The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. APPROACH AND RESULTS: C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. CONCLUSIONS: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.

Observation of a phononic quadrupole topological insulator.

The modern theory of charge polarization in solids is based on a generalization of Berry's phase. The possibility of the quantization of this phase arising from parallel transport in momentum space is essential to our understanding of systems with topological band structures. Although based on the concept of charge polarization, this same theory can also be used to characterize the Bloch bands of neutral bosonic systems such as photonic or phononic crystals. The theory of this quantized polarization has recently been extended from the dipole moment to higher multipole moments. In particular, a two-dimensional quantized quadrupole insulator is predicted to have gapped yet topological one-dimensional edge modes, which stabilize zero-dimensional in-gap corner states. However, such a state of matter has not previously been observed experimentally. Here we report measurements of a phononic quadrupole topological insulator. We experimentally characterize the bulk, edge and corner physics of a mechanical metamaterial (a material with tailored mechanical properties) and find the predicted gapped edge and in-gap corner states. We corroborate our findings by comparing the mechanical properties of a topologically non-trivial system to samples in other phases that are predicted by the quadrupole theory. These topological corner states are an important stepping stone to the experimental realization of topologically protected wave guides in higher dimensions, and thereby open up a new path for the design of metamaterials.

Accumulation and dietary risks of perfluoroalkyl substances in fish and shellfish: A market-based study in Barcelona.

Since the 1940s, per- and polyfluoroalkyl substances (PFAS) have been widely produced and used in various applications due to their unique properties. Consequently, the principal exposure routes of PFAS have been broadly studied, leading to the conclusion that dietary exposure (more specifically, the consumption of fish and seafood) was one of their main contributors. Thus, developing an analytical method that determines the level of PFAS in fish and seafood has become a relevant subject. In this work, a previous analytical method has been optimized to determine 12 PFAS in fish muscle from salmon, tuna, cod, hake, sardine, anchovy, and sole, as well as in seven different seafood species (i.e., cuttlefish, octopus, squid, shrimp, Norway lobster, prawn, and mussel) by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Subsequently, the PFAS profile of the different species was studied to determine if it was consistent with that previously reviewed in the literature and to know the most relevant contribution of PFAS for each species. Finally, human exposure to PFAS through their consumption was estimated by the daily intake for seven different age/gender groups. PFAS were obtained from 0.014 to 0.818 ng g-1 wet weight in fish samples. Sardines, anchovies, and soles presented the highest PFAS levels. However, cod samples also showed some PFAS traces. Regarding seafood, PFAS levels range from 0.03 to 36.7 ng g-1 dry weight for the studied species. A higher concentration of PFAS has been found in the cephalopods' spleens and the crustaceans' heads. PFOS and PFBS were the predominant compounds in each seafood species, respectively. On the other hand, in the case of mussels, which are the less polluted species of the study, contamination by longer-chained PFAS was also observed. Finally, the total intake of PFAS due to fish and shellfish consumption for the Spanish adult population was estimated at 17.82 ng day-1. Nevertheless, none of the analyzed samples exceeded the European Food Safety Authority (EFSA) risk value for the supervised PFAS in any age/gender group reviewed.

microRNA-based signatures obtained from endometrial fluid identify implantative endometrium.

