Biology subjects

Alvarez, A.

Publications and source records attributed to Alvarez, A..

12 recordsLinked to original sources

bioRxiv2026

An Aging Risk-Factor Scale: Biomarkers of Renal Disease and Anemia are Primary Predictors of Three-Year Survival in Common Marmosets (Callithrix jacchus)

Valid animal models are needed to evaluate how age-related changes in kidney function influence healthspan. Aging marmosets frequently develop renal insufficiency with anemia and exhibit reductions in body mass and metabolic rate. However, it remains unclear which age-related changes predict survival and which thresholds indicate increased mortality risk. We prospectively evaluated age, body composition, resting energy expenditure, hematology, and blood chemistry as predictors of 3-year survival in female and male marmosets (n = 66), 2-16 years of age. Objectives were to identify prognostic markers, define high-risk thresholds, and to develop and test a composite risk-factor scale for mortality screening in captivity. A 10-variable model showed the best predictive performance in multivariable Cox proportional hazards modeling, and was retained for further analysis (concordance = 0.881, p < 0.001). ROC curves using Youdens Index and AUC identified high-risk thresholds for predictors in the multivariable model, and threshold-defined categories were evaluated by Kaplan-Meier survival analysis. The 10 binary risk-factors were combined into a composite scale scored from 0 to 10 and tested with Cox regression. The scale explained approximately 42% of variance in survival and each additional risk factor increased mortality risk 1.75-fold (95% CI: 1.43-2.14, p < 0.001). Marmosets with [≥]7 risk factors exhibited a 19-month reduction in survival, and this high-risk threshold predicted 3-year survival with 89.4% accuracy. Results support the scale as a screening tool for mortality risk and highlight the high prevalence of age-associated renal disease and anemia in marmosets.

physiology↗

bioRxiv2026

Coordinated cell and chloroplast growth and its perturbation by chloroplast DNA replication inhibition in green algae

Coordination among cell growth, chloroplast expansion, and organelle genome dynamics is fundamental to algal physiology, yet its regulation remains unclear. We used time-resolved single-cell analyses to examine scaling relationships among cell size, chloroplast volume, nuclear dynamics, and nucleoid organization in Desmodesmus communis and Chlamydomonas reinhardtii under normal conditions and after inhibition of chloroplast DNA replication with nalidixic acid (NAL). Under control conditions, both species showed coordinated scaling among cell, chloroplast, and nuclear size, while nucleoid dynamics were driven mainly by changes in number. NAL disrupted these relationships in a species- and time-dependent manner. In C. reinhardtii, prolonged treatment uncoupled chloroplast and nuclear growth from cell expansion and led to fewer, enlarged nucleoids, consistent with impaired replication. In contrast, D. communis largely maintained coordinated scaling, with effects mainly limited to reduced nucleoid proliferation and delayed division. Temporal analyses indicated that NAL primarily affected nucleoid replication and segregation, with secondary consequences for chloroplast growth and cell-cycle progression. These findings identify chloroplast genome dynamics as a regulatory link between organelle growth and cell division.

cell biology↗

bioRxiv2026

SPPIDER-seq: Sequence-based partner-aware predictor of protein-protein interaction sites

MotivationSequence-based protein-protein interaction (PPI) site predictors typically analyze proteins in isolation, neglecting partner-specific context that is critical for interface specificity, particularly in transient and disordered interactions. ResultsWe introduce SPPIDER-seq, a partner-aware PPI site prediction framework that combines pretrained ESM-2 embeddings with a cross-attention architecture to enable residue-level conditioning on interacting partners. We curated non-redundant protein-peptide interaction datasets from BioLiP and used them to train and benchmark two complementary models: a receptor-centric model optimized for structured interfaces and a peptide-centric model tailored to disordered, motif-driven binding. On blind benchmarks, SPPIDER-seq achieved AUROC values up to 0.797 and MCC values up to 0.269, outperforming AlphaFold3 on peptide-mediated and disordered interfaces while remaining complementary on globular complexes. Application to 341 TP53 interaction partners revealed coherent, partner-specific interface patterns across both structured and intrinsically disordered regions. Availability and ImplementationSPPIDER-seq models, datasets, and the Python code are freely available on the web at: https://github.com/aporollo-lab/SPPIDER-seq and archived on Zenodo at DOI: 10.5281/zenodo.19835990, corresponding to GitHub release v2.0-manuscript. ContactDr. Aleksey Porollo - porollay@ucmail.uc.edu Dr. Jichao Chen - jichao.chen@cchmc.org Supplementary InformationAvailable online with the manuscript.

