αSynuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson's Disease?

Parkinson's Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein αSynuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and this review explores the strong possibility that αSynuclein and mitochondrial dysfunction have an inter-relationship responsible for underlying the disease pathology. Amplifying cycles of mitochondrial dysfunction and αSynuclein toxicity can be envisaged, with either being the disease-initiating factor yet acting together during disease progression. Multiple potential mechanisms exist in which mitochondrial dysfunction and αSynuclein could interact to exacerbate their neurodegenerative properties. Candidates discussed within this review include autophagy, mitophagy, mitochondrial dynamics/fusion/fission, oxidative stress and reactive oxygen species, endoplasmic reticulum stress, calcium, nitrosative stress and αSynuclein Oligomerization

Single-cell sequencing of iPSC-Dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes

Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD), but neuronal cultures are confounded by asynchronous and heterogeneous appearance of disease phenotypes in vitro. Using high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, we identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Pseudotime analysis of genes differentially expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with HDAC4-modulating compounds upregulated genes early in the DE axis and corrected PD-related cellular phenotypes. Our study demonstrates how single-cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

“Learning to Take the Excess Baggage Off”: a Study of Black Women Activists’ Self-care Practices

This research originated in my experiences and observations as a Black woman activist in Milwaukee, Wisconsin. With the untimely deaths of Black feminist foremothers like Audre Lorde and more contemporary Black women activists, such as Erica Garner, I wondered about the burdens of oppression and stress in the lives of Black women activists. Traditional media covers activists’ fatalities, but the question of the health and wellbeing of activists remains largely absent in discourse. Historians often focus on the leadership characteristics and intellectual work of Black women. Yet, leadership narratives can overlook the health of Black women activists. To date, little work has attended to the health and wellness of Black women activists in social justice movements. As a result, tropes of the strong Black woman are reinforced in narratives about Black women as activists, which marginalizes their prioritizing of self-care that is grounded in overall health. The lack of attention to the health of activists places the sustainability of Black women who are at the forefront of movement work in jeopardy, as well as limits our scholarly understanding of the impact of activism in the lives of Black women. “Learning to Take the Excess Baggage Off”: A Study of Black Women Activist’s Self-Care Practices challenges the one-sided narrative of Black women primarily as caregivers and argues that Black women use activism as a way to mitigate stress and prioritize well-being. My dissertation uses semi-structured interviews with thirty-nine participants, participant observations with four of the participants interviewed, and critical self-reflection to map traditions of Black women’s organizing and to analyze the relationship between activism and self-care. I define self-care as “a transformative, on-going process involving practices that are pleasurable, joyful and leads to optimal mental, emotional, spiritual and physical health.” This definition was constructed from the data collected and review of literature. According to this definition, activism is a form of self-care, which is also supported by the research findings. The findings conclude that activism and community networks were frequently used as self-care practices, while economic insecurity and problematic White allyship were major challenges for participants. Moreover, the research categorized participants into an activist typology that includes five categories: embodied activist, activist strategist, full-spectrum activist, civic activist, and activist empaths. Self-care as activism makes an important contribution to feminist scholarship on Black women’s health and wellbeing, and historical scholarship on activism and community ties. Finally, by looking beyond normative assessments of Black women as caregivers, this research raises new questions about the intersections of race, gender, sexuality, activism, and intimacy

The pathogenic relationship of Alpha Synuclein and Mitochondrial dysfunction in sporadic Parkinson's Disease

Parkinsons Disease (PD) is a complex neurodegenerative disorder and a lack of knowledge of the molecular mechanisms responsible for the cause and progression of PD is a major impediment to therapeutic advances. The protein Alpha-Synuclein (αSyn) is a central component in PD pathogenesis, with its increased expression resulting in early onset forms of PD, yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD.An unbiased screen in Saccharomyces cerevisiae identified a number of OXPHOS genes whose deletion sensitised cells to the induced expression of αSyn. Only the combination of partial OXPHOS inhibition and αSyn expression resulted in toxicity and cell death. A similar synergistic relationship was observed in a mammalian PD model of low levels of αSyn expression as the combination of partial OXPHOS inhibition produced a significantly greater amount of cell death after 4 days than the sum of either insult alone.A number of cellular stresses have been observed in PD patients and further investigation into the nature of this αSyn-OXPHOS synergistic relationship has discovered a cellular cascade of events unique to the presence of both these insults in combination. In yeast and mammalian models of PD, the αSyn-OXPHOS model results in early initiation of endoplasmic reticulum (ER) stress, nitric oxide (NO) species, cholesterol dysregulation and OXPHOS dysfunction. These events are followed by the production of reactive oxygen species and cell death. An ER stress inhibitor, sterol inhibitor or NO inhibitor reduced cell death, displaying a potential functional role of these stresses in PD development. A sterol inhibitor reduced αSyn protein levels, implicating the reduction of cholesterol as a potential therapeutic target.This model proposed that mitochondrial dysfunction and αSyn toxicity may exacerbate each other in a self-amplifying cycle that, chronically, could attain a level of damage to cause the observed pathology and account for the late onset nature of the disease. Currently there is no cure or early diagnosis for PD, where intervention strategies could be implemented. Discovering these early events may assist in the identification of biomarkers and early preventative treatment strategies for PD

Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson’s disease

While induced pluripotent stem cell (iPSC) technologies enable the study of inaccessible patient cell types, cellular heterogeneity can confound the comparison of gene expression profiles between iPSC-derived cell lines. Here, we purified iPSC-derived human dopaminergic neurons (DaNs) using the intracellular marker, tyrosine hydroxylase. Once purified, the transcriptomic profiles of iPSC-derived DaNs appear remarkably similar to profiles obtained from mature post-mortem DaNs. Comparison of the profiles of purified iPSC-derived DaNs derived from Parkinson’s disease (PD) patients carrying LRRK2 G2019S variants to controls identified significant functional convergence amongst differentially-expressed (DE) genes. The PD LRRK2-G2019S associated profile was positively matched with expression changes induced by the Parkinsonian neurotoxin rotenone and opposed by those induced by clioquinol, a compound with demonstrated therapeutic efficacy in multiple PD models. No functional convergence amongst DE genes was observed following a similar comparison using non-purified iPSC-derived DaN-containing populations, with cellular heterogeneity appearing a greater confound than genotypic background

Neuronal oscillations in the EEG under varying cognitive load : a comparative study between slow waves and faster oscillations

Objective: This study has been specifically designed to investigate very low frequency neuronal oscillations (VLFO, <0.5Hz) during resting states and during goal-directed tasks of graded difficulty levels, quantify the changes that the slow waves undergo in these conditions and compare them with those for higher frequency bands (namely delta, theta and alpha). Methods: To this end we developed a multistage signal processing methodology comprising blind source separation coupled with a neural network based feature extraction and classification method. Results: Changes in the amplitude and phase of brain sources estimates in the VLF band between rest and task were enhanced with increased task difficulty, but remained lower than those experienced in higher frequency bands. The slow wave variations were also significantly correlated with task performance measures, and hence with the level of task-directed attention. Conclusions: These findings suggest that besides their prominent sensitivity to external stimulation, VLFOs also contribute to the cortical ongoing background activity which may not be specifically related to task-specific attention and performance. Significance Our work provides important insight into the association between VLF brain activity and conventional EEG frequency bands, and presents a novel framework for assessing neural activity during various mental conditions and psychiatric states