STUDY QUESTION: Is it possible to use free and extracellular vesicle-associated microRNAs (miRNAs) from human endometrial fluid (EF) samples as non-invasive biomarkers for implantative endometrium? SUMMARY ANSWER: The free and extracellular vesicle-associated miRNAs can be used to detect implantative endometrium in a non-invasive manner. WHAT IS KNOWN ALREADY: miRNAs and extracellular vesicles (EVs) from EF have been described as mediators of the embryo-endometrium crosstalk. Therefore, the analysis of miRNA from this fluid could become a non-invasive technique for recognizing implantative endometrium. This analysis could potentially help improve the implantation rates in ART. STUDY DESIGN, SIZE, DURATION: In this prospective study, we first optimized different protocols for EVs and miRNA analyses using the EF of a setup cohort (n = 72). Then, we examined differentially expressed miRNAs in the EF of women with successful embryo implantation (discovery cohort n = 15/validation cohort n = 30) in comparison with those for whom the implantation had failed (discovery cohort n = 15/validation cohort n = 30). Successful embryo implantation was considered when pregnancy was confirmed by vaginal ultrasound showing a gestational sac 4 weeks after embryo transfer (ET). PARTICIPANTS/MATERIALS, SETTING, METHODS: The EF of the setup cohort was obtained before starting fertility treatment during the natural cycle, 16-21 days after the beginning of menstruation. For the discovery and validation cohorts, the EF was collected from women undergoing frozen ET on Day 5, and the samples were collected immediately before ET. In this study, we compared five different methods; two of them based on direct extraction of RNA and the other three with an EV enrichment step before the RNA extraction. Small RNA sequencing was performed to determine the most efficient method and find a predictive model differentiating between implantative and non-implantative endometrium. The models were confirmed using quantitative PCR in two sets of samples (discovery and validation cohorts) with different implantation outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: The protocols using EV enrichment detected more miRNAs than the methods based on direct RNA extraction. The two most efficient protocols (using polymer-based precipitation (PBP): PBP-M and PBP-N) were used to obtain two predictive models (based on three miRNAs) allowing us to distinguish between an implantative and non-implantative endometrium. The first Model 1 (PBP-M) (discovery: AUC = 0.93; P-value = 0.003; validation: AUC = 0.69; P-value = 0.019) used hsa-miR-200b-3p, hsa-miR-24-3p and hsa-miR-148b-3p. Model 2 (PBP-N) (discovery: AUC = 0.92; P-value = 0.0002; validation: AUC = 0.78; P-value = 0.0002) used hsa-miR-200b-3p, hsa-miR-24-3p and hsa-miR-99b-5p. Functional analysis of these miRNAs showed strong association with key implantation processes such as in utero embryonic development or transforming growth factor-beta signaling. LARGE SCALE DATA: The FASTQ data are available in the GEO database (access number GSE178917). LIMITATIONS, REASONS FOR CAUTION: One important factor to consider is the inherent variability among the women involved in the trial and among the transferred embryos. The embryos were pre-selected based on morphology, but neither genetic nor molecular studies were conducted, which would have improved the accuracy of our tests. In addition, a limitation in miRNA library construction is the low amount of input RNA. WIDER IMPLICATIONS OF THE FINDINGS: We describe new non-invasive protocols to analyze miRNAs from small volumes of EF. These protocols could be implemented in clinical practice to assess the status of the endometrium before attempting ET. Such evaluation could help to avoid the loss of embryos transferred to a non-implantative endometrium. STUDY FUNDING/COMPETING INTEREST(S): J.I.-P. was supported by a predoctoral grant from the Basque Government (PRE_2017_0204). This study was partially funded by the Grant for Fertility Innovation (GFI, 2011) from Merck (Darmstadt, Germany). It was also supported by the Spanish Ministry of Economy and Competitiveness MINECO within the National Plan RTI2018-094969-B-I00, the European Union's Horizon 2020 research and innovation program (860303), the Severo Ochoa Centre of Excellence Innovative Research Grant (SEV-2016-0644) and the Instituto de Salud Carlos III (PI20/01131). The funding entities did not play any role in the study design, collection, analysis and interpretation of data, writing of the report or the decision to submit the article for publication. The authors declare no competing interests.

"Many people have no idea": a qualitative analysis of healthcare barriers among Yazidi refugees in the Midwestern United States.

