Regulatory T-cell phenotypes in prenatal psychological distress.

BACKGROUND: Experiencing symptoms of psychological distress during pregnancy is common and has been linked to dysregulated immune functioning. In this context, immunoregulatory function is especially relevant because of its crucial role in establishment and maintenance of healthy pregnancy. However, little research has examined associations between women's prenatal psychological distress and immunoregulatory biomarkers. We investigated how symptoms of depression, anxiety, and stress relate to circulating levels of regulatory T-cells (Tregs). MATERIALS AND METHODS: Pregnant Latina women were assessed at around 12 weeks of pregnancy (N = 82). These assessments included blood draws and self-report questionnaires assessing symptoms of depression, state anxiety, pregnancy-related anxiety, and perceived stress. Flow cytometry on PBMCs was used to quantify circulating Tregs, defined as CD3+CD4+CD25hiCD127loFoxP3+, and subpopulations positive for one of the following intra- or extracellular markers, CD45RA, CTLA-4, Helios, PD-1, TIM-3, and TIGIT. We collected 82 samples at 12 weeks. Multivariable linear regressions tested for associations between symptoms of psychological distress and Treg concentrations, adjusted for gestational age. RESULTS: State anxiety symptoms at 12 weeks were negatively associated with parent Treg cell levels (b = -4.02, p = 0.023) and subpopulations Helios+ (b = -3.29, p = 0.019) and TIM3+ (b = -3.17, p = 0.008). Perceived stress was negatively associated with the PD-1+ subpopulation at 12 weeks (b = -4.02, p = 0.023). Depression was not related to Tregs or the subpopulations. CONCLUSION: Our observation that symptoms of anxiety and stress are related to tolerogenic immunology suggests a possible biomechanism explaining correlations of maternal mood disorders with adverse outcomes for mothers and offspring.

An evolutionary perspective on the association between grandmother-mother relationships and maternal mental health among a cohort of pregnant Latina women.

Grandmothers are often critical helpers during a mother's reproductive career. Studies on the developmental origins of health and disease demonstrate how maternal psychological distress can negatively influence fetal development and birth outcomes, highlighting an area in which soon-to-be grandmothers (henceforth "grandmothers") can invest to improve both mother and offspring well-being. Here, we examine if and how a pregnant woman's mental health- specifically, depression, state-anxiety, and pregnancy-related anxiety- is influenced by her relationship with her fetus' maternal and paternal grandmother, controlling for relationship characteristics with her fetus' father. In a cohort of pregnant Latina women in Southern California (N = 216), we assessed social support, geographic proximity, and communication between the fetus' grandmothers and pregnant mother. We assessed maternal mental health with validated questionnaire-based instruments. We find that both social support from and communication with the maternal grandmother were statistically associated with less depression, while no paternal grandmother relationship characteristics were statistically significant in association with any mental health variable. These results align with the idea that maternal grandmothers are more adaptively incentivized to invest in their daughters' well-being during pregnancy than paternal grandmothers are for their daughters-in-law. Results suggest that the positive association of maternal grandmothers with mothers' mental health may not hinge on geographic proximity, but rather, potentially function through emotional support. This work represents a novel perspective describing a psychological and prenatal grandmaternal effect.

How prenatal cortisol levels relate to grandmother-mother relationships among a cohort of Latina women.

