Regulation of mitochondrial proteostasis by the proton gradient.

Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multiproteomic approach to demonstrate the regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca2+ /H+ exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca2+ efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca2+ signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.

The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria.

Mutations in subunits of mitochondrial m-AAA proteases in the inner membrane cause neurodegeneration in spinocerebellar ataxia (SCA28) and hereditary spastic paraplegia (HSP7). m-AAA proteases preserve mitochondrial proteostasis, mitochondrial morphology, and efficient OXPHOS activity, but the cause for neuronal loss in disease is unknown. We have determined the neuronal interactome of m-AAA proteases in mice and identified a complex with C2ORF47 (termed MAIP1), which counteracts cell death by regulating the assembly of the mitochondrial Ca2+ uniporter MCU. While MAIP1 assists biogenesis of the MCU subunit EMRE, the m-AAA protease degrades non-assembled EMRE and ensures efficient assembly of gatekeeper subunits with MCU. Loss of the m-AAA protease results in accumulation of constitutively active MCU-EMRE channels lacking gatekeeper subunits in neuronal mitochondria and facilitates mitochondrial Ca2+ overload, mitochondrial permeability transition pore opening, and neuronal death. Together, our results explain neuronal loss in m-AAA protease deficiency by deregulated mitochondrial Ca2+ homeostasis.

MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity.

Mitochondrial calcium accumulation was recently shown to depend on a complex composed of an inner-membrane channel (MCU and MCUb) and regulatory subunits (MICU1, MCUR1, and EMRE). A fundamental property of MCU is low activity at resting cytosolic Ca(2+) concentrations, preventing deleterious Ca(2+) cycling and organelle overload. Here we demonstrate that these properties are ensured by a regulatory heterodimer composed of two proteins with opposite effects, MICU1 and MICU2, which, both in purified lipid bilayers and in intact cells, stimulate and inhibit MCU activity, respectively. Both MICU1 and MICU2 are regulated by calcium through their EF-hand domains, thus accounting for the sigmoidal response of MCU to [Ca(2+)] in situ and allowing tight physiological control. At low [Ca(2+)], the dominant effect of MICU2 largely shuts down MCU activity; at higher [Ca(2+)], the stimulatory effect of MICU1 allows the prompt response of mitochondria to Ca(2+) signals generated in the cytoplasm.

Developing a Public Health Maternal and Child Health Training Program: Lessons Learned from Five Schools of Public Health.

Maternal and child health (MCH), as a core sub-field of public health, continues to be an essential area in which additional workforce development and investment are needed. Recent public health workforce assessments in the United States reveal there will be a significant number of vacancies in MCH public health positions in the near future, creating the need for a well-trained and skilled public health MCH workforce. In order to address this potential critical workforce gap, the U.S. Department of Health and Human Services, Health Resources and Services Administration's Maternal and Child Health Bureau initiated the Maternal and Child Health Public Health Catalyst Program in 2015 to support the creation of MCH training programs in accredited schools of public health that previously did not have a MCH concentration. This article details the accomplishments and lessons learned from the first five MCH Catalyst Program grantees: Drexel University; Florida International University; Rutgers, The State University of New Jersey; Texas A&M University; and the University at Albany.

Telomere Length and Preterm Birth in Pregnant Mexican-Origin Women.

OBJECTIVES: Despite the obstacles of limited education and employment opportunities-and the stress associated with immigration and pregnancy-Mexican immigrant women have low rates of preterm birth (PTB) compared to the US national average for all races and ethnicities. Stressors during pregnancy, and stressors associated with acculturation, may accelerate cellular aging manifested by shortened telomere length (TL) in pregnant women. Our objectives were to: (1) determine whether women with PTBs had shorter telomere lengths compared to women who had full term births; (2) assess the association of acculturation with TL and PTB. METHODS: This prospective pilot study collected data from 100 self-identified Mexican-origin pregnant women. Survey data included self-administered sociodemographic and acculturation measures and was collected from participants via paper and pen, while biologic data was collected via a single blood draw during a regularly scheduled prenatal visit between 26 and 36 weeks gestation. PTB data was collected from the participant's medical record after delivery. RESULTS: TL was significantly associated with PTB; the median TL of the women with PTB was less than the median TL for the full sample (p = 0.02). Based on regression analysis for PTB vs acculturation, we found no significant associations between acculturation and PTB or TL. CONCLUSIONS FOR PRACTICE: This study provides important evidence of the association between shortened maternal TL and adverse birth outcomes. By linking social, clinical and biologic data, we can enhance our understanding of social determinants that may affect racial and ethnic disparities in preterm birth.

