Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become ...tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER-mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER-mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER-mitochondria interactions and that this is associated with disruption to the VAPB-PTPIP51 interaction and cellular Ca(2+) homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.
In microbial ecology, a fundamental question relates to how community diversity and composition change in response to perturbation. Most studies have had limited ability to deeply sample community ...structure (e.g. Sanger-sequenced 16S rRNA libraries), or have had limited taxonomic resolution (e.g. studies based on 16S rRNA hypervariable region sequencing). Here, we combine the higher taxonomic resolution of near-full-length 16S rRNA gene amplicons with the economics and sensitivity of short-read sequencing to assay the abundance and identity of organisms that represent as little as 0.01% of sediment bacterial communities. We used a new version of EMIRGE optimized for large data size to reconstruct near-full-length 16S rRNA genes from amplicons sheared and sequenced with Illumina technology. The approach allowed us to differentiate the community composition among samples acquired before perturbation, after acetate amendment shifted the predominant metabolism to iron reduction, and once sulfate reduction began. Results were highly reproducible across technical replicates, and identified specific taxa that responded to the perturbation. All samples contain very high alpha diversity and abundant organisms from phyla without cultivated representatives. Surprisingly, at the time points measured, there was no strong loss of evenness, despite the selective pressure of acetate amendment and change in the terminal electron accepting process. However, community membership was altered significantly. The method allows for sensitive, accurate profiling of the "long tail" of low abundance organisms that exist in many microbial communities, and can resolve population dynamics in response to environmental change.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
With a mix of theory, practical advice, and clinical material, this resource for any clinician interested in applying the object relations model to their clinical or academic work. The book outlines ...object relations theory, leveraging clinical vignettes to underline the framework's applicability both in therapy and acute care settings.
•Many implementation science questions can be addressed by experimental designs (e.g., randomized controlled trials RCTs).•Implementation trials differ in important ways, however, from more ...traditional efficacy- or effectiveness-oriented RCTs.•Adaptive designs can determine optimal implementation strategies within an experimental framework.•Quasi-experimental designs can be used to answer implementation science questions in the absence of randomization.•The choice of study designs in implementation science requires balancing scientific, pragmatic, and ethical issues.
Implementation science is focused on maximizing the adoption, appropriate use, and sustainability of effective clinical practices in real world clinical settings. Many implementation science questions can be feasibly answered by fully experimental designs, typically in the form of randomized controlled trials (RCTs). Implementation-focused RCTs, however, usually differ from traditional efficacy- or effectiveness-oriented RCTs on key parameters. Other implementation science questions are more suited to quasi-experimental designs, which are intended to estimate the effect of an intervention in the absence of randomization. These designs include pre-post designs with a non-equivalent control group, interrupted time series (ITS), and stepped wedges, the last of which require all participants to receive the intervention, but in a staggered fashion. In this article we review the use of experimental designs in implementation science, including recent methodological advances for implementation studies. We also review the use of quasi-experimental designs in implementation science, and discuss the strengths and weaknesses of these approaches. This article is therefore meant to be a practical guide for researchers who are interested in selecting the most appropriate study design to answer relevant implementation science questions, and thereby increase the rate at which effective clinical practices are adopted, spread, and sustained.
The endoplasmic reticulum (ER) and mitochondria form tight functional contacts that regulate several key cellular processes. The formation of these contacts involves "tethering proteins" that ...function to recruit regions of ER to mitochondria. The integral ER protein VAPB (VAMP associated protein B and C) binds to the outer mitochondrial membrane protein, RMDN3/PTPIP51 (regulator of microtubule dynamics 3) to form one such set of tethers. Recently, we showed that the VAPB-RMDN3 tethers regulate macroautophagy/autophagy. Small interfering RNA (siRNA) knockdown of VAPB or RMDN3 to loosen ER-mitochondria contacts stimulates autophagosome formation, whereas overexpression of VAPB or RMDN3 to tighten contacts inhibit their formation. Artificial tethering of ER and mitochondria via expression of a synthetic linker protein also reduces autophagy and this artificial tether rescues the effects of VAPB- or RMDN3-targeted siRNA loss on autophagosome formation. Finally, our studies revealed that the modulatory effects of ER-mitochondria contacts on autophagy involve their role in mediating ITPR (inositol 1,4,5-trisphosphate receptor) delivery of Ca
2+
from ER stores to mitochondria.
The heterogeneous Fenton process in the presence of Fe-containing minerals is ubiquitous in nature and widely deployed in wastewater treatment. While there have been extensive relevant studies, the ...dependence on pH of the nature and extent of oxidant generation and key reaction pathways remain unclear. Herein, the adsorption and decomposition of formate and H2O2 were quantified in the presence of ferrihydrite within the pH range of 3.0–6.0, and experiments with methyl phenyl sulfoxide were conducted to distinguish between HO• and weaker oxidant(s) which react via oxygen atom transfer including ferryl ion (FeIVO2+) and/or ferric hydroperoxo intermediates (FeIII(O2H)). Both HO• and FeIVO2+/FeIII(O2H) are concurrently produced on the surface over the acidic to near-neutral pH range. Despite the simultaneous formation of both oxidants, HO• is the major oxidant responsible for substrate oxidation in the interfacial boundary layer with FeIVO2+/FeIII(O2H) exhibiting limited exposure to substrates. With an increase of pH, the yield of both oxidants is inhibited by the decreasing availability of surface sites due to ferrihydrite particle aggregation. Increasing pH also favors the nonradical decay of H2O2 as evident from the consistent oxidant production rate relative to the surface area (SSA) despite an accelerated H2O2 decay rate relative to SSA with pH increase.
