Biology subjects

Jacobs, T.

Publications and source records attributed to Jacobs, T..

13 recordsLinked to original sources

bioRxiv2026

Cerebellar influences on neocortical development in humans and mice

The cerebellum has long been considered a late-maturing structure subordinate to neocortical development, therefore its potential role as an early driver of cortical organization remains largely unexplored. Using two large longitudinal neuroimaging cohorts of developing children together with lesion experiments in mice, we show that early cerebellar morphology may drive neocortical maturation in a regionally specific manner. These cross-species findings implicate the cerebellum as a possible regulator of neocortical organization.

neuroscience↗

bioRxiv2026

A spatial atlas of the seaweed CO2-fixation machinery reveals a unique Rubisco condensation mechanism

Seaweeds (macroalgae) are important primary producers that sustain food webs in coastal ecosystems. Most algae accelerate inorganic carbon assimilation by actively concentrating CO2 in a Rubisco-rich specialized organelle called the pyrenoid. However, the molecular composition of this pathway is unknown in seaweeds. Here, we investigated the intracellular localization of 160 proteins associated with CO2 acquisition in the green seaweed Ulva (Sea lettuce). We assign 68 proteins to different pyrenoid subdomains and identify a consensus Ulva Rubisco binding motif revealing the molecular logic of the Ulva pyrenoid. We reveal Seaweed Ulva Pyrenoid Assembly 1 (SUPA1) as the core pyrenoid assembly factor. We show that Rubisco condensation is driven by a unique mechanism: the helical folding of SUPA1 motifs upon Rubisco binding, combined with steric hindrance that halves the available Rubisco binding sites from eight to four. Our data gives an unprecedented sub-cellular spatial understanding on seaweed carbon fixation and provides insights into the evolution of this important pathway in the global carbon cycle.

cell biology↗

bioRxiv2026

TGF-β signaling regulates epithelial permeability in Drosophila ovaries by modulating adhesion independent of actomyosin contractility

Epithelial morphogenesis and homeostasis rely on dynamic remodeling of cell-cell junctions. Tricellular junctions (TCJs) at cell vertices are key sites that control epithelial permeability and plasticity, yet how TCJs are remodeled remains unclear. In the follicular epithelium (FE) in Drosophila ovaries, TCJs open transiently in a process called patency to allow passage of yolk proteins for uptake by the oocyte. We investigated how a gradient of TGF-{beta} signaling activity suppresses patency in a graded manner across the FE. We show that TGF-{beta} signaling blocks patency in a cell-autonomous manner by strengthening E-Cadherin (E-Cad)-based adhesion through inducing E-Cad transcription and preventing its removal from cell vertices. In parallel, TGF-{beta} signaling activates myosin II through Rho-Rok signaling. However, myosin II activity is dispensable for TGF-{beta}-mediated suppression of patency. We show that TGF-{beta} signaling controls TCJ remodeling in follicle cells primarily by reinforcing E-Cad-based adhesion, in part through upregulating p120-catenin. Our findings disentangle the roles of adhesion and actomyosin contractility in maintaining TCJ integrity and reveal how a tissue-scale morphogen gradient is translated into graded epithelial permeability.

developmental biology↗

bioRxiv2026

Sex-specific associations between astrocytic reactivity and cognitive decline in unimpaired elderly

INTRODUCTIONAstrocyte reactivity may contribute to increased Alzheimers disease (AD) risk in women. Although higher plasma glial fibrillary acidic protein (GFAP) levels have been reported in women, few studies have investigated sex-specific relationships with other plasma AD biomarkers and cognition. METHODSParticipants were enrolled in the Memory Education and Research Initiative, a longitudinal community-based cohort, and underwent evaluation including blood biomarker sampling. The Alzheimers Disease Neuroimaging Initiative (ADNI) was included as a replication cohort. RESULTSUnimpaired women exhibited higher plasma GFAP levels than men (N=584). Higher baseline GFAP was associated with worse longitudinal episodic memory, exclusively in women. In addition, both higher baseline and increasing GFAP levels over time were associated with lower longitudinal plasma A{beta}42/40 ratio. The key results were replicated in the ADNI cohort. DISCUSSIONThese findings suggest that astrocytic reactivity is more pronounced in women and may contribute to sex-specific vulnerability to AD-related pathology and cognitive decline.

neuroscience↗

bioRxiv2025

Functional Connectome of Superagers Reveals Early Markers of Resilience and Vulnerability to Alzheimers Disease