BACKGROUND: The COVID-19 pandemic has shed new light on inequities in healthcare access faced by immigrant and refugee communities. To address ongoing disparities, there is an urgent need for ecological approaches to better understand the barriers that hinder and resources that facilitate access to healthcare. This study investigates barriers to healthcare system access faced by Yazidi refugees in the Midwestern United States. METHODS: Informed by the Interpretative Phenomenological Approach, three focus group meetings with a community advisory board were conducted between September 2019 and January 2020. The nine-member focus group included social workers, healthcare providers, and members of the Yazidi community. Meeting recordings were transcribed into English, coded for themes, and validated. RESULTS: We describe themes related to specific barriers to healthcare access; analyze the influence of relational dynamics in the focus group; explore experiential themes related to healthcare access in the Yazidi community, and finally interpret our findings through a social-ecological lens. CONCLUSION: Community agencies, healthcare organizations, policymakers, and other stakeholders must work together to develop strategies to reduce systemic barriers to equitable care. Community representation in priority-setting and decision-making is essential to ensure relevance, acceptability, and utilization of developed strategies.

Environmental control programs the emergence of distinct functional ensembles from unconstrained chemical reactions.

Many approaches to the origin of life focus on how the molecules found in biology might be made in the absence of biological processes, from the simplest plausible starting materials. Another approach could be to view the emergence of the chemistry of biology as process whereby the environment effectively directs "primordial soups" toward structure, function, and genetic systems over time. This does not require the molecules found in biology today to be made initially, and leads to the hypothesis that environment can direct chemical soups toward order, and eventually living systems. Herein, we show how unconstrained condensation reactions can be steered by changes in the reaction environment, such as order of reactant addition, and addition of salts or minerals. Using omics techniques to survey the resulting chemical ensembles we demonstrate there are distinct, significant, and reproducible differences between the product mixtures. Furthermore, we observe that these differences in composition have consequences, manifested in clearly different structural and functional properties. We demonstrate that simple variations in environmental parameters lead to differentiation of distinct chemical ensembles from both amino acid mixtures and a primordial soup model. We show that the synthetic complexity emerging from such unconstrained reactions is not as intractable as often suggested, when viewed through a chemically agnostic lens. An open approach to complexity can generate compositional, structural, and functional diversity from fixed sets of simple starting materials, suggesting that differentiation of chemical ensembles can occur in the wider environment without the need for biological machinery.

Approach to classify, separate, and enrich objects in groups using ensemble sorting.

The sorting of objects into groups is a fundamental operation, critical in the preparation and purification of populations of cells, crystals, beads, or droplets, necessary for research and applications in biology, chemistry, and materials science. Most of the efforts exploring such purification have focused on two areas: the degree of separation and the measurement precision required for effective separation. Conventionally, achieving good separation ultimately requires that the objects are considered one by one (which can be both slow and expensive), and the ability to measure the sorted objects by increasing sensitivity as well as reducing sorting errors. Here we present an approach to sorting that addresses both critical limitations with a scheme that allows us to approach the theoretical limit for the accuracy of sorting decisions. Rather than sorting individual objects, we sort the objects in ensembles, via a set of registers which are then in turn sorted themselves into a second symmetric set of registers in a lossless manner. By repeating this process, we can arrive at high sorting purity with a low set of constraints. We demonstrate both the theory behind this idea and identify the critical parameters (ensemble population and sorting time), and show the utility and robustness of our method with simulations and experimental systems spanning several orders of scale, sorting populations of macroscopic beads and microfluidic droplets. Our method is general in nature and simplifies the sorting process, and thus stands to enhance many different areas of science, such as purification, enrichment of rare objects, and separation of dynamic populations.

Late life depressive symptoms and cognitive function among older Mexican adults: the past and the present.

