Biology subjects

Guerra, M.

Publications and source records attributed to Guerra, M..

6 recordsLinked to original sources

bioRxiv2026

Early developmental placental defects and pregnancy loss in lupus mice expressing human TLR8

Anti-phospholipid (APL) autoantibodies confer a high risk for adverse pregnancy outcomes, especially in Systemic Lupus Erythematosus (SLE). While human TLR8 (huTLR8) has been implicated in APL antibody-mediated placental injury in vitro, its in vivo role in pregnancy is unexplored. We report a novel mouse model of pregnancy loss in SLE-prone mice expressing huTLR8. Placental analysis revealed early developmental defects starting post-implantation, including a thin junctional zone, impaired vascularization, infarcts, and inflammation. Profound immune dysregulation was evident at E8.5 including increased myeloid cells and CD8 T cells and decreased uterine natural killer (uNK) cells. RNA sequencing revealed downregulated pregnancy-specific glycoproteins, reduced uNK cell-associated genes, and an upregulated myeloid cell signature. Bone marrow chimera studies demonstrated preferential activation of huTLR8-expressing placental Ly6C+ monocytes. Spatial transcriptomics at E9.5 confirmed uNK cell loss, decreased IL15 expression by both stromal and myeloid cells, and discrete inflammatory aggregates in the maternal layers containing myeloid cells and IFN{gamma}-expressing CD8 T cells. We propose that huTLR8, likely through myeloid cell activation and cytolytic T cell recruitment, drives placental injury in the context of SLE and APL autoantibodies. This model provides a valuable platform to dissect early pathogenic events in APL-associated pregnancy loss and identify new therapeutic targets.

immunology↗

bioRxiv2025

A T-cell Intrinsic Role for APOL1 Risk Alleles in Allograft Rejection

African Americans have an increased risk of kidney disease due to exonic variants in Apolipoprotein-L1 (G1 and G2). These prevalent variants have also been linked with kidney rejection, but outside of association with African ancestry, underpinning causal mechanisms are unknown. We investigated T-cell function using transgenic mice with physiologic expression of wild type (G0-), G1-, or G2-APOL1. Mice with variant APOL1 showed greater CD8+T-cell activation with expansion of a central memory (TCM) subset. Stimulated G1-CD8+T-cells showed enhanced proliferation and cytokine production, which reversed with APOL1 inhibition. In MHC-mismatched cardiac transplants, G1-mice demonstrated greater CD8+T-cell infiltration and reduced survival. Bulk transcriptome of G1-CD8+T-cells, and single-cell transcriptome of graft infiltrating TCMs, showed enrichment of canonical T-cell receptor (TCR) pathways including Ca2+-signaling. G1-CD8+T-cells demonstrated baseline ER-Ca2+ depletion followed by sustained increases in cytosolic-Ca2+ upon TCR stimulation. G1-CD8+T-cells were more sensitive to Ca2+ chelation, or store-operated Ca2+ entry inhibition, and relatively resistant to calcineurin antagonism vs. G0-CD8+T-cells. Analogously, in a kidney transplant cohort, APOL1-variant recipients developed rejection when they had elevated peripheral TCMs before transplantation and despite significantly higher tacrolimus levels vs G0/G0-AAs with rejection. In summary, we unravel an excitatory T-cell intrinsic mechanism for APOL1 exonic variants, causally linking them with kidney rejection.

immunology↗

bioRxiv2024

Polymer-tethered quenched fluorescent probes for enhanced imaging of tumor associated proteases

