TSH-CHECK-1 test: diagnostic accuracy and potential application to initiating treatment for hypothyroidism in patients on anti-tuberculosis drugs.

Thyroid-stimulating hormone (TSH) promotes expression of thyroid hormones which are essential for metabolism, growth, and development. Second-line drugs to treat tuberculosis (TB) can cause hypothyroidism by suppressing thyroid hormone synthesis. Therefore, TSH levels are routinely measured in TB patients receiving second-line drugs, and thyroxin treatment is initiated where indicated. However, standard TSH tests are technically demanding for many low-resource settings where TB is prevalent; a simple and inexpensive test is urgently needed

Dynamics of the Multiplicity of Cellular Infection in a Plant Virus

Recombination, complementation and competition profoundly influence virus evolution and epidemiology. Since viruses are intracellular parasites, the basic parameter determining the potential for such interactions is the multiplicity of cellular infection (cellular MOI), i.e. the number of viral genome units that effectively infect a cell. The cellular MOI values that prevail in host organisms have rarely been investigated, and whether they remain constant or change widely during host invasion is totally unknown. Here, we fill this experimental gap by presenting the first detailed analysis of the dynamics of the cellular MOI during colonization of a host plant by a virus. Our results reveal ample variations between different leaf levels during the course of infection, with values starting close to 2 and increasing up to 13 before decreasing to initial levels in the latest infection stages. By revealing wide dynamic changes throughout a single infection, we here illustrate the existence of complex scenarios where the opportunity for recombination, complementation and competition among viral genomes changes greatly at different infection phases and at different locations within a multi-cellular host

GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation

Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic ß-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in ß-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 ß-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of ß-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1a) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in ß-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated ß-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression

Can medical therapy mimic the clinical efficacy or physiological effects of bariatric surgery?

The number of bariatric surgical procedures performed has increased dramatically. This review discusses the clinical and physiological changes, and in particular, the mechanisms behind weight loss and glycaemic improvements, observed following the gastric bypass, sleeve gastrectomy and gastric banding bariatric procedures. The review then examines how close we are to mimicking the clinical or physiological effects of surgery through less invasive and safer modern interventions that are currently available for clinical use. These include dietary interventions, orlistat, lorcaserin, phentermine/topiramate, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, pramlintide, dapagliflozin, the duodenal–jejunal bypass liner, gastric pacemakers and gastric balloons. We conclude that, based on the most recent trials, we cannot fully mimic the clinical or physiological effects of surgery; however, we are getting closer. A ‘medical bypass' may not be as far in the future as we previously thought, as the physician's armamentarium against obesity and type 2 diabetes has recently got stronger through the use of specific dietary modifications, novel medical devices and pharmacotherapy. Novel therapeutic targets include not only appetite but also taste/food preferences, energy expenditure, gut microbiota, bile acid signalling, inflammation, preservation of β-cell function and hepatic glucose output, among others. Although there are no magic bullets, an integrated multimodal approach may yield success. Non-surgical interventions that mimic the metabolic benefits of bariatric surgery, with a reduced morbidity and mortality burden, remain tenable alternatives for patients and health-care professionals

Proposal, project, practice, pause: developing a framework for evaluating smart domestic product engagement

Smart homes are fast becoming a reality, with smart TVs, smart meters and other such “smart” devices/systems already representing a substantial household presence. These, which we collectively term “smart domestic products” (SDPs), will need to be promoted, adopted, and normalized into daily routines. Despite this, the marketing canon lacks a substantive discourse on pertinent research. We look to help correct this by melding ideas from organizational sociology, innovation diffusion and appropriation studies, and service dominant logic. Consequently, we suggest a framework for research that responds directly to the specific characteristics of SDPs. Using the SDP eco-system as a context, our framework emphasizes the interplay of embeddedness, practice, value and engagement. It comprises a four-stage horizontal/ longitudinal axis we describe as proposal, project, practice and pause. Cross-sectionally we focus on value, and combine aspects of existing thought to suggest how this impacts each stage of our engagement continuum. We subsequently identify perceived personal advantage as the resultant of these two axes and propose this as the key for understanding consumer and SDP sociomaterial engagement. This article also advances a definition of SDPs and ends with an agenda for further research

Gut Microbiota, Probiotics and Diabetes

Diabetes is a condition of multifactorial origin, involving several molecular mechanisms related to the intestinal microbiota for its development. In type 2 diabetes, receptor activation and recognition by microorganisms from the intestinal lumen may trigger inflammatory responses, inducing the phosphorylation of serine residues in insulin receptor substrate-1, reducing insulin sensitivity. In type 1 diabetes, the lowered expression of adhesion proteins within the intestinal epithelium favours a greater immune response that may result in destruction of pancreatic β cells by CD8+ T-lymphocytes, and increased expression of interleukin-17, related to autoimmunity. Research in animal models and humans has hypothesized whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota. We have shown in this review that a large body of evidence suggests probiotics reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability. Such effects increase insulin sensitivity and reduce autoimmune response. However, further investigations are required to clarify whether the administration of probiotics can be efficiently used for the prevention and management of diabetes

