Alzheimer's Disease, time to turn the tide.
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ABSTRACT:
SUBMITTER: Sensi SL
PROVIDER: S-EPMC6224239 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
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Project description:Alzheimer's disease (AD) is the most common type of neurodegenerative disorder. Amyloid-beta (Aβ) plaques are integral to the "amyloid hypothesis," which states that the accumulation of Aβ peptides triggers a cascade of pathological events leading to neurodegeneration and ultimately AD. While the FDA approved aducanumab, the first Aβ-targeted therapy, multiple safe and effective treatments will be needed to target the complex pathologies of AD. γ-Secretase is an intramembrane aspartyl protease that is critical for the generation of Aβ peptides. Activity and specificity of γ-secretase are regulated by both obligatory subunits and modulatory proteins. Due to its complex structure and function and early clinical failures with pan inhibitors, γ-secretase has been a challenging drug target for AD. γ-secretase modulators, however, have dramatically shifted the approach to targeting γ-secretase. Here we review γ-secretase and small molecule modulators, from the initial characterization of a subset of NSAIDs to the most recent clinical candidates. We also discuss the chemical biology of γ-secretase, in which small molecule probes enabled structural and functional insights into γ-secretase before the emergence of high-resolution structural studies. Finally, we discuss the recent crystal structures of γ-secretase, which have provided valuable perspectives on substrate recognition and molecular mechanisms of small molecules. We conclude that modulation of γ-secretase will be part of a new wave of AD therapeutics.
| S-EPMC8725520 | biostudies-literature
Project description:Insulin resistance (IR), defined as an attenuated biological response to circulating insulin, is a fundamental defect in obesity and type 2 diabetes (T2D), and is also linked to a wide spectrum of pathological conditions, such as non-alcoholic fatty liver disease (NAFLD), cognitive impairment, endothelial dysfunction, chronic kidney disease (CKD), polycystic ovary syndrome (PCOS), and some endocrine tumors, including breast cancer. In obesity, the unbalanced production of pro- and anti-inflammatory adipocytokines can lead to the development of IR and its related metabolic complications, which are potentially reversible through weight-loss programs. The Mediterranean diet (MedDiet), characterized by high consumption of extra-virgin olive oil (EVOO), nuts, red wine, vegetables and other polyphenol-rich elements, has proved to be associated with greater improvement of IR in obese individuals, when compared to other nutritional interventions. Also, recent studies in either experimental animal models or in humans, have shown encouraging results for insulin-sensitizing nutritional supplements derived from MedDiet food sources in the modulation of pathognomonic traits of certain IR-related conditions, including polyunsaturated fatty acids from olive oil and seeds, anthocyanins from purple vegetables and fruits, resveratrol from grapes, and the EVOO-derived, oleacein. Although the pharmacological properties and clinical uses of these functional nutrients are still under investigation, the molecular mechanism(s) underlying the metabolic benefits appear to be compound-specific and, in some cases, point to a role in gene expression through an involvement of the nuclear high-mobility group A1 (HMGA1) protein.
| S-EPMC7230471 | biostudies-literature
Project description:INTRODUCTION:Every year, HIV-associated tuberculosis (TB) deprives 350,000 mainly young people of productive and healthy lives.People die because TB is not diagnosed and treated in those with known HIV infection and HIV infection is not diagnosed in those with TB. Even in those in whom both HIV and TB are diagnosed and treated, this often happens far too late. These deficiencies can be addressed through the application of new scientific evidence and diagnostic tools. DISCUSSION:A strategy of starting antiretroviral therapy (ART) early in the course of HIV infection has the potential to considerably reduce both individual and community burden of TB and needs urgent evaluation for efficacy, feasibility and broader social and economic impact. Isoniazid preventive therapy can reduce the risk of TB and, if given strategically in addition to ART, provides synergistic benefit. Intensified TB screening as part of the "Three I's" strategy should be conducted at every clinic, home or community-based attendance using a symptoms-based algorithm, and new diagnostic tools should increasingly be used to confirm or refute TB diagnoses. Until such time when more sensitive and specific TB diagnostic assays are widely available, bolder approaches such as empirical anti-TB treatment need to be considered and evaluated. Patients with suspected or diagnosed TB must be screened for HIV and given cotrimoxazole preventive therapy and ART if HIV-positive. Three large randomized trials provide conclusive evidence that ART initiated within two to four weeks of start of anti-TB treatment saves lives, particularly in those with severe immunosuppression. The key to ensuring that these collaborative activities are delivered is the co-location and integration of TB and HIV services within the health system and the community. CONCLUSIONS:Progress towards reducing HIV-associated TB deaths can be achieved through attention to simple and deliverable actions on the ground.