As populations age, identifying the neurobiological basis of cognitive resilience is critical for delaying or preventing Alzheimers disease (AD). While most older adults experience memory decline, a subset known as superagers (SA) maintains youthful memory into late life, offering a unique window into protective mechanisms against neurodegeneration. Here, we identified a functional connectivity (FC) signature, termed Alzheimers-resilient connectome (ARC), that robustly differentiates SA from age-matched patients with AD. Using resting-state fMRI in a discovery cohort (N = 290), we identified ARC derived from machine learning classifiers that distinguished SA from AD with high accuracy (AUC = 0.85), and validated the replicability of the ARC in an independent replication cohort (N = 143). ARC involved prefrontal, temporal and insular networks and was strongly associated with brain age. When applied to cognitively unimpaired (CU) adults (discovery cohort: N = 818 and replication cohort: N = 497), ARC-based subtyping revealed SA-like and AD-like subgroups with similar baseline cognitive performance but markedly divergent longitudinal trajectories. SA-like CU individuals showed slower cognitive decline, reduced amyloid-{beta} accumulation, and lower risk of conversion to mild cognitive impairment and AD, reinforcing the ARC signature as a potential early indicator of resilience. Genome-wide association analysis identified CLYBL and FRMD6 as novel genetic modulators associated with these divergent aging phenotypes. Together, our findings position ARC as a sensitive and generalizable biomarker of resilience, enabling early risk stratification and precision prevention for AD.

neuroscience↗

bioRxiv2024

Spatiotemporal transcriptomic niches of complement pathway and serine protease inhibitor activation in aging and infection

Aging is a multifactorial and complex physiological process, affecting every organ with characteristic manifestations. Understanding the molecular mechanisms that drive aging processes is crucial to targeting age-related disorders. Recent reports suggest that severe post-infection syndromes can partially accelerate aging. However, the underlying gene-encoded regulatory interplay, whether being shared or distinct between aging and infection biology are poorly understood. Here, we employed spatial transcriptomics to establish a multi-organ atlas (brain, heart, kidney, liver, lung, and spleen) across the mouse lifespan (4, 17, and 26 months). Dissecting high-quality fresh-frozen tissue samples at unbiased molecular resolution, we found both organ-specific and cross-organ gene dysregulation upon aging. We identified age-related trajectories in gene expression and cell state, some only detectable within their spatial context, and provide validation at subcellular resolution. The most prominent effect was organ-wide immune system activation with spatially variable severity. We therefore evaluated how aging mimics the expression signatures observed in systemic infection, using spatial transcriptomics slices from young mice infected with Plasmodium berghei ANKA. While on the gene level the effect sizes caused by the infection outweighed those of aging, we reveal a shared activation of the early complement pathway (C4b) and serine protease inhibitors (Serpin gene family) within by phenotype distinct spatial niches. We show that this common RNA signature is driven by tissue-specific cell types and eventually affects protein levels in the aged brain, rendering them a target for future mechanistic and drug discovery studies. Taken together, our study provides a coherent in-depth and cross-organ transcriptomics atlas to systematically study aging and infection in the mouse at spatiotemporal resolution. Key highlightsO_LILarge-scale and high-resolution atlas of spatial transcriptomics from six organs to study aging and systemic infection across two mouse cohorts. C_LIO_LIStrong transcriptional alterations found in distinct organ-specific niches for aging and acute malaria, with organ- and cell type-associated immune responses. C_LIO_LIDysregulation of early complement proteases (C4b) and serine protease inhibitors (Serpina3n) as common theme across central nervous system and peripheral organs. C_LI

molecular biology↗

bioRxiv2024

Elucidating the neuropathological and molecular heterogeneity of amyloid-beta and tau in Alzheimer's disease through machine learning and transcriptomic integration

Discerning functional brain network variations related to neuropathological aggregates in Alzheimers disease (AD), including amyloid-{beta} (A{beta}) and phosphorylated tau (p-tau), is crucial for understanding their link to cognitive decline and underlying molecular mechanisms. However, these variations are often confounded by normal aging-related changes, complicating interpretation. To address this challenge, we first defined Alzheimers continuum cases (A{beta} positive (A+), n = 129) and normal elderly (A{beta} negative (A-), n = 160) using cerebral spinal fluid amyloid levels, and then applied a novel deep learning approach to resting-state connectivity using functional magnetic resonance imaging (fMRI) of the 289 subjects to disentangle A+-specific dimensions in brain network alterations from those shared with A- individuals. The identified A+-specific dimensions were further refined to predict individual A{beta} and p-tau levels separately. We observed that resulting brain signatures, defined from A+-specific dimensions for predicting these two CSF biomarkers, were both attributed to the right superior temporal and anterior cingulate cortices and associated with attention and memory domains. When linking the brain signatures to gene expression data from a public transcriptomic atlas, we found that the brain signatures were associated with molecular pathways involving synaptic dysfunction and disruptions in pathways containing activity of excitatory neurons, astrocytes, and microglia. For A--shared dimensions, the A{beta}-linked brain signature involved the left fusiform and right middle cingulate cortices, correlating with the language cognitive measurement and language-related molecular pathways. The p-tau-linked signature predominantly involved the right insula and inferior temporal cortices, correlating with the aging-related molecular pathways. Collectively, our findings provided new insights in understanding of Alzheimers continuum pathological biomarkers.