Objective: To evaluate associations between depression and individual cognitive domains and how changes in depressive symptoms relate to cognition three years later in the context of Mexico, a developing country experiencing rapid aging.Method: Data comes from the 2012 and 2015 waves of the Mexican Health and Aging Study (n = 12,898, age 50+). Depression is ascertained using a modified Center for Epidemiologic Studies - Depression Scale. Cognition is assessed using verbal learning, verbal memory, visual scanning, verbal fluency, visuospatial ability, visual memory, and orientation tasks. Depressive symptoms and cognitive functioning were both measured in 2012 and 2015. Scores across cognitive domains are modeled using ordinary least squares regression, adjusting for demographic, health, and economic covariates.Results: When depression and cognition were measured concurrently in 2015, depression exhibited associations with all cognitive domains. When considering a respondent's history of depression, individuals who had elevated depressive symptoms in 2012 and recovered by 2015 continued to exhibit poorer cognitive function in 2015 in verbal learning, verbal memory, visual scanning, and verbal fluency tasks compared to individuals who were neither depressed in 2012 nor 2015.Conclusions: Depression was associated with cognition across cognitive domains among older Mexican adults. Despite improvements in depressive symptomatology, formerly depressed respondents continued to perform worse than their counterparts without a history of depression on several cognitive tasks. In addition to current mental health status, researchers should consider an individual's history of depression when assessing the cognitive functioning of older adults.

Mitochondrial implications in human pregnancies with intrauterine growth restriction and associated cardiac remodelling.

Intrauterine growth restriction (IUGR) is an obstetric complication characterised by placental insufficiency and secondary cardiovascular remodelling that can lead to cardiomyopathy in adulthood. Despite its aetiology and potential therapeutics are poorly understood, bioenergetic deficits have been demonstrated in adverse foetal and cardiac development. We aimed to evaluate the role of mitochondria in human pregnancies with IUGR. In a single-site, cross-sectional and observational study, we included placenta and maternal peripheral and neonatal cord blood mononuclear cells (PBMC and CBMC) from 14 IUGR and 22 control pregnancies. The following mitochondrial measurements were assessed: enzymatic activities of mitochondrial respiratory chain (MRC) complexes I, II, IV, I + III and II + III, oxygen consumption (cell and complex I-stimulated respiration), mitochondrial content (citrate synthase [CS] activity and mitochondrial DNA copy number), total ATP levels and lipid peroxidation. Sirtuin3 expression was evaluated as a potential regulator of bioenergetic imbalance. Intrauterine growth restriction placental tissue showed a significant decrease of MRC CI enzymatic activity (P < 0.05) and CI-stimulated oxygen consumption (P < 0.05) accompanied by a significant increase of Sirtuin3/ß-actin protein levels (P < 0.05). Maternal PBMC and neonatal CBMC from IUGR patients presented a not significant decrease in oxygen consumption (cell and CI-stimulated respiration) and MRC enzymatic activities (CII and CIV). Moreover, CS activity was significantly reduced in IUGR new-borns (P < 0.05). Total ATP levels and lipid peroxidation were preserved in all the studied tissues. Altered mitochondrial function of IUGR is especially present at placental and neonatal level, conveying potential targets to modulate obstetric outcome through dietary interventions aimed to regulate Sirtuin3 function.

Cohort Differences in Cognitive Impairment and Cognitive Decline Among Mexican-Americans Aged 75 Years or Older.

Research suggests that the prevalence and incidence of cognitive impairment among older adults is decreasing. This analysis used data from 9 waves (1993-2016) of the Hispanic Established Populations for the Epidemiologic Study of the Elderly to assess cognitive status and cognitive decline for 2 cohorts of Mexican-Americans aged ≥75 years in 1993-1994 versus 2004-2005. Logistic regression, joint longitudinal survival models, and illness-death models for interval-censored data were used to examine cohort differences in the odds of prevalent cognitive impairment, trajectories of cognitive decline, and the risk of 10-year incident cognitive impairment, respectively. Results indicated that compared with the 1993-1994 cohort, the 2004-2005 cohort had higher odds for prevalent cognitive impairment (odds ratio = 2.51, 95% confidence interval (CI): 1.92, 3.29), particularly among participants with <4 years of education (odds ratio = 2.99, 95% CI: 2.14, 4.18). Conversely, the 2004-2005 cohort exhibited significantly slower rates of cognitive decline (߈ = 0.50, 95% CI: 0.39, 0.62) and had a significantly lower risk of incident cognitive impairment (hazard ratio = 0.75, 95% CI: 0.62, 0.91) compared with the 1993-1994 cohort. This analysis provides mixed results for cohort trends in the cognitive health of older Mexican-Americans. Continued research is needed to identify risk factors that contribute to these population-level trends.

