The RBR (RING-BetweenRING-RING) or TRIAD two RING fingers and a DRIL (double RING finger linked) E3 ubiquitin ligases comprise a group of 12 complex multidomain enzymes. This unique family of E3 ...ligases includes parkin, whose dysfunction is linked to the pathogenesis of early-onset Parkinson's disease, and HOIP (HOIL-1-interacting protein) and HOIL-1 (haem-oxidized IRP2 ubiquitin ligase 1), members of the LUBAC (linear ubiquitin chain assembly complex). The RBR E3 ligases share common features with both the larger RING and HECT (homologous with E6-associated protein C-terminus) E3 ligase families, directly catalysing ubiquitin transfer from an intrinsic catalytic cysteine housed in the C-terminal domain, as well as recruiting thioester-bound E2 enzymes via a RING domain. Recent three-dimensional structures and biochemical findings of the RBRs have revealed novel protein domain folds not previously envisioned and some surprising modes of regulation that have raised many questions. This has required renaming two of the domains in the RBR E3 ligases to more accurately reflect their structures and functions: the C-terminal Rcat (required-for-catalysis) domain, essential for catalytic activity, and a central BRcat (benign-catalytic) domain that adopts the same fold as the Rcat, but lacks a catalytic cysteine residue and ubiquitination activity. The present review discusses how three-dimensional structures of RBR (RING1-BRcat-Rcat) E3 ligases have provided new insights into our understanding of the biochemical mechanisms of these important enzymes in ubiquitin biology.
This article reviews the role of psychological factors in the development of persistent pain and disability, with a focus on how basic psychological processes have been incorporated into theoretical ...models that have implications for physical therapy. To this end, the key psychological factors associated with the experience of pain are summarized, and an overview of how they have been integrated into the major models of pain and disability in the scientific literature is presented. Pain has clear emotional and behavioral consequences that influence the development of persistent problems and the outcome of treatment. Yet, these psychological factors are not routinely assessed in physical therapy clinics, nor are they sufficiently utilized to enhance treatment. Based on a review of the scientific evidence, a set of 10 principles that have likely implications for clinical practice is offered. Because psychological processes have an influence on both the experience of pain and the treatment outcome, the integration of psychological principles into physical therapy treatment would seem to have potential to enhance outcomes.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Sarcopenia is an age-related syndrome characterised by progressive and generalised loss of skeletal muscle mass and strength; it is a major contributor to the risk of physical frailty, functional ...impairment in older people, poor health-related quality of life and premature death. Many different definitions have been used to describe sarcopenia and have resulted in varying estimates of prevalence of the condition. The most recent attempts of definitions have tried to integrate information on muscle mass, strength and physical function and provide a definition that is useful in both research and clinical settings. This review focuses on the epidemiology of the three distinct physiological components of sarcopenia, and highlights the similarities and differences between their patterns of variation with age, gender, geography and time and the individual risk factors that cluster selectively with muscle mass, strength and physical function. Methods used to measure muscle mass, strength and physical functioning and how differences in these approaches can contribute to the varying prevalence rates will also be described. The evidence for this review was gathered by undertaking a systematic search of the literature. The descriptive characteristics of muscle mass, strength and function described in this review point to the urgent need for a consensual definition of sarcopenia incorporating these parameters.
The increasingly disputed concept of gentrification‐induced displacement is combining with the argument that the poor benefit from social mix to produce a theoretical case for ‘positive ...gentrification'. The notion that new middle‐class residents not only attract more investment but bring opportunities for ‘upward social mobility' to low‐income people who manage to stay in gentrifying areas has become policy orthodoxy. While there are scholarly challenges to the extent of these benefits, the disadvantages of imposed social mix on low‐income communities even where they are not physically displaced remain under‐researched. This article helps to fill this gap by reporting on research into the experience of long‐term low‐income residents of gentrifying neighbourhoods who managed to stay put. The research explores notions of social mix, place and displacement among residents of secure community housing in Melbourne, Australia (the equivalent of small‐scale social housing in Europe and North America) with the object of establishing whether the absence of physical displacement is sufficient to ameliorate gentrification's negative impacts. The findings demonstrate that transformations in shops and meeting places, and in the nature of local social structure and government interventions, cause a sense of loss of place even without physical displacement.
