Multiple Biological Systems Research Articles

Heat stress alters the ovarian proteome in pre-pubertal gilts.

Heat stress (HS) occurs when exogenous and metabolic heat accumulation exceeds heat dissipation; a thermal imbalance that compromises female reproduction. This study investigated the hypothesis that HS alters the ovarian proteome and negatively impacts proteins engaged with insulin signaling, inflammation, and ovarian function. Prepubertal gilts (n = 19) were assigned to one of three environmental groups: thermoneutral with ad libitum feed intake (TN; n = 6), thermoneutral pair-fed (PF; n = 6), or heat stress (HS; n = 7). For 7 d, HS gilts were exposed to 12-hour cyclic temperatures of 35.0 ± 0.2°C and 32.2 ± 0.1°C, while TN and PF gilts were housed at 21.0 ± 0.1°C. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on ovarian protein homogenates. Relative to TN gilts, 178 proteins were altered (P ≤ 0.05, log2foldchange ≥ 1) by HS, with 76 increased and 102 decreased. STRING gene ontology classified and identified 45 biological processes including those associated with chaperone protein refolding, cytoplasmic translational initiation, and immune activation; with a protein-protein interaction web network of 158 nodes and 563 edges connected based on protein function (FDR ≤ 0.05). Relative to PF, HS altered 330 proteins (P ≤ 0.05, log2foldchange ≥ 1), with 151 increased and 179 decreased. Fifty-seven biological pathways associated with protein function and assembly, RNA processing, and metabolic processes were identified, with a protein-protein interaction network of 303 nodes and 1606 edges. Comparing HS with both the TN and PF treatments, 72 ovarian proteins were consistently altered by HS with 68 nodes and 104 edges, with biological pathways associated with translation and gene expression. This indicates that HS alters the ovarian proteome and multiple biological pathways and systems in prepubertal gilts; changes that potentially contribute to female infertility.

An easy to use tool for the analysis of subcellular mRNA transcript colocalisation in smFISH data

Single molecule fluorescence in situ hybridisation (smFISH) has become a valuable tool to investigate the mRNA expression of single cells. However, it requires a considerable amount of programming expertise to use currently available open-source analytical software packages to extract and analyse quantitative data about transcript expression. Here, we present FISHtoFigure, a new software tool developed specifically for the analysis of mRNA abundance and co-expression in QuPath-quantified, multi-labelled smFISH data. FISHtoFigure facilitates the automated spatial analysis of transcripts of interest, allowing users to analyse populations of cells positive for specific combinations of mRNA targets without the need for computational image analysis expertise. As a proof of concept and to demonstrate the capabilities of this new research tool, we have validated FISHtoFigure in multiple biological systems. We used FISHtoFigure to identify an upregulation in the expression of Cd4 by T-cells in the spleens of mice infected with influenza A virus, before analysing more complex data showing crosstalk between microglia and regulatory B-cells in the brains of mice infected with Trypanosoma brucei brucei. These analyses demonstrate the ease of analysing cell expression profiles using FISHtoFigure and the value of this new tool in the field of smFISH data analysis.

Universal recording of immune cell interactions in vivo.

Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function1. To study these 'kiss-and-run' interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts)2, an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4+ T helper cells and antigen-presenting cells, however. Here we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8+ T cells by dendritic cells, reveal the steady-state cellular partners of regulatory T cells and identify germinal centre-resident T follicular helper cells on the basis of their ability to interact cognately with germinal centre B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalogue of the immune populations that physically interact with intestinal epithelial cells at the steady state and profile the evolution of the interactome of lymphocytic choriomeningitis virus-specific CD8+ T cells in multiple organs following systemic infection. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems.

Minimalist Tetrazine N-Acetyl Muramic Acid Probes for Rapid and Efficient Labeling of Commensal and Pathogenic Peptidoglycans in Living Bacterial Culture and During Macrophage Invasion.

