Biology subjects

Katz, J.

Publications and source records attributed to Katz, J..

8 recordsLinked to original sources

bioRxiv2026

Porphyromonas gingivalis promotes lipid droplet-mediated microglial dysfunction

Growing evidence supports a strong association between periodontitis and Alzheimers disease (AD), yet the mechanisms linking these conditions remain poorly defined. In neurodegenerative disorders, including AD, microglia are often characterized by increased lipid droplet (LD) accumulation, heightened activation, and impaired function. In this study, we examined whether Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, promotes LD accumulation in microglia and disrupts their function. We found that Pg infection induces robust LD accumulation in BV2 microglial cells and in microglia from Pg-infected App KI mice. This Pg-driven LD buildup was closely associated with elevated reactive oxygen species (ROS) production, impaired phagocytic ability, and altered activation. Notably, pharmacological inhibition of LD with a triglyceride synthesis inhibitor effectively reversed Pg-induced LD accumulation, mitigated ROS production, and restored phagocytic function, thus underscoring the critical role of lipid metabolism in regulating microglial function. These findings support a model in which, in the context of periodontitis, systemic dissemination of periodontal pathogens promotes LD accumulation in microglia, and this metabolic alteration exacerbates microglia dysfunction via a self-reinforcing cycle of excessive oxidative stress and impaired phagocytosis, potentially accelerating AD progression.

neuroscience↗

bioRxiv2025

Metabolic reprogramming in the spinal cord drives the transition to pain chronicity

Acute injuries can progress into painful states that endure long after healing. The mechanisms underlying this transition remain unclear, but metabolic adaptations to the bioenergy demands imposed by injury are plausible contributors. Here we show that peripheral injury activates AKT/mTORC1 in afferent segments of the mouse spinal cord, redirecting local core metabolism toward biomass production while simultaneously suppressing autophagy-mediated biomass reclamation. This metabolic shift supports neuroplasticity, but creates a resource bottleneck that depletes critical spinal cord nutrients. Preventing this depletion with a modified diet normalizes biomass generation and autophagy and halts the transition to chronic pain. This effect, observed across multiple pain models, requires activation of the nutrient sensors, sirtuin-1 and AMPK, as well as restoration of autophagy. The findings identify metabolic reprogramming and consequent autophagy suppression as key drivers of the progression to pain chronicity and highlight nutritional and pharmacological interventions that could prevent this progression after surgery or other physical traumas.

neuroscience↗

bioRxiv2024

Long-term Tolerance to Islet Transplantation via Targeted Reduction of beta cell-specific T cells.

Type 1 diabetes (T1D) results from insulin insufficiency due to the loss or dysfunction of pancreatic beta cells following T cell-mediated autoimmune attack. Currently the only long-term therapy is daily exogenous insulin replacement. The ideal curative approach is the durable restoration of functional islets via transplantation. To date the limiting factors impeding realization of this goal is the lack of a cost effective and limitless source of high-quality islets suitable for transplantation and the ability to provide long-term islet graft acceptance without prolonged need for deleterious immunosuppression. Ongoing clinical trials are testing islets derived from human induced pluripotent stem cells (iPSC); however, long-term acceptance of islet graft will require a effective therapeutic strategy to prevent engrafted islet destruction by pre-existing islet-antigen specific T cells. Here we demonstrate in the NOD mouse model for T1D that autologous islet graft acceptance can be achieved by the targeted elimination of (re)-activated islet-reactive CD4+ and CD8+ T effector (Teff) cells in the initial post-transplantation period by using a short-acting, combination therapy that results in the elimination of islet-reactive Teff cells by exacerbation of their natural DNA damage response (DDR) to drive apoptosis while at the same time maintaining endogenous Treg cells. Article HighlightsO_LIActivated beta-cell reactive CD4+ and CD8+ T effector cells undergo a profound DNA-damage response which is targetable by small molecule inhibitors of the p53 and cell cycle pathways that lead to apoptosis. C_LIO_LIThe use of a combination of MDM2 and WEE1 inhibitors, which termed "p53 potentiation with checkpoint abrogation" (PPCA), conferred significant therapeutic efficacy in treating mouse models of new onset T1D. C_LIO_LISpecific targeting of these T effector cells by PPCA results in a loss of inflammatory T cell subsets, notably proliferation CD4+ Th0 and Th1 subsets and CD8+ T effector memory cells, as determined by single cell RNA-seq studies with the preservation of T regulatory cells. C_LIO_LIWhen autologous islet grafts are given to established diabetic NOD mice, a single course of PPCA results in long-term islet graft acceptance, restoration of normoglycemia and loss of beta cell specific CD4+ and CD8+ T cells. C_LIO_LIPPCA shows promise as a potential means of estimating islet graft tolerance in T1D recipients of islet graft transplantation. C_LI

immunology↗

bioRxiv2024

Clonal Parabacteroides from Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn's Disease Complications