In addition to serving as respiratory electron shuttle, ferri-cytochrome c (cyt c) acts as a peroxidase; i.e., it catalyzes the oxidation of organic substrates by H2O2. This peroxidase function plays ...a key role during apoptosis. Typical peroxidases have a five-coordinate heme with a vacant distal coordination site that permits the iron center to interact with H2O2. In contrast, native cyt c is six-coordinate, as the distal coordination site is occupied by Met80. It thus seems counterintuitive that native cyt c would exhibit peroxidase activity. The current work scrutinizes the origin of this structure–function mismatch. Cyt c-catalyzed peroxidase reactions show an initial lag phase that is consistent with the in situ conversion of a precatalyst to an active peroxidase. Using mass spectrometry, we demonstrate the occurrence of cyt c self-oxidation in the presence of H2O2. The newly generated oxidized proteoforms are shown to possess significantly enhanced peroxidase activity. H2O2-induced modifications commence with oxidation of Tyr67, followed by permanent displacement of Met80 from the heme iron. The actual peroxidase activation step corresponds to subsequent side chain carbonylation, likely at Lys72/73. The Tyr67-oxidized/carbonylated protein has a vacant distal ligation site, and it represents the true peroxidase-active structure of cyt c. Subsequent self-oxidation eventually causes deactivation. It appears that this is the first report that identifies H2O2-induced covalent modifications as an essential component for the peroxidase activity of “native” cyt c.
Although RAF kinases are critical for controlling cell growth, their mechanism of activation is incompletely understood. Recently, dimerization was shown to be important for activation. Here we show ...that the dimer is functionally asymmetric with one kinase functioning as an activator to stimulate activity of the partner, receiver kinase. The activator kinase did not require kinase activity but did require N-terminal phosphorylation that functioned allosterically to induce cis-autophosphorylation of the receiver kinase. Based on modeling of the hydrophobic spine assembly, we also engineered a constitutively active mutant that was independent of Ras, dimerization, and activation-loop phosphorylation. As N-terminal phosphorylation of BRAF is constitutive, BRAF initially functions to activate CRAF. N-terminal phosphorylation of CRAF was dependent on MEK, suggesting a feedback mechanism and explaining a key difference between BRAF and CRAF. Our work illuminates distinct steps in RAF activation that function to assemble the active conformation of the RAF kinase.
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•RAF dimers are asymmetric with one component allosterically activating the other•N-terminal phosphorylation but not kinase activity is required on the activator•Dimerization induces cis-autophosphorylation of the RAF activation loop•Mutations that stabilize the active conformation do not require dimerization
RAF kinase dimerization is important for its activation. Dimerization allosterically induces the active kinase conformation through the asymmetric phosphorylation of the activation loop on one molecule, which activates the second molecule by inducing its cis-autophosphorylation.
STUDY QUESTION
What is the degree of intrinsic insulin resistance (IR) in women with polycystic ovary syndrome (PCOS) and the relative contribution of BMI to overall IR based on meta-analysis of gold ...standard insulin clamp studies?
SUMMARY ANSWER
We report an inherent reduction (−27%) of insulin sensitivity (IS) in PCOS patients, which was independent of BMI.
WHAT IS ALREADY KNOWN
PCOS is prevalent, complex and underpinned by IR but controversies surround the degree of intrinsic IR in PCOS, the effect of BMI and the impact of the different diagnostic criteria (NIH versus Rotterdam) in PCOS.
STUDY DESIGN, SIZE, DURATION
A systematic review and meta-analysis of Medline and All EBM databases was undertaken of studies published up to 30 May 2015. Studies were included if premenopausal women diagnosed with PCOS were compared with a control group for IS, measured by the gold standard euglycaemic–hyperinsulinaemic clamp. The systematic review adheres to the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analyses were performed using mixed modelling and magnitude-based inferences expressed as mean effect ±99% CI. We inferred the effect was small, moderate or large relative to a smallest important change of −3.7% or 3.8% derived by standardisation. Effects were deemed unclear when the CI overlapped smallest important positive and negative values. Effects were qualified with probabilities reflecting uncertainty in the magnitude of the true value (likely, 75–95%; very likely, 95–99.5%; most likely, >99.5%).
PARTICIPANTS/MATERIALS, SETTING, METHOD
A total of 4881 articles were returned from the search. Of these, 28 articles were included in the meta-analysis.
