RNA-binding proteins (RBPs) are critical players in RNA expression and metabolism, thus, the proper regulation of this class of proteins is critical for cellular health. Regulation of RBPs often ...occurs through post-translational modifications (PTMs), which allow the cell to quickly and efficiently respond to cellular and environmental stimuli. PTMs have recently emerged as important regulators of RBPs implicated in neurodegenerative disorders, in particular amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we summarize how disease-associated PTMs influence the biophysical properties, molecular interactions, subcellular localization, and function of ALS/FTD-linked RBPs, such as FUS and TDP-43. We will discuss how PTMs are believed to play pathological, protective, or ambiguous roles in these neurodegenerative disorders.
Research in recent years has begun to tackle the impact of post-translational modifications (PTMs) on neurodegenerative disease-associated RNA binding proteins, such as FUS and TDP-43.Alterations in arginine methylation of FUS and abnormal phosphorylation, acetylation, oxidation, nitrosylation, ubiquitination, and proteolytic cleavage of TDP-43 are observed in postmortem brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients.Changes in the PTM landscape of FUS and TDP-43 seen in ALS and FTD alter the biophysical properties, molecular interactions, subcellular localization, and function of FUS and TDP-43.Some disease-linked PTMs may accelerate the disease process (e.g., by promoting mislocalization or aberrant phase separation), whereas others may act as ‘brakes’, attempting to correct other primary cellular issues that occur earlier in disease.
Highlights • Methamphetamine continues to pose a significant public health problem in the U.S. • This review provides an update to the literature on methamphetamine use and addiction. • Current ...treatments for methamphetamine dependence are only modestly effective. • Future directions include development of medications with novel molecular targets.
Post‐translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating ...protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA‐binding protein TAR DNA‐binding protein (TDP‐43), is hyperphosphorylated in disease on several C‐terminal serine residues, a process generally believed to promote TDP‐43 aggregation. Here, we however find that Casein kinase 1δ‐mediated TDP‐43 hyperphosphorylation or C‐terminal phosphomimetic mutations reduce TDP‐43 phase separation and aggregation, and instead render TDP‐43 condensates more liquid‐like and dynamic. Multi‐scale molecular dynamics simulations reveal reduced homotypic interactions of TDP‐43 low‐complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP‐43, but suppress accumulation of TDP‐43 in membrane‐less organelles and promote its solubility in neurons. We speculate that TDP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP‐43 aggregation.
Synopsis
C‐terminal hyperphosphorylation of TDP‐43, a pathological hallmark of several neurodegenerative disorders, enhances the liquidity of TDP‐43 condensates and suppresses TDP‐43 condensation and aggregation, shedding a new light on this TDP‐43 disease‐linked posttranslational modification.
TDP‐43 phosphorylation by CK1δ or C‐terminal phosphomimetic mutations suppress TDP‐43 phase separation and aggregation.
C‐terminal phosphomimetic mutations enhance liquidity and dynamics of TDP‐43 condensates.
Suppression of phase separation is associated with loss of protein‐protein interactions in the C‐terminus and enhanced solvation of negatively charged groups.
TDP‐43 bearing C‐terminal phosphomimetic mutations fails to condense into stress‐induced membrane‐less compartments and remains dispersed.
C‐terminal TDP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP‐43 aggregation, rather than a driver of neuropathology as previously assumed.
BACKGROUND AND PURPOSE—Neurophysiological models of rehabilitation and recovery suggest that a large volume of specific practice is required to induce the neuroplastic changes that underlie ...behavioral recovery. The primary objective of this meta-analysis was to explore the relationship between time scheduled for therapy and improvement in motor therapy for adults after stroke by (1) comparing high doses to low doses and (2) using metaregression to quantify the dose–response relationship further.
METHODS—Databases were searched to find randomized controlled trials that were not dosage matched for total time scheduled for therapy. Regression models were used to predict improvement during therapy as a function of total time scheduled for therapy and years after stroke.
RESULTS—Overall, treatment groups receiving more therapy improved beyond control groups that received less (g=0.35; 95% confidence interval, 0.26–0.45). Furthermore, increased time scheduled for therapy was a significant predictor of increased improvement by itself and when controlling for linear and quadratic effects of time after stroke.
CONCLUSIONS—There is a positive relationship between the time scheduled for therapy and therapy outcomes. These data suggest that large doses of therapy lead to clinically meaningful improvements, controlling for time after stroke. Currently, trials report time scheduled for therapy as a measure of therapy dose. Preferable measures of dose would be active time in therapy or repetitions of an exercise.