Crohns disease (CD) has been traditionally viewed as a chronic inflammatory disease that cause gut wall thickening and complications, including fistulas, by mechanisms not understood. By focusing on Parabacteroides distasonis (presumed modern succinate-producing commensal probiotic), recovered from intestinal microfistulous tracts (cavernous fistulous micropathologies CavFT proposed as intermediate between mucosal fissures and fistulas) in two patients that required surgery to remove CD-damaged ilea, we demonstrate that such isolates exert pathogenic/pathobiont roles in mouse models of CD. Our isolates are clonally-related; potentially emerging as transmissible in the community and mice; proinflammatory and adapted to the ileum of germ-free mice prone to CD-like ileitis (SAMP1/YitFc) but not healthy mice (C57BL/6J), and cytotoxic/ATP-depleting to HoxB8-immortalized bone marrow derived myeloid cells from SAMP1/YitFc mice when concurrently exposed to succinate and extracts from CavFT-derived E. coli, but not to cells from healthy mice. With unique genomic features supporting recent genetic exchange with Bacteroides fragilis-BGF539, evidence of international presence in primarily human metagenome databases, these CavFT Pdis isolates could represent to a new opportunistic Parabacteroides species, or subspecies ( cavitamuralis) adapted to microfistulous niches in CD.

genomics↗

bioRxiv2023

Foodscapes for Salmon and Other Mobile Consumers in River Networks

Mobile consumers track fluctuating resources across heterogeneous landscapes to grow and survive. In river networks, the abundance and accessibility of food and the costs of foraging vary between habitats and through time, providing a shifting mosaic of growth opportunities for mobile consumers. However, a framework integrating the spatiotemporal dynamics of growth potential within riverscapes has been lacking. Here we present the concept of "foodscapes" to depict the dynamic changes in food abundance, food accessibility, and foraging costs that contribute to spatial and temporal variation of fish growth in rivers. Drawing on case studies of salmonid fishes from Alaska to California, we illustrate that "healthy" foodscapes provide a plethora of foraging opportunities--promoting diverse life history strategies that potentially enhance population stability. We identify knowledge gaps in understanding foodscapes, and approaches for management that focus on restoring trophic pathways which support diverse foraging and growth opportunities for fish in river networks.

ecology↗

bioRxiv2022

Inhibitory interneurons within the deep dorsal horn integrate convergent sensory input to regulate motor performance

To achieve smooth motor performance in a changing sensory environment, motor outputs must be constantly updated in response to sensory feedback. Inhibitory interneurons in the spinal cord play an essential role in shaping motor activity by gating the transmission of sensory information and setting the pattern and rhythm of motor neurons. Here, we identify the medial deep dorsal horn of the spinal cord as a "hot zone" of convergent proprioceptive and cutaneous information from the hindlimb, where inhibitory neurons show increased responsiveness to sensory input and are preferentially recruited during locomotion in comparison to excitatory neurons. We identify a novel population of glycinergic inhibitory neurons within the deep dorsal horn that express parvalbumin (dPV) and receive convergent proprioceptive and cutaneous input from the paw. We show that dPVs possess intrinsic properties that support spontaneous discharge, even in the absence of synaptic input. However, a drug cocktail mimicking descending input (5-HT, dopamine, NMDA) amplifies dPV output, while cutaneous and proprioceptive inputs shape the temporal dynamics of dPV activity. These findings suggest dPV-mediated inhibition is modulated by behavioral state and can be fine-tuned by sensory input. Using intersectional genetic strategies, we selectively target spinal cord dPVs and demonstrate their capacity to provide divergent ipsilateral inhibition to both pre-motor and motor networks of the ventral horn, thereby controlling the timing and magnitude of cutaneous-evoked muscle activity. Manipulating the activity of dPVs during treadmill locomotion results in altered limb kinematics at the transition of stance to swing and altered step cycle timing at increased speeds. To investigate the effects of manipulating dPV activity on broader sets of motor behaviors, we used depth vision and machine learning to quantify and scale naturalistic behavior. We find that although sub-movements remain stable, the transitions between sub-movements are reduced, suggesting a role in movement switching. In sum, our study reveals a new model by which sensory convergence and inhibitory divergence produce a surprisingly flexible influence on motor networks to increase the diversity of mechanisms by which sensory input facilitates smooth movement and context-appropriate transitions. HighlightsO_LIInhibitory deep dorsal horn interneurons integrate convergent proprioceptive and cutaneous sensory inputs from the paw and are preferentially recruited during locomotion. C_LIO_LIDeep dorsal horn parvalbumin+ interneurons (dPVs) represent a population of glycinergic interneurons that can provide sustained inhibitory control. C_LIO_LISensory input engages dPVs to facilitate inhibition with high temporal precision and reduced variability. C_LIO_LIdPVs contribute to the ipsilateral inhibitory control of motor and premotor networks of the ventral horn, thereby gating the magnitude and timing of cutaneous-evoked flexor and extensor muscle activity. C_LIO_LIIn vivo, dPVs modulate gait dynamics in a state- and phase-dependent manner, to ensure smooth movement transitions between step-cycle phases and naturalistic sub-movements. C_LI