bioinformatics↗

bioRxiv2025

Phospho-eIF2B-epsilon links stress response-driven translation to amyloidogenesis in Alzheimer's disease

A central etiopathogenic event in Alzheimers disease (AD) is the accumulation of amyloid {beta}-peptide (A{beta}) derived from the amyloidogenic processing of the amyloid precursor protein, a pathway initiated by BACE1. Chronic activation of the Integrated Stress Response is linked to AD, typically through eIF2 phosphorylation, which selectively enhances translation of key stress-responsive mRNAs like ATF4 and BACE1. We investigated a novel regulatory mechanism mediated by Glycogen Synthase Kinase-3{beta} (GSK-3{beta}) a hyperactive kinase in AD, on the translational factor eIF2B, the guanine nucleotide exchange factor (GEF) for eIF2. The methodology combined cellular and molecular biology approaches (western blot, ELISA, immunofluorescence, and luciferase assays) using pharmacological inhibitors and plasmid transfection in established cell models, along with computational structural modeling (AlphaFold3). Findings were validated in post-mortem human brain tissue, with statistical analyses (t-tests and ANOVA) applied throughout. We treated cells (SH-SY5Y) with a GSK-3{beta} inhibitor (NP031112) or overexpressed a constitutively active GSK-3{beta} mutant (GSK-3{beta}-S9A) to modulate GSK-3{beta} activity. GSK-3{beta} inhibition significantly reduced ATF4 and BACE1 protein levels in SH-SY5Y cells in a dose-dependent manner as we tested by western blot (P<0.001), independent of eIF2 phosphorylation. This effect was translational, as the inhibitor still reduced BACE1 levels when transcription was blocked. Crucially, NP031112 reversed stress-induced eIF2B{varepsilon} phosphorylation at Ser540 (P<0.001). Furthermore, H2O2-induced A{beta}1-42 secretion by SH-SY5Y cells was significantly reversed by GSK-3{beta} inhibition (P<0.001). Luciferase reporter assays using the BACE1 5 untranslated region (5 UTR) confirmed that both eIF2B{varepsilon} silencing and a phosphomimetic mutant eIF2B{varepsilon}-S540E increased BACE1 5 UTR-driven translation (P<0.001), demonstrating that reduced functional eIF2B enhances BACE1 translation. Finally, immunohistofluorescence and western blot analysis of human AD hippocampi showed a significant increase in pS540-eIF2B{varepsilon}, ATF4, and BACE1 levels in AD patients compared to non-demented controls (P<0.001 for all three). Our findings establish a novel GSK-3{beta}-eIF2B{varepsilon}-BACE1 axis that links stress response dysregulation to amyloidogenesis, independent of canonical eIF2 phosphorylation. The phosphorylation of eIF2B{varepsilon} functionally mimics the effects of eIF2 phosphorylation by reducing the available functional eIF2B pool, thereby reprogramming translation to favour the production of stress proteins like ATF4 and BACE1. We proposed eIF2B{varepsilon} phosphorylation is a key etiological mechanism in AD.

neuroscience↗

bioRxiv2025

Aging Leads to Altered Physiological Reactivity in Response to Repeated Social Separation Stress in a Nonhuman Primate Model

