Biosynthesis of Mitochondrial Porin and Insertion into the Outer Mitochondrial Membrane of Neuruspora crassa

Mitochondrial porin, the major protein of the outer mitochondrial membrane is synthesized by free cytoplasmic polysomes. The apparent molecular weight of the porin synthesized in homologous or heterologous cell-free systems is the same as that of the mature porin. Transfer in vitro of mitochondrial porin from the cytosolic fraction into the outer membrane of mitochondria could be demonstrated. Before membrane insertion, mitochondrial porin is highly sensitive to added proteinase; afterwards it is strongly protected. Binding of the precursor form to mitochondria occurs at 4°C and appears to precede insertion into the membrane. Unlike transfer of many precursor proteins into or across the inner mitochondrial membrane, assembly of the porin is not dependent on an electrical potential across the inner membrane

Quaternary structure of a G-protein coupled receptor heterotetramer in complex with Gi and Gs

Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Assessing the Effectiveness of a Performance Evaluation System in the Public Health Care Sector: Some Novel Evidence from the Tuscany Region Experience

Since 80's the introduction of New Public Management principles has promoted the use of performance measurement to drive a more efficient, effective and accountable public sector. The adoption of a sophisticated and comprehensive multidimensional performance measurement system, which looks beyond traditional financial measures, based on organization strategies, such as the balanced scorecard, has thus been suggested. This revolution in the public management came together with the devolution processes that involved most European public health systems. Set within this context, in the last decade, each of the twenty Italian regions developed its own management tools. Among others, the Tuscan performance evaluation system (PES) has been valued as a particularly innovative and comprehensive system. This paper reports the novel experience of the Tuscan PES; in particular, it measures PES effectiveness and discusses the critical factors that could have led to the PES success. Five are the critical success factors identified by researchers: the visual reporting system, the linkage between PES and CEO's reward system, the public disclosure of data, the high level of employees and managers involvement into the entire process and the strong political commitment. All those factors run together to achieve better results; however, the process of development of the system plays a pivotal role. Scholars suggest the use of a constructive approach in order to gain effective changes in human organization. According to this stream of literature, this paper contributes by the novel experience of the Tuscan PES in addressing as a further fruitful application of the constructivist approach in healthcare

Toward characterization and definition of fibromyalgia severity

<p>Abstract</p> <p>Background</p> <p>There are no standard criteria for defining or assessing severity of fibromyalgia (FM) as a condition as fibromyalgia is associated with multiple symptom domains. The objective of this study was to evaluate whether patient self-reported severity of FM is associated with severity of pain and sleep interference and the presence of core co-morbidities.</p> <p>Methods</p> <p>We recruited individuals ≥ 18 years of age with a clinician-confirmed diagnosis of FM ≥ 3 months and a current pain rating >2 on a 0-10 numeric rating scale (NRS). Patients completed a questionnaire by mail in which they self-rated their FM severity (very mild, mild, moderate, and severe), their current pain severity and extent of sleep interference (NRS; mild, 0-3; moderate, 4-6, severe, 7-10), and provided information (yes/no) on the presence of core comorbidities (symptoms of depression, anxiety, sleep problems, back pain, neck pain) and medication use for FM. The core symptoms of FM were stratified to assist with patient characterization. Analysis of variance (ANOVA) was used to explore the relationship between self-reported FM severity and continuous variables (pain severity and sleep interference), and Mantel-Haenszel chi-square analysis was used to evaluate the trend in the proportions of patients reporting use of medications and core symptoms of FM by severity of FM. To complement patient-reported FM severity and to understand physicians' perspectives, a survey was performed among 28 physician specialists (rheumatology, neurology, anesthesiology/pain management, family practice, internal medicine, and psychiatry) to determine what they assessed when evaluating FM severity in clinical practice.</p> <p>Results</p> <p>The population (N = 129) of FM patients was predominantly female (89.1%), with a mean age of 49.4 ± 11.0 years, and 81.4% reported duration ≥ 2 years. Self-reported FM severity was moderate/severe in 86.0% of patients; mean current pain score was 6.40 ± 2.19 (moderate), and mean sleep interference score was 7.28 ± 2.23 (severe). Greater FM severity was significantly associated with higher levels of current pain and sleep interference (p < 0.0001), the proportion of patients reporting FM medication use (p = 0.0001), and the presence of core comorbidities (p < 0.05). Pain, functional disability, and fatigue severity were ranked as the top three criteria by the highest proportion of physicians when evaluating FM severity.</p> <p>Conclusion</p> <p>With higher self-reported FM severity, patients have greater pain and sleep interference as well as increased frequency of core comorbidities. Further investigation into understanding FM severity is warranted.</p