INTRODUCTION: As part of the human reproductive strategy, mothers receive childcare assistance from others. For kin, allomothers are adaptively incentivized to provide assistance due to inclusive fitness benefits. Previous studies across a broad range of populations identify grandmothers as particularly consistent allomothers. Minimal attention has been paid to the possibility that allomothers may begin investing in offspring quality during the prenatal stage of life. Here, we innovate within the area of grandmother allocare research by examining the prenatal stage of life and biopsychosocial mechanisms by which prenatal grandmother effects may be enacted. METHODS: Data derive from the Mothers' Cultural Experiences study, a cohort of 107 pregnant Latina women in Southern California. At <16 weeks' gestation, we administered questionnaires, collected morning urine samples, and measured cortisol by enzyme-linked immunosorbent assay, correcting for specific gravity. We measured the soon-to-be maternal and paternal grandmothers' relationship quality, social support, frequency of seeing each other, communicating, and geographic proximity to pregnant mothers, that is, their daughters and daughters-in-law. These measures were self-reported by the pregnant mothers. We assessed how grandmother constructs related to the pregnant women's depression, stress, anxiety, and cortisol levels. RESULTS: We observed benefits conferred by maternal grandmothers for mothers' prenatal mental health and lower cortisol levels. Paternal grandmothers also conferred mental health benefits to pregnant daughters-in-law, but higher cortisol levels. CONCLUSION: Our results suggest that grandmothers, especially maternal grandmothers, are able to improve their inclusive fitness by caring for pregnant daughters, and allomother support may positively impact prenatal health. This work extends the traditional cooperative breeding model by identifying a prenatal grandmother effect, and, by examining a maternal biomarker.

Association of pica with cortisol and inflammation among Latina pregnant women.

Pica, the urge to consume items generally not considered food, such as dirt, raw starch, and ice, are particularly common among pregnant women. However, the biology of pica in pregnancy is not well understood. Therefore, this study aimed to assess how pica relates to endocrine stress and immune biomarkers in a cohort of pregnant Latina women in Southern California. Thirty-four women completed a structured pica questionnaire. Maternal urinary cortisol and plasma cytokine levels were measured between 21 and 31 weeks' gestation. Associations between pica during pregnancy and biomarkers were assessed using linear regression models adjusting for gestational age. Twelve (35.3%) of the pregnant women reported pica (geophagy and amylophagy) during pregnancy. In multivariate models, those who engaged in pica had higher levels of cortisol (ß: 0.37, 95% CI: 0.01, 0.073) and lower levels of IL-1ß (ß: -0.06, 95% CI: -0.11, -0.02), IL-8 (ß: -0.30, 95% CI: -0.56, -0.05), IL-21 (ß: -0.35, 95% CI: -0.63, -0.08), and type-1 inflammation composite (ß: -0.29, 95% CI: -0.44, -0.14) than women who did not engage in pica. These results suggest that biological stress and immune response differ for women with pica compared to those without. This study suggests novel physiological covariates of pica during pregnancy. Further research is needed to better understand the mechanisms and temporality underlying the observed associations between pica and endocrine and immune biomarkers.

Sociopolitical stressors are associated with psychological distress in a cohort of Latina women during early pregnancy.

Research suggests that the 2016 US election was a potential stressor among Latinos residing in the United States. Sociopolitical stressors targeted toward ethnic minority communities and become embodied through psychosocial distress. The current study investigates if and how sociopolitical stressors related to the 45th President, Donald Trump, and his administration are associated with psychological distress in early pregnancy of Latina women living in Southern California during the second half of his term. This cross-sectional analysis uses data from the Mothers' Cultural Experiences study (n = 90) collected from December 2018 to March 2020. Psychological distress was assessed in three domains: depression, state anxiety, and pregnancy-related anxiety. Sociopolitical stressors were measured through questionnaires about sociopolitical feelings and concerns. Multiple linear regression models examined the relationship between sociopolitical stressors and mental health scores, adjusting for multiple testing. Negative feelings and a greater number of sociopolitical concerns were associated with elevated pregnancy-related anxiety and depressive symptoms. The most frequently endorsed concern was about issues of racism (72.3%) and women's rights (62.4%); women endorsing these particular concerns also had higher scores on depression and pregnancy-related anxiety. No significant associations were detected with state anxiety after correction for multiple testing. This analysis is cross-sectional and cannot assess causality in the associations between sociopolitical stressors and distress. These results are consistent with the hypothesis that the 2016 election, the subsequent political environment, and the anti-immigrant rhetoric and policies of former President Trump and his administration were sources of stress for Latinos residing in the United States.

Staying alive enhances both women's and men's fitness.

We argue that Benenson et al. need to consider not only sex differences in the effects of care on offspring survival but also in age-specific fertility when predicting how longevity affects fitness. We review evidence that staying alive has important effects on both women's and men's fitness, and encourage consideration of alternative explanations for observed sex differences in threat responses.

