Biology subjects

Flores, S.

Publications and source records attributed to Flores, S..

8 recordsLinked to original sources

bioRxiv2026

Reduced phosphatases and hyperphosphorylated glutamatergic receptors persist from early to late stages of prion disease

Synapse loss occurs early in prion disease, yet the intracellular signaling driving this dysregulation remains poorly understood. Evidence of neuronal hyperactivity was reported in humans with sporadic and familial CJD as well as in the early stages of prion disease in mice (strain 22L). Here we perform a longitudinal study of prion-infected mice (strain RML) and show an increase in the immediate-early gene, Arc, suggesting this is a conserved response to prions. We also observed a persistent decrease in phosphatase abundance (PP1 and PP2B) starting at the earliest timepoint (preclinical) in the cerebral cortex. At this stage, mGluR5 dimers and phosphorylated AMPA receptors were increased. By clinical disease onset, mGluR5 dimers declined, and activity shifted toward NMDA receptor activation, marked by GluN2B hyperphosphorylation. Together, these findings suggest that early phosphatase reduction accompanies neuronal hyperactivity and precedes substantial inflammation. Elucidating the mechanisms driving this early phosphatase loss and its role in neuronal hyperactivity may reveal novel therapeutic targets for prion disease.

neuroscience↗

bioRxiv2026

Aquaporin-4 mislocalization from astrocyte endfeet prolongs survival in a prion-cerebral amyloid angiopathy model

Aquaporin 4 (AQP4) water channels are polarized to astrocytic endfeet at blood vessel interfaces, and lose polarity in vascular diseases, including stroke, chronic traumatic encephalopathy, and Alzheimers disease. AQP4 modulates water influx and efflux in the interstitial fluid, yet how AQP4 localization impacts cerebral amyloid angiopathy (CAA) remains poorly understood. Here we show that astrocytic end feet and AQP4 are displaced from amyloid-bearing vessels in a prion-CAA mouse model that expresses GPI-anchorless PrPC. Displacing AQP4 genetically through deleting alpha-syntrophin (Snta1-/-) led to a marked prolongation in survival, together with reduced microglial inflammation and C1q, in prion-CAA-affected mice. Additionally, synaptic structural proteins were better maintained. Finally, the level and distribution of prion aggregates were similar among the mice, indicating that prion conversion and spread was not affected. These results suggest that reducing AQP4 water channel function slows the decline in a vascular amyloid disease by reducing neuroinflammation.

neuroscience↗

bioRxiv2025

Bioprospection of culturable soil-borne bacteria with biotechnological potential for use in priming defense

BackgroundThe plant root microbiome is central to disease resistance and stress resilience. In intensive tomato production, prolonged agrochemical use disrupts microbial communities, reducing their protective functions and enabling pathogen establishment. MethodsWe integrated 16S rRNA amplicon sequencing with culture-dependent isolation to analyze microbiome shifts in tomato plants across healthy, asymptomatic, and symptomatic states in a nematode-infested field. Network analysis and machine learning were used to identify key taxa. Isolates were screened for plant growth-promoting rhizobacteria (PGPR) and nematicidal activity, and selected strains were evaluated in planta under pathogen challenge. ResultsMicrobial diversity and community complexity declined with disease severity. Gaiella occulta emerged as a potential biomarker of plant health. From 223 isolates, 45 strains exhibited PGPR and nematicidal traits. Ten were tested in tomato plants, where treatments conferred systemic resistance to Pseudomonas syringae pv tomato without fitness cost. Four strains, primarily Pseudomonas and Bacillus, triggered immune priming, enhanced root development, and three of them were co-isolated from a single asymptomatic plant. ConclusionsOur findings highlight the potential of targeted bacterial consortia to restore microbiome balance and activate immune responses in tomato. These results support the rational design of synthetic microbial communities (SynComs) for sustainable, microbiome-based crop protection.

immunology↗

bioRxiv2022

Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here we report that reducing Ube3a-ATS by antisense oligonucleotides in juvenile or adult maternal Ube3a knockout mice rescues the abnormal electroencephalogram rhythms and sleep disturbance, two prominent clinical features of Angelman syndrome. Importantly, the degree of phenotypic improvement correlates with the increase of Ube3a protein levels. These results indicate that the therapeutic window of genetic therapies for Angelman syndrome is broader than previously thought, and electroencephalogram power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies.

neuroscience↗

bioRxiv2022

Neuroimaging within the Dominantly Inherited Alzheimer's Network (DIAN): PET and MRI

The Dominantly Inherited Alzheimer Network (DIAN) Observational Study is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). This rare form of Alzheimer disease (AD) is caused by mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. As individuals from these families have a 50% chance of inheriting the familial mutation, this provides researchers with a well-matched cohort of carriers vs non-carriers for case-control studies. An important trait of ADAD is that the age at symptom onset is highly predictable and consistent for each specific mutation, allowing researchers to estimate an individuals point in their disease time course prior to symptom onset. Although ADAD represents only a small proportion (approximately 0.1%) of all AD cases, studying this form of AD allows researchers to investigate preclinical AD and the progression of changes that occur within the brain prior to AD symptom onset. Furthermore, the young age at symptom onset (typically 30-60 years) means age-related comorbidities are much less prevalent than in sporadic AD, thereby allowing AD pathophysiology to be studied independent of these confounds. A major goal of the DIAN Observational Study is to create a global resource for AD researchers. To that end, the current manuscript provides an overview of the DIAN magnetic resonance imaging (MRI) and positron emission tomography (PET) protocols and highlights the key imaging results of this study to date.