Designing perturbative metamaterials from discrete models.

Identifying material geometries that lead to metamaterials with desired functionalities presents a challenge for the field. Discrete, or reduced-order, models provide a concise description of complex phenomena, such as negative refraction, or topological surface states; therefore, the combination of geometric building blocks to replicate discrete models presenting the desired features represents a promising approach. However, there is no reliable way to solve such an inverse problem. Here, we introduce 'perturbative metamaterials', a class of metamaterials consisting of weakly interacting unit cells. The weak interaction allows us to associate each element of the discrete model with individual geometric features of the metamaterial, thereby enabling a systematic design process. We demonstrate our approach by designing two-dimensional elastic metamaterials that realize Veselago lenses, zero-dispersion bands and topological surface phonons. While our selected examples are within the mechanical domain, the same design principle can be applied to acoustic, thermal and photonic metamaterials composed of weakly interacting unit cells.

Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 G2019S -Parkinson's disease.

BACKGROUND: Mutations in leucine rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). Mitochondrial and autophagic dysfunction has been described as etiologic factors in different experimental models of PD. We aimed to study the role of mitochondria and autophagy in LRRK2 G2019S -mutation, and its relationship with the presence of PD-symptoms. METHODS: Fibroblasts from six non-manifesting LRRK2 G2019S -carriers (NM-LRRK2 G2019S ) and seven patients with LRRK2 G2019S -associated PD (PD-LRRK2 G2019S ) were compared to eight healthy controls (C). An exhaustive assessment of mitochondrial performance and autophagy was performed after 24-h exposure to standard (glucose) or mitochondrial-challenging environment (galactose), where mitochondrial and autophagy impairment may be heightened. RESULTS: A similar mitochondrial phenotype of NM-LRRK2 G2019S and controls, except for an early mitochondrial depolarization (54.14% increased, p = 0.04), was shown in glucose. In response to galactose, mitochondrial dynamics of NM-LRRK2 G2019S improved (- 17.54% circularity, p = 0.002 and + 42.53% form factor, p = 0.051), probably to maintain ATP levels over controls. A compromised bioenergetic function was suggested in PD-LRRK2 G2019S when compared to controls in glucose media. An inefficient response to galactose and worsened mitochondrial dynamics (- 37.7% mitochondrial elongation, p = 0.053) was shown, leading to increased oxidative stress. Autophagy initiation (SQTSM/P62) was upregulated in NM-LRRK2 G2019S when compared to controls (glucose + 118.4%, p = 0.014; galactose + 114.44%, p = 0.009,) and autophagosome formation increased in glucose media. Despite of elevated SQSTM1/P62 levels of PD-NM G2019S when compared to controls (glucose + 226.14%, p = 0.04; galactose + 78.5%, p = 0.02), autophagosome formation was deficient in PD-LRRK2 G2019S when compared to NM-LRRK2 G2019S (- 71.26%, p = 0.022). CONCLUSIONS: Enhanced mitochondrial performance of NM-LRRK2 G2019S in mitochondrial-challenging conditions and upregulation of autophagy suggests that an exhaustion of mitochondrial bioenergetic and autophagic reserve, may contribute to the development of PD in LRRK2 G2019S mutation carriers.

Tunable, synchronized frequency down-conversion in magnetic lattices with defects.