The dynein light chain 8 (LC8) binds predominantly "in-register" to a multivalent intrinsically disordered partner.

Dynein light chain 8 (LC8) interacts with intrinsically disordered proteins (IDPs) and influences a wide range of biological processes. It is becoming apparent that among the numerous IDPs that interact with LC8, many contain multiple LC8-binding sites. Although it is established that LC8 forms parallel IDP duplexes with some partners, such as nucleoporin Nup159 and dynein intermediate chain, the molecular details of these interactions and LC8's interactions with other diverse partners remain largely uncharacterized. LC8 dimers could bind in either a paired "in-register" or a heterogeneous off-register manner to any of the available sites on a multivalent partner. Here, using NMR chemical shift perturbation, analytical ultracentrifugation, and native electrospray ionization MS, we show that LC8 forms a predominantly in-register complex when bound to an IDP domain of the multivalent regulatory protein ASCIZ. Using saturation transfer difference NMR, we demonstrate that at substoichiometric LC8 concentrations, the IDP domain preferentially binds to one of the three LC8 recognition motifs. Further, the differential dynamic behavior for the three sites and the size of the fully bound complex confirmed an in-register complex. Dynamics measurements also revealed that coupling between sites depends on the linker length separating these sites. These results identify linker length and motif specificity as drivers of in-register binding in the multivalent LC8-IDP complex assembly and the degree of compositional and conformational heterogeneity as a promising emerging mechanism for tuning of binding and regulation.

Oxytocin increases inhibitory synaptic transmission and blocks development of long-term potentiation in the lateral amygdala.

Oxytocin (OT) is a neuroactive peptide that influences the processing of fearful stimuli in the amygdala. In the central nucleus of the amygdala, the activation of OT receptors alters neural activity and ultimately suppresses the behavioral response to a fear conditioned stimulus. Receptors for OT are also found in the lateral amygdala (LA), and infusion of OT into the basolateral amygdala complex affects the formation and consolidation of fear memories. Yet, how OT receptor activation alters neurons and neural networks in the LA is unknown. In this study we used whole cell electrophysiological recordings to determine how OT-receptor activation changes synaptic transmission and synaptic plasticity in the LA of Sprague-Dawley rats. Our results demonstrate that OT-receptor activation results in a 200% increase in spontaneous inhibitory transmission in the LA that leads to the activation of presynaptic GABAB receptors. The activation of these receptors inhibits excitatory transmission in the LA, blocking long-term potentiation of cortical inputs onto LA neurons. Hence, this study provides the first demonstration that OT influences synaptic transmission and plasticity in the LA, revealing a mechanism that could explain how OT regulates the formation and consolidation of conditioned fear memories in the amygdala.NEW & NOTEWORTHY This study investigates modulation of synaptic transmission by oxytocin (OT) in the lateral amygdala (LA). We demonstrate that OT induces transient increases in spontaneous GABAergic transmission by activating interneurons in the basolateral amygdala. The resultant increase in GABA release in the LA activates presynaptic GABAB receptors on both inhibitory and excitatory inputs onto LA neurons, reducing release probability at these synapses. We subsequently demonstrate that OT modulates synaptic plasticity at cortical inputs to the LA.

Plant-Pathogenic Agrobacterium tumefaciens Strains Have Diverse Type VI Effector-Immunity Pairs and Vary in In-Planta Competitiveness.

The type VI secretion system (T6SS) is used by gram-negative bacteria to translocate effectors that can antagonize other bacterial cells. Models predict the variation in collections of effector and cognate immunity genes determine competitiveness and can affect the dynamics of populations and communities of bacteria. However, the outcomes of competition cannot be entirely explained by compatibility of effector-immunity (EI) pairs. Here, we characterized the diversity of T6SS loci of plant-pathogenic Agrobacterium tumefaciens and showed that factors other than EI pairs can impact interbacterial competition. All examined strains encode T6SS active in secretion and antagonism against Escherichia coli. The spectra of EI pairs as well as compositions of gene neighborhoods are diverse. Almost 30 in-planta competitions were tested between different genotypes of A. tumefaciens. Fifteen competitions between members of different species-level groups resulted in T6SS-dependent suppression in in-planta growth of prey genotypes. In contrast, ten competitions between members within species-level groups resulted in no significant effect on the growth of prey genotypes. One strain was an exceptional case and, despite encoding a functional T6SS and toxic effector protein, could not compromise the growth of the four tested prey genotypes. The data suggest T6SS-associated EI pairs can influence the competitiveness of strains of A. tumefaciens, but genetic features have a significant role on the efficacy of interbacterial antagonism.

