Huntington's disease (HD) is an inherited, dominant neurodegenerative disorder caused by an abnormal expansion of CAG triplets in the huntingtin gene (htt). Despite extensive efforts to modify the ...progression of HD thus far only symptomatic treatment is available. Recent work suggests that treating invertebrate and mice HD models with metformin, a well-known AMPK activator which is used worldwide to treat type 2-diabetes, reduces mutant huntingtin from cells and alleviates many of the phenotypes associated to HD. Herein we report statistical analyses of a sample population of participants in the Enroll-HD database, a world-wide observational study on HD, to assess the effect of metformin intake in HD patients respect to cognitive status using linear models. This cross-sectional study shows for the first time that the use of metformin associates with better cognitive function in HD patients.
Alzheimer's, Parkinson's and Huntington's diseases can be caused by mutations that enhance protein aggregation, but we still do not know enough about the molecular players of these pathways to ...develop treatments for these devastating diseases. Here, we screen for mutations that might enhance aggregation in Caenorhabditis elegans, to investigate the mechanisms that protect against dysregulated homeostasis. We report that the stomatin homologue UNC‐1 activates neurohormonal signalling from the sulfotransferase SSU‐1 in ASJ sensory/endocrine neurons. A putative hormone, produced in ASJ, targets the nuclear receptor NHR‐1, which acts cell autonomously in the muscles to modulate polyglutamine repeat (polyQ) aggregation. A second nuclear receptor, DAF‐12, functions oppositely to NHR‐1 to maintain protein homeostasis. Transcriptomics analyses of unc‐1 mutants revealed changes in the expression of genes involved in fat metabolism, suggesting that fat metabolism changes, controlled by neurohormonal signalling, contribute to protein homeostasis. Furthermore, the enzymes involved in the identified signalling pathway are potential targets for treating neurodegenerative diseases caused by disrupted protein homeostasis.
Synopsis
A neurohormonal signal emanating from Caenorhabditis elegans ASJ neurons modulates protein homeostasis in the body wall muscles. The signal depends on the stomatin homologue UNC‐1 in neurons and the nuclear receptor NHR‐1 in muscles.
Electrical synapse disruption modulates protein homeostasis in a non‐cell autonomous manner in C. elegans.
PolyQ aggregation in muscles is modulated by a neurohormonal signal involving the sulfotransferase SSU‐1 and sulfatases SUL‐2 and SUL‐3.
The nuclear receptor NHR‐1 is a transcription factor that regulates lipid gene expression to modulate proteostasis in the muscle.
A neurohormonal signal emanating from Caenorhabditis elegans ASJ neurons modulates protein homeostasis in the body wall muscles. The signal depends on the stomatin homologue UNC‐1 in neurons and the nuclear receptor NHR‐1 in muscles.
Intravenous augmentation therapy with human alpha-1 proteinase inhibitor for the management of respiratory disease is recommended for people with alpha-1 antitrypsin deficiency (AATD) who are ...nonsmokers or former smokers. Augmentation therapy usually requires weekly administration at the hospital or clinic and poses an additional burden for patients due to interference with daily life, including work and social activities. Self-administration is a useful alternative to overcome this limitation, but there is a lack of published information on clinical outcomes. We report two cases of individuals with AATD at different stages of the disease who were successfully managed with self-administered augmentation therapy, with increased satisfaction because of the independence gained, lack of interference with clinical stability, and no relevant safety issues.
National and international organizations have introduced policies aimed at sustainable development. These policies are designed to encourage sustainable forms of business to meet the Sustainable ...Development Goals (SDGs) of the 2030 Agenda. Regional inequalities in sustainable development may be exacerbated by disparate levels of innovation. This paper analyzes the variations between clusters of countries according to the degree to which they have achieved the SDGs and their levels of innovation facilitators. Two types of analyses were employed. First, cluster analysis was used to examine changes in groups of regions with similar innovation characteristics between 2015 and 2020. Data for 122 countries were gathered from the World Bank, the SDG Index, and the Global Innovation Index. Second, multiple linear regression analysis was used to assess the power of the variables in the model to explain the level of sustainable development. The results reveal four clusters (low, medium, high, and very high innovative facilitators and sustainable development), as well as movements between those clusters from 2015 to 2020. The multiple linear regression analysis shows that the variables have explanatory power with respect to the dependent variable of sustainable development. This analysis also reveals different degrees of importance of the variables for each cluster. The findings highlight the need to consider the limitations of economic growth in terms of innovation facilitators to promote sustainable development. If policymakers recognize the limitations of economic growth and the physical ecosystem, degradation of the environment can be avoided, even when there is innovation. Global and individual social welfare can thus be ensured. This study offers valuable insights into how to achieve sustainable development through innovation facilitators by providing in-depth knowledge of the individual characteristics of innovation systems and considering the limitations of economic growth.
Data from manual healthspan assays of the nematode Caenorhabditis elegans (C. elegans) can be complex to quantify. The first attempts to quantify motor performance were done manually, using the ...so-called thrashing or body bends assay. Some laboratories have automated these approaches using methods that help substantially to quantify these characteristic movements in small well plates. Even so, it is sometimes difficult to find differences in motor behaviour between strains, and/or between treated vs untreated worms. For this reason, we present here a new automated method that increases the resolution flexibility, in order to capture more movement details in large standard Petri dishes, in such way that those movements are less restricted. This method is based on a Cartesian robot, which enables high-resolution images capture in standard Petri dishes. Several cameras mounted strategically on the robot and working with different fields of view, capture the required C. elegans visual information. We have performed a locomotion-based healthspan experiment with several mutant strains, and we have been able to detect statistically significant differences between two strains that show very similar movement patterns.
