Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERα)-positive (ER+) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER+ breast cancer cells. FFAs activated both the ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERα and mTOR signaling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER+ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERα and mTOR signaling cross-talk would be tested to prevent ER+ breast cancers in obese postmenopausal women

Effects of the Distribution of Female Primates on the Number of Males

The spatiotemporal distribution of females is thought to drive variation in mating systems, and hence plays a central role in understanding animal behavior, ecology and evolution. Previous research has focused on investigating the links between female spatiotemporal distribution and the number of males in haplorhine primates. However, important questions remain concerning the importance of spatial cohesion, the generality of the pattern across haplorhine and strepsirrhine primates, and the consistency of previous findings given phylogenetic uncertainty. To address these issues, we examined how the spatiotemporal distribution of females influences the number of males in primate groups using an expanded comparative dataset and recent advances in Bayesian phylogenetic and statistical methods. Specifically, we investigated the effect of female distributional factors (female number, spatial cohesion, estrous synchrony, breeding season duration and breeding seasonality) on the number of males in primate groups. Using Bayesian approaches to control for uncertainty in phylogeny and the model of trait evolution, we found that the number of females exerted a strong influence on the number of males in primate groups. In a multiple regression model that controlled for female number, we found support for temporal effects, particularly involving female estrous synchrony: the number of males increases when females are more synchronously receptive. Similarly, the number of males increases in species with shorter birth seasons, suggesting that greater breeding seasonality makes defense of females more difficult for male primates. When comparing primate suborders, we found only weak evidence for differences in traits between haplorhines and strepsirrhines, and including suborder in the statistical models did not affect our conclusions or give compelling evidence for different effects in haplorhines and strepsirrhines. Collectively, these results demonstrate that male monopolization is driven primarily by the number of females in groups, and secondarily by synchrony of female reproduction within groups

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

The Chicago Health and Life Experiences of Women Couples Study: Protocol for a Study of Stress, Hazardous Drinking, and Intimate Partner Aggression Among Sexual Minority Women and Their Partners

BackgroundLarge gaps exist in research on alcohol use and intimate partner aggression (IPA) among sexual minority women (SMW; eg, lesbian, bisexual). Dyadic research with SMW and their partners can illuminate how couple-level factors operate in conjunction with individual-level factors to shape well-being in this understudied and vulnerable population. Given the traditionally gendered lens with which women are primarily viewed as victims and men as perpetrators, understanding the dynamics of IPA in same-sex female couples can also advance research and practice related to IPA more generally. ObjectiveGuided by a recent extension of the minority stress model that includes relational (couple-level) sexual minority stress and the I-cubed theoretical perspective on IPA, we will collect individual and dyadic data to better characterize the links between hazardous drinking and IPA among SMW and their partners. First, this study aims to examine the associations among minority stress, hazardous drinking, and IPA in SMW and their partners. Minority stressors will be assessed as both individual and couple-level constructs, thus further extending the minority stress model. Second, we aim to examine potential mediators and moderators of the associations among minority stress, hazardous drinking, and IPA. Finally, we aim to test models guided by the I-cubed theoretical perspective that includes instigating (eg, relationship conflict), impelling (eg, negative affect and trait anger), and inhibiting (eg, relationship commitment and emotion regulation) or disinhibiting (eg, hazardous drinking) influences on IPA perpetration. MethodsThis United States National Institutes of Health–funded project will draw from a large and diverse cohort of SMW currently enrolled in the Chicago Health and Life Experiences of Women (CHLEW) study—a 21-year longitudinal study of risk factors and consequences associated with SMW hazardous drinking. SMW currently enrolled in the CHLEW and their partners will be invited to participate in the CHLEW Couples Study. By analyzing dyadic data using actor-partner interdependence models, we will examine how each partner’s minority stress, hazardous drinking, and IPA experiences are associated with both her own and her partner’s minority stress, hazardous drinking, and IPA perpetration. ResultsData collection began in February 2021 and will likely continue through 2023. Initial results should be available by mid-2024. ConclusionsThe CHLEW Couples Study will fill important gaps in knowledge and provide the basis for future research aimed at clarifying the causal pathways linking hazardous drinking and IPA among SMW. This will support the development of culturally appropriate targeted individual and dyadic prevention and intervention strategies. International Registered Report Identifier (IRRID)DERR1-10.2196/2808

Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development

De novo germline mutations in the RNA helicase DDX3X account for 1%–3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.Using human and mouse genetics, Lennox et al. identify 107 mutations in DDX3X, demonstrating DDX3X is essential for cortical development. A striking correlation between the severity of clinical mutations and abnormal RNA metabolism highlights unappreciated mechanisms of DDX3X syndrome

Vortex-Dominated Aeolian Activity at InSight's Landing Site, Part 1: Multi-Instrument Observations, Analysis, and Implications

We report the aeolian changes observed in situ by NASA's InSight lander during the first 400 sols of operations: Granule creep, saltation, dust removal, and the formation of dark surface tracks. Aeolian changes are infrequent and sporadic. However, on sols, when they do occur, they consistently appear between noon to 3 p.m., and are associated with the passage of convective vortices during periods of high vortex activity. Aeolian changes are more frequent at elevated locations, such as the top surfaces of rocks and lander footpads. InSight observed these changes using, for the first time, simultaneous in-situ and orbital imaging and high-frequency meteorological, seismological, and magnetic measurements. Seismometer measurements of ground acceleration constrain the timing and trajectory of convective vortex encounters, linking surface changes to source vortices. Magnetometer measurements show perturbations in magnetic field strength during the passage of convective vortices consistent with charged-particle motion. Detachment of sand-scale particles occurs when high background winds and vortex-induced turbulence provide a peak surface friction wind speed above the classic saltation fluid threshold. However, detachment of dust- and granule-scale particles also occurred when the surface friction wind speed remained below this threshold. This may be explained by local enhancement of the surface roughness and other effects described here and further studied in Part 2 (Baker et al., 2021). The lack of saltation and bright dust-coated surfaces at the InSight landing site implies surface stability and the onset of particle motion may be suppressed by dust “cushioning.” This differentiates the InSight landing site from other areas on Mars that exhibit more aeolian activity.ISSN:0148-0227ISSN:2169-909