Progressive Resistance Exercise and Parkinson's Disease: A Review of Potential Mechanisms

This paper reviews the therapeutically beneficial effects of progressive resistance exercise (PRE) on Parkinson's disease (PD). First, this paper discusses the rationale for PRE in PD. Within the first section, the review discusses the central mechanisms that underlie bradykinesia and muscle weakness, highlights findings related to the central changes that accompany PRE in healthy individuals, and extends these findings to individuals with PD. It then illustrates the hypothesized positive effects of PRE on nigro-striatal-thalamo-cortical activation and connectivity. Second, it reviews recent findings of the use of PRE in individuals with PD. Finally, knowledge gaps of using PRE on individuals with PD are discussed along with suggestions for future research

Structural insights into the function of the catalytically active human Taspase1

19 pags., 7 figs., 2 tabs.Taspase1 is an Ntn-hydrolase overexpressed in primary human cancers, coordinating cancer cell proliferation, invasion, and metastasis. Loss of Taspase1 activity disrupts proliferation of human cancer cells in vitro and in mouse models of glioblastoma. Taspase1 is synthesized as an inactive proenzyme, becoming active upon intramolecular cleavage. The activation process changes the conformation of a long fragment at the C-terminus of the α subunit, for which no full-length structural information exists and whose function is poorly understood. We present a cloning strategy to generate a circularly permuted form of Taspase1 to determine the crystallographic structure of active Taspase1. We discovered that this region forms a long helix and is indispensable for the catalytic activity of Taspase1. Our study highlights the importance of this element for the enzymatic activity of Ntn-hydrolases, suggesting that it could be a potential target for the design of inhibitors with potential to be developed into anticancer therapeutics.This project has been funded in whole with Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Chemical Biology Consortium contract no. HHSN261200800001E

Feasibility of High-Throughput Genome-Wide Genotyping using DNA from Stored Buccal Cell Samples

It is unclear if buccal cell samples contain sufficient human DNA with adequately sized fragments for high throughput genetic bioassays. Yet buccal cell sample collection is an attractive alternative to gathering blood samples for genetic epidemiologists engaged in large-scale genetic biomarker studies. We assessed the genotyping efficiency (GE) and genotyping concordance (GC) of buccal cell DNA samples compared to corresponding blood DNA samples, from 32 Nurses’ Health Study (NHS) participants using the Illumina Infinium 660W-Quad platform. We also assessed how GE and GC accuracy varied as a function of DNA concentration using serial dilutions of buccal DNA samples. Finally we determined the nature and genomic distribution of discordant genotypes in buccal DNA samples. The mean GE of undiluted buccal cell DNA samples was high (99.32%), as was the GC between the paired buccal and blood samples (99.29%). GC between the dilutions versus the undiluted buccal DNA was also very high (greater than 97%), though both GE and GC notably declined at DNA concentrations less than 5 ng/μl. Most (greater than 95%) genotype determinations in buccal cell samples were of the “missing call” variety (as opposed to the “alternative genotype call” variety) across the spectrum of buccal DNA concentrations studied. Finally, for buccal DNA concentration above 1.7 ng/ul, discordant genotyping calls did not cluster in any particular chromosome. Buccal cell-derived DNA represents a viable alternative to blood DNA for genotyping on a high-density platform

Feasibility of High-Throughput Genome-Wide Genotyping using DNA from Stored Buccal Cell Samples

It is unclear if buccal cell samples contain sufficient human DNA with adequately sized fragments for high throughput genetic bioassays. Yet buccal cell sample collection is an attractive alternative to gathering blood samples for genetic epidemiologists engaged in large-scale genetic biomarker studies. We assessed the genotyping efficiency (GE) and genotyping concordance (GC) of buccal cell DNA samples compared to corresponding blood DNA samples, from 32 Nurses’ Health Study (NHS) participants using the Illumina Infinium 660W-Quad platform. We also assessed how GE and GC accuracy varied as a function of DNA concentration using serial dilutions of buccal DNA samples. Finally we determined the nature and genomic distribution of discordant genotypes in buccal DNA samples. The mean GE of undiluted buccal cell DNA samples was high (99.32%), as was the GC between the paired buccal and blood samples (99.29%). GC between the dilutions versus the undiluted buccal DNA was also very high (>97%), though both GE and GC notably declined at DNA concentrations less than 5 ng/μl. Most (>95%) genotype determinations in buccal cell samples were of the “missing call” variety (as opposed to the “alternative genotype call” variety) across the spectrum of buccal DNA concentrations studied. Finally, for buccal DNA concentration above 1.7 ng/ul, discordant genotyping calls did not cluster in any particular chromosome. Buccal cell-derived DNA represents a viable alternative to blood DNA for genotyping on a high-density platform

