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Determining the driving factors shaping genetic architecture of complex traits in recently admixed populations

Understanding the genetic architecture of complex traits in admixed populations remains challenging due to heterogeneous genetic backgrounds and demographic histories. Mischaracterizing admixture can bias genetic association estimates and limit the generalizability of biomedical findings. Here, we systematically evaluate how evolutionary forces&--including admixture, natural selection, and demographic history--jointly shape complex trait architecture and influence genome-wide association stud...

— Kim, M. S., Durvasula, A., Zhang, X. 2025-12-16 00:00:00

Alzheimer disease risk variant rs11218343 determines functional expression of SORL1 in microglia

Rs11218343 is a non-coding variant of genome-wide significance for sporadic Alzheimer disease (AD) with one of the most protective effects known. It localizes to SORL1, encoding the AD risk factor SORLA. Still, the functional significance of rs11218343 for AD related processes remains unclear. We used iPSC lines from donors, or genome-engineered to carry major and minor rs11218343 alleles, to study the impact of rs11218343 genotype on brain cell activities. We show that rs11218343 uniquely co...

— Willnow, T., Gorniak-Walas, M., Telugu, N. S., Rudolph, I.-M., Diecke, S. 2025-12-16 00:00:00

Neuroligin-2 is ubiquitinated by Nedd4l to control developmental astrocyte morphogenesis.

Astrocytes of the central nervous system have an intricate and highly branched morphology. Proper development of perisynaptic astrocyte processes is necessary for the tripartite synapse development, maturation, and function. However, how astrocyte morphogenesis is controlled, and the specific molecules orchestrating this development are largely unknown. Previously, we identified Neuroligins (NLs) 1-3 as regulators of astrocyte morphogenesis by forming transcellular adhesions with neuronal neu...

— Eroglu, C., Sakers, K., Ramirez, J. J., Elazar, N., Nagendren, L., Soderblom, E. J. 2025-12-16 00:00:00

Multi-task Intracranial EEG recordings reveal a Comprehensive Role of the Human Dorsal Anterior Insula in High-Level Cognition

The dorsal anterior insula (dAI) is widely recognized as a cornerstone of human cognition. However, its functional characterization remains the subject of considerable debate and competing theories. Embracing a "shift in viewpoint" approach - defining a brain region's function through the observation of the same neural population across diverse experimental contexts - this study used intracranial EEG (iEEG) recordings from a large cohort of patients to investigate the sub-second neural respon...

— Chatard, B., Dupin, M., Petton, M., Bontemps, B., Minotti, L., Kahane, P., Rheims, S., Bastin, J., Lachaux, J.-P. 2025-12-16 00:00:00

The Inferior Frontal Sulcus, not the Anterior Insula, acts as a late-stage attentional gate for the fast rejection of salient but irrelevant sensory inputs during cognitive tasks

The ability to prioritize behaviorally relevant stimuli is essential for efficient cognition, particularly in distracting environments. The anterior insula (AI), a key node of the salience network, has been proposed to support this selection process by detecting salient events. A similar function, however, has also been attributed to the inferior frontal sulcus (IFS), located at the intersection of the ventral and dorsal attention networks. Here, we directly compared the respective contributi...

— Chatard, B., Dupin, M., Petton, M., Bontemps, B., Minotti, L., Kahane, P., RHEIMS, S., Lachaux, J.-P. 2025-12-16 00:00:00

Loose coupling between Ca2+ channels and release sensors as a synaptic correlate of higher order brain function

In the mature neocortex, functionally distinct areas are built by the same archetypes of neurons, but depending on the area, these neurons and their synapses are engaged in very different functions, ranging from lower order processing of sensory information to higher order associations and cognitive functions. We found significant differences in the functional presynaptic nanoarchitectures of the same types of pyramidal neuron synapses, depending on whether they are located in the prefrontal ...

— Schwarze, M., Bornschein, G., Brunner, A., Arshia, A., Brachtendorf, S., Schmidt, H. 2025-12-16 00:00:00

Attention to Psuedo-Tone Melodies Enhances Cortical but Not Brainstem Responses in Humans

Auditory selective attention, the ability to focus on specific sounds while ignoring competitors, enables communication in complex soundscapes. Though attention clearly modulates cortical responses to sound, whether and where this modulation occurs in subcortical structures remains disputed. Here, we use electroencephalography to record cortical and subcortical (auditory brainstem responses, ABRs) activity during a selective attention task. Human participants attend to a 3-note melody in one ...