The Agrobacterium Type VI Secretion System: A Contractile Nanomachine for Interbacterial Competition.

The bacterial type VI secretion system (T6SS) is a contractile nanomachine dedicated to delivering molecules out of bacterial cells. T6SS-encoding loci are in the genome sequences of many Gram-negative bacteria, and T6SS has been implicated in a plethora of roles. In the majority of cases, the T6SSs deliver effector proteins in a contact-dependent manner to antagonize other bacteria. Current models suggest that the effectors are deployed to influence social interactions in microbial communities. In this chapter, we describe the structure, function, and regulation of the T6SS and its effectors. We provide focus on the T6SS of Agrobacterium tumefaciens, the causative agent of crown gall disease, and relate the role of the T6SS to the ecology of A. tumefaciens.

Maternal grandmothers buffer the effects of ethnic discrimination among pregnant Latina mothers.

Ethnic discrimination during pregnancy is linked to maternal psychological distress, adverse birth outcomes and increased offspring morbidity and mortality. An evolutionary perspective reframes offspring health issues as a risk to maternal fitness. We argue that kin may be evolutionarily motivated to buffer psychosocial stressors for the mother during pregnancy. Previously, we found that the relationship of a pregnant woman with her own mother (fetus' maternal grandmother) had a positive association on maternal prenatal psychology, above and beyond her relationship with her fetus' father. Here, we ask if grandmothers buffer mothers' prenatal psychological distress from ethnic discrimination. Using self-report data collected from 216 pregnant Latina women living in Southern California, we found discrimination to be significantly, positively associated with depression, anxiety, and stress in linear regression models. Maternal grandmother communication attenuated the association of discrimination and all three psychological distress measures, adjusting for the mother's relationship with the father. Maternal grandmother emotional support similarly significantly moderated the relationship of discrimination with depression and anxiety. We did not observe any significant interactions for paternal grandmother relationships. Geographic proximity was not a significant stress buffer. Results suggest the important role maternal grandmothers play in perinatal mental health, and that these benefits exist uncoupled from geographic proximity.

Which social media platforms facilitate monitoring the opioid crisis?

Social media can provide real-time insight into trends in substance use, addiction, and recovery. Prior studies have used platforms such as Reddit and X (formerly Twitter), but evolving policies around data access have threatened these platforms' usability in research. We evaluate the potential of a broad set of platforms to detect emerging trends in the opioid epidemic. From these, we created a shortlist of 11 platforms, for which we documented official policies regulating drug-related discussion, data accessibility, geolocatability, and prior use in opioid-related studies. We quantified their volumes of opioid discussion, capturing informal language by including slang generated using a large language model. Beyond the most commonly used Reddit and X, the platforms with high potential for use in opioid-related surveillance are TikTok, YouTube, and Facebook. Leveraging many different social platforms, instead of a single platform, safeguards against sudden changes to data access and may better capture all populations that use opioids than any single platform.

Cell-free assays reveal the HIV-1 capsid protects reverse transcripts from cGAS.

Retroviruses can be detected by the innate immune sensor cyclic GMP-AMP synthase (cGAS), which recognizes reverse-transcribed DNA and activates an antiviral response. However, the extent to which HIV-1 shields its genome from cGAS recognition remains unclear. To study this process in mechanistic detail, we reconstituted reverse transcription, genome release, and innate immune sensing of HIV-1 in a cell-free system. We found that wild-type HIV-1 capsids protect their genomes from cGAS even after completion of reverse transcription. Viral DNA could be "deprotected" by thermal stress, capsid mutations, or reduced concentrations of inositol hexakisphosphate (IP6) that destabilize the capsid. Strikingly, capsid inhibitors also disrupted viral cores and dramatically potentiated cGAS activity, both in vitro and in cellular infections. Our results provide biochemical evidence that the HIV-1 capsid lattice conceals the genome from cGAS and that chemical or physical disruption of the viral core can expose HIV-1 DNA and activate innate immune signaling.

