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Interactions between lipid bilayers and the membrane-proximal regions of membrane-associated proteins play important roles in regulating membrane protein structure and function. The T-cell antigen receptor is an assembly of eight single-pass membrane-spanning subunits on the surface of T lymphocytes that initiates cytosolic signaling cascades upon binding antigens presented by MHC-family proteins on antigen-presenting cells. Its ζ-subunit contains multiple cytosolic immunoreceptor tyrosine-based activation motifs involved in signal transduction, and this subunit by itself is sufficient to couple extracellular stimuli to intracellular signaling events. Interactions of the cytosolic domain of ζ (ζcyt) with acidic lipids have been implicated in the initiation and regulation of transmembrane signaling. ζcyt is unstructured in solution. Interaction with acidic phospholipids induces structure, but its disposition when bound to lipid bilayers is controversial. Here, using surface plasmon resonance and neutron reflection, we characterized the interaction of ζcyt with planar lipid bilayers containing mixtures of acidic and neutral lipids. We observed two binding modes of ζcyt to the bilayers in dynamic equilibrium: one in which ζcyt is peripherally associated with lipid headgroups and one in which it penetrates deeply into the bilayer. Such an equilibrium between the peripherally bound and embedded forms of ζcyt apparently controls accessibility of the immunoreceptor tyrosine-based activation signal transduction pathway. Our results reconcile conflicting findings of the ζ structure reported in previous studies and provide a framework for understanding how lipid interactions regulate motifs to tyrosine kinases and may regulate the T-cell antigen receptor biological activities for this cell-surface receptor system.

Background: prior literature suggests that comorbidity with depression significantly worsens the health state of people with chronic diseases. Objective: the present study examines whether depressed mood increased medical care use for patients with a comorbid physical disease. Design, setting and subjects: the study was a population-based study (KORA-Age), with 3,938 participants aged 64–94. Methods: we investigated differences in health services use in participants with and without depressed mood (Geriatric Depression Scale). A further adjustment for disease was done and differences were examined with the Mann–Whitney U test. The incidence rate ratios (IRRs) for doctors’ appointments or the number of days in hospital were explored with (zero-inflated) negative binomial regression models. Results: there are increased self-neglecting behaviours and medical comorbidities in participants with depressed mood. Depressed mood increased participants’ use of medical services (P< 0.0001). Among participants who visited the doctor during the last 3 months, those with depressed mood had more visits than those without depressed mood, irrespective of somatic comorbidities (P< 0.0001 and P< 0.05 for ill and healthy, respectively). Additionally, patients with coexisting depressed mood and physical disease visited the doctor’s practice significantly more often. Having depressed mood significantly increases the likelihood for more doctor visits (IRR = 1.5, CI = 1.3–1.7) and longer hospital stays (IRR = 1.9, CI = 1.6–2.3). In participants with somatic comorbidities the risk is even greater (IRR = 1.6, CI = 1.3–2, for the number of doctors visits and IRR = 2, CI = 1.4–2.9, for the number of days in the hospital). Conclusions: results suggest that patients with depressed mood had increased use of health-care services overall, particularly those with somatic comorbidities.

Protein phosphatase 5 is involved in the regulation of kinases and transcription factors. The dephosphorylation activity is modulated by the molecular chaperone Hsp90, which binds to the TPR-domain of protein phosphatase 5. This interaction is dependent on the C-terminal MEEVD motif of Hsp90. We show that C-terminal Hsp90 fragments differ in their regulation of the phosphatase activity hinting to a more complex interaction. Also hydrodynamic parameters from analytical ultracentrifugation and small-angle X-ray scattering data suggest a compact structure for the Hsp90-protein phosphatase 5 complexes. Using crosslinking experiments coupled with mass spectrometric analysis and structural modelling we identify sites, which link the middle/C-terminal domain interface of C. elegans Hsp90 to the phosphatase domain of the corresponding kinase. Studying the relevance of the domains of Hsp90 for turnover of native substrates we find that ternary complexes with the glucocorticoid receptor (GR) are cooperatively formed by full-length Hsp90 and PPH-5. Our data suggest that the direct stimulation of the phosphatase activity by C-terminal Hsp90 fragments leads to increased dephosphorylation rates. These are further modulated by the binding of clients to the N-terminal and middle domain of Hsp90 and their presentation to the phosphatase within the phosphatase-Hsp90 complex.

