Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals

Oxidation of proteins by reactive oxygen species is associated with aging, oxidative stress, and many diseases. Although free and protein-bound methionine residues are particularly sensitive to oxidation to methionine sulfoxide derivatives, these oxidations are readily repaired by the action of methionine sulfoxide reductase (MsrA). To gain a better understanding of the biological roles of MsrA in metabolism, we have created a strain of mouse that lacks the MsrA gene. Compared with the wild type, this mutant: (i) exhibits enhanced sensitivity to oxidative stress (exposure to 100% oxygen); (ii) has a shorter lifespan under both normal and hyperoxic conditions; (iii) develops an atypical (tip-toe) walking pattern after 6 months of age; (iv) accumulates higher tissue levels of oxidized protein (carbonyl derivatives) under oxidative stress; and (v) is less able to up-regulate expression of thioredoxin reductase under oxidative stress. It thus seems that MsrA may play an important role in aging and neurological disorders.     

Conditional destabilization of the TPLATE complex impairs endocytic internalization

In plants, endocytosis is essential for many developmental and physiological processes, including regulation of growth and development, hormone perception, nutrient uptake, and defense against pathogens. Our toolbox to modulate this process is, however, rather limited. Here, we report a conditional tool to impair endocytosis. We generated a partially functional TPLATE allele by substituting the most conserved domain of the TPLATE subunit of the endocytic TPLATE complex (TPC). This substitution destabilizes TPC and dampens the efficiency of endocytosis. Short-term heat treatment increases TPC destabilization and reversibly delocalizes TPLATE from the plasma membrane to aggregates in the cytoplasm. This blocks FM uptake and causes accumulation of various known endocytic cargoes at the plasma membrane. Short-term heat treatment therefore transforms the partially functional TPLATE allele into an effective conditional tool to impair endocytosis. Next to their role in endocytosis, several TPC subunits are also implicated in actin-regulated autophagosomal degradation. Inactivating TPC via the WDX mutation, however, does not impair autophagy, thus enabling specific and reversible modulation of endocytosis in planta.

Endocytosis is an evolutionarily conserved eukaryotic pathway by which extracellular material and plasma membrane (PM) components are internalized via vesicles (1, 2). Clathrin-mediated endocytosis (CME), relying on the scaffolding protein clathrin, is the most prominent and the most studied endocytic pathway (3–5). As clathrin does not interact directly with the PM, nor does it recognize cargoes, adaptor proteins are required to act as essential links between the clathrin coat and the PM (6). In plant cells, material selected for CME is recognized by two adaptor complexes, the adaptor complex 2 (AP-2) and the TPLATE complex (TPC) (7–9). In contrast to TPC, single subunit mutants of AP-2 are viable (7, 8, 10–13) and AP-2 recruitment and dynamics appear to rely on TPC function (8, 14).TPC represents an ancestral adaptor complex, which is however absent in present-day metazoans and yeasts. It was experimentally identified as an octameric complex in Arabidopsis and as a hexametric complex in Dictyostelium (8, 15). Plants, however, are the only eukaryotic supergroup identified so far where TPC is essential for life (8, 15), as knockout or severe knockdown of single subunits of TPC in Arabidopsis leads to pollen or seedling lethality, respectively (8, 13). Two TPC subunits, AtEH1/Pan1 and AtEH2/Pan1, were not associated with the other TPC core components when the complex was forced into the cytoplasm by truncating the TML subunit and did not copurify with the other TSET components in Dictyostelium. This indicates that they may be auxiliary components to the core TPC (8, 15). These AtEH/Pan1 proteins were recently identified as important players in actin-regulated autophagy in plants. AtEH/Pan1 proteins recruit several components of the endocytic machinery to the autophagosomes, and are degraded together with them under stress conditions (16). However, whether this pathway serves to degrade specific cargoes or to regulate the endocytic machinery itself (17), and whether the whole TPC is required for this degradation pathway, remains unclear.Genetic and chemical tools to manipulate endocytosis have been extensively investigated via interfering with the functions of endocytic players, such as clathrin (18–22), adaptor proteins (7, 10–12, 14, 23–25), and dynamin-related proteins (26–30). The chemical inhibitors originally used to affect CME in plants have recently been described to possess undesirable side effects (31) or to affect proteins that are not only specific for endocytosis: for example, clathrin itself, as it is also involved in TGN trafficking (19, 22). The same is true for several genetic tools currently available to affect CME in plants (18, 21, 22, 30). Manipulation of TPC, functioning exclusively at the PM, represents a very good candidate to affect CME more specifically. So far however, there are no chemical tools to target TPC functions or dominant-negative mutants available. Inducible silencing works, but causes seedling lethality and takes several days to become effective (8). The only tools to manipulate TPC function in viable plants consist of knock-down mutants with very mild reduction of expression and consequently similar mild effects on CME (8, 14, 16, 32).     

