Environmental triggers of Parkinson's disease - Implications of the Braak and dual-hit hypotheses.

Idiopathic Parkinson's disease (PD) may take decades to develop, during which many risk or protective factors may come into play to initiate the pathogenesis or modify its progression to clinical PD. The lack of understanding of this prodromal phase of PD and the factors involved has been a major hurdle in the study of PD etiology and preventive strategies. Although still controversial, the Braak and dual-hit hypotheses that PD may start peripherally in the olfactory structures and/or the gut provides a theoretical platform to identify the triggers and modifiers of PD prodromal development and progression. This is particularly true for the search of environmental causes of PD as the olfactory structures and gut are the major human mucosal interfaces with the environment. In this review, we lay out our personal views about how the Braak and dual-hit hypotheses may help us search for the environmental triggers and modifiers for PD, summarize available experimental and epidemiological evidence, and discuss research gaps and strategies.

Sex differences in neurocognitive screening among adults living with HIV in China.

HIV-infected (HIV+) women may be more vulnerable to neurocognitive impairment (NCI) due to psychological and physiological factors but previous studies show mixed findings. We investigated the neurocognitive performances in HIV+ versus HIV- women and men. This cross-sectional analysis included 669 HIV+ patients (223 women) and 1338 HIV-uninfected (HIV-) controls (446 women) which were frequency matched on sex, education, and 5-year age categories. NCI was screened using the Mini-mental State Examination. Psychomotor speed was assessed using timed alternating hand sequence test. Prevalence of NCI was higher among women versus men in the HIV+ group (16.1% vs 10.5%) but not the HIV- group (4.3% vs 3.5%). HIV+ women performed worse compared to men on psychomotor speed, orientation, attention, and calculation, whereas HIV- women performed worse compared to men on attention and calculation. Adjusted interaction effects of HIV status × sex (women vs men) were significant on orientation, attention, and calculation, and marginally significant on psychomotor speed (p = 0.053). In multivariable models, among both HIV+ women and men, less years of education and depressive symptoms were associated with NCI. Waist-to-hip ratio above the cut-off was strongly associated with NCI among HIV+ women. HIV+ women perform worse on cognitive measures compared to HIV+ men. The association of central obesity with NCI in HIV+ women should be noted.

Low body mass index and efavirenz use are independently associated with self-reported fatigue in HIV-infected patients.

This retrospective cohort study was conducted from January 2009 to July 2016 to explore the occurrence and risk factors of self-reported fatigue within the first 6 months after receiving antiretroviral treatment (ART) among patients living with HIV in Taizhou City of Zhejiang province, Eastern China. In total, 1163 HIV-infected patients with a median follow-up duration of 27.8 months were included in the analysis. Among them, 261 (22.4%) reported fatigue within the first 6 months after ART. In the multivariable logistic regression analysis, self-reported fatigue within the first 6 months after ART was negatively associated with junior middle-school education or above, baseline CD4 cell count of 200-349 and >350 cells/µL (vs < 200 cells/µL), overweight at baseline (vs normal weight) but positively associated with ≥50 years old at initiation of ART (vs <30 years old), underweight at baseline, use of efavirenz (EFV) in the first-line regimen. Our data suggest that earlier initiation of ART and higher body mass index are preferred to restore the energy of HIV-infected patients with the EFV use in the era of ART in China.

In situ imaging of mRNA transcripts based on split-aptamer and split protein in living cells.

Messenger RNA (mRNA) is an essential component of cell development and growth. However, the detection of endogenous mRNA in living cells is currently limited. To address this issue, we have developed a novel strategy that comprises split-aptamer and split fluorescent protein dual-color, "turn-on" probes that specifically target mRNA with complementary sequences. Our split-aptamer and split-protein-initiated fluorescence complementation (sAPiFC) approach for live-cell imaging has demonstrated selectivity, stability, and capability for targeting various mRNAs.

Allosteric Activation of Protein Phosphatase 5 with Small Molecules.