— Figarola, V., Li, Y., Tierney, A. T., Dick, F., Noyce, A., Maddox, R. K., Shinn-Cunningham, B. G. 2025-12-16 00:00:00

Crowding drives terminal investment in a generalist pest

Apart from genotype and environment, several fitness related traits of individuals are also influenced by the conditions experienced by their parents, i.e., by parental effects. To uncover the underlying physiological or molecular mechanisms, most studies analyze specific drivers in isolation, such as parental age or the degree of crowding experienced by the parents. However, potential interaction effects between different aspects of parental context are poorly understood. We analyzed the com...

— Govindarajan, S., Patra, D., Agashe, D. 2025-12-15 00:00:00

Morphological and molecular characterisation of Orientia tsutsugamushi grown in tick cells

Orientia tsutsugamushi (Ot), the causative agent of scrub typhus, is an obligate intracellular bacterium naturally maintained in Leptotrombidium mites, yet its interactions within arthropod hosts remain poorly understood. Here, we developed two tick cell lines, Ixodes scapularis ISE6 and Rhipicephalus microplus BME/CTVM23, as arthropod models to investigate the intracellular life cycle of Ot strains TA686 and Karp. Both strains efficiently infected and replicated within tick cells, with ISE6 ...

— Rogowska-van der Molen, M., Gallo, F., Bell-Sakyi, L., Salje, J. 2025-12-15 00:00:00

Symbiosis through lysis: prophage activation underlies Lactiplantibacillus plantarum probiotic function

The release of bacterial bioactive molecules across the gut barrier is a crucial yet poorly understood step in microbe-host communication. Here we unravel a phage-driven mechanism that enables this process in a nutritional symbiont. In Lactiplantibacillus plantarum NC8 (LpNC8), we identify a stress-inducible prophage, pp2, that undergoes genotoxic-stress-dependent activation and triggers holin-lysin-mediated lysis. This controlled lytic program produces phage particles together with extracell...

— Zhu, C., Manuse, S., Perrier, Q., Akherraz, H., Ramos, C. I., Zhang, M., Grangeasse, C., Leulier, F., Matos, R. C. 2025-12-15 00:00:00

Beyond the core: endemic microbiota drive functional and microdiversity differences across salamander populations

Population-specific variation in animal microbiomes is well documented, yet the functional consequences and underlying mechanisms remain poorly understood. To address this, we conducted genome-resolved metagenomic analyses on gut and skin microbiomes from four populations of Pyrenean brook salamanders (Calotriton asper) inhabiting two distinct environments (Pyrenean subalpine brooks and Atlantic montane streams). From paired faecal and skin swab samples, we reconstructed 539 and 43 metagenome...

— Aizpurua, O., Brenner, E., Martin-Bideguren, G., Garin-Barrio, I., Cabido, C., Alberdi, A. 2025-12-15 00:00:00

Postnatal increase in MRTF-dependent transcription reduces EGFR activation and proliferation of apical but not basal NSCs

In the ventricular-subventricular zone (V-SVZ), both apical and basal NSCs undergo quiescence and proliferation. The epidermal growth factor receptor (EGFR) and interactions with the extracellular matrix are key regulators of adult NSC proliferation and quiescence, respectively. Here, we show that activation of EGFR significantly declines after the first postnatal weeks in apical NSCs. This decline is accompanied by a shift in serum responsive factor (SRF)-dependent transcription in apical NS...

— Shen, Y., Baur, K., Irmler, M., Beckers, J., Mandl, C., Hoelzl-Wenig, G., Ciccolini, F. 2025-12-15 00:00:00

Glycolysis and hexosamine biosynthesis pathways are key for inflammatory protein maturation and leukocyte adhesion to human aortic valve cells

Inflammation and metabolism reprogramming are hallmarks of calcific aortic valve disease (CAVD). Recent studies link inflammation to hyperglycolysis and calcification in valve interstitial cells (VICs). The metabolism of valve endothelial cells (VECs) has received less attention despite both resident valve cells are exposed to alike inflammatory clues involved in the biosynthesis of pathologically relevant glycoproteins during the early stages of CAVD. On this basis, we investigated the outco...