Impacto del polvo sahariano en la incidencia de síndrome coronario agudo

Introduction and objectivesAsian desert dust has recently been recognized as a trigger for acute myocardial infarction. The inflow of dust from the Sahara into Spain impairs air quality due to an increase in particulate matter concentrations in the ambient air. The aim of the present study was to elucidate whether Saharan dust events are associated with the incidence of acute coronary syndrome (ACS) in patients living near North Africa, the major global dust source.MethodsWe prospectively collected data on hospitalizations due to ACS in 2416 consecutive patients from a tertiary care hospital (Canary Islands, Spain) from December 2012 to December 2017. Concentrations of particulate matter with an aerodynamic diameter 10 microns or smaller (PM₁₀) and reactive gases were measured in the European Air Quality Network implemented in the Canary Islands. We applied the time-stratified case crossover design using conditional Poisson regression models to estimate the impact of PM₁₀ Saharan dust events on the incidence of ACS.ResultsThe occurrence of Saharan dust events observed 0 to 5 days before the onset of ACS was not significantly associated with the incidence of ACS. Incidence rate ratios (IRR) of PM₁₀ levels 1, 2, 3, 4 and 5 days before ACS onset (for changes in 10 μg/m³) were 1.27 (95%CI, 0.87-1.85), 0.92 (95%CI, 0.84-1.01), 0.74 (95%CI, 0.45-1.22), 0.98 (95%CI, 0.87-1.11), and 0.95 (95%CI, 0.84-1.06), respectively.ConclusionsExposure to Saharan desert dust is unlikely to be associated with the incidence of ACS.     

A randomized comparison of repeat stenting with balloon angioplasty in patients with in-stent restenosis

OBJECTIVES: This randomized trial compared repeat stenting with balloon angioplasty (BA) in patients with in-stent restenosis (ISR). BACKGROUND: Stent restenosis constitutes a therapeutic challenge. Repeat coronary interventions are currently used in this setting, but the recurrence risk remains high. METHODS: We randomly assigned 450 patients with ISR to elective stent implantation (224 patients) or conventional BA (226 patients). Primary end point was recurrent restenosis rate at six months. Secondary end points included minimal lumen diameter (MLD), prespecified subgroup analyses, and a composite of major adverse events. RESULTS: Procedural success was similar in both groups, but in-hospital complications were more frequent in the balloon group. After the procedure MLD was larger in the stent group (2.77 +/- 0.4 vs. 2.25 +/- 0.5 mm, p < 0.001). At follow-up, MLD was larger after stenting when the in-lesion site was considered (1.69 +/- 0.8 vs. 1.54 +/- 0.7 mm, p = 0.046). However, the binary restenosis rate (38% stent group, 39% balloon group) was similar with the two strategies. One-year event-free survival (follow-up 100%) was also similar in both groups (77% stent vs. 71% balloon, p = 0.19). Nevertheless, in the prespecified subgroup of patients with large vessels (> or =3 mm) the restenosis rate (27% vs. 49%, p = 0.007) and the event-free survival (84% vs. 62%, p = 0.002) were better after repeat stenting. CONCLUSIONS: In patients with ISR, repeat coronary stenting provided better initial angiographic results but failed to improve restenosis rate and clinical outcome when compared with BA. However, in patients with large vessels coronary stenting improved the long-term clinical and angiographic outcome.     

Embedded Pragmatic Trials in Dementia Care: Realizing the Vision of the NIA IMPACT Collaboratory

Close to 6 million Americans have Alzheimer's disease (AD) or Alzheimer's disease and related dementia (AD/ADRD). These high-need, high-cost patients are vulnerable to receiving poor quality uncoordinated care, ultimately leading to adverse health outcomes, poor quality of life, and misuse of resources. Improving the care of persons living with dementia (PLWD) and their caregivers is an urgent public health challenge that must be informed by high-quality evidence. Although prior research has elucidated opportunities to improve AD/ADRD care, the adoption of promising interventions has been stymied by the lack of research evaluating their effectiveness when implemented under real-world conditions. Embedded pragmatic clinical trials (ePCTs) in healthcare systems have the potential to accelerate the translation of evidence-based interventions into clinical practice. Building from the foundation of the National Institutes of Healthcare Systems Collaboratory, in September 2019 the National Institute on Aging Imbedded Pragmatic AD/ADRD Clinical Trials (IMPACT) Collaboratory was launched. Its mission is to build the nation's capacity to conduct ePCTs within healthcare systems for PLWD and their caregivers by (1) developing and disseminating best practice research methods, (2) supporting the design and conduct of ePCTs including pilot studies, (3) building investigator capacity through training and knowledge generation, (4) catalyzing collaboration among stakeholders, and (5) ensuring the research includes culturally tailored interventions for people from diverse backgrounds. This report presents the rationale, structure, key activities, and markers of success for the overall NIA IMPACT Collaboratory. The articles that follow in this special Issue describe the specific work of its 10 core working groups and teams. J Am Geriatr Soc 68:S1–S7, 2020 .