Comprehensive microRNA expression profiling of the hematopoietic hierarchy.

The hematopoietic system produces a large number of highly specialized cell types that are derived through a hierarchical differentiation process from a common stem cell population. miRNAs are critical players in orchestrating this differentiation. Here, we report the development and application of a high-throughput microfluidic real-time quantitative PCR (RT-qPCR) approach for generating global miRNA profiles for 27 phenotypically distinct cell populations isolated from normal adult mouse hematopoietic tissues. A total of 80,000 RT-qPCR assays were used to map the landscape of miRNA expression across the hematopoietic hierarchy, including rare progenitor and stem cell populations. We show that miRNA profiles allow for the direct inference of cell lineage relations and functional similarity. Our analysis reveals a close relatedness of the miRNA expression patterns in multipotent progenitors and stem cells, followed by a major reprogramming upon restriction of differentiation potential to a single lineage. The analysis of miRNA expression in single hematopoietic cells further demonstrates that miRNA expression is very tightly regulated within highly purified populations, underscoring the potential of single-cell miRNA profiling for assessing compartment heterogeneity.

Promises and challenges in pharmacoepigenetics.

Pharmacogenetics, the study of how interindividual genetic differences affect drug response, does not explain all observed heritable variance in drug response. Epigenetic mechanisms, such as DNA methylation, and histone acetylation may account for some of the unexplained variances. Epigenetic mechanisms modulate gene expression and can be suitable drug targets and can impact the action of nonepigenetic drugs. Pharmacoepigenetics is the field that studies the relationship between epigenetic variability and drug response. Much of this research focuses on compounds targeting epigenetic mechanisms, called epigenetic drugs, which are used to treat cancers, immune disorders, and other diseases. Several studies also suggest an epigenetic role in classical drug response; however, we know little about this area. The amount of information correlating epigenetic biomarkers to molecular datasets has recently expanded due to technological advances, and novel computational approaches have emerged to better identify and predict epigenetic interactions. We propose that the relationship between epigenetics and classical drug response may be examined using data already available by (1) finding regions of epigenetic variance, (2) pinpointing key epigenetic biomarkers within these regions, and (3) mapping these biomarkers to a drug-response phenotype. This approach expands on existing knowledge to generate putative pharmacoepigenetic relationships, which can be tested experimentally. Epigenetic modifications are involved in disease and drug response. Therefore, understanding how epigenetic drivers impact the response to classical drugs is important for improving drug design and administration to better treat disease.

Healthcare provider perceptions of safety culture: A multi-site study using the safety attitudes questionnaire.

Introduction: Patient safety culture, the way in which members of a healthcare organisation think about and prioritise safety, has been linked to positive patient outcomes. The aim of this study was to use the Safety Attitudes Questionnaire (SAQ) to measure the safety culture in a variety of healthcare settings located in the province of Munster of Ireland. Methods: The SAQ was applied in six healthcare settings in the Munster province of Ireland between December 2017 and November 2019. The attitudes of healthcare staff towards six domains of safety culture were assessed over 32 Likert-scaled items. The mean, median, interquartile range and percent positive scores for each domain were calculated for the study population, and subgroup analyses were carried out between study sites and professions. Results for each setting were compared to international benchmarking data. Chi-Squared tests were used to determine whether study site or profession were related to domain scores. Reliability analysis was carried out using Cronbach's alpha. Results: Study participants (n = 1749) comprising doctors, pharmacists, nurses, and healthcare assistants, were found to have positive attitudes towards patient safety culture but scored poorly in the domains Working Conditions and Perceptions of Management. Perceptions of safety culture were more positive in smaller healthcare settings, and amongst nurses and HCAs. The survey had acceptable internal consistency. Conclusions: In this study investigating the safety culture of healthcare organisations in Ireland, study participants had generally positive attitudes towards the safety culture in their organisation, however working conditions, perceptions of management, and medication incident reporting were identified as key areas for improvement.

