Malaria remains a major public health issue, infecting nearly 220 million people every year. The spread of drug-resistant strains of
around the world threatens the progress made against this disease. ...Therefore, identifying druggable and essential pathways in
parasites remains a major area of research. One poorly understood area of parasite biology is the formation of disulfide bonds, which is an essential requirement for the folding of numerous proteins. Specialized chaperones with thioredoxin (Trx) domains catalyze the redox functions necessary for breaking incorrect and forming correct disulfide bonds in proteins. Defining the substrates of these redox chaperones is difficult and immunoprecipitation based assays cannot distinguish between substrates and interacting partners. Further, the substrate or client interactions with the redox chaperones are usually transient in nature. Activity based crosslinkers that rely on the nucleophilic cysteines on Trx domains and the disulfide bond forming cysteines on clients provide an easily scalable method to trap and identify the substrates of Trx-domain containing chaperones. The cell permeable crosslinker divinyl sulfone (DVSF) is active only in the presence of nucleophilic cysteines in proteins and, therefore, traps Trx domains with their substrates, as they form mixed disulfide bonds during the course of their catalytic activity. This allows the identification of substrates that rely on Trx activity for their folding, as well as discovering small molecules that interfere with Trx domain activity. Graphic abstract: Identification of thioredoxin domain substrates via divinylsulfone crosslinking and immunoprecipitation-mass spectrometry.
Malaria remains a major public health issue, infecting nearly 220 million people every year. The spread of drug-resistant strains of Plasmodium falciparum around the world threatens the progress made ...against this disease. Therefore, identifying druggable and essential pathways in P. falciparum parasites remains a major area of research. One poorly understood area of parasite biology is the formation of disulfide bonds, which is an essential requirement for the folding of numerous proteins. Specialized chaperones with thioredoxin (Trx) domains catalyze the redox functions necessary for breaking incorrect and forming correct disulfide bonds in proteins. Defining the substrates of these redox chaperones is difficult and immunoprecipitation based assays cannot distinguish between substrates and interacting partners. Further, the substrate or client interactions with the redox chaperones are usually transient in nature. Activity based crosslinkers that rely on the nucleophilic cysteines on Trx domains and the disulfide bond forming cysteines on clients provide an easily scalable method to trap and identify the substrates of Trx-domain containing chaperones. The cell permeable crosslinker divinyl sulfone (DVSF) is active only in the presence of nucleophilic cysteines in proteins and, therefore, traps Trx domains with their substrates, as they form mixed disulfide bonds during the course of their catalytic activity. This allows the identification of substrates that rely on Trx activity for their folding, as well as discovering small molecules that interfere with Trx domain activity.Graphic abstract:Identification of thioredoxin domain substrates via divinylsulfone crosslinking and immunoprecipitation-mass spectrometry.
Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive ...and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
The purpose of this study was to determine if recommendations made as a result of the administration of the Cougar Home Safety Assessment Version 4.0 (CHSA 4.0) were effective in causing older ...residents to make environmental safety modifications in their homes. Initial data were collected during the administration of the CHSA 4.0 in the homes of 40 older people in four northeastern states. After completing the initial assessments, the researchers provided the participants with recommendations for improving the environmental safety of their homes. Approximately one month later, each home was reassessed with the CHSA 4.0. Overall, improvement in environmental safety was demonstrated in the homes with the greatest increases being in fire safety, emergency phone number placement, and bathroom safety. A t-test demonstrated a significant gain in compliance (t = 7.8, p < .001) by comparing the difference between the mean initial and reassessment home safety scores. A very large effect size (Cohen’s d = 1.7) was also found, indicating a high magnitude of difference between initial and reassessment safety ratings. The assessment proved to be beneficial in increasing the environmental safety of homes.
Exercise is associated with altered gut microbial composition, but studies have not investigated whether the gut microbiota and associated metabolites are modulated by exercise training in humans. We ...explored the impact of 6 wk of endurance exercise on the composition, functional capacity, and metabolic output of the gut microbiota in lean and obese adults with multiple-day dietary controls before outcome variable collection.
Thirty-two lean (n = 18 9 female) and obese (n = 14 11 female), previously sedentary subjects participated in 6 wk of supervised, endurance-based exercise training (3 d·wk) that progressed from 30 to 60 min·d and from moderate (60% of HR reserve) to vigorous intensity (75% HR reserve). Subsequently, participants returned to a sedentary lifestyle activity for a 6-wk washout period. Fecal samples were collected before and after 6 wk of exercise, as well as after the sedentary washout period, with 3-d dietary controls in place before each collection.