Older adults often suffer from vitamin D deficiency and from the frailty syndrome charac-terized by different physical limitations, complicating independent everyday life. Previous studies have suggested a relationship between vitamin D status and the frailty syndrome, but results have been partly inconsistent, particularly regarding the shape of the association. Therefore, our aim was to further assess the association of 25-hydroxyvitamin D (25(OH)D) serum levels and frailty in older participants.Cross-sectional population-based study.The study population included 478 men and 462 women of the KORA (COoperative health research in the Region of Augsburg)-Age study born before 1944 examined in 2009.Classification of participants into different frailty states was performed according to the following criteria: weight loss, exhaustion, physical inactivity, slowness, and weakness. PARTICIPANTS who met 1-2 or ≥ 3 of the 5 criteria were classified as prefrail or frail, respectively. Total 25(OH)D was measured in non-fasting serum samples with an enhanced chemiluminescence immunoassay. Sequential logistic regression models adjusted for age, sex, season, lifestyle factors, diseases and biomarkers including parathyroid hormone (PTH) were calculated.High levels of 25(OH)D were inversely associated with being prefrail (N=351) or frail (N=38) in the model adjusted for age, sex, season and lifestyle factors. Compared to levels15 ng/ml, odds ratios (ORs) (95% confidence intervals (CIs) were 0.52 (0.34-0.78) for levels of 15-20 ng/ml, 0.55 (0.37-0.81) for levels of 20-30 ng/ml and 0.32 (0.21-0.51) for levels ≥ 30 ng/ml. Additional adjustment for potential mediators including PTH only slightly attenuated these associations. For single frailty-components, significantly decreased ORs were found for exhaustion, physical inactivity and slowness comparing 25(OH)D levels ≥ 30 ng/ml with levels15 ng/ml.Subjects with 25(OH)D serum levels ≥ 15 ng/ml were less frequently prefrail or frail.

Objective Physical activity is suggested to play a key role in the prevention of several chronic diseases. However, data on the association between physical activity and multimorbidity are lacking. Methods Using data from 1007 men and women aged 65–94 years who participated in the population-based KORA (Cooperative Health Research in the Region of Augsburg)-Age project conducted in Augsburg/Germany and two adjacent counties in 2008/09, 13 chronic conditions were identified, and physical activity scores were calculated based on the self-reported physical activity scale for the elderly (PASE). Multivariable sex-specific logistic regression was applied to determine the association of the continuous physical activity score with multimorbidity (≥ 2 out of 13 diseases). Results Physical activity (mean PASE score ± SD) was higher in men (125.1 ± 59.2) than in women (112.2 ± 49.2). Among men, the odds ratio (OR) for multimorbidity was 0.73 (95% CI: 0.60–0.90) for a 1 standard deviation increase of the PASE score. No significant results could be observed for women (OR: 1.05; 95% CI: 0.83–1.33). Conclusion We demonstrated an inverse association between physical activity and multimorbidity among men. Further prospective studies have to confirm the temporality of effects.

Objective We aimed to examine the association between various sleep disturbances and falls among older individuals from the general population while considering the influence of age and dizziness. Methods Data were derived from the population-based cross-sectional KORA (Cooperative Health Research in the Region of Augsburg)-Age study, whereby information was conducted in standardized telephone interviews with 4127 men and women aged ⩾65 years in 2008 and 2009. Unstratified and stratified (by age and dizziness) multivariable logistic regression model analyses were performed. Results The multivariable analysis showed a marginally significant association between trouble staying asleep and ⩾1 fall in the previous year (odds ratio [OR], 1.23 [95% confidence interval (CI), 1.01–1.50]). This association was more pronounced in participants older than the age of 75 years (OR, 1.58 [95% CI, 1.16–2.16]) and in individuals without dizziness (OR, 1.35 [95% CI, 1.04–1.76]). There was no association between daytime sleepiness and falls in the fully-adjusted models, but the odds of falls in the previous year in individuals older than the age of 75 years were significantly higher for individuals with difficulty falling asleep. Although sleep duration was not associated with falls in multivariable analyses when stratified by dizziness, sleep duration of 9 h daily was significantly associated with higher odds of experiencing at least one fall in the previous year. Conclusions Our study suggested that the positive relationship between a trend towards longer sleep duration, trouble falling and staying asleep, and falls is strongest in older individuals and in individuals who did not experience dizziness in the previous year.