Traumatic Brain Injury Related Hospitalizations: Factors Associated with In-hospital Mortality among Elderly Patients Hospitalized with a TBI.

Background: This study aims to describe TBI-related hospitalizations for the whole population and identify factors associated with in-hospital mortality among elderly (≥65 years) patients hospitalized with TBI in Texas.Methods: Using Texas Hospital Discharge Data from 2012 to 2014, TBI-related hospitalizations were identified using International Classification of Diseases - Ninth Revision - Clinical Modification (ICD-9-CM) codes. Rates for age and gender were estimated using U.S. Census data. Univariate and multivariate analyses were used to identify factors associated with in-hospital mortality among those aged at least 65 years.Results: There were 51,419 TBI-related hospitalizations from 2012 to 2014 in Texas. Falls were the leading cause of TBI-related hospitalizations 6235 (36.64%), 6595 (38.40%), and 5412 (37.59%) for 2012, 2013, and 2014, respectively. Males had higher rates of hospitalizations while rates were highest for those above 80 years of age. Compared to Whites, Hispanics had 1.18 higher adjusted odds of in-hospital mortality [OR = 1.18: 95% CI (1.01-1.40)]. Similarly, adjusted odds of in-hospital mortality were higher among males [OR = 1.55: 95% CI (1.36-1.77)].Conclusion: This study provided evidence of demographic disparities in the burden and outcome of TBI in Texas, findings could serve as a foundation for targeted TBI prevention interventions.

Chlamydia trachomatis Is Associated With Medically Indicated Preterm Birth and Preeclampsia in Young Pregnant Women.

BACKGROUND: Studies on Chlamydia trachomatis-associated pregnancy outcomes are largely conflicting, ignoring the heterogeneous natures of pregnancy complications and potential effect modification by maternal age. This study determined if prenatal C. trachomatis infection is associated with preterm birth (PTB) and preeclampsia subtypes. METHODS: A retrospective cohort study was conducted using 22,772 singleton pregnancies with a prenatal C. trachomatis diagnostic test. Spontaneous and medically indicated PTBs, and term and preterm preeclampsia were outcomes. Modified Poisson regression calculated relative risk (RR) and 95% confidence intervals (CI) with propensity score adjustments stratified by maternal ages <25 and ≥25 years. RESULTS: Overall, C. trachomatis was significantly associated with term preeclampsia (adjusted RR [RRadj], 1.88; 95% CI, 1.38-2.57). Among young women (age <25 years), C. trachomatis was significantly associated with medically indicated PTB (RRadj, 2.29; 95% CI, 1.38-3.78) and term preeclampsia (RRadj, 1.57; 95% CI, 1.05-2.36) in propensity-adjusted models. No significant associations in older women were detected. CONCLUSION: C. trachomatis was associated with medically indicated PTB and term preeclampsia in young women. Associations between chlamydia and perinatal outcomes may depend on the subtype of PTB and preeclampsia, which should be investigated through mechanistic studies.

Estimating Evacuation Shelter Deficits in the Houston-Galveston Metropolitan Area.