The activation of PP5 is essential for a variety of cellular processes, as it participates in a variety of biological pathways by dephosphorylating substrates. However, activation of PP5 by small molecules has been a challenge due to its native "self-inhibition" mechanism, which is controlled by the N-terminal TPR domain and the C-terminal αJ helix. Here, we reported the discovery of DDO-3733, a well-identified TPR-independent PP5 allosteric activator, which facilitates the dephosphorylation process of downstream substrates. Considering the negative regulatory effect of PP5 on heat shock transcription factor HSF1, pharmacologic activation of PP5 by DDO-3733 was found to reduce the HSP90 inhibitor-induced heat shock response. These results provide a chemical tool to advance the exploration of PP5 as a potential therapeutic target and highlight the value of pharmacological activation of PP5 to reduce heat shock toxicity of HSP90 inhibitors.

The impact of manufacturing servitization on consumption-based carbon rebound effect: A global value chain research perspective.

This study investigates the causal effect of manufacturing servitization on the consumption-based carbon rebound effect, employing the empirical approach based on the value-added trade and SBM-DEA model. The results show that improving the servitization level will lead to a significant decrease in the consumption-based carbon rebound effect of the global manufacturing industry. Moreover, the main paths through which the manufacturing servitization inhibits the consumption-based carbon rebound effect are the human capital and government management. We also find that the impact of manufacturing servitization is more substantial in advanced manufacturing and developed economies, which is smaller in manufacturing sectors with higher global value chain positions and lower export penetration levels. These findings suggest that improving the level of manufacturing servitization helps alleviate the consumption-based carbon rebound effect and is conducive to achieving the target of global carbon emission reduction.

Design of Tracers in Fluorescence Polarization Assay for Extensive Application in Small Molecule Drug Discovery.

Development of fluorescence polarization (FP) assays, especially in a competitive manner, is a potent and mature tool for measuring the binding affinities of small molecules. This approach is suitable for high-throughput screening (HTS) for initial ligands and is also applicable for further study of the structure-activity relationships (SARs) of candidate compounds for drug discovery. Buffer and tracer, especially rational design of the tracer, play a vital role in an FP assay system. In this perspective, we provided different kinds of approaches for tracer design based on successful cases in recent years. We classified these tracers by different types of ligands in tracers, including peptide, nucleic acid, natural product, and small molecule. To make this technology accessible for more targets, we briefly described the basic theory and workflow, followed by highlighting the design and application of typical FP tracers from a perspective of medicinal chemistry.

Nearly 100% selective and visible-light-driven methane conversion to formaldehyde via. single-atom Cu and Wδ.

Direct solar-driven methane (CH4) reforming is highly desirable but challenging, particularly to achieve a value-added product with high selectivity. Here, we identify a synergistic ensemble effect of atomically dispersed copper (Cu) species and partially reduced tungsten (Wδ+), stabilised over an oxygen-vacancy-rich WO3, which enables exceptional photocatalytic CH4 conversion to formaldehyde (HCHO) under visible light, leading to nearly 100% selectivity, a very high yield of 4979.0 µmol·g-1 within 2 h, and the normalised mass activity of 8.5 × 106 µmol·g-1Cu·h-1 of HCHO at ambient temperature. In-situ EPR and XPS analyses indicate that the Cu species serve as the electron acceptor, promoting the photo-induced electron transfer from the conduction band to O2, generating reactive •OOH radicals. In parallel, the adjacent Wδ+ species act as the hole acceptor and the preferred adsorption and activation site of H2O to produce hydroxyl radicals (•OH), and thus activate CH4 to methyl radicals (•CH3). The synergy of the adjacent dual active sites boosts the overall efficiency and selectivity of the conversion process.

Small molecules targeting molecular chaperones for tau regulation: Achievements and challenges.