N-Acetyl muramic acid (NAM) probes containing alkyne or azide groups are commonly used to investigate aspects of cell wall synthesis because of their small size and ability to incorporate into bacterial peptidoglycan (PG). However, copper-catalyzed alkyne-azide cycloaddition (CuAAC) reactions are not compatible with live cells, and strain-promoted alkyne-azide cycloaddition (SPAAC) reaction rates are modest and, therefore, not as desirable for tracking the temporal alterations of bacterial cell growth, remodeling, and division. Alternatively, the tetrazine-trans-cyclooctene ligation (Tz-TCO), which is the fastest known bioorthogonal reaction and not cytotoxic, allows for rapid live-cell labeling of PG at biologically relevant time scales and concentrations. Previous work to increase reaction kinetics on the PG surface by using tetrazine probes was limited because of low incorporation of the probe. Described here are new approaches to construct a minimalist tetrazine (Tz)-NAM probe utilizing recent advancements in asymmetric tetrazine synthesis. This minimalist Tz-NAM probe was successfully incorporated into pathogenic and commensal bacterial PG where fixed and rapid live-cell, no-wash labeling was successful in both free bacterial cultures and in coculture with human macrophages. Overall, this probe allows for expeditious labeling of bacterial PG, thereby making it an exceptional tool for monitoring PG biosynthesis for the development of new antibiotic screens. The versatility and selectivity of this probe will allow for real-time interrogation of the interactions of bacterial pathogens in a human host and will serve a broader utility for studying glycans in multiple complex biological systems.

Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel therapeutic class for treating anemia in patients with chronic kidney disease. Small molecule analogs of α-ketoglutarate (AKG), an essential substrate for 2-oxoglutarate-dependent dioxygenases (2-OGDDs), including prolyl hydroxylase domain proteins (PHDs), inhibit PHDs pharmacologically and thereby prevent HIF degradation. HIF stabilization alleviates anemia through several stimulatory effects on erythropoiesis, but it also affects the expression of many anemia-unrelated genes whose protein products exert important functions in vivo. Therefore, the pleiotropic effects of HIF stabilization under normoxic conditions deserve to be examined in more detail. Specifically, we believe that particular attention should be given to epigenetic modifications among the various AKG-based metabolic systems that may be altered by HIF-PHIs. It is noteworthy that AKG has been reported to exert health-protective actions. AKG-based metabolic systems include enzymes associated with the tricarboxylic acid cycle and amino acid metabolism, as well as 2-OGDD-mediated processes, which play important roles in many biological reactions. In this review, we examine the multifaceted effects of HIF-PHIs, encompassing not only their on-target effect of HIF stabilization but also their off-target inhibitory effects on various AKG-based metabolic systems. Furthermore, we examine its potential relevance to cardiovascular complications, based on clinical and animal studies suggesting its involvement in vascular calcification, thrombogenesis and heart failure. In conclusion, although HIF-PHIs offer a promising avenue for anemia treatment in CKD patients, their broader impact on multiple biological systems raises substantial concerns. The intricate interplay between HIF stabilization, AKG competition and cardiovascular complications warrants extensive, long-term investigations to ensure the safety and usefulness of HIF-PHIs in clinical practice.

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy.

Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood-brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review.

The proteomic fingerprint in infants with single ventricle heart disease in the interstage period: evidence of chronic inflammation and widespread activation of biological networks.

Children with single ventricle heart disease (SVHD) experience significant morbidity across systems and time, with 70% of patients experiencing acute kidney injury, 33% neurodevelopmental impairment, 14% growth failure, and 5.5% of patients suffering necrotizing enterocolitis. Proteomics is a method to identify new biomarkers and mechanisms of injury in complex physiologic states. Infants with SVHD in the interstage period were compared to similar-age healthy controls. Serum samples were collected, stored at -80°C, and run on a panel of 1,500 proteins in single batch analysis (Somalogic Inc., CO). Partial Least Squares-Discriminant Analysis (PLS-DA) was used to compare the proteomic profile of cases and controls and t-tests to detect differences in individual proteins (FDR <0.05). Protein network analysis with functional enrichment was performed in STRING and Cytoscape. PLS-DA readily discriminated between SVHD cases (n = 33) and controls (n = 24) based on their proteomic pattern alone (Accuracy = 0.96, R2 = 0.97, Q2 = 0.80). 568 proteins differed between groups (FDR <0.05). We identified 25 up-regulated functional clusters and 13 down-regulated. Active biological systems fell into six key groups: angiogenesis and cell proliferation/turnover, immune system activation and inflammation, altered metabolism, neural development, gastrointestinal system, and cardiac physiology and development. We report a clear differentiation in the circulating proteome of patients with SVHD and healthy controls with >500 circulating proteins distinguishing the groups. These proteomic data identify widespread protein dysregulation across multiple biologic systems with promising biological plausibility as drivers of SVHD morbidity.