MAIN RESULTS AND THE ROLE OF CHANCE
Overall IS was lower in women with PCOS compared with controls (mean effect −27%, 99% CI ±6%; large, most likely lower). A higher BMI exacerbated the reduction in IS by −15% (±8%; moderate, most likely lower) in PCOS compared with control women. There was no clear difference in IS between women diagnosed by the original National Institutes of Health (NIH) criteria alone compared with those diagnosed by the Rotterdam criteria. Low levels of sex hormone-binding globulin (SHBG) were associated with reduced levels of IS (−10%, ±10%; small, very likely negative), which was not confounded by BMI.
LIMITATIONS, REASONS FOR CAUTION
This systematic review and meta-analysis inherited the confounding problems of small sample sizes, missing data (e.g. some hormones, waist and hip girths) and the lack of Rotterdam criteria phenotype reporting, limiting the evidence synthesis and meta-analysis.
WIDER IMPLICATIONS OF THE FINDINGS
BMI has a greater impact on IS in PCOS than in controls. SHBG appears a potentially valuable marker of IR in PCOS, whereas testosterone after adjustment for BMI demonstrated an unexpected interplay with IS which warrants further investigation.
STUDY FUNDING/COMPETING INTERESTS
This work was supported by grants from the National Health & Medical Research Council (NHMRC), grant number 606553 (H.J.T., N.K.S.), as well as Monash University. H.J.T. is an NHMRC Research Fellow. N.K.S. is supported through the Australian Government's Collaborative Research Networks (CRN) programme. The funding bodies played no role in the design, methods, data management or analysis or in the decision to publish. All authors declare no conflict of interests.
REGISTRATION NUMBER
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•Belsky’s (1984) process of parenting model is empirically supported.•Parenting is multi-determined by child, parent, and social factors.•Predictors of parenting are complex and ...interactive.•Predictors of fathers’ and mothers’ parenting differ in important ways.
Jay Belsky’s process of parenting model, published in 1984, continues to be widely referenced within the scientific literature. The main premise of this model is that parenting is multiply determined and is influenced by characteristics of the parent, child, and social context. In this review, we survey the theoretical and empirical literature that has accumulated related to the model within the past 30 years, with a focus on interactions among contextual factors and the applicability of the process model to the parenting of fathers. Specifically, we review in depth the domains of parental personality, parental depression, child negative emotionality, and marital quality, with more concise overviews of literature covering parental developmental history and social support. In line with Belsky’s original article, we focus on predictors of parenting during infancy and the early childhood period (i.e., birth to 5 years). Although in many ways the process model has stood the test of time and continues to be supported empirically, we recommend ways the model could be expanded based on updated current theory and research on the process of parenting in early childhood.
Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. ...High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vibrio vulnificus and V. parahaemolyticus in the estuarine-marine environment are of human health significance and may be increasing in pathogenicity and abundance. Vibrio illness originating from ...dermal contact with Vibrio laden waters or through ingestion of seafood originating from such waters can cause deleterious health effects, particularly if the strains involved are resistant to clinically important antibiotics. The purpose of this study was to evaluate antimicrobial susceptibility among these pathogens. Surface-water samples were collected from three sites of recreational and commercial importance from July to September 2009. Samples were plated onto species-specific media and resulting V. vulnificus and V. parahaemolyticus strains were confirmed using polymerase chain reaction assays and tested for antimicrobial susceptibility using the Sensititre® microbroth dilution system. Descriptive statistics, Friedman two-way Analysis of Variance (ANOVA) and Kruskal-Wallis one-way ANOVA were used to analyze the data. Vibrio vulnificus (n = 120) and V. parahaemolyticus (n = 77) were isolated from all sampling sites. Most isolates were susceptible to antibiotics recommended for treating Vibrio infections, although the majority of isolates expressed intermediate resistance to chloramphenicol (78% of V. vulnificus, 96% of V. parahaemolyticus). Vibrio parahaemolyticus also demonstrated resistance to penicillin (68%). Sampling location or month did not significantly impact V. parahaemolyticus resistance patterns, but V. vulnificus isolates from St. Martin's River had lower overall intermediate resistance than that of the other two sampling sites during the month of July (p = 0.0166). Antibiotics recommended to treat adult Vibrio infections were effective in suppressing bacterial growth, while some antibiotics recommended for pediatric treatment were not effective against some of the recovered isolates. To our knowledge, these are the first antimicrobial susceptibility data of V. vulnificus and V. parahaemolyticus recovered from the Chesapeake Bay. These data can serve as a baseline against which future studies can be compared to evaluate whether susceptibilities change over time.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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