We study frequency conversion in nonlinear mechanical lattices, focusing on a chain of magnets as a model system. We show that, by inserting mass defects at suitable locations, we can introduce localized vibrational modes that nonlinearly couple to extended lattice modes. The nonlinear interaction introduces an energy transfer from the high-frequency localized modes to a low-frequency extended mode. This system is capable of autonomously converting energy between highly tunable input and output frequencies, which need not be related by integer harmonic or subharmonic ratios. It is also capable of obtaining energy from multiple sources at different frequencies with a tunable output phase, due to the defect synchronization provided by the extended mode. Our lattice is a purely mechanical analogue of an opto-mechanical system, where the localized modes play the role of the electromagnetic field and the extended mode plays the role of the mechanical degree of freedom.This article is part of the theme issue 'Nonlinear energy transfer in dynamical and acoustical systems'.

Routine lower gastrointestinal endoscopy for radiographically confirmed acute diverticulitis. In whom and when is it indicated?

INTRODUCTION: international guidelines recommend a routine colonoscopy to rule out advanced neoplasm after an acute diverticulitis event. However, in recent years, this recommendation has been called into question following the advent of computerized tomography (CT), particularly with regard to uncomplicated diverticulitis. Furthermore, colonoscopy is associated with a risk and additional costs. OBJECTIVE: to understand the diagnostic yield, quality and safety of colonoscopy in the setting of acute diverticulitis. METHODS: this was a retrospective study of all patients diagnosed with acute diverticulitis via CT between 2005 and 2013, who subsequently underwent a colonoscopy. RESULTS: two hundred and sixteen patients diagnosed with acute diverticulitis via CT were enrolled. These included 58 cases with complicated diverticulitis (27%) and 158 with uncomplicated diverticulitis (73%). An advanced neoplasm was found in 12 patients (5.6%); 11.7% were complicated and 3.2% were uncomplicated (p = 0.02). No major complications were identified. The quality was low but improved over time; the complete procedure rate was 88%, an effective preparation was achieved in 75% and excision of polyps < 2 cm was performed in 78% of cases. The optimum colonoscopy quality cu-off was 9.5 weeks. CONCLUSION: routine colonoscopy is advisable after a complicated diverticulitis event but its recommendation is unclear with regard to uncomplicated episodes. Colonoscopy is safe even when performed early. The overall quality is low but may be optimized via a subsequent endoscopy, two months after a diverticulitis diagnosis.

Sociocultural variability in the Latino population: Age patterns and differences in morbidity among older US adults.

BACKGROUND: The US Latino population is rapidly aging and becoming increasingly diverse with respect to nativity and national origin. Increased longevity along with medical advancements in treatment have resulted in a higher number of older Latinos living with morbidity. Therefore, there is a need to understand variability in Latino health among older adults. OBJECTIVES: This paper documents mid- and late-life health differences in morbidity by race/ethnicity, nativity, and country of origin among adults aged 50 and older. METHODS: We use data from the 2000-2015 National Health Interview Survey to calculate age-and gender-specific proportions based on reports of five morbidity measures: hypertension, heart disease, stroke, cancer, and diabetes among non-Latino Whites and seven Latino subgroups. RESULTS: The foreign-born from Mexico, Cuba, and Central/South America, regardless of gender, exhibit an immigrant advantage for heart disease and cancer in comparison to non-Latino Whites across all age categories. Conversely, island-born Puerto Ricans are generally characterized with higher levels of morbidity. Similarly, US-born Puerto Ricans and Mexicans exhibit morbidity patterns indicative of their minority status. Latinos, regardless of gender, were more likely to report diabetes than non-Latino Whites. Hypertension and stroke have significant variability in age patterns among US-and foreign-born Latinos. CONCLUSION: Recognizing the importance of within-Latino heterogeneity in health is imperative if researchers are to implement social services and health policies aimed at ameliorating the risk of disease. CONTRIBUTION: Considering intersectional ethnic, nativity, and country-of-origin characteristics among older Latinos is important to better understand the underlying causes of racial/ethnic disparities in morbidity across the life course.