180 Differences in Gene Expression in Granulosa Cells Harvested from Fertile and Sub-Fertile Beef Heifers

Abstract Infertility in beef replacement heifers is one of the leading contributors to economic losses in the cow-calf sector of the beef production industry. Successful reproduction is complex, involving multiple tissues and biological systems. This complexity makes identifying the leading causes of subfertility difficult. One potential source of fertility issues is poor oocyte health. As developing oocytes are dependent on granulosa cells (GCs) and physically coupled with GCs, we hypothesized that the gene expression profile would be different between the GCs from fertile heifers and those from sub-fertile heifers. The objective of this study was to identify differences in gene expression in GCs collected from beef heifers of differing fertility status, either fertile or sub-fertile. To gather this information, Angus-Simmental crossbred heifers underwent an estrus synchronization and fixed-time artificial insemination (AI) protocol (7-Day CO-synch + CIDR). At 41 days post-AI, heifers were pregnancy checked through ultrasound and palpation. Heifers pregnant to AI were classified as fertile (n = 8). Any heifers that remained non-pregnant following AI were exposed to bulls of proven fertility for 61 days. Bull-exposed heifers were evaluated for pregnancy 34 days after the bulls were removed. The non-pregnant heifers following both AI and natural service were classified as sub-fertile (n = 5). Pregnancies were terminated in fertile heifers, and heifers from both groups were allowed to resume normal cyclicity before GCs being harvested. RNA was extracted from GCs and quality was checked for each sample. Total RNA from GCs of 13 heifers was subjected to the library preparation and sequencing on the Nova-Seq platform. Through the application of DESeq2, 79 genes were identified as significantly differentially expressed genes (DEGs) with P-value &amp;lt; 0.05 and absolute (log2 fold change) &amp;gt; 0.5 including DNER, HOXD10, CD52, CXCL12, and HOXD11. DEGs, along with co-expressed genes, were over-represented in pathways associated with the regulation of MAP kinase activity, regulation of serine/threonine kinase activity, MHC protein binding, and plasma membrane signaling receptor complex. Through the pursuit of knowledge regarding the function of top DEGs, increased sample size, and more diverse sample collection time points, we may improve our understanding of the causation of heifer fertility issues. Improving our knowledge of heifer infertility has the potential to develop therapeutic options, and in turn, increase the efficiency and sustainability of cow-calf production systems.

The Gut Microbiota - Brain Axis: Potential Mechanism of Drug Addiction.

As a chronic encephalopathy, drug addiction is responsible for millions of deaths per year around the world. The gut microbiome is a crucial component of the human microbiome. Through dynamic bidirectional communication along the 'gut-brain axis,' gut bacteria cooperate with their hosts to regulate the development and function of the immune, metabolic, and nervous systems. These processes may affect human health because some brain diseases are related to the composition of gut bacteria, and disruptions in microbial communities have been implicated in neurological disorders. We review the compositional and functional diversity of the gut microbiome in drug addiction. We discuss intricate and crucial connections between the gut microbiota and the brain involving multiple biological systems and possible contributions by the gut microbiota to neurological disorders. Finally, the treatment of probiotics and fecal transplantation was summarized. This was done to further understand the role of intestinal microecology in the pathogenesis of drug addiction and to explore new methods for the treatment of drug addiction.

The gut microbiota-brain axis in neurological disorder.