Social relationships are critical for maintaining physical health and psychological wellbeing. Since nearly 1 in 4 adults aged 65 years or older are socially isolated, there is a strong need to understand how repeated social stress negatively impacts health outcomes. Using a nonhuman primate model of social aging (i.e., marmosets), we examined whether individuals transitioning into old age ("peri-geri") or individuals who were already geriatric ("very-geri") showed differences in measures of hypothalamic-pituitary axis (HPA) activity, markers of metabolic and immune function, and reunion social behavior in response to repeated social separation challenges (SSC). We found female marmosets, especially peri-geri females, had higher HPA reactivity and better HPA recovery than male marmosets, but this difference diminished in older, very-geri marmosets. HPA activity was correlated with multiple outcomes including locomotive behavior and grooming, changes in blood glucose levels, and neutrophil counts. Moreover, marmosets who approached their partner more and were groomed less during reunions had higher cortisol levels the following day. Interestingly, we found two distinct HPA profiles among our marmosets with half showing strong HPA responses (reactors) and the other half showing little or no HPA response (non-reactors). Non-reactors had less weight gain/more weight loss; elevated levels of calcium, phosphorus, and white blood cells; and received less grooming and social contact time during reunion. Overall, old-aged marmosets who show attenuated HPA responses may have different vulnerabilities to negative health and behavioral outcomes during social stress, and male marmosets appear more likely to present with this HPA non-reactor phenotype earlier in aging.

physiology↗

bioRxiv2025

A Pilot Study of Transcranial Magnetic Stimulation and the Right Teaching Parietal Junction

Theory of Mind (ToM) is conceptualized as the ability to infer the thoughts and feelings of others. Many studies have found that ToM abilities play a central role in collaborative communication between adults, with teachers performing more effectively when they have high levels of ToM. One of the main brain regions implicated in ToM is the right temporoparietal junction (rTPJ), which is thought to be responsible for evaluating a persons belief formation process. The current study had participants engage in a Lego model building task consisting of a director who instructed a builder on how to create duplicate models from a prototype that only the director could see. The rTPJ of the director was targeted for excitatory (10 Hz) transcranial magnetic stimulation (TMS) and inhibitory (1 Hz) TMS. There was a trend such that there was a decrease in the amount of time needed and an increase in accuracy between excitatory TMS and sham TMS (the control). The opposite pattern was observed between inhibitory TMS and sham TMS. These results suggest that teaching abilities are likely at least partially dependent on the rTPJ.

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↗

bioRxiv2025

Validation of Body Condition Scoring as a Screening Test for Low Body Condition and Obesity in Common Marmosets (Callithrix jacchus)

Assessing body weight is common practice for monitoring health in common marmosets (Callithrix jacchus). Body composition analysis via quantitative magnetic resonance (QMR) is a more in-depth assessment allowing measurements of lean and fat mass, but it is expensive and remains unavailable to most. Alternatively, body condition scoring (BCS) is an instrument-free method for visually inspecting and palpating lean and fat tissue. Animals are rated for lean and fat mass abundance, using an ordinal scale with species-specific descriptions as reference. However, modified BCS systems developed for other species are being used, because no BCS system has been fully validated for marmosets. The accuracy of BCS in identifying marmosets with poor body condition or obesity remains unknown. We assessed an adapted BCS for marmosets (n=68, 2-16 years). Objectives were to 1) determine whether BCS predicts body weight and body composition, and 2) evaluate the performance of BCS as a screening test for low body condition and obesity in marmosets, in comparison to QMR body composition analysis. BCS predicted body weight and body composition (F(15, 166)=7.51, Wilks {Lambda}=0.240, p<0.001), and was better at predicting low lean mass and obesity, than at predicting low adiposity. Marmosets with low BCS had higher odds of low lean mass (B=3.37, (95% CI, 0.95-5.78), OR=29.0, p=0.006). Marmosets with excessively high BCS had higher odds of obesity (B=2.72, (95% CI, 1.07-4.38), OR=15.23, p=0.001). The accuracy of BCS suggests it can serve as an instrument-free method to screen for low body condition (79.4%-91.2%) and obesity (77.9%) in marmosets. Research highlightsO_LIWe evaluated body condition scoring (BCS) as a screening tool for detecting low body condition and obesity in marmosets by comparing it to diagnoses based on quantitative magnetic resonance, the gold-standard method for body composition analysis. C_LIO_LIBCS was more accurate at detecting low lean mass and obesity than low adiposity, with marmosets having low BCS showing higher odds of low lean mass and those with excessively high BCS having higher odds of obesity. C_LIO_LIResults suggest that BCS can serve as an instrument-free method to screen for low body condition and obesity in marmosets, enabling early detection of health decline and guiding the need for further diagnostic testing and treatment. C_LI