Fluorescence-based contrast agents enable real-time detection of solid tumors and their neovasculature, making them ideal for use in image-guided surgery. Several agents have entered late-stage clinical trials or secured FDA approval, suggesting they are likely to become standard of care in cancer surgeries. One of the key parameters to optimize in contrast agent is molecular size, which dictates much of the pharmacokinetic and pharmacodynamic properties of the agent. Here, we describe the development of a class of protease-activated quenched fluorescent probes in which a N-(2-hydroxypropyl)methacrylamide copolymer is used as the primary scaffold. This copolymer core provides a high degree of probe modularity to generate structures that cannot be achieved with small molecules and peptide probes. We used a previously validated cathepsin substrate and evaluated the effects of length and type of linker as well as positioning of the fluorophore/quencher pair on the polymer core. We found that the polymeric probes could be optimized to achieve increased over-all signal and tumor-to-background ratios compared to the reference small molecule probe. Our results also revealed multiple structure-activity relationship trends that can be used to design and optimize future optical imaging probes. Furthermore, they confirm that a hydrophilic polymer is an ideal scaffold for use in optical imaging contrast probes, allowing a highly modular design that enables efficient optimization to maximize probe accumulation and overall biodistribution properties.

bioengineering↗

bioRxiv2017

Diabetes and dementia incidence in Latin America; a 10/66 population-based cohort study

BackgroundDiabetes prevalence is already high in middle income countries, particularly among older people. Current evidence on diabetes as a risk factor for dementia is limited to cohort studies in high income countries. Few studies carried out fasting glucose assessments to identify undiagnosed cases, and assess diabetes control. We aimed to determine the association between both diagnosed diabetes and total diabetes (including undiagnosed cases) and incident dementia, examining also the impact of glycaemic control on dementia risk.\n\nMethodsPopulation-based cohort studies of those aged 65 years and over in sites in Cuba, Dominican Republic, Puerto Rico, Peru, Venezuela, and Mexico. Diagnosed diabetes was assessed through self-reported diagnosis, and undiagnosed diabetes through fasting blood samples (glucose >= 7mmol/L). Blood pressure, smoking, underactivity and waist circumference were assessed from questionnaires and physical examination. Incident 10/66 dementia (and subtypes), and mortality, were ascertained three to five years later.\n\nResults12,297 interviews were completed at baseline, with 80-95% responding by site. The at risk cohort comprised 10,945 dementia-free individuals, of whom 8,171 (75%) provided blood samples. Mean age varied from 72.0 to 75.1 years by site. Total diabetes prevalence was 43.5% in Puerto Rico, ranging from 11.5% to 27.0% in other sites. Most diabetes cases (50.2% to 68.4%) were not controlled (fasting glucose >7.0 mmol/L). 7,000 participants were followed up for 26,423 person-years with 659 incident dementia cases, and 905 dementia free deaths. Total diabetes was associated with incident 10/66 dementia (pooled meta-analysed adjusted sub-hazard ratio [pASHR] 1.25, 95% CI, 1.05-1.49, I2=48.6%), with a stronger association for uncontrolled (pASHR 1.47, 95% CI 1.19-1.81, I2=49.6%) than controlled cases (pASHR 1.29, 95% CI 0.95-1.74, I2=13.3%). Total diabetes was strongly associated with the incidence of vascular dementia (pASHR 2.25, 95% CI 1.24-4.08, I2=23.7%), but not Alzheimers Disease (pASHR 0.99, 95% CI 0.70-1.42, I2=49.0%).\n\nConclusionsDiabetes, particularly when poorly controlled, may increase dementia risk. There is considerable scope for improved detection and control of diabetes among older people in these settings, and hence an opportunity to carry out proof of concept prevention trials. Overlapping epidemics of these age dependent disorders will challenge poorly-resourced health systems in the future.

epidemiology↗

bioRxiv2017

Leg Length, Skull Circumference, And The Incidence Of Dementia In Latin America And China; A 10/66 Population-Based Cohort Study