There is evidence that loneliness and unemployment each have a negative impact on public health. Both are experienced across the life course and are of increasing concern in light of the COVID-19 ...pandemic. This review seeks to examine the strength and direction of the relationship between loneliness and unemployment in working age individuals, and in particular the potential for a self-reinforcing cycle with combined healthcare outcomes. A systematic search was undertaken in Medline, PubMed, PsycINFO, Embase and EconLit from inception to December 2020. PRISMA reporting guidelines were followed throughout this review, study quality was assessed using the Joanna Briggs Institute checklist and results were summarised in a narrative synthesis. English language studies evaluating the relationship between loneliness and unemployment in higher income western countries were included. Thirty-seven studies were identified; 30 cross-sectional and 7 longitudinal. Loneliness was measured by a direct question or loneliness scale while unemployment was self-reported or retrieved from a national register. A positive association between unemployment and increased loneliness was observed across all studies. Thus, across the life-course a clear yet complex relationship exists between unemployment and greater experience of loneliness. The magnitude of this relationship increases with the severity of loneliness and appears to peak at age 30–34 and 50–59. Logistic regression provided the greatest consistency at statistical significance revealing at least a 40% increase in the likelihood of reporting loneliness when unemployed. Recent longitudinal studies identified in this review found higher levels of loneliness following job loss, but also that loneliness was predictive of unemployment suggesting potential bi-directionality in the relationship. This bi-directionality may create a multiplier effect between loneliness and unemployment to form a self-reinforcing relationship and greater health concerns for those most at risk. Thus, review findings suggest the need for cross-sector awareness and intervention to tackle both loneliness and unemployment.
•Unemployment is related to feeling lonely.•Stronger association of unemployment with severe experience of loneliness.•Greatest connection between loneliness and unemployment at age 30–34 and 50-59.•Potential for a bi-directional relationship between loneliness and unemployment.•Greater understanding is needed in the face of COVID-19 recovery.
Abstract Background Atherosclerosis, a leading cause of mortality, necessitates effective management of hypercholesterolemia, specifically elevated low‐density lipoprotein cholesterol (LDL‐C). The ...emergence of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has revolutionised lipid‐lowering. PCSK9i demonstrates substantial LDL‐C reduction and cardiovascular benefits, particularly in statin‐intolerant or nonresponsive individuals. However, the potential pleiotropic effects of PCSK9i, especially on arterial stiffness, remain a subject of investigation. This systematic review and meta‐analysis seek to provide a nuanced understanding of the potential pleiotropic effects of PCSK9i, specifically on arterial health. The primary objective was to analyse the influence of PCSK9i on arterial stiffness, extending beyond traditional lipid‐lowering metrics and contributing to a more comprehensive approach to cardiovascular risk reduction. Methods A systematic search was conducted across major databases, clinical trial registries and grey literature. Inclusion criteria comprised adults in prospective cohort studies undergoing PCSK9i augmentation in lipid‐lowering therapy, with a focus on arterial stiffness measured by pulse wave velocity (PWv). Random‐effects meta‐analyses, sensitivity analyses and meta‐regression models were employed to assess the pooled effect of adding PCSK9i to lipid‐lowering interventions on arterial stiffness. Results Five studies (158 participants) met the inclusion criteria, demonstrating a significant reduction in PWv (mean difference: −2.61 m/s 95% CI: −3.70, −1.52; ES: −1.62 95% CI: −2.53, −.71) upon adding PCSK9i to lipid‐lowering interventions. Subgroup analysis and meta‐regression models suggested potential sex‐based and baseline PWv‐dependent variations, emphasising patient‐specific characteristics. Conclusion The meta‐analysis provides robust evidence that adding PCSK9i to lipid‐lowering interventions significantly improves arterial stiffness, indicating broader vascular benefits beyond LDL‐C reduction.
The potential of microplastics as carriers of metals Godoy, V.; Blázquez, G.; Calero, M. ...
Environmental pollution (1987),
December 2019, 2019-Dec, 2019-12-00, 20191201, Letnik:
255, Številka:
Pt 3
Journal Article
Recenzirano
Microplastics can adsorb chemical pollutants such as metals or pharmaceuticals, and transferred them along the food chain. In this work, an investigation of the adsorption of Cd, Co, Cr, Cu, Ni, Pb ...and Zn by five different types of microplastics was performed in Milli-Q water and natural waters (seawater, urban wastewater and irrigation water) via a series of batch adsorption experiments. The effects of concentration of metals and physicochemical characteristics of polymers were particularly studied. Results revealed a significant adsorption of lead, chromium and zinc on microplastics, especially on polyethylene and polyvinyl chloride. In the case of polyethylene terephthalate, it showed little adsorption capacity. Specific surface, porosity and morphology are characteristics that affect the molecular interactions. The adsorption isotherms were better described by Langmuir model, which indicates that the main adsorption mechanism might be chemical adsorption. Finally, results obtained in natural waters indicated that dissolved organic matter may play a major role on metal adsorption on microplastics. Results showed an enhancement of metal adsorption in waters with high chemical and biological oxygen demands as urban wastewater and irrigation water.