physiology↗

bioRxiv2024

Long-term effects of psilocybin on dynamic and effectivity connectivity of fronto-striatal-thalamic circuits

Psilocybin has been shown to induce fast and sustained improvements in mental well-being across various populations, yet its long-term mechanisms of action are not fully understood. Initial evidence suggests that longitudinal functional and structural brain changes implicate fronto-striatal-thalamic (FST) circuitry, a broad system involved in goal-directed behavior and motivational states. Here, we apply empirical methods and computational modeling to resting-state fMRI data from a within-subject longitudinal psilocybin trial in psychedelic-naive healthy volunteers. We first show increases in FST dynamic activity four weeks after a full dose of psilocybin. We then proceed to mechanistically account for these increased dynamics, by showing that reduced structural constraints underlie increased FST dynamic activity post psilocybin. Further, we show that these reduced structural constraints come along with increased bottom-up and reduced top-down modulation of FST circuits. While cortical reductions in top-down modulation are linked to regional 5-HT2A receptor availability, increased information outflow via subcortical and limbic regions relate to local D2 receptor availability. Together, these findings show that increased FST flexibility weeks after psilocybin administration is linked to serotonergic-mediated decreases in top-down information flow and dopaminergic-mediated increases in bottom-up information flow. This long-term functional re-organization of FST circuits may represent a common mechanism underling the potential clinical efficacy of psilocybin across various neuropsychiatric disorders including substance abuse, major depression, and anorexia. Significance StatementFronto-striatal-thalamic systems, which underlie motivation and reward, go through profound functional and structural changes following psilocybin administration. We leveraged longitudinal fMRI data from a within-subject psilocybin trial in psychedelic-naive healthy participants to show that psilocybin increases fronto-striatal-thalamic dynamic activity as well as flexibility four weeks after dosing. Computational modeling revealed that this increased flexibility is mechanistically caused by reduced structural constraints on functional dynamics. Further long-term changes included increased bottom-up and reduced top-down information flow mediated by the serotonergic and dopaminergic systems. This long-term functional re-organization of fronto-striatal-thalamic circuits may reflect a common mechanism underlying clinical symptoms improvements across diagnostic groups, such as increased openness, improved well-being, and reductions in anhedonia, apathy, and substance craving.

neuroscience↗

bioRxiv2024

Dickeya ananae sp. nov., pectinolytic bacterium isolated from pineapple (Ananas comosus)

