PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implication

Aridity and land use negatively influence a dominant species' upper critical thermal limits

Understanding the physiological tolerances of ectotherms, such as thermal limits, is important in predicting biotic responses to climate change. However, it is even more important to examine these impacts alongside those from other landscape changes: such as the reduction of native vegetation cover, landscape fragmentation and changes in land use intensity (LUI). Here, we integrate the observed thermal limits of the dominant and ubiquitous meat ant Iridomyrmex purpureus across climate (aridity), land cover and land use gradients spanning 270 km in length and 840 m in altitude across northern New South Wales, Australia. Meat ants were chosen for study as they are ecosystem engineers and changes in their populations may result in a cascade of changes in the populations of other species. When we assessed critical thermal maximum temperatures (CTmax) of meat ants in relation to the environmental gradients we found little influence of climate (aridity) but that CTmax decreased as LUI increased. We found no overall correlation between CTmax and CTmin. We did however find that tolerance to warming was lower for ants sampled from more arid locations. Our findings suggest that as LUI and aridification increase, the physiological resilience of I. purpureus will decline. A reduction in physiological resilience may lead to a reduction in the ecosystem service provision that these populations provide throughout their distribution

Recognising the agency of people with dementia.

People with dementia have been assumed to possess weak or even no agency, so this paper provides a novel contribution to academic debate by examining their actual potential for agency. The author draws on findings from a qualitative study of everyday decision-making by people with dementia that aimed to identify the role of social factors (such as gender) in influencing their involvement in decisions. Whilst decision-making constitutes a form of deliberative agency, the research also identified when agency was alternatively habituated, embodied or emotional. The Economic and Social Research Council-funded research was undertaken in the North of England. Existing theoretical perspectives on agency are critiqued, particularly in relation to rationality, language and individualised agency. The study highlighted that people with dementia who lack deliberative capacity can nonetheless demonstrate creative capacity for agency. A more expansive concept of agency is needed in social science theory that is informed by the experiences of cognitively disabled people

IgE to epitopes of Ara h 2 enhance the diagnostic accuracy of Ara h 2‐specific IgE

© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: Understanding the discrepancy between IgE sensitization and allergic reactions to peanut could facilitate diagnosis and lead to novel means of treating peanut allergy. Objective: To identify differences in IgE and IgG4 binding to peanut peptides between peanut-allergic (PA) and peanut-sensitized but tolerant (PS) children. Methods: PA (n = 56), PS (n = 42) and nonsensitized nonallergic (NA, n = 10) patients were studied. Synthetic overlapping 15-mer peptides of peanut allergens (Ara h 1-11) were spotted onto microarray slides, and patients' samples were tested for IgE and IgG4 binding using immunofluorescence. IgE and IgG4 levels to selected peptides were quantified using ImmunoCAP. Diagnostic model comparisons were performed using likelihood-ratio tests between each specified nominal logistic regression models. Results: Seven peptides on Ara h 1, Ara h 2, and Ara h 3 were bound more by IgE of PA compared to PS patients on the microarray. IgE binding to one peptide on Ara h 5 and IgG4 binding to one Ara h 9 peptide were greater in PS than in PA patients. Using ImmunoCAP, IgE to the Ara h 2 peptides enhanced the diagnostic accuracy of Ara h 2-specific IgE. Ratios of IgG4/IgE to 4 out of the 7 peptides were higher in PS than in PA subjects. Conclusions: Ara h 2 peptide-specific IgE added diagnostic value to Ara h 2-specific IgE. Ability of peptide-specific IgG4 to surmount their IgE counterpart seems to be important in established peanut tolerance.This work was supported by the Medical Research Council (MRC Clinical Research Training Fellowship G090218, MRC Centenary Early Career Award and MRC Clinician Scientist Fellowship MR/M008517/1, all awarded to A. F. Santos), the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust; the US Department of Agriculture, Agricultural Research Service (USDA-ARS6054-43440-046-00D; USDA-NIFA) and the National Peanut Board (GRANT12229460).info:eu-repo/semantics/publishedVersio

Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans

Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10–15 d after the onset of COVID-19 symptoms. However, due to the recent emergence of SARS-CoV-2 in the human population, it is not known how long antibody responses will be maintained or whether they will provide protection from reinfection. Using sequential serum samples collected up to 94 d post onset of symptoms (POS) from 65 individuals with real-time quantitative PCR-confirmed SARS-CoV-2 infection, we show seroconversion (immunoglobulin (Ig)M, IgA, IgG) in >95% of cases and neutralizing antibody responses when sampled beyond 8 d POS. We show that the kinetics of the neutralizing antibody response is typical of an acute viral infection, with declining neutralizing antibody titres observed after an initial peak, and that the magnitude of this peak is dependent on disease severity. Although some individuals with high peak infective dose (ID50 > 10,000) maintained neutralizing antibody titres >1,000 at >60 d POS, some with lower peak ID50 had neutralizing antibody titres approaching baseline within the follow-up period. A similar decline in neutralizing antibody titres was observed in a cohort of 31 seropositive healthcare workers. The present study has important implications when considering widespread serological testing and antibody protection against reinfection with SARS-CoV-2, and may suggest that vaccine boosters are required to provide long-lasting protection

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications

Promiscuous affairs of PKB/AKT isoforms in metabolism

The protein kinase B (PKB) family encompasses three isoforms; PKBα (AKT1), PKBβ (AKT2) and PKBγ (AKT3). PKBα and PKBβ but not PKBγ, are prominently expressed in classical insulin-sensitive tissues like liver, muscle and fat. Transgenic mice deficient for PKBα, PKBβ or PKBγ have been analysed to study the roles of PKB isoforms in metabolic regulation. Until recently, only loss of PKBβ was reported to result in metabolic disorders, especially insulin resistance, in humans and mice. However, a new study has shown that PKBα-deficient mice can show enhanced glucose tolerance accompanied by improved β-cell function and higher insulin sensitivity in adipocytes. These findings prompted us to review the relevant literature on the regulation of glucose metabolism by PKB isoforms in liver, skeletal muscle, adipocytes and pancreas