Evacuation is frequently used by emergency managers and other officials as part of an overall approach to reducing the morbidity and mortality associated with hurricane landfall. In this study, the evacuation shelter capacity of the Houston-Galveston Metropolitan Statistical Area (MSA) was spatially assessed and shelter deficits in the region were estimated. These data provide essential information needed to eliminate shelter deficits and ensure a successful evacuation from a future storm. Spatial statistical methods-Global Moran's I, Anselin Local Moran's I (Local Indicators of Spatial Association [LISA]), and Hot Spot Analysis (Getis-Ord Gi*) were used to assess for regional spatial autocorrelation and clustering of evacuation shelters in the Houston-Galveston MSA. Shelter deficits were estimated in four ways-the aggregate deficit for the Houston-Galveston MSA, by evacuation Zip-Zone, by county, and by distance or radii of evacuation Zip-Zone. Evacuation shelters were disproportionately distributed in the region, with lower capacity shelters clustered closer to evacuation Zip-Zones (50 miles from the Coastal Zip-Zone), and higher capacity shelters clustered farther away from the zones (120 miles from the Coastal Zip-Zone). The aggregate shelter deficit for the Houston-Galveston MSA was 353,713 persons. To reduce morbidity and mortality associated with future hurricanes in the Houston-Galveston MSA, authorities should consider the development and implementation of policies that would improve the evacuation shelter capacity of the region. Eliminating shelter deficits, which has been done successfully in the state of Florida, is an essential element of protecting the public from hurricane impacts.

Dynamic Patterns of Testosterone Levels in Individuals and Risk of Prostate Cancer among Hypogonadal Men: A Longitudinal Study.

PURPOSE: We investigated whether dynamic patterns of testosterone levels contribute to risk of prostate cancer. MATERIALS AND METHODS: We used data on 376 untreated men with hypogonadism (testosterone 12.1 nmol/l or less) recruited from a urology office in Germany. Age at study entry served as a surrogate for age at the first detection of testosterone below 12.1 nmol/l. We derived 3 indicators, including the coefficient of variation, the ratio of the largest decline relative to the mean and the median of maximum declines, to measure the dynamic patterns of testosterone in an individual. RESULTS: Our findings suggest that the later that testosterone dropped below 12.1 nmol/l in a man, the less the lifetime risk of prostate cancer in that individual (HR 0.68, 95% CI 0.57-0.82). Further declines or dynamic variations of testosterone were associated with increased risk of prostate cancer (high vs low coefficient of variation HR 4.88, 95% CI 1.97-12.08, high vs low ratio of largest decline relative to mean HR 8.45, 95% CI 2.82-25.37 and high vs low median of maximum declines HR 2.70, 95% CI 1.15-6.35). CONCLUSIONS: To our knowledge this study is the first to provide evidence of the association between dynamic patterns of testosterone and prostate cancer development. This may have substantial clinical impacts on prostate cancer prevention.

Asthma prevalence and school-related hazardous air pollutants in the US-México border area.

BACKGROUND: Asthma is the most common chronic disease in children and has been linked to high levels of ambient air pollution and certain hazardous air pollutants (HAPs). Outdoor pollutants such as benzene, released by car emissions, and organic chemicals found in diesel exhaust, as well as particles and irritant gases, including nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3), contribute to an increased prevalence of respiratory diseases such as asthma. OBJECTIVES: The objectives of this study were to: 1) conduct a screening survey to identify high risk for asthma among school-age children in Hidalgo County, and, 2) study the potential health impact of school-related exposure to HAPs pertaining to asthma risk. METHODS: We carried out a quantitative cross-sectional study combining a school-based asthma screening survey across 198 schools in Hidalgo County, Texas, with information on school neighborhood environments, including census tract-level information on hazardous air pollutants (HAPs) and socioeconomic status (SES) in the respective school neighborhoods. HAPs levels were assessed based on the EPA 2011 National-Scale Air Toxics Assessment (NATA) while SES information was assessed using data from the 2010-2014 American Community Survey. RESULTS: 2930 students completed the asthma screening survey and results showed an overall asthma prevalence of 9.4%, slightly higher than the national and state prevalence. Participants in the 14-18 years old age group showed a much higher asthma prevalence of 16.7%. When assessing school-neighborhood characteristics, our results revealed no significant differences in asthma prevalence across census tracts with different SES levels. For HAPs, in the single-pollutant model, chlorine levels showed a significant linear trend for prevalence of asthma (p=0.03) while hydrochloric acid had a marginally significant linear trend (p=0.08). The association with chlorine remained significant in the multi-pollutant model. CONCLUSIONS: Asthma prevalence among school-age children in Hidalgo County, Texas, is 9.4%, which is slightly higher than the state rate, especially among young adults, ages 14-18 years who had an asthma rate of 16.7%. Results support an association between exposures to school-neighborhood HAPs and risk for pediatric asthma, especially as related to chlorine. No significant effects of school-level SES on asthma risk were observed.