neuroscience↗

bioRxiv2024

Rho/Rok-dependent regulation of actomyosin contractility at tricellular junctions controls epithelial permeability in Drosophila

Cell contacts in epithelia are remodeled to regulate paracellular permeability and to control passage of migrating cells, but how barrier function is modulated while preserving epithelial integrity is not clear. In the follicular epithelium of Drosophila ovaries, tricellular junctions (TCJs) open transiently in a process termed patency to allow passage of externally produced yolk proteins for uptake by the oocyte. Here we show that modulation of actomyosin contractility at cell vertices controls TCJ permeability. Before patency, circumferential actomyosin bundles are anchored at apical follicle cell vertices, where tension-sensing junctional proteins, Rho-associated kinase (Rok), and active Myosin II accumulate and maintain vertices closed. TCJ opening is initiated by redistribution of Myosin II from circumferential bundles to a medial pool, accompanied by decreasing tension on vertices. This transition requires activation of Cofilin-dependent F-actin disassembly by the phosphatase Slingshot and Myosin II inactivation by Myosin light chain phosphatase, and is counteracted by Rok. Accordingly, constitutive activation of Myosin or of Rho signaling prevent vertex opening, whereas reduced Myosin II or Rok activity cause excessive vertex opening. Thus, the opening of intercellular gaps in the follicular epithelium relies on relaxation of actomyosin contractility rather than active actomyosin-based pulling forces. Conversely, F-actin assembly is required for closing intercellular gaps after patency. Our findings are consistent with a force transduction model in which TCJ integrity is maintained by vertex-anchored contractile actomyosin. We propose that the cell-type-specific organization of actomyosin at cell vertices determines the mode of contractility-dependent regulation of epithelial permeability.

developmental biology↗

bioRxiv2023

Antimicrobial Activity of NK Cells to Trypanosoma cruzi Infected Human Primary Keratinocytes

Infection with the protozoan parasite Trypanosoma cruzi is causative for Chagas disease, which is a highly neglected tropical disease prevalent in Latin America. Humans are primary infected through vectorial transmission by blood-sucking triatomine bugs. The parasite enters the human host through mucous membranes or small skin lesions. Since keratinocytes are the predominant cell type in the epidermis, they play a critical role in detecting disruptions in homeostasis and aiding in pathogen elimination by the immune system in the human skin as alternative antigen-presenting cells. Interestingly, keratinocytes also act as a reservoir for T. cruzi, as the skin has been identified as a major site of persistent infection in mice with chronic Chagas disease. Moreover, there are reports of the emergence of T. cruzi amastigote nests in the skin of immunocompromised individuals who are experiencing reactivation of Chagas disease. This observation implies that the skin may serve as a site for persistent parasite presence during chronic human infection too and underscores the significance of investigating the interactions between T. cruzi and skin cells. Consequently, the primary objective of this study was to establish and characterize the infection kinetics in human primary epidermal keratinocytes (hPEK). Our investigation focused on surface molecules that either facilitated or hindered the activation of natural killer (NK) cells, which play a crucial role in controlling the infection. To simulate the in vivo situation in humans, an autologous co-culture model was developed to examine the interactions between T. cruzi infected keratinocytes and NK cells. We evaluated the degranulation, cytokine production, and cytotoxicity of NK cells in response to the infected keratinocytes. We observed a strong activation of NK cells by infected keratinocytes, despite minimal alterations in the expression of activating or inhibitory ligands on NK cell receptors. However, stimulation with recombinant interferon-gamma (IFN-{gamma}), a cytokine known to be present in significant quantities during chronic T. cruzi infections in the host, resulted in a substantial upregulation of these ligands on primary keratinocytes. Overall, our findings suggest the crucial role of NK cells in controlling acute T. cruzi infection in the upper layer of the skin and shed light on keratinocytes as potential initial targets of infection.

immunology↗

bioRxiv2022

Acute manipulation and real-time visualization of membrane trafficking and exocytosis in Drosophila