Abnormal post-translational modification of microtubule-associated protein Tau (MAPT) is a prominent pathological feature in Alzheimer's disease (AD). Previous research has focused on designing small molecules to target Tau modification, aiming to restore microtubule stability and regulate Tau levels in vivo. However, progress has been hindered, and no effective Tau-targeted drugs have been successfully marketed, which urgently requires more strategies. Heat shock proteins (HSPs), especially Hsp90 and Hsp70, have been found to play a crucial role in Tau maturation and degradation. This review explores innovative approaches using small molecules that interact with the chaperone system to regulate Tau levels. We provide a comprehensive overview of the mechanisms involving HSPs and their co-chaperones in the Tau regulation cycle. Additionally, we analyze small molecules targeting these chaperone systems to modulate Tau function. By understanding the characteristics of the molecular chaperone system and its specific impact on Tau, we aim to provide a perspective that seeks to regulate Tau levels through the manipulation of the molecular chaperone system and ultimately develop effective treatments for AD.

Olfaction and kidney function in community-dwelling older adults.

BACKGROUND: In older adults, kidney function declines with age. People with advanced kidney diseases may have poor olfaction. However, it is unclear whether poor olfaction is a marker for declining renal function or future risk of chronic kidney disease (CKD). We therefore investigated olfaction in relation to kidney function and risk of CKD. METHODS: These secondary data analyses were limited to participants of the year 3 clinical visit of the Health Aging and Body Composition Study. The analytic sample size varied between 1427 to 2531, depending on participant eligibility and data availability for each analysis. Olfaction was tested using the Brief Smell Identification Test (B-SIT), defined as anosmia (score≤6), hyposmia (7-8), moderate (9-10), and good function (10-11) at baseline. We estimated glomerular filter rate (eGFR) at baseline and seven years later using the CKD-EPI creatinine-cystatin C equation, and defined incident CKD as eGFR<60 ml/min/1.73m2 and eGFR decline ≥1 ml/min/1.73m2/year. Further, we identified CKD hospitalization events from hospitalization and death records. We used inverse probability weighting and weighted multivariable regressions to account for censoring in the prospective analyses and used absolute risk regression to account for competing risk of death. RESULTS: At baseline, compared to participants with good olfaction, the multivariable-adjusted mean eGFR was 3.00 ml/min/1.73m2 lower (95% confidence interval (CI): -5.25, -0.75) for those with anosmia and 1.87 lower (95% CI: -3.94, 0.21) for those with hyposmia with a P for linear trend < 0.001. Those with anosmia at baseline was had a significantly lower eGFR seven years later (-5.31, 95% CI: -8.58, -2.04, P for trend = 0.002), but the association was attenuated after further accounting for baseline eGFR (-2.37, 95%CI: -4.91, 0.16, P for linear trend = 0.147). Olfactory function was not associated with incident CKD or CKD hospitalization. CONCLUSION: In older adults > age 70 years, poor olfaction is associated with lower kidney function, but not future CKD risk. These associations should be further investigated in relatively younger population.

Blood Cholesterol Decreases as Parkinson's Disease Develops and Progresses.

BACKGROUND: Literature shows an inverse association of circulating cholesterol level with the risk of Parkinson's disease (PD); this finding has important ramifications, but its interpretation has been debated. OBJECTIVE: To longitudinally examine how blood total cholesterol changes during the development of PD. METHODS: In the Health, Aging and Body Composition study (n = 3,053, 73.6±2.9 years), blood total cholesterol was measured at clinic visit years 1, 2, 4, 6, 8, 10, and 11. We first examined baseline cholesterol in relation to PD risk, adjusting for potential confounders and competing risk of death. Then, by contrasting the observed with expected cholesterol levels, we examined the trajectory of changes in total cholesterol before and after disease diagnosis. RESULTS: Compared to the lowest tertile of baseline total cholesterol, the cumulative incidence ratio of PD and 95% confidence interval was 0.41 (0.20, 0.86) for the second tertile, and 0.69 (0.35, 1.35) for the third tertile. In the analysis that examined change of total cholesterol level before and after PD diagnosis, we found that its level began to decrease in the prodromal stage of PD and became statistically lower than the expected values ∼4 years before disease diagnosis (observed-expected difference, -6.68 mg/dL (95% confidence interval: -13.14, -0.22)). The decreasing trend persisted thereafter; by year-6 post-diagnosis, the difference increased to -13.59 mg/dL (95% confidence interval: -22.12, -5.06), although the linear trend did not reach statistical significance (p = 0.10). CONCLUSION: Circulating total cholesterol began to decrease in the prodromal stage of PD, which may in part explain its reported inverse association with PD.