Structure and function of the mitochondrial calcium uniporter complex.

The mitochondrial calcium uniporter (MCU) is the critical protein of the inner mitochondrial membrane mediating the electrophoretic Ca²âº uptake into the matrix. It plays a fundamental role in the shaping of global calcium signaling and in the control of aerobic metabolism as well as apoptosis. Two features of mitochondrial calcium signaling have been known for a long time: i) mitochondrial Ca²âº uptake widely varies among cells and tissues, and ii) channel opening strongly relies on the extramitochondrial Ca²âº concentration, with low activity at resting [Ca²âº] and high capacity as soon as calcium signaling is activated. Such complexity requires a specialized molecular machinery, with several primary components can be variably gathered together in order to match energy demands and protect from toxic stimuli. In line with this, MCU is now recognized to be part of a macromolecular complex known as the MCU complex. Our understanding of the structure and function of the MCU complex is now growing promptly, revealing an unexpected complexity that highlights the pleiotropic role of mitochondrial Ca²âº signals. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

The mitochondrial calcium uniporter (MCU): molecular identity and physiological roles.

The direct measurement of mitochondrial [Ca(2+)] with highly specific probes demonstrated that major swings in organellar [Ca(2+)] parallel the changes occurring in the cytosol and regulate processes as diverse as aerobic metabolism and cell death by necrosis and apoptosis. Despite great biological relevance, insight was limited by the complete lack of molecular understanding. The situation has changed, and new perspectives have emerged following the very recent identification of the mitochondrial Ca(2+) uniporter, the channel allowing rapid Ca(2+) accumulation across the inner mitochondrial membrane.

Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-ß (CaMKK-ß).

Autophagy is the main lysosomal catabolic process that becomes activated under stress conditions, such as amino acid starvation and cytosolic Ca(2+) upload. However, the molecular details on how both conditions control autophagy are still not fully understood. Here we link essential amino acid starvation and Ca(2+) in a signaling pathway to activate autophagy. We show that withdrawal of essential amino acids leads to an increase in cytosolic Ca(2+), arising from both extracellular medium and intracellular stores, which induces the activation of adenosine monophosphate-activated protein kinase (AMPK) via Ca(2+)/calmodulin-dependent kinase kinase-ß (CaMKK-ß). Furthermore, we show that autophagy induced by amino acid starvation requires AMPK, as this induction is attenuated in its absence. Subsequently, AMPK activates UNC-51-like kinase (ULK1), a mammalian autophagy-initiating kinase, through phosphorylation at Ser-555 in a process that requires CaMKK-ß. Finally, the mammalian target of rapamycin complex C1 (mTORC1), a negative regulator of autophagy downstream of AMPK, is inhibited by amino acid starvation in a Ca(2+)-sensitive manner, and CaMKK-ß appears to be important for mTORC1 inactivation, especially in the absence of extracellular Ca(2+). All these results highlight that amino acid starvation regulates autophagy in part through an increase in cellular Ca(2+) that activates a CaMKK-ß-AMPK pathway and inhibits mTORC1, which results in ULK1 stimulation.

Foreign-born status and risk of gestational diabetes mellitus by years of residence in the United States.

