Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic Conductances in Arcuate Kisspeptin Neurons by Diminishing Voltage-Gated Potassium Currents.

Synaptic and intrinsic properties interact to sculpt neuronal output. Kisspeptin neurons in the hypothalamic arcuate nucleus help convey homeostatic estradiol feedback to central systems controlling fertility. Estradiol increases membrane depolarization induced by GABAA receptor activation in these neurons. We hypothesized that the mechanisms underlying estradiol-induced alterations in postsynaptic response to GABA, and also AMPA, receptor activation include regulation of voltage-gated potassium currents. Whole-cell recordings of arcuate kisspeptin neurons in brain slices from ovariectomized (OVX) and OVX+estradiol (OVX+E) female mice during estradiol negative feedback revealed that estradiol reduced capacitance, reduced transient and sustained potassium currents, and altered voltage dependence and kinetics of transient currents. Consistent with these observations, estradiol reduced rheobase and action potential latency. To study more directly interactions between synaptic and active intrinsic estradiol feedback targets, dynamic clamp was used to simulate GABA and AMPA conductances. Both GABA and AMPA dynamic clamp-induced postsynaptic potentials (PSPs) were smaller in neurons from OVX than OVX+E mice; blocking transient potassium currents eliminated this difference. To interrogate the role of the estradiol-induced changes in passive intrinsic properties, different Markov model structures based on the properties of the transient potassium current in cells from OVX or OVX+E mice were combined in silico with passive properties reflecting these two endocrine conditions. Some of tested models reproduced the effect on PSPs in silico, revealing that AMPA PSPs were more sensitive to changes in capacitance. These observations support the hypothesis that PSPs in arcuate kisspeptin neurons are regulated by estradiol-sensitive mechanisms including potassium conductances and membrane properties.SIGNIFICANCE STATEMENT Kisspeptin neurons relay estradiol feedback to gonadotropin-releasing hormone neurons, which regulate the reproductive system. The fast synaptic neurotransmitters GABA and glutamate rapidly depolarize arcuate kisspeptin neurons and estradiol increases this depolarization. Estradiol reduced both potassium current in the membrane potential range typically achieved during response to fast synaptic inputs and membrane capacitance. Using simulated GABA and glutamate synaptic inputs, we showed changes in both the passive and active intrinsic properties induced by in vivo estradiol treatment affect the response to synaptic inputs, with capacitance having a greater effect on response to glutamate. The suppression of both passive and active intrinsic properties by estradiol feedback thus renders arcuate kisspeptin neurons more sensitive to fast synaptic inputs.

Identification of tRNA-derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer.

Despite recent advances in targeted therapies, the molecular mechanisms driving breast cancer initiation, progression, and metastasis are minimally understood. Growing evidence indicate that transfer RNA (tRNA)-derived small RNAs (tsRNA) contribute to biological control and aberrations associated with cancer development and progression. The runt-related transcription factor 1 (RUNX1) transcription factor is a tumor suppressor in the mammary epithelium whereas RUNX1 downregulation is functionally associated with breast cancer initiation and progression. We identified four tsRNA (ts-19, ts-29, ts-46, and ts-112) that are selectively responsive to expression of the RUNX1 tumor suppressor. Our finding that ts-112 and RUNX1 anticorrelate in normal-like mammary epithelial and breast cancer lines is consistent with tumor-related activity of ts-112 and tumor suppressor activity of RUNX1. Inhibition of ts-112 in MCF10CA1a aggressive breast cancer cells significantly reduced proliferation. Ectopic expression of a ts-112 mimic in normal-like mammary epithelial MCF10A cells significantly increased proliferation. These findings support an oncogenic potential for ts-112. Moreover, RUNX1 may repress ts-112 to prevent overactive proliferation in breast epithelial cells to augment its established roles in maintaining the mammary epithelium.

Race, Medicaid Coverage, and Equity in Maternal Morbidity.