•Viral respiratory infections are historically associated with psychosis.•Viruses likely increase the risk of developing schizophrenia via immune activation.•COVID-19 can cause both neuropsychiatric ...symptoms and massive immune response.•Other human coronaviruses have been associated with psychotic disorders.•COVID-19 may increase risk for later development of psychotic disorders.
The historical association between respiratory infections and neuropsychiatric symptoms dates back centuries, with more recent literature highlighting a link between viral infections and schizophrenia. Maternal influenza infection during pregnancy has been associated with the development of schizophrenia in offspring. Viral infections in neonates, children, and adolescents have also been associated with later development of schizophrenia. Neuroinvasive and/or systemic infections are thought to increase risk for psychopathology via inflammatory mechanisms, particularly when exposure occurs during critical neurodevelopmental windows. Several human coronaviruses (HCoVs) have been associated with psychotic disorders and increasing reports of the neuropsychiatric manifestations of COVID-19 suggest it has neuroinvasive properties similar to those of other HCoVs. These properties, in conjunction with its ability to generate a massive inflammatory response, suggest that COVID-19 may also contribute to future psychopathology. This review will summarize the psychopathogenic mechanisms of viral infections and discuss the neuroinvasive and inflammatory properties of COVID-19 that could contribute to the development of psychotic disorders, with a focus on in utero, neonatal, and childhood exposure.
In 2 meta-analyses involving 58 studies and 59,575 participants, we quantitatively summarized the relative reliability and validity of continuous (i.e., dimensional) and discrete (i.e., categorical) ...measures of psychopathology. Overall, results suggest an expected 15% increase in reliability and 37% increase in validity through adoption of a continuous over discrete measure of psychopathology alone. This increase occurs across all types of samples and forms of psychopathology, with little evidence for exceptions. For typical observed effect sizes, the increase in validity is sufficient to almost halve sample sizes necessary to achieve standard power levels. With important caveats, the current results, considered with previous research, provide sufficient empirical and theoretical basis to assume a priori that continuous measurement of psychopathology is more reliable and valid. Use of continuous measures in psychopathology assessment has widespread theoretical and practical benefits in research and clinical settings. (Contains 3 footnotes, 9 tables, and 6 figures.)
An electrochemical advanced oxidation process (EAOP) is demonstrated with a catalytic cathode capable of simultaneously catalyzing the hydrogen evolution reaction (HER) and the oxygen reduction ...reaction (ORR) with resultant in situ generation of atomic hydrogen (H*) and hydrogen peroxide (H2O2). A palladium-coated carbon-PTFE gas diffusion electrode (Pd/C GDE) was used as a catalytic cathode with hydroxyl radical (•OH) formed as a result of the reaction of electrogenerated H* with H2O2. As both the HER and ORR can be induced to occur at the same cathode, the H*/GDE process results in more effective degradation of organic contaminants than can be achieved by a conventional H*/H2O2 process involving direct addition of H2O2. At circumneutral pH, 82.7% of added formate was degraded after 2 h treatment at an applied potential of −1.0 V vs Ag/AgCl with relatively low concentrations of generated H2O2 remaining in the solution. We also show that H* and H2O2 (and thus •OH) can be electrogenerated effectively over a wide range of pH (3.2–7.0). These results suggest that by in situ generation of H* and H2O2, the H*/GDE process is able to produce significant amounts of •OH without external chemical addition and thus offers an alternative method for abatement of aqueous organic contaminants.
Telemental health conducted via videoconferencing (TMH-V) has the potential to improve access to care, and providers' attitudes toward this innovation play a crucial role in its uptake. This ...systematic review examined providers' attitudes toward TMH-V through the lens of the unified theory of acceptance and use of technology (UTAUT). Findings suggest that providers have positive overall attitudes toward TMH-V despite describing multiple drawbacks. Therefore, the relative advantages of TMH-V, such as its ability to increase access to care, may outweigh its disadvantages, including technological problems, increased hassle, and perceptions of impersonality. Providers' attitudes may also be related to their degree of prior TMH-V experience, and acceptance may increase with use. Limitations and implications of findings for implementation efforts are discussed.
Public Health Significance
Mental health providers can conduct appointments remotely via videoconferencing, a form of telemental health (TMH-V) which can increase access to care for patients who live far from specialty providers or have difficulty leaving their homes. It is important to understand providers' attitudes toward this technology, as they play a crucial role in whether this service will be widely adopted by health-care systems and will therefore be offered to patients. The current review found that providers feel positive toward TMH-V despite reporting multiple drawbacks; this suggests that the relative advantages of TMH-V, such as its ability to increase access to care, may outweigh its disadvantages, including technological problems, increased hassle, and perceptions of feeling impersonal.
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