The gut microbiota (GM) plays an important role in the physiology and pathology of the host. Microbiota communicate with different organs of the organism by synthesizing hormones and regulating body activity. The interaction of the central nervous system (CNS) and gut signaling pathways includes chemical, neural immune and endocrine routes. Alteration or dysbiosis in the gut microbiota leads to different gastrointestinal tract disorders that ultimately impact host physiology because of the abnormal microbial metabolites that stimulate and trigger different physiologic reactions in the host body. Intestinal dysbiosis leads to a change in the bidirectional relationship between the CNS and GM, which is linked to the pathogenesis of neurodevelopmental and neurological disorders. Increasing preclinical and clinical studies/evidence indicate that gut microbes are a possible susceptibility factor for the progression of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and autism spectrum disorder (ASD). In this review, we discuss the crucial connection between the gut microbiota and the central nervous system, the signaling pathways of multiple biological systems and the contribution of gut microbiota-related neurological disorders.

Associations of prenatal and childhood Pb exposure with allostatic load in adolescence: Findings from the ELEMENT cohort study

The biological pathways which link lead (Pb) and long-term outcomes are unclear, though rodent models and a few human studies suggest Pb may alter the body's stress response systems, which over time, can elicit dysregulated stress responses with cumulative impacts. This study examined associations between prenatal and early childhood Pb exposure and adolescent allostatic load, an index of an individual's body burden of stress in multiple biological systems, and further examined sex-based associations. Among 391 (51% male) participants in the ELEMENT birth cohort, we related trimester-specific maternal blood Pb, 1-month postpartum maternal tibia and patella Pb, and child blood Pb at 12–24 months to an allostatic load index in adolescence comprised of biomarkers of cardiovascular, metabolic, neuroendocrine, and immune function. The results were overall mixed, with prenatal exposure, particularly maternal bone Pb, being positively associated with allostatic load, and early childhood Pb showing mixed results for males and females. In adjusted Poisson regression models, 1 mcg/g increase in tibia Pb was associated with a 1% change in expected allostatic load (IRR = 1.01; 95%CI 0.99, 1.02). We found a significant Pb × sex interaction (IRR = 1.05; 95%CI 1.01, 1.10); where males saw an increasing percent change in allostatic load as 12 month Pb levels increased compared to females who saw a decreasing allostatic load. Further examination of allostatic load will facilitate the determination of potential mechanistic pathways between developmental toxicant exposures and later-in-life cardiometabolic outcomes.

Black Mothers' Concern for Their Children as a Measure of Vicarious Racism-Related Vigilance and Allostatic Load.

This study investigates the relationship between allostatic load and a novel form of altruistic racism-related fear, or concern for how racism might harm another, which we term vicarious racism-related vigilance. Using a subsample of Black mothers from the African American Women's Heart & Health Study (N = 140), which includes detailed health and survey data on a community sample of Black women in the San Francisco Bay Area, this study investigates the relationship between Black mothers' experiences with racism-related vigilance as it relates to their children and allostatic load-a multisystem metric of underlying health across multiple biological systems. Findings indicate that vicarious racism-related vigilance was positively associated with allostatic load (i.e., worse health). Findings highlight the salience of vicarious racism-related vigilance for the health of Black mothers, underscoring how intersections between race, gender, and parenthood result in susceptibility to unique forms of health-harming stress.

Malnourished Microbes: Host-Microbiome Interactions in Child Undernutrition.

Childhood undernutrition is a major global health burden that is only partially resolved by nutritional interventions. Both chronic and acute forms of child undernutrition are characterized by derangements in multiple biological systems including metabolism, immunity, and endocrine systems. A growing body of evidence supports a role of the gut microbiome in mediating these pathways influencing early life growth. Observational studies report alterations in the gut microbiome of undernourished children, while preclinical studies suggest that this can trigger intestinal enteropathy, alter host metabolism, and disrupt immune-mediated resistance against enteropathogens, each of which contribute to poor early life growth. Here, we compile evidence from preclinical and clinical studies and describe the emerging pathophysiological pathways by which the early life gut microbiome influences host metabolism, immunity, intestinal function, endocrine regulation, and other pathways contributing to child undernutrition. We discuss emerging microbiome-directed therapies and consider future research directions to identify and target microbiome-sensitive pathways in child undernutrition.