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•PE, PP, PS and PVC showed fast adsorption to metals after 120 h of contact.•Sorption equilibrium fit better with Langmuir model than Freundlich model.•Cr and Pb were the metals adsorbed in most quantity in Milli-Q and natural waters.•Dissolved organic matter and pH influence the adsorption in natural waters.•Specific surface, porosity and morphology play important roles in the adsorption.
Main finding of the work: PE, PP, PS and PVC showed high potential as metal carriers. Combination of all properties of polymers influences the adsorption behavior. Higher adsorption was found in natural water with high organic matter content.
The Galaxy And Mass Assembly (GAMA) survey is one of the largest contemporary spectroscopic surveys of low redshift galaxies. Covering an area of ∼286 deg2 (split among five survey regions) down to a ...limiting magnitude of r < 19.8 mag, we have collected spectra and reliable redshifts for 238 000 objects using the AAOmega spectrograph on the Anglo-Australian Telescope. In addition, we have assembled imaging data from a number of independent surveys in order to generate photometry spanning the wavelength range 1 nm–1 m. Here, we report on the recently completed spectroscopic survey and present a series of diagnostics to assess its final state and the quality of the redshift data. We also describe a number of survey aspects and procedures, or updates thereof, including changes to the input catalogue, redshifting and re-redshifting, and the derivation of ultraviolet, optical and near-infrared photometry. Finally, we present the second public release of GAMA data. In this release, we provide input catalogue and targeting information, spectra, redshifts, ultraviolet, optical and near-infrared photometry, single-component Sérsic fits, stellar masses, Hα-derived star formation rates, environment information, and group properties for all galaxies with r < 19.0 mag in two of our survey regions, and for all galaxies with r < 19.4 mag in a third region (72 225 objects in total). The data base serving these data is available at http://www.gama-survey.org/.
Poor removal of many pharmaceuticals and personal care products (PPCPs) in sewage treatment leads to their discharge into the receiving waters, where they may cause negative effects. Their ...elimination from the water column depends of several processes, including photochemical and biological degradation. We have focused this research on comparing the degradation kinetics of a wide number (n=33) of frequently detected PPCPs considering different types of water, pH and solar irradiation. For those compounds that were susceptible of photodegradation, their rates (k) varied from 0.02 to 30.48h−1 at pH7, with the lowest values for antihypertensive and psychiatric drugs (t1/2>1000h). Modification of the pH turned into faster disappearance of most of the PPCPs (e.g., k=0.072 and 0.066h−1 for atenolol and carbamazepine at pH4, respectively). On the other hand, biodegradation was enhanced by marine bacteria in many cases, for example for mefenamic acid, caffeine and triclosan (k=0.019, 0.01 and 0.04h−1, respectively), and was faster for anionic surfactants. Comparing photodegradation and biodegradation processes, hydrochlorothiazide and diclofenac, both not biodegradable, were eliminated exclusively by irradiation (t1/2=0.15–0.43h and t1/2=0.14–0.17h, respectively). Salicylic acid and phenylbutazone were efficiently photo (t1/2<3h) and biodegraded (t1/2=116–158h), whereas some compounds such as ibuprofen, carbamazepine and atenolol had low degradation rates by any of the processes tested (t1/2=23–2310h), making then susceptible to persist in the aquatic media.
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•Photolysis and biodegradation kinetics were studied for 33 organic compounds.•pH and salinity play a significant role in photo and biodegradation processes.•Faster biodegradation rates were observed for most compounds in seawater.•Carbamazepine and amitriptyline were among the most recalcitrant compounds.•Degradation half-lives in water were reported for the first time for albuterol.
This research analyzes the potential use of the olive stone as a low-cost biosorbent for Cr (III) from aqueous solutions in a continuous system. First, experiments were carried out in fixed-bed ...column to test the influence of various parameters on breakthrough and saturation time. The breakthrough and saturation time increase with the decrease of the flow rate. The same effect is shown when the bed depth is increased. The olive stone sorption capacity,
q
e, increases as the inlet Cr (III) concentration increases until a value close to 0.800
mg/g is reached, then
q
e remains constant. Column data obtained at different conditions were described using the Adams–Bohart, Thomas, Yoon and Nelson, and Dose–Response models. The breakthrough curve prediction by the Adams–Bohart and Dose–Response models were found to be very satisfactory. In particular, the Adams–Bohart model can be used to represent the initial region of breakthrough curve, whereas the Dose–Response model is the one which best reproduces the whole curve for all the inlet Cr (III) concentrations used. Finally, a study of pH evolution was carried out. The pH increases at the beginning, subsequently decreasing as time passes until practically reaching the initial value.
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