β-diversity analysis revealed that exercise-induced alterations of the gut microbiota were dependent on obesity status. Exercise increased fecal concentrations of short-chain fatty acids in lean, but not obese, participants. Exercise-induced shifts in metabolic output of the microbiota paralleled changes in bacterial genes and taxa capable of short-chain fatty acid production. Lastly, exercise-induced changes in the microbiota were largely reversed once exercise training ceased.
These findings suggest that exercise training induces compositional and functional changes in the human gut microbiota that are dependent on obesity status, independent of diet and contingent on the sustainment of exercise.
A review of composite lattice structures Hunt, Christopher J.; Morabito, Francescogiuseppe; Grace, Chris ...
Composite structures,
03/2022, Letnik:
284
Journal Article
Recenzirano
Composite materials have now been adopted in a wide range of applications, primarily due to their weight-saving potential. Overwhelmingly so, these materials have been used in laminated or monolithic ...structural components. Moving towards lattice configurations, in which the structure is formed from a network of connected members, can offer unparalleled structural efficiencies. From a structural standpoint, composites are ideal materials for the formation of lattice structures as their anisotropic properties can be exploited within the mainly uniaxially stressed members. However, from a manufacturing standpoint, they present a range of challenges that, so far, has largely limited their application within industry. Within this field, there is now a wide range of different approaches to creating composite lattice structures that are under development. This paper organises and assesses the current work on these technologies, with the core focus being on their associated manufacturing methodologies. Three main classifications are identified based on the geometry and intended use of the structure, and progress made in each is highlighted alongside key remaining hurdles to widespread implementation.
Large‐scale, polycrystalline WTe2 thin films are synthesized by atmospheric chemical vapor reaction of W metal films with Te vapor catalyzed by H2Te intermediates, paving a way to understanding the ...synthesis mechanism for low bonding energy tellurides and toward synthesis of single‐crystalline telluride nanoflakes. Through‐plane and in‐plane thermal conductivities of single‐crystal WTe2 flakes and polycrystalline WTe2 thin films are measured for the first time. Nanoscale grains and disorder in WTe2 thin films suppress the in‐plane thermal conductivity of WTe2 greatly, which is at least 7.5 times lower than that of the single‐crystalline flakes.
Large‐scale, polycrystalline WTe2 thin films are synthesized by atmospheric chemical vapor reaction of W metal films with Te vapor catalyzed by H2Te intermediates, paving a way to understanding the synthesis mechanism for low bonding energy tellurides and toward synthesis of single‐crystalline telluride nanoflakes. Through‐plane and in‐plane thermal conductivities of single‐crystal WTe2 flakes and polycrystalline WTe2 thin films are measured for the first time. Nanoscale grains and disorder in WTe2 thin films suppress the in‐plane thermal conductivity of WTe2 greatly, which is at least 7.5 times lower than that of the single‐crystalline flakes.
Using the MoS2‐WTe2 heterostructure as a model system combined with electrochemical microreactors and density function theory calculations, it is shown that heterostructured contacts enhance the ...hydrogen evolution reaction (HER) activity of monolayer MoS2. Two possible mechanisms are suggested to explain this enhancement: efficient charge injection through large‐area heterojunctions between MoS2 and WTe2 and effective screening of mirror charges due to the semimetallic nature of WTe2. The dielectric screening effect is proven minor, probed by measuring the HER activity of monolayer MoS2 on various support substrates with dielectric constants ranging from 4 to 300. Thus, the enhanced HER is attributed to the increased charge injection into MoS2 through large‐area heterojunctions. Based on this understanding, a MoS2/WTe2 hybrid catalyst is fabricated with an HER overpotential of −140 mV at 10 mA cm−2, a Tafel slope of 40 mV dec−1, and long stability. These results demonstrate the importance of interfacial design in transition metal dichalcogenide HER catalysts. The microreactor platform presents an unambiguous approach to probe interfacial effects in various electrocatalytic reactions.
Catalysis of the hydrogen evolution reaction at MoS2/WTe2 heterostructures is investigated with electrochemical microreactors. This study carefully determines that efficient charge injection from WTe2 to MoS2 leads to improved catalytic performance. The insights gained from microreactors are applied to a real catalyst system through the synthesis of MoS2/WTe2 hybrid nanostructures with enhanced catalytic performance.
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