Nef is the viral gene product employed by the majority of primate lentiviruses to overcome restriction by tetherin (BST-2 or CD317), an interferon-inducible transmembrane protein that inhibits the detachment of enveloped viruses from infected cells. Although the mechanisms of tetherin antagonism by HIV-1 Vpu and HIV-2 Env have been investigated in detail, comparatively little is known about tetherin antagonism by SIV Nef. Here we demonstrate a direct physical interaction between SIV Nef and rhesus macaque tetherin, define the residues in Nef required for tetherin antagonism, and show that the anti-tetherin activity of Nef is dependent on clathrin-mediated endocytosis. SIV Nef co-immunoprecipitated with rhesus macaque tetherin and the Nef core domain bound directly to a peptide corresponding to the cytoplasmic domain of rhesus tetherin by surface plasmon resonance. An analysis of alanine-scanning substitutions identified residues throughout the N-terminal, globular core and flexible loop regions of Nef that were required for tetherin antagonism. Although there was significant overlap with sequences required for CD4 downregulation, tetherin antagonism was genetically separable from this activity, as well as from other Nef functions, including MHC class I-downregulation and infectivity enhancement. Consistent with a role for clathrin and dynamin 2 in the endocytosis of tetherin, dominant-negative mutants of AP180 and dynamin 2 impaired the ability of Nef to downmodulate tetherin and to counteract restriction. Taken together, these results reveal that the mechanism of tetherin antagonism by Nef depends on a physical interaction between Nef and tetherin, requires sequences throughout Nef, but is genetically separable from other Nef functions, and leads to the removal of tetherin from sites of virus release at the plasma membrane by clathrin-mediated endocytosis., Author Summary Tetherin (BST-2, CD317 or HM1.24) is an interferon-inducible cellular restriction factor that prevents the release of enveloped viruses from infected cells. Human and simian immunodeficiency viruses have evolved to use different viral proteins to overcome the anti-viral effects of tetherin. Whereas HIV-1 Vpu and HIV-2 Env counteract human tetherin, most SIVs use the accessory protein Nef to counteract tetherin in their non-human primate hosts. Here we show that the mechanism of tetherin antagonism by SIV Nef involves a direct physical interaction between the core domain of Nef and the cytoplasmic domain of tetherin, which results in the removal of tetherin from sites of virus assembly and release on the cell surface by a mechanism that depends on clathrin and dynamin 2. The Nef-mediated internalization of tetherin leads to the accumulation of tetherin within lysosomal compartments, suggesting that, similar to CD4− and MHC I-downregulation, Nef promotes the lysosomal degradation of tetherin.

Multimorbidity is a common problem in aged populations with a wide range of individual and societal consequences. The objective of the study was to explore patterns of comorbidity and multimorbidity in an elderly population using different analytical approaches. Data were gathered from the population-based KORA-Age project, which included 4,127 persons aged 65-94 years living in the city of Augsburg and its two surrounding counties in Southern Germany. Information on the presence of 13 chronic conditions was collected in a standardized telephone interview and a self-administered questionnaire. Patterns of comorbidity and multimorbidity were analyzed using prevalence figures, logistic regression models and exploratory tetrachoric factor analysis. The prevalence of multimorbidity (≥2 diseases) was 58.6% in the total sample. Hypertension and diabetes (Odds Ratio [OR] 2.95, 99.58% confidence interval [CI] [2.19-3.96]), as well as hypertension and stroke (OR 2.00, 99.58% CI [1.26-3.16]) most often occurred in combination. This association was independent of age, sex and the presence of other conditions. Using factor analysis, we identified four patterns of multimorbidity: the first pattern includes cardiovascular and metabolic diseases, the second includes joint, liver, lung and eye diseases, the third covers mental and neurologic diseases and the fourth pattern includes gastrointestinal diseases and cancer. 44% of the persons were assigned to at least one of the four multimorbidity patterns; 14% could be assigned to both the cardiovascular/metabolic and the joint/liver/lung/eye pattern. Further common pairs were the mental/neurologic pattern combined with the cardiovascular/metabolic pattern (7.2%) or the joint/liver/lung/eye pattern (5.3%), respectively. Our results confirmed the existence of co-occurrence of certain diseases in elderly persons, which is not caused by chance. Some of the identified patterns of multimorbidity and their overlap may indicate common underlying pathological mechanisms.