The role of education in the association between race/ethnicity/nativity, cognitive impairment, and dementia among older adults in the United States.

BACKGROUND: Older Black and Hispanic adults are more likely to be cognitively impaired than older White adults. Disadvantages in educational achievement for minority and immigrant populations may contribute to disparities in cognitive impairment. OBJECTIVE: Examine the role of education in racial/ethnic and nativity differences in cognitive impairment/no dementia (CIND) and dementia among older US adults. METHODS: Data comes from the 2012 Health and Retirement Study. A total of 19,099 participants aged ≥50 were included in the analysis. Participants were categorized as having normal cognition, CIND, or dementia based on the Telephone Interview for Cognitive Status (TICS) or questions from a proxy interview. We document age and educational differences in cognitive status among White, Black, US-born Hispanic, and foreign-born Hispanic adults by sex. Logistic regression is used to quantify the association between race/ethnicity/nativity, education, and cognitive status by sex. RESULTS: Among women, foreign-born Hispanics have higher odds of CIND and dementia than Whites. For men, Blacks have higher odds for CIND and dementia compared to Whites. The higher odds for CIND and dementia across race/ethnic and nativity groups was reduced after controlling for years of education but remained statistically significant for older Black and US-born Hispanic adults. Controlling for education reduces the odds for CIND (women and men) and dementia (men) among foreign-born Hispanics to nonsignificance. CONTRIBUTION: These results highlight the importance of education in CIND and dementia, particularly among foreign-born Hispanics. Addressing inequalities in education can contribute to reducing racial/ethnic/nativity disparities in CIND and dementia for older adults.

Mitochondrial toxicity and caspase activation in HIV pregnant women.

To assess the impact of HIV-infection and highly active anti-retroviral treatment in mitochondria and apoptotic activation of caspases during pregnancy and their association with adverse perinatal outcome. Changes of mitochondrial parameters and apoptotic caspase activation in maternal peripheral blood mononuclear cells were compared at first trimester of pregnancy and delivery in 27 HIV-infected and -treated pregnant women versus 24 uninfected pregnant controls. We correlated immunovirological, therapeutic and perinatal outcome with experimental findings: mitochondrial DNA (mtDNA) content, mitochondrial protein synthesis, mitochondrial function and apoptotic caspase activation. The HIV pregnancies showed increased adverse perinatal outcome (OR: 4.81 [1.14-20.16]; P < 0.05) and decreased mtDNA content (42.66 ± 5.94%, P < 0.01) compared to controls, even higher in naïve participants. This depletion caused a correlated decrease in mitochondrial protein synthesis (12.82 ± 5.73%, P < 0.01) and function (20.50 ± 10.14%, P < 0.001), not observed in controls. Along pregnancy, apoptotic caspase-3 activation increased 63.64 ± 45.45% in controls (P < 0.001) and 100.00 ± 47.37% in HIV-pregnancies (P < 0.001), in correlation with longer exposure to nucleoside analogues. HIV-infected women showed increased obstetric problems and declined genetic and functional mitochondrial parameters during pregnancy, especially those firstly exposed to anti-retrovirals. The apoptotic activation of caspases along pregnancy is emphasized in HIV pregnancies promoted by nucleoside analogues. However, we could not demonstrate direct mitochondrial or apoptotic implication in adverse obstetric outcome probably because of the reduced sample size.

HIV-1 promonocytic and lymphoid cell lines: an in vitro model of in vivo mitochondrial and apoptotic lesion.

