Paradoxical dominant negative activity of an immunodeficiency-associated activating variant.

encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction.

Effects of disturbances on aboveground biomass of alpine meadow in the Yellow River Source Zone, Western China.

A field experiment quantifies the impacts of two external disturbances (mowing-simulated grazing and number of pika) on aboveground biomass (AGB) in the Yellow River Source Zone from 2018 to 2020. AGB was estimated from drone images for 27 plots subject to three levels of each disturbance (none, moderate, and severe). The three mowing severities bear a close relationship with AGB and its annual change.

Insulin at 100 years - is rebalancing its action key to fighting obesity-related disease?

One hundred years ago, insulin was purified and administered to people with diabetes to lower blood glucose, suppress ketogenesis and save lives. A century later, insulin resistance (IR) lies at the heart of the obesity-related disease pandemic. Multiple observations attest that IR syndrome is an amalgamation of gain and loss of insulin action, suggesting that IR is a misnomer.

Things we can do now that we could not do before: Developing and using a cross-scalar, state-wide database to support geomorphologically-informed river management.

A fundamental premise of river management is that practitioners understand the resource they are working with. In river management this requires that baseline information is available on the structure, function, health and trajectory of rivers. Such information provides the basis to contextualise, to plan, to be proactive, to prioritise, to set visions, to set goals and to undertake objective, pragmatic, transparent and evidence-based decision making.

Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function.

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited.

Anti-Insulin Receptor Antibodies Improve Hyperglycemia in a Mouse Model of Human Insulin Receptoropathy.

Loss-of-function mutations in both alleles of the human insulin receptor gene (INSR) cause extreme insulin resistance (IR) and usually death in childhood, with few effective therapeutic options. Bivalent antireceptor antibodies can elicit insulin-like signaling by mutant INSR in cultured cells, but whether this translates into meaningful metabolic benefits in vivo, wherein the dynamics of insulin signaling and receptor recycling are more complex, is unknown. To address this, we adopted a strategy to model human insulin receptoropathy in mice, using recombinase delivered by adeno-associated virus to knockout endogenous hepatic acutely in floxed mice (liver insulin receptor knockout [L-IRKO] + GFP), before adenovirus-mediated add back of wild-type (WT) or mutant human Two murine anti-INSR monoclonal antibodies, previously shown to be surrogate agonists for mutant INSR, were then tested by intraperitoneal injections.

Managing sediment (dis)connectivity in fluvial systems.

Globally, rivers systems are under considerable and increasing threat from multiple anthropogenic stresses, including different types of direct (e.g. channel engineering) and indirect human impacts (e.

Growth of Listeria monocytogenes Inoculated on Packaged Fresh-Cut Turnips Stored at 4 and 10°C.

Abstract: The ecology of Listeria monocytogenes has been previously investigated in various whole and minimally processed raw vegetables, but not in turnips. A 2018 national Canadian recall for packaged fresh-cut turnips contaminated with L. monocytogenes raised concerns about turnips being able to support the growth of this microorganism.

Author Correction: Engaging with research impact assessment for an environmental science case study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Engaging with research impact assessment for an environmental science case study.

Impact assessment is embedded in many national and international research rating systems. Most applications use the Research Impact Pathway to track inputs, activities, outputs and outcomes of an invention or initiative to assess impact beyond scholarly contributions to an academic research field (i.e.

What's in a name? A naming convention for geomorphic river types using the River Styles Framework.

Meaningful iteration between place-based knowledge of rivers and generalised, theoretically-framed understandings is a significant challenge in river science and management. How can we communicate knowledge of the inherent complexity of river systems in light of managerial quests for simple, easy-to-apply frameworks that can be used by a wide range of practitioners, such that we can meaningfully transfer experiences in river science and management from one situation to another? Identification, definition, classification and naming are vital parts of this process. In a sense, a name is like a 'brand', for which a consistency of product is expected.

Evaluation of anti-insulin receptor antibodies as potential novel therapies for human insulin receptoropathy using cell culture models.

Aims/hypothesis: Bi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have been shown to activate two mutant receptors, S323L and F382V. This study evaluates four well-characterised murine anti-INSR monoclonal antibodies recognising distinct epitopes (83-7, 83-14, 18-44, 18-146) as surrogate agonists for potential targeted treatment of severe insulin resistance arising from insulin receptoropathies.

Metformin in non-diabetic hyperglycaemia: the GLINT feasibility RCT.