neuroscience↗

bioRxiv2020

Quantifying Epithelial Plasticity as a Platform to Reverse Epithelial Injury

Epithelial surfaces lining the lung serve as the primary environmental gaseous interface, and are subject to common life-limiting diseases, including COPD (Chronic Obstructive Pulmonary Disease). Despite the critical role of epithelial cells in pulmonary health and disease, quantitative models are lacking but are required given the large patient to patient variability to characterize the epithelial plasticity that follows injury. We have identified a series of assessments to quantitatively identify the changes that occur in the epithelium and to identify targets that reverse injury. The injured epithelium has decreased ciliary function and monolayer height, which in the case of cells derived from COPD patients results in an overall disorganization of structure. Injury causes the cells to shift to an unjammed state, with corresponding increases in the velocity correlation length implicating cell shape and stiffness as fundamental to the injury response. Specific inhibitors of actin polymerization (LatA), of MAPK/ERK kinase (U0126) and Nrf-2 pathway activation (CDDO-Me) push the epithelium back towards a jammed state with decreased cell movement and correlation length, as well as improve barrier function and CBF. These studies attest to cell intrinsic properties that allow for a transition to an unjammed state, and that quantitative phenotypic analysis can identify potential specific pharmacologic targets in a given patient and provide insight into basic mechanisms of cellular damage. One Sentence SummaryEnvironmental toxins undermine tissue integrity by manipulating transitions from jammed to unjammed states, thereby mimicking or inducing disease.

cell biology↗

bioRxiv2018

T cells instruct dendritic cells to produce inflammasome independent IL-1β causing systemic inflammation

While IL-1{beta} is critical for anti-microbial host defense, it is also a key mediator of autoimmune inflammation. Inflammasome activation following pathogenic insults is known to result in IL-1{beta} production. However, the molecular events that produce IL-1{beta} during T cell driven autoimmune diseases remain unclear. Here, we have discovered an inflammasome-independent pathway of IL-1{beta} production that is triggered upon cognate interactions between dendritic cells and effector CD4 T cells. Analogous to inflammasome activation, this \"T cell-instructed IL-1{beta} also relies on two independent signaling events. TNF produced by activated CD4 T cells engages TNFR signaling on DCs leading to pro-IL-1{beta} synthesis. Subsequently, FasL, also expressed by effector CD4 T cells, engages Fas on DCs leading to caspase-8 dependent pro-IL-1{beta} cleavage. Remarkably, this two-step mechanism is completely independent of pattern recognition receptor activation. IL-1{beta} produced upon cognate DC-effector CD4 T cell interaction causes wide spread leukocyte infiltration, a hallmark of systemic inflammation as well as autoimmune pathology. This study has uncovered a novel feature of DC-T cell cross-talk that allows for active IL-1{beta} secretion independent of innate sensing pathways and provides a mechanistic explanation for IL-1{beta} production and its downstream consequences in CD4 T cell driven autoimmune pathology.

immunology↗