Intracellular trafficking of secretory proteins plays key roles in animal development and physiology, but tools for investigating dynamics of membrane trafficking have been limited to cultured cells. Here we present a system that enables acute manipulation and real-time visualization of membrane trafficking through reversible retention of proteins in the endoplasmic reticulum (ER) in living multicellular organisms. By adapting the "retention using selective hooks" (RUSH) approach to Drosophila, we show that trafficking of GPI-linked, secreted, and transmembrane proteins can be controlled with high temporal precision in intact animals and cultured organs. We demonstrate the potential of this approach by analyzing the kinetics of ER exit and apical secretion and the spatiotemporal dynamics of tricellular junction assembly in epithelia of living embryos. Furthermore, we show that controllable ER-retention enables tissue-specific depletion of secretory protein function. The system is broadly applicable to visualize and manipulate membrane trafficking in diverse cell types in vivo.

cell biology↗

bioRxiv2021

Tracheal tube fusion in Drosophila involves release of luminal exosomes from multivesicular bodies

Extracellular vesicles (EVs) comprise diverse types of cell-released membranous structures that are thought to play important roles in intercellular communication. Despite extensive work on the formation and functions of EVs in cultured cells, studies of EVs in vivo have remained scarce. We report here that EVs are present in the developing lumen of tracheal tubes in Drosophila embryos. We defined two distinct EV subpopulations, one of which contains the Munc13-4 homologue Staccato (Stac) and is spatially and temporally associated with tracheal tube fusion events. The formation of Stac-positive luminal EVs depends on the tip-cell-specific GTPase Arl3, which is also required for the formation of Stac-positive multivesicular bodies, suggesting that Stac-EVs derive from fusion of Stac-MVBs with the luminal membrane in tip cells during anastomosis formation. The GTPases Rab27 and Rab35 cooperate downstream of Arl3 to promote Stac-MVB formation and tube fusion. We propose that Stac-MVBs act as membrane reservoirs that facilitate tracheal lumen fusion in a process regulated by Arl3, Rab27, Rab35, and Stac/Munc13-4.

developmental biology↗

bioRxiv2021

T cells expressing multiple co-inhibitory molecules in acute malaria are not exhausted but exert a suppressive function

Overwhelming activation of T cells in acute malaria is associated with severe outcomes. Thus, counter-regulation by anti-inflammatory mechanisms is indispensable for an optimal resolution of disease. Using Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice, we performed a comprehensive analysis of co-inhibitory molecules expressed on CD4+ and CD8+ T cells using an unbiased cluster analysis approach. We identified similar T cell clusters co-expressing several co-inhibitory molecules like programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) in the CD4+ and the CD8+ T cell compartment. Interestingly, despite expressing co-inhibitory molecules, which are associated with T cell exhaustion in chronic settings, these T cells were more functional compared to activated T cells that were negative for co-inhibitory molecules. However, T cells expressing high levels of PD-1 and LAG-3 also conferred suppressive capacity and thus resembled type I regulatory T cells. To our knowledge, this is the first description of malaria-induced CD8+ T cells with suppressive capacity. Importantly, we found an induction of T cells with a similar co-inhibitory rich phenotype in Plasmodium falciparum infected patients. In conclusion, we demonstrate that malaria-induced T cells expressing co-inhibitory molecules are not exhausted, but acquire additional suppressive capacity, which might represent an immune regulatory pathway to prevent further activation of T cells during acute malaria.

immunology↗

bioRxiv2020

Regulation of blood cell transdifferentiation by oxygen sensing neurons in Drosophila

Transdifferentiation generates specialized cell types independent of stem or progenitor cells. Despite the unique process, it remains poorly understood how transdifferentiation is regulated in vivo. Here we reveal a mechanism of environmental control of blood cell transdifferentiation in a Drosophila model of hematopoiesis. Functional lineage tracing provides evidence for transdifferentiation from macrophage-like plasmatocytes to crystal cells that execute melanization. Interestingly, this transdifferentiation is promoted by neuronal activity of a specific subset of sensory neurons, in the caudal sensory cones of the larva. Crystal cells develop from plasmatocyte clusters surrounding the sensory cones, triggered by environmental conditions: oxygen sensing, and the atypical guanylyl cyclase Gyc88E specifically expressed in the sensory cone neurons, drive plasmatocyte-to-crystal cell transdifferentiation. Our findings reveal an unexpected functional and molecular link of environment-monitoring sensory neurons that govern blood cell transdifferentiation in vivo, suggesting similar principles in vertebrate systems where environmental sensors and blood cell populations coincide. HighlightsO_LIFunctional lineage tracing reveals in vivo transdifferentiation in a Drosophila model of hematopoiesis C_LIO_LIActive sensory neurons of the caudal sensory cones promote blood cell transdifferentiation in the Drosophila larva C_LIO_LIEnvironmental oxygen sensing and atypical guanylyl cyclase activity in sensory cone neurons drive blood cell transdifferentiation C_LI

developmental biology↗