— Sanchez-Bayuela, T., Peral-Rodrigo, M., Lopez, J., Gomez, C., Perez-Riesgo, E., Lopez-Andres, N., Fernandez, N., San Roman, J. A., Sanchez Crespo, M., Garcia-Rodriguez, C. 2025-12-15 00:00:00

Retrotransposon Activation in the Aged and Alzheimer's Disease Brain Examined by Nanopore Long-read DNA Sequencing

Background Cellular defenses against retrotransposable elements (RTEs) weaken with age and RTEs have been reported to contribute to Alzheimer's disease (AD) pathogenesis by promoting neuroinflammation. The mechanisms implicated include DNA damage promoted by retrotransposition and interferon system activation by RTE-derived cDNA intermediates. LINE-1 (L1) retrotransposons are of particular interest because they are the only autonomously active RTEs in the human genome. Results To investigate ...

— Kelsey, M. M. G., Chongtham, A., LaCava, J., Taylor, M. S., Boeke, J. D., Gage, F. H., Seluanov, A., Gorbunova, V., Pereira, A. C., Sedivy, J. M. 2025-12-15 00:00:00

RAFTER: a releasing factor tethered RNA editing system for quantifying mRNA translation

Measurement of mRNA translational efficiency has heavily relied on quantifying the amount of polysome-associated RNAs which would not always reflect the efficient translation. To address this, we developed RAFTER, which combined RNA editing enzyme with translation releasing factor to selectively label successfully translated RNAs. The translational efficiency estimated based on RAFTER correlated well with that by Ribo-seq and Polysome-seq, but with greatly simplified workflow, which enables i...

— Chen, W., Sun, Z., Dong, P., Yan, H., Wen, X., Li, Y., Jiang, F., Fang, L., Wang, X. 2025-12-15 00:00:00

The shifting dynamics of ancestry and culture at a post-Roman crossroads

The collapse of the western Roman Empire in the 5th century created a period of geopolitical upheaval, driven by Barbarians dispersing into the former Empire and reshaping post-Roman communities. While there is now evidence for a major genetic impact of these migrations into specific regions of Europe, it is unknown whether these changes in ancestry were uniform across the continent. We investigate present-day Slovenia, a crucial crossroad connecting the Roman East and West and the gate to It...

— Vyas, D. N., Koncz, I., Milavec, T., Leskovar, T., Farago, N., Tian, Y., Bausovac, M., Mende, B. G., Francalacci, P., Bavec, U., Bester, H., Borzacconi, A., Brezigar, B., Friedrich, R., Gaspari, A., Giostra, C., Hincak, Z., Karo, S., Kruh, A., Mason, P., Modi, A., Perko, M., Radzeviciute, R., Ratej, R., Saccheri, P., Szecsenyi-Nagy, A., Travan, L., Udovc, K., Vai, S., Zupanek, B., Caramelli, D., Krause, J., Pohl, W., Vida, T., Geary, P. J., Veeramah, K. R. 2025-12-15 00:00:00

RBProximity-CLIP Enables Subcellular Mapping of RNA-Binding Protein Interactions at Nucleotide Resolution

RNA-binding proteins (RBPs) enable post-transcriptional gene regulation (PTGR) through specific interactions with RNA molecules, influencing processes ranging from nuclear processing and export to cytoplasmic localization, translation, storage and degradation. A key determinant of PTGR processes is the subcellular compartmentalization of RBPs, which dictates RNA targets they can access and the regulation performed in that environment. To characterize RBP-RNA interactions at subcellular resolu...

— Nowak, I., Polash, A. H., Huynh, H. T., Kaur, M., Lobo, V., Scutenaire, J., Fong, M., Alluhaibi, G., Anastasakis, D. G., Hafner, M., Benhalevy, D., Sarshad, A. 2025-12-15 00:00:00

Identification of sodium/myo-inositol transporter 1 as a major determinant of arterial contractility

Background: As the sodium/ myoinositol transporter (SMIT1) is a positive regulator of Kv7.4/7.5 channels in arterial smooth muscle we postulated that altering SMIT1 expression could have a major impact upon vascular reactivity. Consequently, this study aimed to characterise the effects of changes of SMIT1 membrane abundance on vascular tone and the molecular mechanisms involved. Methods: Isometric tension recording on 2nd order mesenteric arteries and left anterior coronary arteries from male...

— Forrester, E. A., Garland, C. J., Barrese, V., Albert, A. P., Greenwood, I. A. 2025-12-15 00:00:00

Evaluation of Detection Methods for Wastewater Surveillance of Antimicrobial-Resistant Bacteria from Healthcare Facilities

Carbapenem resistance is an urgent public health threat. Wastewater surveillance could support antimicrobial resistance monitoring at long-term care facilities (LTCFs). Feasibility of wastewater sampling (via composite or passive sampler, and sewer biofilm swabs) for carbapenemase genes (blaKPC, blaVIM, blaOXA-48-like, blaNDM, and blaIMP) detected by qPCR or GeneXpert(R) Carba-R from a LTCF was assessed over 16 months and compared to clinical infections. blaKPC, blaOXA-48-like, and blaVIM wer...