Recently, species clustering within Dickeya zeae has been identified as complex, encompassing validly published names, including D. oryzae and D. parazeae, with some strains potentially delineating new species. In this study, genomes of strains isolated from a bacterial heart rot outbreak in pineapple (Ananas comosus var. comosus) on Oahu, Hawaii, along with two strains from pineapple in Malaysia, were sequenced. Orthologous average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values among the sequenced genomes ranged from 98.93-99.9% and 91.8-99.9%, respectively, supporting the classification of seven strains within the same species. Comparisons of ANI and dDDH values between these seven strains and type strains of D. zeae, D. parazeae, and D. oryzae ranged from 94.4-95.9% and 57.2-66.5%, respectively. These values fall below the proposed boundaries for new species designation, supporting the delineation of a novel species. Phylogenetic analyses, including 16S rRNA, gapA, multi-locus sequence analysis (MLSA) of 10 housekeeping genes, whole-genome, and pangenome analyses, were concordant and revealed a distinct monophyletic clade, separating these strains from other members of the D. zeae complex, with D. oryzae as the closest relative. Notably, a nitrogen fixation gene cluster comprising 28 genes, similar to the Klebsiella spp. nitrogenase gene cluster, was found in the genome of the seven pineapple strains. Based on polyphasic approaches, including ANI, dDDH, biochemical, physiological, and phylogenomic analyses, we propose the reclassification in a new species of the five pineapple strains from Hawaii A5391, A5410T, A5611, A6136, and A6137, together with the two pineapple strains from Malaysia CFBP 1272 and CFBP 1278, previously classified as D. zeae. We propose the name Dickeya ananae sp. nov. for this taxon, represented by the type strain A5410T (= ICMP 25020T = LMG 33197T).

microbiology↗

bioRxiv2023

Plasticity in the functional properties of NMDA receptors improves motor circuit performance during severe energy stress

Brain energy stress leads to neuronal hyperexcitability followed by a rapid loss of function and cell death. In contrast, the frog brainstem switches into a state of extreme metabolic resilience that allows them to maintain motor function during hypoxia as they emerge from hibernation. NMDA receptors (NMDARs) are Ca2+-permeable glutamate receptors that contribute to the loss of homeostasis during hypoxia. Therefore, we hypothesized that hibernation leads to plasticity that reduces the role of NMDARs within neural networks to improve function during energy stress. To test this, we assessed a circuit with a large involvement of NMDAR synapses, the brainstem respiratory network of female bullfrogs, Lithobates catesbeianus. Contrary to our expectations, hibernation did not alter the role of NMDARs in generating network output, nor did it affect the amplitude, kinetics, and hypoxia sensitivity of NMDAR currents. Instead, hibernation strongly reduced NMDAR Ca2+ permeability and enhanced desensitization during repetitive stimulation. Under severe hypoxia, the normal NMDAR profile caused network hyperexcitability within minutes, which was mitigated by blocking NMDARs. After hibernation, the modified complement of NMDARs protected against hyperexcitability, as disordered output did not occur for at least one hour in hypoxia. These findings uncover state-dependence in the plasticity of NMDARs, whereby multiple changes to receptor function improve neural performance during energy stress without interfering with its normal role during healthy activity. Significance StatementNeural circuits lose homeostasis during severe energy stress, and NMDA-glutamate receptors play a major role in this response. In contrast, frogs have the remarkable capacity to use plasticity that improves circuit function from minutes to hours during hypoxia, likely as an adaptation to survive emergence from hibernation. We found this occurs, in part, through modification of NMDA receptors that renders them less permeable to Ca2+ and more likely to desensitize during high activity states. These NMDA receptor modifications do not influence normal network function but protect against hyperexcitability caused by hypoxia. This work points to endogenous plasticity mechanisms that improve network function during energy stress without altering circuit function when the brain is well-oxygenated.

neuroscience↗

bioRxiv2019

Benchmarking Single-Cell RNA Sequencing Protocols for Cell Atlas Projects

Single-cell RNA sequencing (scRNA-seq) is the leading technique for charting the molecular properties of individual cells. The latest methods are scalable to thousands of cells, enabling in-depth characterization of sample composition without prior knowledge. However, there are important differences between scRNA-seq techniques, and it remains unclear which are the most suitable protocols for drawing cell atlases of tissues, organs and organisms. We have generated benchmark datasets to systematically evaluate techniques in terms of their power to comprehensively describe cell types and states. We performed a multi-center study comparing 13 commonly used single-cell and single-nucleus RNA-seq protocols using a highly heterogeneous reference sample resource. Comparative and integrative analysis at cell type and state level revealed marked differences in protocol performance, highlighting a series of key features for cell atlas projects. These should be considered when defining guidelines and standards for international consortia, such as the Human Cell Atlas project.

genomics↗