This study aims to examine the impact of the different waves of the COVID-19 pandemic on the connectedness of the BRICS (Brazil, Russia, India, China, and South Africa) term structure of interest ...rates and its components (level, slope and curvature). For that purpose, this research applies the time-varying parameter vector autoregression (TVP-VAR) approach in order to assess the direction of spillovers among countries and factors and measure their contribution to the connectedness system. Our results show that the total connectedness measure changes over time, and the level and curvature components show connectedness that persists longer than the slope component, both in the first wave of the COVID-19 pandemic. Brazil and South Africa would appear as net transmitters of shocks, whereas China and India are net receivers. Finally, the most significant differences in the net dynamic connectedness between transmitters and receivers were focused on before and during the first wave of the COVID-19 pandemic crisis. Some additional impacts were observed during the last waves of the coronavirus pandemic. To our best knowledge, this is the first study on the connectedness between the yield curves of the BRICS economies and the COVID-19 crisis uncertainty according to the coronavirus MCI, by decomposing the yield curve into its factors (level, slope, and curvature).
Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester and triglycerides between plasma lipoprotein particles HDL and LDL/VLDL, resulting in equilibration between ...these lipoprotein fractions. Therapy that modulates HDL metabolism to increase HDL-c levels could be an effective strategy to reduce residual cardiovascular risk since it is estimated that for each mg/dL increase in plasma HDL cholesterol, there could be a 2-3% decrease in cardiovascular risk. Modification of the lipoprotein profile by CETP inhibitors is promising, but the beneficial effect of reducing coronary heart disease risk has not yet been proven. To date, four CETP inhibitors have advanced to phase 3 cardiovascular outcome clinical trials, and two have been terminated for off-target adverse effects and lack of efficacy. This perspective will summarize recent events, new research developments, and the discovery of new classes of CETP inhibitors.
To investigate PGRMC1-precipitating proteins in human endometrial stromal cells (ESC) to understand its role during in vitro decidualization.
Prospective observational study.
Academic fertility ...center.
Fifteen fertile oocyte donors.
Isolated ESCs decidualized in vitro and used in pulldown assays.
GST-PGRMC1-precipitated proteins identified in nondecidualized ESC (ndESC) and ESC decidualized via a long (8 days) or short (4 days) decidualization protocol (dESC).
Using pulldown assays and mass spectrometry, decidualization was evaluated by prolactin secretion (ELISA) and cytoskeleton morphology (F-actin staining). The protein interactions were validated by colocalization and coimmunoprecipitation. The pulldown and mass spectrometry analysis identified 21, 24, and 24 new significant GST-PGRMC1-precipitated proteins in ndESC, long dESC, and short dESC, respectively, compared with controls. The functional annotation analysis categorized these proteins mainly into endomembrane system and mitochondria cellular components, both related to adenosine triphosphate (ATP) generation and transport activity, protein biosynthesis and posttranslational processing, vesicle trafficking, and protection against oxidative stress activities. Monoamine oxidase B (MAOB) and B-cell receptor-associated protein 31 (BAP31) were identified in dESC from both decidualization protocols. PGRMC1-MAOB/BAP31 interactions were confirmed by immunofluorescence and coimmunoprecipitation in dESC.
Novel GST-PGRMC1-precipitated proteins discovered in ESC suggest that this protein is implicated in deep remodeling of ESC during decidualization and aggregates mainly with proteins involved in biosynthesis, intracellular transport, and mitochondrial activity.
Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system. Although there is currently no definite cure for MS, new therapies have recently been developed based ...on a continuous search for new biomarkers.
MS diagnosis relies on the integration of clinical, imaging and laboratory findings as there is still no singlepathognomonicclinical feature or diagnostic laboratory biomarker. The most commonly laboratory test used is the presence of immunoglobulin G oligoclonal bands (OCB) in cerebrospinal fluid of MS patients. This test is now included in the 2017 McDonald criteria as a biomarker of dissemination in time. Nevertheless, there are other biomarkers currently in use such as kappa free light chain, which has shown higher sensitivity and specificity for MS diagnosis than OCB. In addition, other potential laboratory tests involved in neuronal damage, demyelination and/or inflammation could be used for detecting MS.
CSF and serum biomarkers have been reviewed for their use in MS diagnosis and prognosis to stablish an accurate and prompt MS diagnosis, crucial to implement an adequate treatment and to optimize clinical outcomes over time.
Myotonic Dystrophy type 1 (DM1) is a muscular dystrophy with a multi-systemic nature. It was one of the first diseases in which repeat associated non-ATG (RAN) translation was described in 2011, but ...has not been further explored since. In order to enhance our knowledge of RAN translation in DM1, we decided to study the presence of DM1 antisense (DM1-AS) transcripts (the origin of the polyglutamine (polyGln) RAN protein) using RT-PCR and FISH, and that of RAN translation via immunoblotting and immunofluorescence in distinct DM1 primary cell cultures, e.g., myoblasts, skin fibroblasts and lymphoblastoids, from ten patients. DM1-AS transcripts were found in all DM1 cells, with a lower expression in patients compared to controls. Antisense RNA foci were found in the nuclei and cytoplasm of a subset of DM1 cells. The polyGln RAN protein was undetectable in all three cell types with both approaches. Immunoblots revealed a 42 kD polyGln containing protein, which was most likely the TATA-box-binding protein. Immunofluorescence revealed a cytoplasmic aggregate, which co-localized with the Golgi apparatus. Taken together, DM1-AS transcript levels were lower in patients compared to controls and a small portion of the transcripts included the expanded repeat. However, RAN translation was not present in patient-derived DM1 cells, or was in undetectable quantities for the available methods.
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