— Warren, E., VanDerslice, J., Benson, L. S., Brazelton, W. J., Tanner, W., Lyons, A. K., Whitehill, F., Coulliette-Salmond, A., Fusco, S., Weidhaas, J. 2025-12-15 00:00:00

Scratching on French PDO cheese surfaces sheds light on an unexplored microbial genomic and metabolic diversity

Cheeses are fermented dairy products consumed worldwide. Their global diversity results from various local variables, including technological practices, as well as the metabolic activity of diverse microorganisms. In Europe, this typicity is exemplified by Protected Designation of Origin (PDO) cheeses, for which genetic diversity remains largely unexplored. Combining culturomics (n = 373 bacterial genomes) and metagenomic (n = 146 metagenomes), we performed a national-scale survey of the micr...

— Gardon, H., Tabuteau, S., Irlinger, F., Dugat-Bony, E., Barbe, V., Callon, C., Cantuti Gendre, J., Cruaud, C., Delbes, C., Gavory, F., Loux, V., Mohellibi, N., Neuveglise, C., Renault, P., Rue, O., Theil, S., Aury, J.-M., HERVE, V. 2025-12-15 00:00:00

A meta-analysis of environmental sequencing data reveals the global distribution and hidden diversity of marine anaerobic ciliates

Anaerobic protists are diverse, ecologically important members of anoxic microbial communities, acting as grazers, nutrient cyclers, and partners in multi-domain associations, yet remain understudied relative to anaerobic prokaryotes. Ciliates are particularly abundant and diverse in anoxia, but their global diversity and distribution are largely unknown. Here, we conducted a meta-analysis of public 18S rDNA datasets, along with one dataset generated here, to assess the global diversity and e...

— Schrecengost, A., Frates, E., Al-Haj, A. N., Fulweiler, R. W., Beinart, R. A. 2025-12-15 00:00:00

Bacteriophage PAK_P3 genome structuration and dynamics during infection of Pseudomonas aeruginosa reveal specific interactions patterns

Bacteriophages, or phages, are highly abundant and diverse genomic entities that play an important role in microbial ecology, evolution, and horizontal gene transfer. While the dynamic changes in genome organization in cellular organisms have been well described, the 3D folding of phage genomes during the infection of their host is extremely limited. Understanding how phage genomes fold, invade and rearrange the genome of their host to functionally organize the optimal expression of their gen...

— Bignaud, A., Lamy-Besnier, Q., Conti, D., Thierry, A., Girard, F., Misson, P., Koszul, R., Debarbieux, L., Marbouty, M. 2025-12-15 00:00:00

The role of heavy metals in the co-selection of plasmid-borne metal and antibiotic resistance genes from industrially contaminated sediments.

A comprehensive understanding of the sources and drivers of antimicrobial resistance is essential for effective antimicrobial stewardship. Co-selection is now recognised as a significant driver of antimicrobial resistance, with established links between heavy metal exposure and the presence of bacteria with antimicrobial resistance. The precise mechanisms that drive this process in the environment are co-resistance, cross-resistance, and co-regulation, but their respective impacts remain larg...

— Gillieatt, B. F., Thai, M., Cain, A. K., Zadoks, R. N., Coleman, N. V., Kertesz, M. A. 2025-12-15 00:00:00

Genome-scale dissection of phase-variable gene function in Campylobacter jejuni using a stabilized phasotype library

Phase variation (PV) enables bacterial pathogens to rapidly alter their surface structures through reversible mutations in simple sequence repeats, promoting immune evasion and environmental adaptation. In Campylobacter jejuni, the stochastic nature of PV has hindered the systematic functional analysis of phase-variable genes (PVGs). Here, we introduce PV-GenShift, a genome-scale screening platform built on a genetically stabilized library of phase-locked C. jejuni variants. By fixing the ON/...