The association of female reproductive factors with glaucoma and related traits: A systematic review

TOPIC: This systematic review summarizes the existing evidence for the association between female reproductive factors (age at menarche, parity, oral contraceptive (OC) use, age at menopause, and postmenopausal hormone (PMH) use) and intraocular pressure (IOP) or open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding the association between female reproductive factors and glaucoma may shed light on disease pathogenesis and aid clinical prediction and personalized treatment strategies. Importantly, some factors are modifiable which may lead to new therapies. METHODS: Two reviewers independently extracted articles in Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases to identify relevant studies. Eligibility criteria included studies with human subjects over 18 years of age; a measured exposure of at least one of the following: age at menarche, parity, OC use, age at menopause, PMH use; a measured outcome of either IOP or OAG; a cohort, case-control, cross-sectional or randomized-controlled trial design; and a reported measure of association including hazard, risk or odds ratio or mean difference with associated confidence intervals. RESULTS: We included a total of 27 studies. Substantial differences in study design, exposure and treatment levels, treatment duration and variable reporting precluded meaningful quantitative synthesis of the identified studies. Overall, relatively consistent associations between PMH use and lower IOP were identified. With respect to OAG, estrogen-only PMH use may be associated with lower OAG risk and this association may be modified by race. No significant associations were found with combined estrogen + progesterone PMH use. No strong associations between parity, or age at menarche and glaucoma were found, but a younger age at menopause was associated with increased glaucoma risk, and adverse associations were identified with longer duration of OC use, though no overall association with OC use was found. CONCLUSION: The association between PMH use and lower IOP/OAG risk is a potentially clinically relevant and modifiable risk factor and should be investigated further, although this needs to be interpreted in the context of a high risk of bias across included studies. There is a need for future research examining associations with IOP specifically, and how the relationship between genetic factors and OAG risk may be influenced by female reproductive factors

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size

Predictors of starting and stopping chemsex in men who have sex with men in England: findings from the AURAH2 prospective study

BACKGROUND: Chemsex (the use of psychoactive drugs in sexual contexts) has been associated with HIV acquisition and other STIs, so there is benefit in identifying those most likely to start chemsex to offer risk reduction interventions such as pre-exposure prophylaxis (PrEP). To date, there have been no data from a longitudinal study analysing factors most associated with starting and stopping chemsex. METHODS: The prospective cohort study, Attitudes to and Understanding Risk of Acquisition of HIV over Time (AURAH2), collected 4 monthly and annual online questionnaire data from men who have sex with men (MSM) from 2015 to 2018. We investigate the association of sociodemographic factors, sexual behaviours and drug use with starting and stopping chemsex among 622 men who completed at least one follow-up questionnaire. Poisson models with generalised estimating equations were used to produce risk ratios (RRs) accounting for multiple starting or stopping episodes from the same individual. Multivariable analysis was adjusted for age group, ethnicity, sexual identity and university education. FINDINGS: In the multivariable analysis, the under 40 age group was significantly more likely to start chemsex by the next assessment (RR 1.79, 95% CI 1.12 to 2.86). Other factors which showed significant association with starting chemsex were unemployment (RR 2.10, 95% CI 1.02 to 4.35), smoking (RR 2.49, 95% CI 1.63 to 3.79), recent condomless sex (CLS), recent STI and postexposure prophylaxis (PEP) use in the past year (RR 2.10, 95% CI 1.33 to 3.30). Age over 40 (RR 0.71, 95% CI 0.51 to 0.99), CLS, and use of PEP (RR 0.64, 95% CI 0.47 to 0.86) and PrEP (RR 0.47, 95% CI 0.29 to 0.78) were associated with lower likelihood of stopping chemsex by the next assessment. INTERPRETATION: Knowledge of these results allows us to identify men most likely to start chemsex, thus providing an opportunity for sexual health services to intervene with a package of risk mitigation measures, especially PrEP use

The Prevalence of Cognitive Impairment Among Adults With Incident Heart Failure: The “Reasons for Geographic and Racial Differences in Stroke” (REGARDS) Study