neuroscience↗

bioRxiv2022

Substrate topology and cognate immunity modulate antibacterial toxicity of Tae cell wall hydrolases

Members of the bacterial T6SS amidase effector (Tae) superfamily of toxins are delivered between competing bacteria to degrade cell wall peptidoglycan. Although Taes share a common substrate, they exhibit distinct antimicrobial potency across different competitor species. To investigate the molecular basis governing these differences, we quantitatively defined the functional determinants of Tae1 from Pseudomonas aeruginosa PAO1 using a combination of nuclear magnetic resonance (NMR) and a high-throughput in vivo genetic approach called deep mutational scanning (DMS). As expected, combined analyses confirmed the role of critical residues near the Tae1 catalytic center. Unexpectedly, DMS revealed substantial contributions to enzymatic activity from a much larger, ring-like functional hot spot extending around the entire circumference of the enzyme. Comparative DMS across distinct growth conditions highlighted how functional contribution of different surfaces is highly context-dependent, varying alongside composition of targeted cell walls. These observations suggest that Tae1 engages with the intact cell wall network through a more distributed three-dimensional interaction interface than previously appreciated, providing an explanation for observed differences in antimicrobial potency across divergent Gram-negative competitors. Further binding studies of several Tae1 variants with their cognate immunity protein demonstrate that requirements to maintain protection from Tae activity may be a significant constraint on the mutational landscape of tae1 toxicity in the wild. In total, our work reveals that Tae diversification has likely been shaped by multiple independent pressures to maintain interactions with binding partners that vary across bacterial species and conditions.

biochemistry↗

bioRxiv2020

Immune factor of bacterial origin protects ticks against host microbial commensals

Hard ticks are blood-feeding arthropods that carry and transmit microbes to their vertebrate hosts1. Tick-borne disease cases have been on the rise over the last several decades, drawing much-needed attention to the molecular interplay between transmitted pathogens and their human hosts. However, far less is known about how ticks control their own microbes, which is critical for understanding how zoonotic transmission cycles persist. We previously found that ticks horizontally acquired an antimicrobial toxin gene from bacteria known as domesticated amidase effector 2 (dae2)2. Here we show that this effector from the tick vector Ixodes scapularis (Dae2Is) has structurally and biochemically diverged from ancestral bacterial representatives, expanding its antibacterial targeting range to include host skin microbes. Disruption of dae2Is increases the burden of skin-associated staphylococci within I. scapularis and adversely affects tick fitness, suggesting resistance of host microbes may be important for the parasitic blood-feeding lifestyle. In contrast, Dae2Is has no intrinsic ability to kill Borrelia burgdorferi, the tick-borne bacterium of Lyme disease. Our observations suggest that ticks have evolved to tolerate their own symbionts while resisting host skin commensals, which we discover are natural opportunistic pathogens of ticks. This work moves our understanding of vector biology beyond a human-centric view: just as tick commensals are pathogenic to humans, so too do our commensals pose a threat to ticks. These observations illuminate how a complex and mirrored set of interkingdom interactions between blood-feeding vectors, their hosts, and associated microbes can ultimately lead to disease.

evolutionary biology↗

bioRxiv2018

Dynamic Prediction During Perception of Everyday Events

The ability to predict what is going to happen in the near future is integral for daily functioning. Previous research suggests that predictability varies over time, with increases in prediction error at those moments that people perceive as boundaries between meaningful events. These moments also tend to be points of rapid change in the environment. Eye tracking provides a method for continuous measurement of prediction as participants watch a movie of an actor performing a series of actions. In two studies, we used eye tracking to study the time course of prediction around event boundaries. In both studies, viewers looked at objects that were about to be touched by the actor shortly before the objects were contacted, demonstrating predictive looking. However, this behavior was modulated by event boundaries: looks to to-be-contacted objects near event boundaries were less likely to be early and more likely to be late, compared to looks to objects contacted within events. This result is consistent with theories proposing that event segmentation results from transient increases in prediction error.\n\nSignificance StatementThe ability to predict what will happen in the near future is integral for adaptive functioning, and although there has been extensive research on predictive processing, the dynamics of prediction at the second by second level during the perception of naturalistic activity has never been explored. The current studies therefore describe results from a novel task, the Predictive Looking at Action Task (PLAT) that can be used to investigate the dynamics of predictive processing. Demonstrating the utility of this task to investigate predictive processing, this task was applied to study the predictions made by Event Segmentation Theory, which suggests that people experience event boundaries at times of change and unpredictability in the environment. The results of these studies are of interest to communities investigating the dynamic comprehension and segmentation of naturalistic events and to communities studying visual perception of naturalistic activity.

neuroscience↗