Nurture commodified? An investigation into commercial human milk supply chains

The material conditions in which women provide breast milk range widely, on the basis of their class and geographical provenance. The commercialisation of breast milk provision throws up questions related to debates on the transnational reconfiguration of social reproduction as they intersect with discourses on motherhood and healthy child development as well as contemporary processes of commodification of the body and the emergence of new gendered forms of atypical work in the global economy (Bakker 2007; LeBaron 2010; Steans & Tepe 2010). This article presents a study of the first commercial human milk processor in India, NeoLacta Lifesciences that obtained an export license for the Australian market in 2017. These practices may be seen to be part of a wider Reproductive Industrial Complex (Vertommen 2016), in which women’s reproductive bodily capacities are enrolled in wider economic and financial processes, instantiating new relations between gender, race, economies and care. This article employs a feminist political economy framework that places into dialogue analyses of social reproduction and commodification with feminist science/technology studies and medical/political anthropology in order to analyse the social, political, and technical processes that transform breast milk into a commodity that is internationally traded and the implications of this for contemporary understandings of work and gender

Upregulation of MMP-13 and TIMP-1 expression in response to mechanical strain in MC3T3-E1 osteoblastic cells

<p>Abstract</p> <p>Background</p> <p>Mechanical strain plays a significant role in the regulation of bone matrix turnover, which is mediated in part by matrix metalloproteinase (MMP)-13 and tissue inhibitors of matrix metalloproteinase (TIMP)-1. However, little is known about the correlation between mechanical strain and osteoblastic cell activities, including extracellular matrix (ECM) metabolism. Herein, we determined the effect of different magnitudes of cyclic tensile strain (0%, 6%, 12%, and 18%) on MMP-13 and TIMP-1 mRNA and protein expression in MC3T3-E1 osteoblasts. Furthermore, we employed specific inhibitors to examine the role of distinct signal transduction pathways known to mediate cellular responses to mechanical strain.</p> <p>Results</p> <p>We identified a magnitude-dependent increase in MMP-13 and TIMP-1 mRNA and protein levels in response to mechanical strains corresponding to 6%, 12%, and 18% elongation. The strain-induced increases in MMP-13 and TIMP-1 mRNA expression were inhibited by PD098059 and cycloheximide, respectively.</p> <p>Conclusions</p> <p>Our results suggest a mechanism for the regulation of bone matrix metabolism mediated by the differential expression of MMP-13 and TIMP-1 in response to increasing magnitudes of mechanical strain.</p

Recommendations for Kidney Disease Guideline Updating: A Report by the KDIGO Methods Committee

Updating rather than de novo guideline development now accounts for the majority of guideline activities for many guideline development organizations, including Kidney Disease: Improving Global Outcomes (KDIGO), an international kidney disease guideline development entity that has produced guidelines on kidney diseases since 2008. Increasingly, guideline developers are moving away from updating at fixed intervals in favor of more flexible approaches that use periodic expert assessment of guideline currency (with or without an updated systematic review) to determine the need for updating. Determining the need for guideline updating in an efficient, transparent, and timely manner is challenging, and updating of systematic reviews and guidelines is labor intensive. Ideally, guidelines should be updated dynamically when new evidence indicates a need for a substantive change in the guideline based on a priori criteria. This dynamic updating (sometimes referred to as a living guideline model) can be facilitated with the use of integrated electronic platforms that allow updating of specific recommendations. This report summarizes consensus-based recommendations from a panel of guideline methodology professionals on how to keep KDIGO guidelines up to date