Gut Microbiota and Fecal Metabolites Associated With Neurocognitive Impairment in HIV-Infected Population.

Gut microbiota dysbiosis has been associated with many neurological diseases. However, how microbiota composition and metabolism relate to neurocognitive impairment (NCI) in HIV-infected individuals is largely unknown. In this study, a total of 102 HIV infected participants were classified into two groups-those with NCI and those without-using the global deficit score (GDS). Fecal samples were collected from the participants for 16S rRNA gene sequencing and untargeted metabolomics. The plasma level of 25 hydroxy-vitamin D (25(OH)D) was also evaluated. Although α-diversity and ß-diversity were comparable, the HIV patients with NCI were significantly different from those without NCI in terms of abundance of several gut microbiota. The decreased abundance of butyrate-producing bacteria (BPB) and increased abundance of Klebsiella were related with NCI and carotid intima-media thickness (CIMT). Significant differences in fecal metabolites were also found between individuals with versus without NCI, including increased bile acids and bioactive lipids, decreased vitamin D, terpenoids, and resolvin D1 in the NCI group. Furthermore, the perturbed metabolic profile was closely related to BPB and Klebsiella. In addition, a low level of vitamin D was associated with NCI and CIMT. Both fecal and plasma vitamin D were positively correlated with BPB. Our results show that BPB and Klebsiella and the associated metabolites are associated with NCI in people with HIV. In addition, vitamin D, both in feces and blood, was associated with NCI and BPB, suggesting a protective effect of vitamin D on NCI.

Effects of Docosahexanoic Acid on Gut Microbiota and Fecal Metabolites in HIV-Infected Patients With Neurocognitive Impairment: A 6-Month Randomized, Double-Blind, Placebo-Controlled Trial.

Neurocognitive impairment (NCI) and gut microbiota dysbiosis are prevalent in patients with HIV infection. Docosahexanoic acid (DHA) supplementation may alleviate multiple neurocognitive diseases symptoms and plays important role in regulating gut microbiota. However, it is not known whether DHA algae oil supplements can alleviate neurocognitive impairment (NCI) and regulate gut microbiota and fecal metabolites. A randomized, double-blind, placebo-controlled trial was performed on 68 HIV-infected patients with NCI. Participants were randomized to receive a 3.15 g daily DHA algae oil supplement or placebo for 6 months. We collected blood and fecal samples from these patients before and after the trial. Mini mental state examination (MMSE) and neuropsychological tests (NP tests) were administered to assess the cognitive status of participants. The influence of DHA algae oil on the gut microbiota, fecal metabolomics, plasma proinflammatory, and oxidative stress factors was also investigated. There were no significant changes in NCI according to global diagnosis score (GDS) and MMSE score within the two groups, while patients receiving DHA had improvement in several blood lipids, pro-inflammatory and oxidative stress factors. The DHA supplement increased α-diversity indexes, increased abundances of Blautia, Bifidobacterium, Dorea, Lactobacillus, Faecalibacterium, Fusobacterium, and Agathobacter, and decreased abundances of Bacteroides and Prevotella_9. Furthermore, DHA supplement was correlated with improved fecal lipid metabolites as indicated by ceramides, bile acids, glycerophospholipids. In addition, the DHA supplement was associated with altered cholesterol metabolism and purine metabolism pathways. A daily supplement of DHA algae oil for 6 months has been shown to promote favorable transformations in gut microbiota, profiles of fecal metabolomic, and factors responsible for proinflammatory and oxidative stress, which might be beneficial for the prognosis of HIV-infected patients with NCI in the long-term. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04242004, identifier: NCT04242004.

Efficacy Analysis of Percutaneous Endoscopic Lumbar Discectomy Combined with PEEK Rods for Giant Lumbar Disc Herniation: A Randomized Controlled Study.