Joint representation: Modeling a phenomenon with multiple biological systems

Biologists often study particular biological systems as models of a phenomenon of interest even if they already know that the phenomenon is produced by diverse mechanisms and hence none of those systems alone can sufficiently represent it. To understand this modeling practice, the present paper provides an account of how multiple model systems can be used to study a phenomenon that is produced by diverse mechanisms. Even if generalizability of results from a single model system is significantly limited, generalizations concerning specific aspects of mechanisms often hold across certain ranges of biological systems, which enables multiple model systems to jointly represent such a phenomenon. Comparing mechanisms that operate in different biological systems as examples of the same phenomenon also facilitates characterization and investigation of individual mechanisms. I also compare my account with two existing accounts of the use of multiple model systems and argue that my account is distinct from and complementary to them.

Building a coordinated response to prevent and respond to Adverse Childhood Experiences (ACEs) in Europe: The Tutor of Resilience program

Over the last decades, EU institutions have pushed Member States towards substantial review of National child protection systems along the interdisciplinary and multi-agency collaboration between key actors in the child protection system and the capacity building of professionals on effective actions to prevent, identify and respond to violence against children. Resilience is the process of multiple biological, psychological, social, and ecological systems interacting in ways that help individuals to regain, sustain, or improve their mental wellbeing when challenged by one or more risk factors. Based on these assumptions, the Tutor of Resilience (ToR) training program was delivered within the European program against child maltreatment "PEARLS for Children", to build up a multisectoral network of professionals - medical care practitioners, educators, social services providers and police officers - trained to build resilience in children and families dealing with the critical developmental milestones for the onset of adverse childhood experiences (ACEs), in Italy, Lithuania, and Poland. The ToR included 6 phases: needs assessment to identify each professional category's educational gaps in ACEs; the ToR initial training and the action plan design based on the resilience-enabling principles delivered during the training; the ToR program implementation professionals conduct on the field; the follow-up after 5/6 months of program implementation, followed by a set of cascade trainings based on the ToR model, delivered by the 70 trained professionals to 221 professionals belonging to the 4 target professional category in the 3 countries. At the end, an international closure meeting was conducted to share multi-sectoral lessons learned, results, and sustainability of the ToR program.

Extreme plasticity of reproductive state in a female rodent

Successful sexual reproduction relies on the coordination of multiple biological systems, yet traditional concepts of biological sex often ignore the natural plasticity in morphology and physiology underlying sex. Most female mammals develop a patent (i.e., opened) vaginal entrance (introitus) prenatally or postnatally before or during puberty, usually under the influence of estrogens, and remain patent for the remainder of their lifespan1. An exception is the southern African giant pouched rat (Cricetomys ansorgei), whose vaginal introitus remains sealed well into adulthood2. Here, we explore this phenomenon and report that the reproductive organs and the vaginal introitus can undergo astounding and reversible transformation. Non-patency is characterized by reduced uterine size and the presence of a sealed vaginal introitus. Furthermore, the female urine metabolome shows that patent and non-patent females profoundly differ in their urine content, a reflection of differences in physiology and metabolism. Surprisingly, patency state did not predict fecal estradiol or progesterone metabolite concentrations. Exploring the plasticity that exists in reproductive anatomy and physiology can uncover that traits long considered 'fixed' in adulthood can become plastic under specific evolutionary pressures. Moreover, the barriers to reproduction that such plasticity creates present unique challenges to maximizing reproductive potential.

Interactive effects of maternal physiological arousal and regulation on maternal sensitivity: Replication and extension in an independent sample.

This study examined the extent to which mothers' physiological arousal (i.e., skin conductance level [SCL] augmentation) and regulation (i.e., respiratory sinus arrhythmia [RSA] withdrawal) interacted to predict subsequent maternal sensitivity. Mothers' (N=176) SCL and RSA were measured prenatally during a resting baseline and while watching videos of crying infants. Maternal sensitivity was observed during a free-play task and the still-face paradigm when their infants were 2months old. The results demonstrated that higher SCL augmentation but not RSA withdrawal predicted more sensitive maternal behaviors as a main effect. Additionally, SCL augmentation and RSA withdrawal interacted, such that well-regulated maternal arousal was associated with greater maternal sensitivity at 2months. Further, the interaction between SCL and RSA was only significant for the negative dimensions of maternal behavior used to derive the measure of maternal sensitivity (i.e., detachment and negative regard) suggesting that well-regulated arousal is particularly important for inhibiting the tendency to engage in negative maternal behaviors. The results replicate findings from mothers in previous studies and demonstrate that the interactive effects of SCL and RSA in relation to parenting outcomes are not sample specific. Considering joint effects of physiological responding across multiple biological systems may enhance understanding of the antecedents of sensitive maternal behavior.