| S-EPMC3499795 | biostudies-literature
Project description:The decline of the European oyster Ostrea edulis across its biogeographic range has been driven largely by over-fishing and anthropogenic habitat destruction, often to the point of functional extinction. However, other negatively interacting factors attributing to this catastrophic decline include disease, invasive species and pollution. In addition, a relatively complex life history characterized by sporadic spawning renders O. edulis biologically vulnerable to overexploitation. As a viviparous species, successful reproduction in O. edulis populations is density dependent to a greater degree than broadcast spawning oviparous species such as the Pacific oyster Crassostrea (Magallana) gigas. Here, we report on the benthic assemblage of O. edulis and the invasive gastropod Crepidula fornicata across three actively managed South coast harbors in one of the few remaining O. edulis fisheries in the UK. Long-term data reveals that numbers of O. edulis sampled within Chichester Harbour have decreased by 96%, in contrast numbers of C. fornicata sampled have increased by 441% over a 19-year period. The recent survey data also recorded extremely low densities of O. edulis, and extremely high densities of C. fornicata, within Portsmouth and Langstone Harbours. The native oyster's failure to recover, despite fishery closures, suggests competitive exclusion by C. fornicata is preventing recovery of O. edulis, which is thought to be due to a lack of habitat heterogeneity or suitable settlement substrate. Large scale population data reveals that mean O. edulis shell length and width has decreased significantly across all years and site groups from 2015 to 2017, with a narrowing demographic structure. An absence of juveniles and lack of multiple cohorts in the remaining population suggests that the limited fishing effort exceeds biological output and recruitment is poor. In the Langstone & Chichester 2017 sample 98% of the population is assigned to a single cohort (modal mean 71.20 ± 8.78 mm, maximum length). There is evidence of small scale (<5 km) geographic population structure between connected harbors; the 2015 Portsmouth and Chichester fishery populations exhibited disparity in the most frequent size class with 36% within 81-90 mm and 33.86% within 61-70 mm, respectively, the data also indicates a narrowing demographic over a short period of time. The prevalence of the disease Bonamiosis was monitored and supports this microgeographic population structure. Infection rates of O. edulis by Bonamia ostreae was 0% in Portsmouth Harbor (n = 48), 4.1% in Langstone (n = 145) and 21.3% in Chichester (n = 48) populations. These data collectively indicate that O. edulis is on the brink of an ecological collapse within the Solent harbors. Without effective intervention to mitigate the benthic dominance by C. fornicata in the form of biologically relevant fishery policy and the management of suitable recruitment substrate these native oyster populations could be lost.
| S-EPMC6397756 | biostudies-literature
Project description:Tide data plays a key role in many marine scientific research fields such as seafloor topography measurement and navigation safety. To obtain reliable tide data, various methods have been proposed, e.g., tide station measurement, satellite altimeter measurement, and differential global positioning system (GPS) buoy measurement. However, these methods suffer from the limitation that continuous observations at different areas might not be always available. In order to provide high-precision as well as continuous real-time tide data, we propose a method based on real-time precise point positioning (RT-PPP) by using International GNSS Service (IGS) real-time service (RTS) products. Firstly, compared with the IGS final products, the accuracy of the RTS satellite orbit and clock is evaluated. Secondly, the positioning performance of RT-PPP is compared with the IGS ultra-fast products. Finally, a robust Vondrak filter is proposed to eliminate the influence of high-frequency noise and errors and to obtain tide results. Experimental results show that three-dimensional (3D) accuracy of the RTS orbit is better than 0.05 m, and also has 0.22 ns less clock bias. An improvement of 60% is achieved for positioning accuracy using RTS products compared to IGS ultra-fast products. Compared with the post-processing PPP method, the double difference (DD) method and tide gauge data, the root mean square (RMS) values of RT-PPP tide are 0.090, 0.194 and 0.167 m, respectively.
