasopressin renin-angiotensin-aldosterone system (RAAS) pathways, whose primary function is to manage water and solute balance. Animals reduce food intake during water deprivation, and upregulation ofPCK1highlights the adaptive response to reduced oral intake via its actions aimed at maintained serum glucose levels. Even with such responses to maintain water balance, hemoconcentration still occurred, prompting a protective downregulation of genes responsible for the production of clotting factors while simultaneously enhancing angiogenesis which is thought to maintains tissue perfusion. In this study, we elucidate the complex mechanisms involved in water balance in the desert-adapted cactus mouse,P. eremicus. By prioritizing a comprehensive analysis of whole-organism physiology and multi-tissue gene expression in a simulated desert environment, we describe the complex and successful response of regulatory processes.
An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens
Authors: Tran SL. , Lebreuilly L. , Cormontagne D. , Samson S. , Tô TB. , Dervyn R. , Grießhammer A. , de la Cuesta-Zuluaga J. , Maier L. , Naas T. , Mura S. , Nicolas J. , Rognan D. , André G. , Ramarao N.
Published: January 2024

The increased incidence of antibiotic resistance and declining discovery of new antibiotics have created a global health crisis, especially for the treatment of infections caused by Gram-negative bacteria. Here, we identify and characterize a molecule, NM102, that displays antimicrobial activity exclusively in the context of infection. NM102 inhibits the activity of the non-essential Mutation Frequency Decline (Mfd) protein by competing with ATP binding to its active site. Inhibition of Mfd by NM102 sensitizes pathogenic bacteria to the host immune response and blocks infections with clinically- relevantKlebsiella pneumoniaeandPseudomonas aeruginosa, without inducing host toxicity. Finally, NM102 inhibits the function of Mfd as a mutation and evolvability factor, thus reducing the bacterial capacity to develop antimicrobial resistance. These data provide a potential roadmap to expand the arsenal of drugs to combat antimicrobial resistance.

Highlight

NM102 is a “first in class” molecule specifically targeting the active site of the bacterial Mfd protein

NM102 has a new mode of action: it inhibits Mfd function during immune stress response

NM102 also inhibits Mfd evolvability function and thereby decreases bacterial resistance to known antibiotics

NM102 effectively treats Gram-negative infections in animal models

NM102 is efficient against clinically relevant resistant bacteria and provides an increased efficacy in combination with the β-lactam meropenem
Antigen-specific age-related memory CD8 T cells induce and track Alzheimer’s-like neurodegeneration
Authors: Panwar Akanksha , Rentsendorj Altan , Jhun Michelle , Cohen Robert M. , Cordner Ryan , Gull Nicole , Pechnick Robert N. , Duvall Gretchen , Mardiros Armen , Golchian David , Schubloom Hannah , Jin Lee-Way , Van Dam Debby , Vermeiren Yannick , De Reu Hans , De Deyn Peter Paul , Raskatov Jevgenij A. , Black Keith L. , Irvin Dwain K. , Williams Brian A. , Wheeler Christopher J.
Published: January 2024

Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer’s disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/fibrillar pTau, however, appears to vary depending on the animal model used. Our prior work suggested that antigen-specific memory CD8 T (“hiT”) cells act upstream of Aβ/pTau after brain injury. Here we examine whetherhiT cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in ourhiT mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. Our work is the first to identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.

Significance Statement

This study changes our view of Alzheimer’s Disease (AD) initiation and progression. Mutations promoting cerebral beta-amyloid (Aβ) deposition guarantee rare genetic forms of AD. Thus, the prevailing hypothesis has been that Aβ is central to initiation and progression of all AD, despite contrary animal and patient evidence. We show that age-related T cells generate neurodegeneration with compelling features of AD in mice, with distinct T cell functions required for pathological initiation and neurodegenerative progression. Knowledge from these mice was applied to successfully predict previously unknown features of human AD and generate novel tools for its clinical management.