Physical, nutritional, and cognitive interventional approaches were effective in reversing frailty among community-living older persons.

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The "MAN antigens" are polypeptides recognized by autoantibodies from a patient with a collagen vascular disease and localized to the nuclear envelope. We now show that one of the human MAN antigens termed MAN1 is a 82.3-kDa protein with an amino-terminal domain followed by two hydrophobic segments and a carboxylterminal tail. The MAN1 gene contains seven proteincoding exons and is assigned to human chromosome 12q14. Its mRNA is approximately 5.5 kilobases and is detected in several different cell types that were examined. Cell extraction experiments show that MAN1 is an integral membrane protein. When expressed in transfected cells, MAN1 is exclusively targeted to the nuclear envelope, consistent with an inner nuclear membrane localization. Protein sequence analysis reveals that MAN1 shares a conserved globular domain of approximately 40 amino acids, which we term the LEM module, with inner nuclear membrane proteins lamina-associated polypeptide 2 and emerin. The LEM module is also present in two proteins of Caenorhabditis elegans. These results show that MAN1 is an integral protein of the inner nuclear membrane that shares the LEM module with other proteins of this subcellular localization.Only a few proteins other than the nuclear lamins, some with various isoforms, have been localized to the inner nuclear membrane during interphase. The first to be identified was avian lamin B receptor (LBR) 1 (1, 2). LBR was subsequently characterized in mammals (3-6), and an immunochemically crossreactive protein has been identified in sea urchins (7). LBR has a nucleoplasmic, amino-terminal domain of approximately 200 amino acids that binds to B-type lamins and chromatin proteins and confers inner nuclear membrane retention (2, 4, 8 -12). The amino-terminal domain of LBR is followed by a hydrophobic domain with eight putative transmembrane segments that is similar in sequence to sterol reductases, including two human proteins of the endoplasmic reticulum, one of which is a 7-dehydrocholesterol reductase (13).Two other integral proteins of the inner nuclear membrane have been termed lamina-associated polypeptides (LAPs). Three related isoforms of rat LAP1 (LAP1A, LAP1B, and LAP1C) were identified by reaction with a single monoclonal antibody and shown to be integral membrane proteins associated with the nuclear lamina (14). LAP1C has a nucleoplasmic amino-terminal domain followed by one transmembrane segment, and the other LAP1 isoforms are probably of similar overall structure, arising from the same gene by alternative RNA splicing (15). LAP2 was also first identified by reaction with a monoclonal antibody and shown to be an integral membrane protein that binds to nuclear lamins and chromatin (16). Several isoforms of LAP2, which have also been called thymopoietins because they were thought to possibly be thymocyte growth factors, are generated by alternative RNA splicing (17-21). Some of the LAP2 isoforms are integral proteins of the inner nuclear membrane, with nucleoplasmic amino-terminal domains and single transmembr...

BackgroundEvidence on preventing Alzheimer’s disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention.MethodsElectronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised.ResultsA total of 44 676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B).InterpretationEvidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.

MAN1 (also known as LEMD3) is an integral protein of the inner nuclear membrane. Recently, mutations in MAN1 have been shown to result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. We show that the nucleoplasmic, C-terminal domain of human MAN1 binds to Smad2 and Smad3 and antagonizes signaling by transforming growth factor-beta (TGF-beta). In a yeast two-hybrid screen using the C-terminal domain of MAN1 as bait, eight positive clones were obtained that encoded Smad3. In direct two-hybrid assays, this portion of MAN1 bound to Smad2 and Smad3. In glutathione-S-transferase precipitation assays, the C-terminal domain of MAN1 bound to Smad2 and Smad3 under stringent conditions. Antibodies against MAN1 were able to co-immunoprecipiate Smad2 from cells, demonstrating that they reside in the same complex in vivo. TGF-beta treatment stimulated transcription from a reporter gene in control cells, but reporter gene stimulation was significantly inhibited in cells overexpressing MAN1 or its C-terminal domain but not its N-terminal domain. TGF-beta-induced cell proliferation arrest was also inhibited in stable cell lines overexpressing MAN1. These results show that the nuclear envelope regulates a signal transduction pathway and have implications for how mutations in nuclear envelope proteins cause different human diseases.

Pre-frailty and frailty with impaired cognitive function, found in 10.7% of this dementia-free population, was associated with an evidently high risk of adverse health outcomes.

The qCSF method is sufficiently rapid, accurate, and precise in measuring CSFs in normal and amblyopic persons. It has great potential for clinical practice.