To explore the association between acculturation among foreign-born (FB) women, gestational diabetes (GDM) and GDM-associated adverse birth outcomes, we conducted a retrospective cohort study of 34,696 singleton pregnancies from Houston, TX, between 2011 and 2022. FB women (n = 18,472) were categorized based on years of residence in US (0-5, 6-10, and > 10 years), while US-born women (n = 16,224) were the reference group. A modified Poisson regression model determined the association between acculturative level and GDM within the entire cohort and stratified by race/ethnicity. Compared to US-born women, FB women with 0-5 years [adjusted relative risk (RRadj.) 1.27, 95% confidence interval [CI] 1.14-1.42)], 6-10 years (RRadj. 1.89, 95%CI 1.68-2.11) and > 10 years in the US (RRadj. 1.85, 95%CI 1.69-2.03) had higher risk of GDM. Results were consistent for all racial/ethnic groups, although associations were not significant at 0-5 years. FB women had lower risk of other adverse pregnancy outcomes, except for preeclampsia with severe features at higher levels of acculturation. Results were similar among those with and without GDM. In conclusion, FB status increases risk of GDM among all racial/ethnic groups but is elevated with higher acculturation levels.

Evaluating the Impact of Fetal Sex on Gestational Diabetes Mellitus Following Interaction with Maternal Characteristics.

Fetal-sex-specific changes to placental immunity and metabolism occur in response to obesity. Few studies have determined if fetal sex interacts with maternal characteristics to alter risk of gestational diabetes mellitus (GDM). Among 43,727 singleton pregnancies, we examined the association between male fetal sex and GDM using log-binomial logistic regression to calculate relative risks (RR) and 95% confidence intervals (CI). Interactions were examined between fetal sex and maternal characteristics on the risk of GDM by calculating relative excess risk due to interaction. After adjusting for body mass index, race/ethnicity, maternal age, education, and gravidity, male fetal sex was not associated with GDM (RRadj. 0.95, 95% CI 0.93, 1.04). We found a positive interaction between male fetal sex and obesity (p = 0.04). Nonobese women with male fetuses were less likely to develop GDM, but in the presence of obesity, an opposite trend was observed. There was a positive interaction between male fetal sex and GDM on the risk of preterm delivery < 37-weeks gestation (p = 0.0006). In response to underlying maternal obesity, fetal sex may modify the risk of GDM. In addition, male fetal sex may increase the occurrence of preterm birth among women with GDM.

Factors Associated with Hurricane Evacuation: A Statistical Meta-Analysis of Studies, 1999-2018.

OBJECTIVE: Hurricane evacuation is one of the strategies employed by emergency management and other agencies to reduce morbidity and mortality associated with hurricanes. However, factors associated with residents' evacuation decision-making have been inconsistent. In this study, we conducted a statistical meta-analysis to identify factors associated with hurricane evacuation as well as moderators of the evacuation decision. METHODS: A systematic literature search identified 36 studies published between 1999 and 2018. Pooled estimates were calculated using random-effects models, and heterogeneity across studies was checked using both Q and I2 statistics. Meta-regression methods were used to identify moderators. Publication bias was assessed using both visual (funnel plots) and statistical methods. RESULTS: Mobile home residence, perception of risk, female sex, and Hispanic ethnicity were statistically associated with hurricane evacuation, while geographic region modified the relationship between Hispanic race and evacuation. CONCLUSIONS: Agencies responsible for preparedness may utilize these findings to identify specific population sub-groups for hurricane evacuation communication and other interventions. Future studies should consider statistical interactions and explore opportunities for research translation to emergency officials.

Hospitalizations Among Children and Youth With Autism in the United States: Frequency, Characteristics, and Costs.

National estimates of hospitalization diagnoses and costs were determined using the 2016 HCUP Kids' Inpatient Database. Children and youth with autism were hospitalized over 45,000 times at over $560 million in costs and 260,000 inpatient days. The most frequent principal diagnoses for hospitalizations of children and youth with autism were epilepsy, mental health conditions, pneumonia, asthma, and gastrointestinal disorders, which resulted in almost $200 million in costs and 150,000 inpatient days. Mental health diagnoses accounted for 24.8% of hospitalizations, an estimated $82 million in costs, and approximately 94,000 inpatient days. Children and youth with autism were more likely hospitalized for epilepsy, mental health diagnoses, and gastrointestinal disorders, and less likely for pneumonia and asthma compared to other children and youth.