Constriction Band Release in a Neonatal Ischemic Limb: A Pediatric Anesthesiology Case Report.

A 1.1 Kg, four-hour-old, 29-weeks-gestation male patient presented with right upper extremity ischemia secondary to neonatal constriction band syndrome. Emergency constriction band release was deemed necessary to facilitate limb salvage. The anesthetic management of this patient required close communication with the surgical team and meticulous attention to the risks of post-reperfusion syndrome and blood loss in this fragile neonate. Limb salvage was ultimately successful, and the patient demonstrated full neurologic recovery at his two-year follow-up visit.

What Do Your Neighbors Think About You? How Perceived Neighbor Attitudes Toward Latinos Influence Mental Health Among a Pregnant Latina Cohort.

Latina women living in the USA experience disproportionately higher rates of psychological distress compared to their non-Latina White counterparts. Poor maternal mental health during pregnancy can contribute to intergenerational mental health disparities. Through this pathway, mothers' experiences, environments, and exposures (henceforth "exposures") during pregnancy become biologically embodied and can negatively affect the fetus and life-long developmental trajectories of her child. One of the exposures that can affect mother-offspring dyads is the neighborhood. With the goal of integrating anthropological and sociological theories to explain mental health disparities among pregnant Latina women, we explored how perceptions of neighbor attitudes may influence mental health during pregnancy. We analyzed self-reported responses from 239 pregnant Latina women in Southern California (131 foreign-born, 108 US-born) on their mental health and perceived attitudes of their neighbors using multiple linear regression models. Among foreign-born Latina women, living in neighborhoods with more favorable views of Latinos was associated with lower depression scores (pooled ß = - .70, SE = .29, p = .019) and lower pregnancy-related anxiety scores (pooled ß = - .11, SE = .05, p = .021), but greater state anxiety scores (pooled ß = .09, SE = .04, p = .021). Among US-born women, there were no associations between neighbor attitudes and mental health. Overall, results suggest that social environments are correlated with mental health and that foreign-born and US-born Latinas have varied mental health experiences in the USA. Our findings highlight the importance of improving aspects of neighborhood cohesion as part of maternal-fetal care management.

The neuropathological landscape of Hispanic and non-Hispanic White decedents with Alzheimer disease.

Despite the increasing demographic diversity of the United States' aging population, there remain significant gaps in post-mortem research investigating the ethnoracial heterogeneity in the neuropathological landscape of Alzheimer Disease (AD). Most autopsy-based studies have focused on cohorts of non-Hispanic White decedents (NHWD), with few studies including Hispanic decedents (HD). We aimed to characterize the neuropathologic landscape of AD in NHWD (n = 185) and HD (n = 92) evaluated in research programs across three institutions: University of California San Diego, University of California Davis, and Columbia University. Only persons with a neuropathologic diagnosis of intermediate/high AD determined by NIA Reagan and/or NIA-AA criteria were included. A frequency-balanced random sample without replacement was drawn from the NHWD group using a 2:1 age and sex matching scheme with HD. Four brain areas were evaluated: posterior hippocampus, frontal, temporal, and parietal cortices. Sections were stained with antibodies against Aß (4G8) and phosphorylated tau (AT8). We compared the distribution and semi-quantitative densities for neurofibrillary tangles (NFTs), neuropil threads, core, diffuse, and neuritic plaques. All evaluations were conducted by an expert blinded to demographics and group status. Wilcoxon's two-sample test revealed higher levels of neuritic plaques in the frontal cortex (p = 0.02) and neuropil threads (p = 0.02) in HD, and higher levels of cored plaques in the temporal cortex in NHWD (p = 0.02). Results from ordinal logistic regression controlling for age, sex, and site of origin were similar. In other evaluated brain regions, semi-quantitative scores of plaques, tangles, and threads did not differ statistically between groups. Our results demonstrate HD may be disproportionately burdened by AD-related pathologies in select anatomic regions, particularly tau deposits. Further research is warranted to understand the contributions of demographic, genetic, and environmental factors to heterogeneous pathological presentations.