Objective: This study describes a randomized controlled trial that assesses percutaneous endoscopic lumbar discectomy (PELD) combined with a polyetheretherketone (PEEK) rod in patients with GLDH (herniation affecting 50% of the sagittal diameter of the spinal canal) and reports the 2-year follow-up outcome. Methods: In all, 243 patients were randomly assigned to undergo PELD or PELD combined with a PEEK rod by generating random numbers with a random number generator. Clinical outcome data, including the numerical rating scale (NRS), were used to assess the patients' back and leg pain, while the Oswestry Disability Index (ODI) was used to quantify pain and disability. Imaging data included intervertebral disc height (IDH), range of motion (ROM), and modified Pfirrmann grades. Results: At the final follow-up, the NRS for back and leg pain and the ODI scores were significantly decreased in both groups. The NRS for back pain and the ODI scores in the PELD + PEEK group (1.32 ± 0.70, 14.10 ± 4.74) were better than those in the PELD group (1.91 ± 0.69, 16.93 ± 4.33) (P < 0.05). The IDH of the PELD + PEEK group (10.54 ± 1.62) was significantly higher than that in the PELD group (9.98 ± 1.90) (P < 0.05). The IDH of the PELD + PEEK group (10.54 ± 1.62) was significantly higher than that in the PELD group (9.98 ± 1.90) (P < 0.05). The IDH of the PELD + PEEK group (10.54 ± 1.62) was significantly higher than that in the PELD group (9.98 ± 1.90) (. Conclusion: For symptomatic patients with GLDH, both PELD and PELD combined with a PEEK rod showed good efficacy. However, the long-term effect of PELD combined with a PEEK rod is better than that of PELD alone. Moreover, PELD combined with a PEEK rod can effectively reduce the recurrence rate. Maximum benefit can be gained if we adhere to strict selection criteria for PELD combined with a PEEK rod.

Posterior percutaneous endoscopic lumbar discectomy combined with the vertical anchoring technique for lumbar disc herniation with distant upward migration.

BACKGROUND: Posterior percutaneous endoscopic lumbar discectomy (PELD) has become a preferred procedure for the treatment of simple lumbar disc herniation (LDH) but has rarely been reported for distant upward migration. The purpose of this research was to investigate the feasibility, safety, clinical efficacy and technical points of posterior PELD combined with the vertical anchoring technique (VAT) for the treatment of LDH with distant upward migration. METHODS: Thirteen patients with distant upward migrated LDH who underwent posterior PELD combined with the VAT from March 2016 to May 2018 were selected. Among these cases, the herniated disc was located at L3/4 in 2 patients, L4/5 in 9 patients and L5/S1 in 2 patients. The operative time, length of hospital stay and postoperative complications were recorded. The visual analogue score (VAS), Oswestry Disability Index (ODI), Japanese Orthopaedic Association (JOA) scores and modified MacNab criteria were used to assess surgical efficacy. RESULTS: All 13 patients underwent successful surgery. We compared the VAS, ODI and JOA scores before and after surgery. The differences were statistically significant (P < 0.05). According to the modified MacNab criteria, 10 patients were assessed as "excellent", 2 patients were assessed as "good" and 1 patient was assessed as "fair" at the last follow-up. The rate of satisfactory outcomes was 92.3%. CONCLUSION: Posterior PELD combined with the VAT is a safe and feasible procedure for the treatment of LDH with distant upward migration and represents a new approach for this type of surgery.

Stronger Association between Insomnia Symptoms and Shorter Telomere Length in Old HIV-Infected Patients Compared with Uninfected Individuals.