In vitro and in vivo insulinotropic properties of the multifunctional frog skin peptide hymenochirin-1B: a structure–activity study

Hymenochirin-1b (Hym-1B; IKLSPETKDNLKKVLKGAIKGAIAVAKMV.NH2) is a cationic, α-helical amphibian host-defense peptide with antimicrobial, anticancer, and immunomodulatory properties. This study investigates the abilities of the peptide and nine analogues containing substitutions of Pro5, Glu6, and Asp9 by either l-lysine or d-lysine to stimulate insulin release in vitro using BRIN-BD11 clonal β cells or isolated mouse islets and in vivo using mice fed a high-fat diet to produce obesity and insulin resistance. Hym-1B produced a significant and concentration-dependent increase in the rate of insulin release from BRIN-BD11 cells without cytotoxicity at concentrations up to 1 µM with a threshold concentration of 1 nM. The threshold concentrations for the analogues were: [P5K], [E6K], [D9K], [P5K, E6K] and [E6K, D9k] 0.003 nM, [E6K, D9K] and [D9k] 0.01 nM, [P5K, D9K] 0.1 nM and [E6k] 0.3 nM. All peptides displayed cytotoxicity at concentrations ≥1 µM except the [P5K] and [D9k] analogues which were non-toxic at 3 µM. The potency and maximum rate of insulin release from mouse islets produced by the [P5K] peptide were significantly greater than produced by Hym-1B. Neither Hym-1B nor the [P5K] analogue at 1 µM concentration had an effect on membrane depolarization or intracellular Ca2+. The [P5K] analogue (1 µM) produced a significant increase in cAMP concentration in BRIN-BD11 cells and stimulated GLP-1 secretion from GLUTag cells. Down-regulation of the protein kinase A pathway by overnight incubation with forskolin completely abolished the insulin-releasing effects of [P5K]hym-1B. Intraperitoneal administration of the [P5K] and [D9k] analogues (75 nmol/kg body weight) to high-fat-fed mice with insulin resistance significantly enhanced glucose tolerance with a concomitant increase in insulin secretion. We conclude that [P5K]hym-1B and [D9k]hym-1B show potential for development into anti-diabetic agents

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Collaborating for Innovation: the socialised management of knowledge

Although the importance of diverse knowledge is widely recognised for open innovation, there may be a gap in our understanding of the social processes that shape how collaborators engage in knowledge exchange. This social gap may be significant because of the powerful, but largely unexplained, role attributed to trust as a social artefact. Moreover, we see trust as a process and that different types of trust are involved in the collaborative process. Thus, this paper uses a qualitative methodology to capture the experiences of innovation collaborators. As explanation of the dynamic interplays of knowledge and trust, we offer a description of phases in the process. Our analysis finds that the relationship moves from transactional to social. The early phases are characterised by technical knowledge, but the later and mature phases are identified with knowledge of the person and by personal trust. The success of innovation is a result of relationships with augmented trust. We found that a fabric of trust is woven from the weft of professional knowledge and the warp of personal knowledge to support innovation. We propose that this developing of relationships might be conceived as becoming more open in the sense of sharing with one another. If so, we seem to have described and offered a social dimension of open innovation

Circadian oscillator proteins across the kingdoms of life : Structural aspects 06 Biological Sciences 0601 Biochemistry and Cell Biology

Circadian oscillators are networks of biochemical feedback loops that generate 24-hour rhythms and control numerous biological processes in a range of organisms. These periodic rhythms are the result of a complex interplay of interactions among clock components. These components are specific to the organism but share molecular mechanisms that are similar across kingdoms. The elucidation of clock mechanisms in different kingdoms has recently started to attain the level of structural interpretation. A full understanding of these molecular processes requires detailed knowledge, not only of the biochemical and biophysical properties of clock proteins and their interactions, but also the three-dimensional structure of clockwork components. Posttranslational modifications (such as phosphorylation) and protein-protein interactions, have become a central focus of recent research, in particular the complex interactions mediated by the phosphorylation of clock proteins and the formation of multimeric protein complexes that regulate clock genes at transcriptional and translational levels. The three-dimensional structures for the cyanobacterial clock components are well understood, and progress is underway to comprehend the mechanistic details. However, structural recognition of the eukaryotic clock has just begun. This review serves as a primer as the clock communities move towards the exciting realm of structural biology