— Yamamoto, S., Lee, K.-i., Kubomura, A., Iyoda, S., Akeda, Y., Shimohata, T., Aikawa, C., Okamura, M., Hojo, F., Osaki, T., Mitobe, J. 2025-12-15 00:00:00

A global deep-sea small protein atlas reveals a reservoir of noncanonical antimicrobial peptides

Small proteins encoded by small open reading frames (smORFs; [≤] 100 aa) represent a largely unexplored dimension of microbial diversity, especially in the deep sea. By analyzing 708 metagenomes from five major deep-sea biomes (hadal trenches, cold seeps, hydrothermal vents, abyssal plains, and seamounts), we constructed the Deep-Sea Small Protein Atlas, comprising 88.7 million smORFs with exceptional novelty and strong habitat specificity. Deep-learning predictions identified 5.47 million ...

— Jiang, Q., Han, Y., Ye, C., Duan, Y., Li, F., Han, Z., Santos-Junior, C. D., Luo, Z.-Q., Dong, X. 2025-12-15 00:00:00

Metabolic reshaping drives novel melanin production from tryptophan in a cystic fibrosis Pseudomonas aeruginosa clinical isolate

Pseudomonas aeruginosa is a human opportunistic pathogen, capable of producing a wide range of metabolites, including pyomelanin. This pigment results from alterations in tyrosine catabolism. Melanin synthesis from tryptophan has never been reported in Pseudomonas. In this study, we describe a tryptophan-derived melanin in P. aeruginosa PAH, a strain that was isolated from a fibrocystic patient. PAH produced a brown pigment when grown in LB or L-tryptophan-supplemented media. Structural analy...

— Appella, M. N. D., Kolender, A. A., Nega, M., Robaldi, S. A., Cassanelli, P. M., Li, N., Liberini, E., Hoijemberg, P., Pelliza, L., Aran, M., Götz, F., Lopez, N. I., Tribelli, P. M. 2025-12-15 00:00:00

Modeling the effects of Huntington disease on age-related genes reveals CXXC4 as an epigenetic target to restore health and excitability of Drd1-expressing striatal neurons

Gene profile studies suggest that neurons may face premature aging in neurodegenerative diseases such as Huntington disease (HD). Cells remodel gene expression to resist molecular damage in aging, but how neurons may engage age-related genes to resist HD remains unknown. Here, we found that transcriptional-aging inversion (TAGI) in the Drd1-expressing striatal neurons (Drd1 SNs) of HD knock-in (Hdh) mice shows discrete patterns in the backdrop of a TAG-like (TAGL) signature, and that TAGI per...

— Arrieta-Lobo, M., Farina, F., Monteagudo Aboy, T., Mair, M., Mendoza, C., Tran, H., Aaronson, J., Rosinski, J., Ellerby, L., Brouillet, E., Botas, J., Neri, C., Megret, L. 2025-12-15 00:00:00

Deliberation is a controllable process governed by desirability and cognitive effort

Humans spend a lifetime making decisions based on incoming sensory information and goals. Prominent theories of perceptual decision-making have described the components of deliberation process, yet they lack a unifying principle that governs how the nervous system tunes the deliberation process across multiple contexts. Desirability (reward) and effort (energy) are major determinants in governing a broad range of human and animal behaviour, such as foraging, walking, and decisions. Here we de...

— Calalo, J. A., Sullivan, S. R., Muscara, N. R., Buggeln, J. H., Ngo, T. T., Short, M. M., Carter, M. J., Kurtzer, I. L., Cashaback, J. G. A. 2025-12-15 00:00:00

Spatial Polarization-Induced Fluorescence Fluctuation Imaging (SPIFFI) Enables Single-shot Super-Resolution and Multidimensional Imaging

Fluorescence super-resolution microscopy has advanced optical imaging into the nanoscale regime, transforming biological and interdisciplinary research. However, conventional wide-field super-resolution techniques often compromise temporal resolution, thereby limiting the ability to capture rapid and transient biological events in living systems. Here, we introduce spatial polarization-induced fluorescence fluctuation imaging (SPIFFI), a multi-channel polarimetric method that enables single-s...

— Guo, W., Feletti, L., Radenovic, A. 2025-12-15 00:00:00

Quantifying (de)Mixing of Disordered Proteins in Molecular Dynamics Simulations

Biomolecular condensates underpin the spatial and temporal organization of cellular biochemistry in the cell. Their architectures often arises from complex, multicomponent mixtures whose behavior is governed by weak, multivalent interactions, frequently mediated by intrinsically disordered regions (IDRs) of proteins. However, current approaches lack generalizable metrics to determine whether IDRs will mix or segregate within condensates. Here, we show that our domain decomposition method can ...

— Morton, W. S., Vacha, R. 2025-12-15 00:00:00