Growing evidence suggests that HIV infection may accelerate biological aging. Insomnia symptoms, particularly in later life, exacerbate cellular aging. We examined the association between insomnia symptoms and leukocyte telomere length (LTL), and further explored how this association was affected by HIV serostatus and age. Data were assessed from 244 HIV-infected individuals ≥40 years and 244 HIV-uninfected individuals who were frequency-matched by age, gender and education level. Insomnia symptoms were assessed by responses to four sleep-related questions covering the past month. We performed multivariable linear regression with logarithmically transformed LTL and reported exponentiated coefficients. HIV-infected individuals had shorter LTL compared to uninfected individuals (geometric mean 0.82 vs 0.89, P=0.052), and this association remained after adjustment for gender, education level, and smoking history (-7.4%, P=0.051) but markedly attenuated after additional adjustment for insomnia and depressive symptoms (-3.7%, P=0.367). Significant interactions between age group (55-82 vs 40-54 years) and insomnia symptoms on LTL were observed in the HIV-infected individuals (-28.4%, P=0.033) but not the uninfected (-17.9%, P=0.250). After stratifying by age group, LTL was independently associated with insomnia symptoms in those 55 years and older among the HIV-infected individuals (-24.5%, P=0.026) but not those 40-54 years old (-9.8%, P=0.428). Our findings suggest that elevated insomnia and depressive symptoms may partly explain the correlation between HIV serostatus and shorter LTL. Significant association between insomnia and shorter LTL observed in elderly HIV-infected but not in uninfected individuals suggest that such adverse effect may begin at an earlier age or is more pronounced in HIV-infected individuals but requires further investigation.

Analysis of residents' willingness to pay to reduce air pollution to improve children's health in community and hospital settings in Shanghai, China.

BACKGROUND: Shanghai, along with many major cities in China, faces deterioration of air quality and increases in air pollution-related respiratory diseases (RDs) in children due to rapid industrialization and urbanization. The Contingent Valuation Method (CVM) was used to qualitatively and quantitatively measure the willingness to pay (WTP) for reducing children's RDs through air quality improvement. METHODS: Between April and May, 2014, 975 face-to-face interviews were collected from parents in a community-based and a hospital-setting in Shanghai. Multiple imputation and the Probit model were used to determine the relationship between the WTP and the related environmental factors, child health factors and the socio-economic status. RESULTS: Most respondents reported being willing to make a financial contribution to improve air quality in both the community (52.6%) and hospital (70.2%) samples. Those in the hospital setting were willing to pay significantly more ¥504 (USD$80.7) compared to the community sample ¥428 ($68.5) as expected. Reasons for those not being willing to pay included lack of disposable income and believing that responsibility of the air quality was a community issue. These did not differ by sample. Annual household income and education were related to WTP. CONCLUSION: This study indicated that parents in Shanghai would be willing to pay for improved air quality. Children's health can be the incentive for the citizens' participation and support in the air quality improvement, therefore, hospital settings may present unique places to improve education about air quality and enhance advocacy efforts. This study also suggested that future environmental policies be addressed more rigorously for targeted populations.

Knowledge, attitudes, and practices (KAP) of the relationship between air pollution and children's respiratory health in Shanghai, China.

To assess the status of, and factors associated with, residents' knowledge, attitudes, and practices (KAP) related to air pollution and respiratory health of children in Shanghai, we conducted a cross-sectional survey. Demographic factors associated with residents' knowledge were identified by multiple logistic regressions. The questionnaires were completed by 972 participants, half from the Shanghai Children Hospital and the other half from the Jiading communities. Half of the participants' scores of knowledge and attitudes were equal or greater than 8.0 on a 9-point scale, over 75% of respondents' practice scores were equal to or less than 4.0. Our studies demonstrated a significant difference of average knowledge scores between the two groups (t = 1.27, p < 0.05). The parents' educational level (OR = 1.89, 2.48) and average annual household income (AAHI) (OR = 2.37, 2.40, 2.12) were the two strongest factors on knowledge awareness. In addition, statistical analysis revealed a significant difference between the two groups in their attitudes towards air quality and their perception of the government's efforts to alleviate it. The hospital and community groups also showed significant differences in practices geared towards protecting their children's health. Nearly 90% of the respondents agreed that improving air quality is the responsibility of every citizen, and the joint action of governments and all citizens should be utilized for enhanced control. In addition, more resources should be allocated towards providing citizens with appropriate practices to help lessen the effects of poor air quality.