BackgroundAdult leg length is influenced by nutrition in the first few years of life. Adult head circumference is an indicator of brain growth. Cross-sectional studies indicate inverse associations with dementia risk, but there have been few prospective studies.\n\nMethodsPopulation-based cohort studies in urban sites in Cuba, Dominican Republic Puerto Rico and Venezuela, and rural and urban sites in Peru, Mexico and China. Sociodemographic and risk factor questionnaires were administered to all participants, and anthropometric measures taken, with ascertainment of incident 10/66 dementia, and mortality, three to five years later.\n\nResultsOf the original at risk cohort of 13,587 persons aged 65 years and over, 2,443 (18.0%) were lost to follow-up; 10,540 persons with skull circumference assessments were followed up for 40,466 person years, and 10,400 with leg length assessments were followed up for 39,954 person years. There were 1,009 cases of incident dementia, and 1,605 dementia free deaths. The fixed effect pooled meta-analysed adjusted subhazard ratio (ASHR) for leg length (highest vs. lowest quarter) was 0.80 (95% CI, 0.66-0.97) and for skull circumference was 1.02 (95% CI, 0.84-1.25), with no heterogeneity of effect between sites (I2=0%). Leg length measurements tended to be shorter at follow-up, particularly for those with baseline cognitive impairment and dementia. However, leg length change was not associated with dementia incidence (ASHR, per cm 1.006, 95% CI 0.992-1.020), and the effect of leg length was little altered after adjusting for baseline frailty (ASHT 0.82, 95% CI 0.67-0.99). A priori hypotheses regarding effect modification by gender or educational level were not supported.\n\nConclusionsConsistent findings across settings provide quite strong support for an association between adult leg length and dementia incidence in late-life. Leg length is a relatively stable marker of early life nutritional programming, which may confer brain reserve and protect against neurodegeneration in later life through mitigation of cardiometabolic risk. Further clarification of these associations could inform predictive models for future dementia incidence in the context of secular trends in adult height, and invigorate global efforts to improve childhood nutrition, growth and development.

epidemiology↗

bioRxiv2017

Reproductive Period, Endogenous Estrogen Exposure And Dementia Incidence Among Women In Latin America And China; A 10/66 Population-Based Cohort Study

BackgroundExposure to endogenous estrogen may protect against dementia, but evidence remains equivocal. Such effects may be assessed more precisely in settings where exogenous estrogen administration is rare. We aimed to determine whether reproductive period (menarche to menopause), and other indicators of endogenous estrogen exposure are inversely associated with dementia incidence\n\nMethodsPopulation-based cohort studies, of women aged 65 years and over in urban sites in Cuba, Dominican Republic Puerto Rico and Venezuela, and rural and urban sites in Peru, Mexico and China. Sociodemographic and risk factor questionnaires were administered to all participants, including ages at menarche, birth of first child, and menopause, and parity, with ascertainment of incident 10/66 dementia, and mortality, three to five years later.\n\nResults9,428 women participated in the baseline phase, with response rates of 72-98% by site. The at risk cohort comprised 8,466 dementia-free women. Mean age at baseline varied from 72.0 to 75.4 years, lower in rural than urban sites and in China than in Latin America. Mean parity was 4.1, generally higher in rural than urban sites and ranging from 2.4-7.2 by site. 6,854 women with baseline reproductive period data were followed up for 26,463 person years. There were 692 cases of incident dementia, and 895 dementia free deaths. Pooled meta-analysed fixed effects, per year, for reproductive period (Adjusted Sub-Hazard Ratio [ASHR] 1.001, 95% CI 0.988-1.015) did not support any association with dementia incidence, with no evidence also for any interaction between APOE genotype and reproductive period (ASHR 0.993, 95% CI 0.947-1.041, I2=39.3%). Similarly no association was observed between incident dementia and; ages at menarche, birth of first child, and menopause: nulliparity; or index of cumulative endogenous estrogen exposure. Greater parity was positively associated with incident dementia (ASHR 1.030, 95% CI 1.002-1.059, I2=0.0%).\n\nConclusionsWe found no evidence to support the theory that natural variation in cumulative exposure to endogenous oestrogens across the reproductive period influences the incidence of dementia in late life.

epidemiology↗