Characteristics Associated With Consistent Handwashing and Satisfaction in the Workplace: A Pilot Survey of U.S. Workers.

BACKGROUND: This study seeks to determine what handwashing facilities are available to workers, predominantly in the manufacturing and service industries, to find out if their workplace has the appropriate resources to conduct proper handwashing and how that affects handwashing satisfaction. METHODS: This cross-sectional study surveyed U.S. adult workers (N = 241) on their workplace handwashing equipment and facilities. The associations between demographic characteristics, consistent handwashing, and handwashing satisfaction were evaluated using Fisher's exact test. FINDINGS: Eighty-eight percent of respondents reported consistent handwashing. Pulling a handle to exit the restroom was negatively associated with handwashing satisfaction (p = .004) and having difficulty with an automatic faucet or dispenser was negatively marginally significant in its association with handwashing consistency (p = .10). CONCLUSION/APPLICATIONS TO PRACTICE: Greater understanding of the available equipment in workplace restroom facilities and how to improve selection and use of that equipment may improve workers' handwashing experiences.

Changes to Timeliness and Completeness of Infectious Disease Reporting in Texas After Implementation of an Epidemiologic Capacity Program.

OBJECTIVES: The objective of this study was to characterize the changes in timeliness and completeness of disease case reporting in Texas in response to an increasing number of foodborne illnesses and high-consequence infectious disease investigations and the Texas Department of State Health Services' new state-funded epidemiologist (SFE) program. METHODS: We extracted electronic disease case reporting data on 42 conditions from 2012 through 2016 in all local health department (LHD) jurisdictions. We analyzed data on median time for processing reports and percentage of complete reports across time and between SFE and non-SFE jurisdictions using Mann-Whitney t tests and z scores. RESULTS: The median time of processing improved from 13 days to 10 days from 2012 to 2016, and the percentage of disease case reports that were complete improved from 19.6% to 27.7%. Most reports were for foodborne illnesses; both timeliness (11 to 7 days) and completeness (20.9% to 23.5%) improved for these reports. CONCLUSIONS: Disease reporting improvements in timeliness and completeness were associated with the SFE program and its enhancement of epidemiologic capacity. SFEs were shown to improve surveillance metrics in LHDs, even in jurisdictions with a high volume of case reports. Adding epidemiologist positions in LHDs produces a tangible outcome of improved disease surveillance.

Epidemiology Surveillance and Capacity Improvement: A Characterization of Texas, 2017.

OBJECTIVES: In response to increasing caseloads of foodborne illnesses and high consequence infectious disease investigations, the Texas Department of State Health Services (DSHS) requested funding from the Texas Legislature in 2013 and 2015 for a new state-funded epidemiologist (SFE) program. METHODS: Primary cross-sectional survey data were collected from 32 of 40 local health departments (LHDs) via an online instrument and analyzed to quantify roles, responsibilities, and training of epidemiologists in Texas in 2017 and compared to similar state health department assessments. RESULTS: Sixty-six percent of SFEs had epidemiology-specific training (eg, master's in public health) compared to 45% in state health department estimates. For LHDs included in this study, the mean number of epidemiologists per 100 000 was 0.73 in medium LHDs and 0.46 in large LHDs. SFE positions make up approximately 40% of the LHD epidemiology workforce of all sizes and 56% of medium-sized LHD epidemiology staff in Texas specifically. CONCLUSIONS: Through this program, DSHS increased epidemiology capacity almost twofold from 0.28 to 0.47 epidemiologists per 100 000 people. These findings suggest that capacity funding programs like this improve epidemiology capacity in local jurisdictions and should be considered in other regions to improve general public health preparedness and epidemiology capacity.