To characterize mitochondrial/apoptotic parameters in chronically human immunodeficiency virus (HIV-1)-infected promonocytic and lymphoid cells which could be further used as therapeutic targets to test pro-mitochondrial or anti-apoptotic strategies as in vitro cell platforms to deal with HIV-infection. Mitochondrial/apoptotic parameters of U1 promonocytic and ACH2 lymphoid cell lines were compared to those of their uninfected U937 and CEM counterparts. Mitochondrial DNA (mtDNA) was quantified by rt-PCR while mitochondrial complex IV (CIV) function was measured by spectrophotometry. Mitochondrial-nuclear encoded subunits II-IV of cytochrome-c-oxidase (COXII-COXIV), respectively, as well as mitochondrial apoptotic events [voltage-dependent-anion-channel-1(VDAC-1)-content and caspase-9 levels] were quantified by western blot, with mitochondrial mass being assessed by spectrophotometry (citrate synthase) and flow cytometry (mitotracker green assay). Mitochondrial membrane potential (JC1-assay) and advanced apoptotic/necrotic events (AnexinV/propidium iodide) were measured by flow cytometry. Significant mtDNA depletion spanning 57.67% (P < 0.01) was found in the U1 promonocytic cells further reflected by a significant 77.43% decrease of mitochondrial CIV activity (P < 0.01). These changes were not significant for the ACH2 lymphoid cell line. COXII and COXIV subunits as well as VDAC-1 and caspase-9 content were sharply decreased in both chronic HIV-1-infected promonocytic and lymphoid cell lines (<0.005 in most cases). In addition, U1 and ACH2 cells showed a trend (moderate in case of ACH2), albeit not significant, to lower levels of depolarized mitochondrial membranes. The present in vitro lymphoid and especially promonocytic HIV model show marked mitochondrial lesion but apoptotic resistance phenotype that has been only partially demonstrated in patients. This model may provide a platform for the characterization of HIV-chronicity, to test novel therapeutic options or to study HIV reservoirs.

Imbalance in mitochondrial dynamics and apoptosis in pregnancies among HIV-infected women on HAART with obstetric complications.

Background: HIV infection and HAART trigger genetic and functional mitochondrial alterations leading to cell death and adverse clinical manifestations. Mitochondrial dynamics enable mitochondrial turnover and degradation of damaged mitochondria, which may lead to apoptosis. Objectives: To evaluate markers of mitochondrial dynamics and apoptosis in pregnancies among HIV-infected women on HAART and determine their potential association with obstetric complications. Methods: This controlled, single-site, observational study without intervention included 26 HIV-infected pregnant women on HAART and 18 control pregnancies and their newborns. Maternal PBMCs and neonatal cord blood mononuclear cells (CBMCs) were isolated at the first trimester of gestation and at delivery. The placenta was homogenized at 5% w/v. Mitochondrial dynamics, fusion events [mitofusin 2 (Mfn2)/ß-actin] and fission events [dynamin-related protein 1 (Drp1/ß-actin)] and apoptosis (caspase 3/ß-actin) were assessed by western blot analysis. Results: Obstetric complications were significantly more frequent in pregnancies among HIV-infected women [OR 5.00 (95% CI 1.21-20.70)]. Mfn2/ß-actin levels in PBMCs from controls significantly decreased during pregnancy (202.13 ±â€¯57.45%), whereas cases maintained reduced levels from the first trimester of pregnancy and no differences were observed in CBMCs. Mfn2/ß-actin and Drp1/ß-actin contents significantly decreased in the placenta of cases. Caspase 3/ß-actin levels significantly increased during pregnancy in PBMCs of cases (50.00 ±â€¯7.89%), remaining significantly higher than in controls. No significant differences in caspase 3/ß-actin content of neonatal CBMCs were observed, but there was a slight increased trend in placenta from cases. Conclusions: HIV- and HAART-mediated mitochondrial damage may be enhanced by decreased mitochondrial dynamics and increased apoptosis in maternal and placental compartments but not in the uninfected fetus. However, direct effects on mitochondrial dynamics and implication of apoptosis were not demonstrated in adverse obstetric outcomes.