BACKGROUND: Severe maternal morbidity (SMM) affects 50,000 deliveries in the United States annually, with around 1.5 times the rates among Medicaid-covered relative to privately covered deliveries. Furthermore, large racial inequities exist in SMM for non-Hispanic Black women and Hispanic women with rates being 2.1 and 1.4 times higher than White women, respectively. This study aimed to compare the differences in SMM among women of different races/ethnicities and delivery insurance types. Quantifying the rates of SMM based on the intersection of race/ethnicity and insurance status can help to elucidate how multiple forms of oppression and racism may contribute to the substantial inequities in SMM among Black women. METHODS: Using hospital discharge data from the Healthcare Cost and Utilization Project National Inpatient Sample (years 2016 and 2017), we conducted multivariate logistic models to evaluate equity in maternal outcomes among women with different primary payers, overall and stratified by race/ethnicity. RESULTS: We found a rate of SMM equal to 138.3 per 10,000 deliveries. Differences in the rate of SMM among non-Hispanic Black, non-Hispanic Asian, and Hispanic women relative to White women were lower among Medicaid-covered deliveries relative to deliveries of all payer types. For example, among all payers, Black women had 2.17 (221.3 vs. 102.1 per 10,000) times the rate of SMM compared with White women; however, among Medicaid-covered deliveries, Black women had 1.84 (227.3 vs. 123.2) times the rate. Despite increased risk associated with Medicaid coverage (adjusted odds ratio, 1.12; 95% confidence interval, 1.07-1.16), the risk was no longer significant in the stratified regression including Black women (adjusted odds ratio, 1.06; 95% confidence interval, 0.98-1.15). CONCLUSIONS: Our findings suggest that Black women with Medicaid do not have higher rates of SMM relative to Black women with private insurance. National and state policy efforts should continue to focus on addressing structural racism and other socioeconomic drivers of adverse maternal outcomes, including barriers to high-quality care among women with Medicaid coverage.

Mental Health Conditions Increase Severe Maternal Morbidity By 50 Percent And Cost $102 Million Yearly In The United States.

Perinatal mental health disorders are increasingly acknowledged as contributors to adverse maternal outcomes. We analyzed data from the Healthcare Cost and Utilization Project National Inpatient Sample (2016 and 2017) to estimate hospitalization cost, length-of-stay, and severe maternal morbidity associated with perinatal mental health disorders overall, as well as stratified by payer and by specific mental health category. We found that people with mental health disorders had $458 higher costs per delivery hospitalization and 50 percent higher rates of severe maternal morbidity compared with people without mental health disorders. We estimated increased annual delivery hospitalization costs of $102 million in the US among people with perinatal mental health conditions compared with those without. Furthermore, people diagnosed with trauma- or stress-related mental health disorders had even higher rates of hospitalization costs-$825 higher per delivery-and 87 percent higher rates of severe maternal morbidity compared with people without those diagnoses. These findings provide important information for perinatal mental health program feasibility and cost-effectiveness analyses and suggest the need for increased focus on trauma- and stress-related disorders.

Associations Between Comorbidities and Severe Maternal Morbidity.

OBJECTIVE: To evaluate the associations between the number of chronic conditions and maternal race and ethnicity (race) with the risk of severe maternal morbidity. METHODS: Using the National Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality, years 2016-2017, we examined risk of severe maternal morbidity among 1,480,925 delivery hospitalizations among women of different races and with different numbers of comorbid conditions using multivariable logistic regression. RESULTS: The rate of severe maternal morbidity was 139.7 per 10,000 deliveries. Compared with women with no comorbidities (rate 48.5/10,000), there was increased risk of severe maternal morbidity among women with one comorbidity (rate 238.6; odds ratio [OR] 5.0, 95% CI 4.8-5.2), two comorbidities (rate 379.9; OR 8.1, 95% CI 7.8-8.5), or three or more comorbidities (rate 560; OR 12.1, 95% CI 11.5-12.7). In multivariable regressions, similar associations were noted for women with one (adjusted odds ratio [aOR] 4.4, 95% CI 4.2-4.6), two (aOR 6.6, 95% CI 6.3-6.9), or three or more comorbidities (aOR 9.1, 95% CI 8.7-9.6). Black women had higher rates of comorbid conditions than all other racial and ethnic groups, with 55% (95% CI 54-56%) of Black women having no comorbidities, compared with 67% (95% CI 67-68%) of White women, 68% (95% CI 67-69%) of Hispanic women, and 72% (95% CI 71-73%) of Asian women. CONCLUSION: We found a dose-response relationship between number of comorbidities and risk of severe maternal morbidity, with the highest rates of severe maternal morbidity among women with three or more comorbidities. Focusing on the prevention and treatment of chronic conditions among women of childbearing age may have the potential to improve maternal outcomes across races and ethnicities.