| S-EPMC7288304 | biostudies-literature
Project description:FK506 binding protein 51kDa (FKBP51/FKBP5) is part of a mature heat shock protein 90kDa (Hsp90) chaperone complex that preserves tau. Microarray analysis of human brains reveal that FKBP51 gene expression selectively increased with age and Alzheimer's disease, which correlated with demethylation of the regulatory regions in the FKBP5 gene. Moreover, FKBP51 levels significantly correlated with Braak pathological staging. In addition, we show that in brains devoid of FKBP51, tau levels are reduced. Recombinant FKBP51 and Hsp90 synergize to block tau clearance through the proteasome and produce T22-positive tau oligomers. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved tau species, including phosphorylated and oligomeric tau that have been linked to Alzheimer's disease pathogenesis. FKBP51 blocked amyloid formation and decreased tangle load in the brain. These alterations in tau turnover and aggregate structure culminated in enhanced neurotoxicity. We propose a model where age-associated increases in FKBP51 levels can out-compete the association of other pro-degradation Hsp90 co-chaperones, resulting in neurotoxic tau accumulation. Thus, strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 could be therapeutically relevant for Alzheimer's disease and other tauopathies. These AD cases were processed simultaneously with the control cases (young and aged) included in GSE11882 Postmortem brain tissue was collected from ADRC brain banks. Cases were preferentially selected where 3 or more brain regions were available
2014-04-21 | E-GEOD-48350 | biostudies-arrayexpress
Project description:Ion channel splice array data from cerebellum brain tissue samples collected from Alzheimer's disease patients. Temporal cortex (Alzheimer's disease affected brain tissue structure) and cerebellum (Alzheimer's disease unaffected brain tissue structure) samples from control subjects were compared to temporal cortex and cerebellum of patients with Alzheimer's disease.
2010-06-11 | E-GEOD-6777 | biostudies-arrayexpress
Project description:BackgroundIntracytoplasmic sperm injection (ICSI) is increasingly used among in vitro fertilization (IVF) cycles without male factor infertility. For couples with prolonged infertility duration, the preferred insemination method may vary across laboratories and clinics. We analyzed whether ICSI is effective for non-male factor infertility with long infertility duration.MethodsSeventeen thousand four hundred seventy-seven IVF/ICSI cycles from women with non-male factor infertility were included, of these 4177 women with infertility duration ≥ 5 years were in the final analysis. Primary outcome was the live birth rate after first embryo transfer. Secondary outcomes were rates of clinical pregnancy and fertilization.ResultsA nonlinear relationship was observed between infertility duration and IVF fertilization rate, which decreased with infertility years up to the turning point (4.8 years). 4177 women with infertility ≥ 5 years were categorized by IVF (n = 3806) or ICSI (n = 371). Live birth rate after first embryo transfer was 43.02% in ICSI and 47.85% in IVF group (adjusted odds ratio (aOR), 0.91; 95% confidence interval (CI), 0.72-1.15). Fertilization rate per metaphaseII (aOR, 1.10; 95% CI, 0.86-1.40) and clinical pregnancy rate (aOR, 0.89; 95% CI, 0.71-1.13) were similar between the two groups. Sensitive analyses (women ≥ 35 years) did not show a benefit of ICSI over IVF.ConclusionsWomen with infertility exceeding 4.8 years had decreased incidence of IVF fertilization. The use of ICSI showed no significant improvement in fertilization and live birth rates for non-male factor couples with ≥ 5 years of infertility.
| S-EPMC9706853 | biostudies-literature