Shared Activities With Parents During Adolescence Predicts Health Risk Across Multiple Biological Systems 22 Years Later.

Although affectively focused dimensions of social relationships are associated with differences in health risk, less research has considered nonaffective features of relationships, such as engaging in shared activities. This study sought to test whether adolescents who engaged in more shared activities with their parents had lower health risk in early midlife across multiple biological markers. Using data from a nationally representative study ( N = 4801), prospective associations between shared activities with parents during adolescence and health risk classifications for measures of inflammation, renal function, glucose homeostasis, and cholesterol 22 years later were examined, along with the potentially confounding roles of childhood socioeconomic status and parent-child relationship satisfaction. Exploratory analyses considered possible indirect effects of cigarette use, alcohol use, and body mass index in adulthood. Engaging in more shared activities with parents was associated with a reduced likelihood of being classified in a high-risk health category for markers of inflammation ( B = -0.02, standard error [SE] = 0.01, p = .040), renal function ( B = -0.08, SE = 002, p = .001), glucose ( B = -0.06, SE = 0.23, p = .011), and high-density lipoprotein ( B = - 0.03, SE = 0.01, p = .021), and overall allostatic load ( B = - 0.02, SE = 0.02, p = .001), beyond demographic and health covariates. Controlling for parental income and relationship satisfaction largely did not affect observed associations. Exploratory tests of indirect effects imply that health behaviors in adulthood may partially account for observed associations. Engaging in more shared activities predicted more optimal health classifications 22 years later, suggesting that the amount of contact between parents and teenagers may have long-lasting beneficial health effects. Furthermore, consideration of nonaffective dimensions of family relationships may provide additional insight into associations between social relationships and health.

TULA-Family Regulators of Platelet Activation.

The two members of the UBASH3/TULA/STS-protein family have been shown to critically regulate cellular processes in multiple biological systems. The regulatory function of TULA-2 (also known as UBASH3B or STS-1) in platelets is one of the best examples of the involvement of UBASH3/TULA/STS proteins in cellular regulation. TULA-2 negatively regulates platelet signaling mediated by ITAM- and hemITAM-containing membrane receptors that are dependent on the protein tyrosine kinase Syk, which currently represents the best-known dephosphorylation target of TULA-2. The biological responses of platelets to collagen and other physiological agonists are significantly downregulated as a result. The protein structure, enzymatic activity and regulatory functions of UBASH3/TULA/STS proteins in the context of platelet responses and their regulation are discussed in this review.

SEX DIMORPHISM IN AGING

Abstract In this symposium, the speakers will discuss how sex can influence aging trajectories using complementary perspectives and approaches across multiple biological scales and systems. Indeed, accumulating evidence across species has revealed that aging is a highly sex-dimorphic process. On the one hand, women outlive men consistently across populations, and most supercentanarians are women. On the other hand, especially after the onset of menopause, women are at increased risk for most age-related diseases (e.g. Alzheimer’s disease, osteoporosis, etc.). However, the molecular pathways underlying such sex-differences in aging and longevity are still largely unexplored and poorly understood. Dr. Austad will discuss how compatibility between the mitochondrial and nuclear genomes during aging is influenced as a function of sex. Dr. Dubal will discuss the impact of sex chromosome complement on cognition with aging in mouse models, and how sex chromosomes may underlie sex-differences in brain aging. Dr. Ucar will discuss work from her lab revealing that the genomic signatures of immune aging in humans are specific to sex. Finally, Dr. Benayoun will discuss how aging of innate immune cells (e.g. macrophages or neutrophils) is regulated by the female vs. male milieu, with sex-specific age-related trajectories remodeling the immune compartment in mice.