Background Cognitive impairment (CI) is estimated to be present in 25%–80% of heart failure (HF) patients, but its prevalence at diagnosis is unclear. To improve our understanding of cognition in HF, we determined the prevalence of CI among adults with incident HF in the REGARDS study. Methods and Results REGARDS is a longitudinal cohort study of adults ≥45 years of age recruited in the years 2003–2007. Incident HF was expert adjudicated. Cognitive function was assessed with the Six-Item Screener. The prevalence of CI among those with incident HF was compared with the prevalence of CI among an age-, sex-, and race-matched cohort without HF. The 436 participants with incident HF had a mean age of 70.3 years (SD 8.9), 47% were female, and 39% were black. Old age, black race, female sex, less education, and anticoagulation use were associated with CI. The prevalence of CI among participants with incident HF (14.9% [95% CI 11.7%–18.6%]) was similar to the non-HF matched cohort (13.4% [11.6%–15.4%]; P < .43). Conclusions A total of 14.9% of the adults with incident HF had CI, suggesting that the majority of cognitive decline occurs after HF diagnosis. Increased awareness of CI among newly diagnosed patients and ways to mitigate it in the context of HF management are warranted

Introducing an automated high content confocal imaging approach for Organs-on-Chips

Organ-Chips are micro-engineered systems that aim to recapitulate the organ microenvironment. Implementation of Organ-Chips within the pharmaceutical industry aims to improve the probability of success of drugs reaching late stage clinical trial by generating models for drug discovery that are of human origin and have disease relevance. We are adopting the use of Organ-Chips for enhancing pre-clinical efficacy and toxicity evaluation and prediction. Whilst capturing cellular phenotype via imaging in response to drug exposure is a useful readout in these models, application has been limited due to difficulties in imaging the chips at scale. Here we created an end-to-end, automated workflow to capture and analyse confocal images of multicellular Organ-Chips to assess detailed cellular phenotype across large batches of chips. By automating this process, we not only reduced acquisition time, but we also minimised process variability and user bias. This enabled us to establish, for the first time, a framework of statistical best practice for Organ-Chip imaging, creating the capability of using Organ-Chips and imaging for routine testing in drug discovery applications that rely on quantitative image data for decision making. We tested our approach using benzbromarone, whose mechanism of toxicity has been linked to mitochondrial damage with subsequent induction of apoptosis and necrosis, and staurosporine, a tool inducer of apoptosis. We also applied this workflow to assess the hepatotoxic effect of an active AstraZeneca drug candidate illustrating its applicability in drug safety assessment beyond testing tool compounds. Finally, we have demonstrated that this approach could be adapted to Organ-Chips of different shapes and sizes through application to a Kidney-Chip.</p

Fried food consumption, genetic risk, and body mass index: gene-diet interaction analysis in three US cohort studies

Objective: To examine the interactions between genetic predisposition and consumption of fried food in relation to body mass index (BMI) and obesity. Design: Prospective cohort study. Setting: Health professionals in the United States. Participants: 9623 women from the Nurses’ Health Study, 6379 men from the Health Professionals Follow-up Study, and a replication cohort of 21 421 women from the Women’s Genome Health Study. Main outcome measure Repeated measurement of BMI over follow-up. Results: There was an interaction between fried food consumption and a genetic risk score based on 32 BMI-associated variants on BMI in both the Nurses’ Health Study and Health Professionals Follow-up Study (P≤0.001 for interaction). Among participants in the highest third of the genetic risk score, the differences in BMI between individuals who consumed fried foods four or more times a week and those who consumed fried foods less than once a week amounted to 1.0 (SE 0.2) in women and 0.7 (SE 0.2) in men, whereas the corresponding differences were 0.5 (SE 0.2) and 0.4 (SE 0.2) in the lowest third of the genetic risk score. The gene-diet interaction was replicated in the Women’s Genome Health Study (P<0.001 for interaction). Viewed differently, the genetic association with adiposity was strengthened with higher consumption of fried foods. In the combined three cohorts, the differences in BMI per 10 risk alleles were 1.1 (SE 0.2), 1.6 (SE 0.3), and 2.2 (SE 0.6) for fried food consumption less than once, one to three times, and four or more times a week (P<0.001 for interaction); and the odds ratios (95% confidence intervals) for obesity per 10 risk alleles were 1.61 (1.40 to 1.87), 2.12 (1.73 to 2.59), and 2.72 (2.12 to 3.48) across the three categories of consumption (P=0.002 for interaction). In addition, the variants in or near genes highly expressed or known to act in the central nervous system showed significant interactions with fried food consumption, with the FTO (fat mass and obesity associated) variant showing the strongest result (P<0.001 for interaction). Conclusion: Our findings suggest that consumption of fried food could interact with genetic background in relation to obesity, highlighting the particular importance of reducing fried food consumption in individuals genetically predisposed to obesity