Background: The treatment of people with diabetes with metformin can reduce cardiovascular disease (CVD) and may reduce the risk of cancer. However, it is unknown whether or not metformin can reduce the risk of these outcomes in people with elevated blood glucose levels below the threshold for diabetes [i.e.

Severe insulin resistance in disguise: A familial case of reactive hypoglycemia associated with a novel heterozygous INSR mutation.

Aim: Hypoglycemia in childhood is very rare and can be caused by genetic mutations or insulin-secreting neoplasms. Postprandial hypoglycemia has previously been associated with insulin receptor (INSR) gene mutations. We aimed to identify the cause of postprandial hypoglycemia in a 10-year-old boy.

The Blurred Line between Form and Process: A Comparison of Stream Channel Classification Frameworks.

Stream classification provides a means to understand the diversity and distribution of channels and floodplains that occur across a landscape while identifying links between geomorphic form and process. Accordingly, stream classification is frequently employed as a watershed planning, management, and restoration tool. At the same time, there has been intense debate and criticism of particular frameworks, on the grounds that these frameworks classify stream reaches based largely on their physical form, rather than direct measurements of their component hydrogeomorphic processes.

Acute knockdown of the insulin receptor or its substrates Irs1 and 2 in 3T3-L1 adipocytes suppresses adiponectin production.

Loss of function of the insulin receptor (INSR) in humans produces severe insulin resistance. Unlike "common" insulin resistance, this is associated with elevated plasma levels of the insulin-sensitising, adipose-derived protein adiponectin. The underlying mechanism for this paradox is unclear, and it is at odds with the acute stimulation of adiponectin secretion reported on insulin treatment of cultured adipocytes.

A randomised controlled trial of computerised cognitive behaviour therapy for the treatment of depression in primary care: the Randomised Evaluation of the Effectiveness and Acceptability of Computerised Therapy (REEACT) trial.

Background: Computerised cognitive behaviour therapy (cCBT) has been developed as an efficient form of therapy delivery with the potential to enhance access to psychological care. Independent research is needed which examines both the clinical effectiveness and cost-effectiveness of cCBT over the short and longer term.

Objectives: To compare the clinical effectiveness and cost-effectiveness of cCBT as an adjunct to usual general practitioner (GP) care against usual GP care alone, for a free-to-use cCBT program (MoodGYM; National Institute for Mental Health Research, Australian National University, Canberra, Australia) and a commercial pay-to-use cCBT program (Beating the Blues(®); Ultrasis, London, UK) for adults with depression, and to determine the acceptability of cCBT and the experiences of users.

Computerised cognitive behaviour therapy (cCBT) as treatment for depression in primary care (REEACT trial): large scale pragmatic randomised controlled trial.

Study Question: How effective is supported computerised cognitive behaviour therapy (cCBT) as an adjunct to usual primary care for adults with depression?

Methods: This was a pragmatic, multicentre, three arm, parallel randomised controlled trial with simple randomisation. Treatment allocation was not blinded. Participants were adults with symptoms of depression (score ≥ 10 on nine item patient health questionnaire, PHQ-9) who were randomised to receive a commercially produced cCBT programme ("Beating the Blues") or a free to use cCBT programme (MoodGYM) in addition to usual GP care.

Quantitative assessment of the relationships among ecological, morphological and aesthetic values in a river rehabilitation initiative.

Promoting community support in rehabilitation efforts through incorporation of aesthetic considerations is an important component of environmental management. This research utilised a small-scale survey methodology to explore relationships among the ecological and morphological goals of scientists and the aesthetic goals of the public using the Twin Streams Catchment, Auckland, New Zealand, as a case study. Analyses using a linear model and a generalised linear mixed model showed statistically significant relationships between perceived naturalness of landscapes and their aesthetic ratings, and among ratings of perceived naturalness and ecological integrity and morphological condition.

Delineation of the IGF-II C domain elements involved in binding and activation of the IR-A, IR-B and IGF-IR.

Objective: Human insulin-like growth factor-I and -II (IGF-I and -II) ligands share a high degree of sequence and structural homology. Despite their similarities, IGF-I and IGF-II exhibit differential receptor binding and activation characteristics. The C domains of IGF-I and IGF-II are the primary determinants of binding specificity to the insulin-like growth factor I receptor (IGF-IR), insulin receptor exon 11- (IR-A) and exon 11+ (IR-B) isoforms.

Claudin-1 Expression Is Elevated in Colorectal Cancer Precursor Lesions Harboring the BRAF V600E Mutation.

Background: Sessile serrated adenomas/polyps (SSA/P) are now recognised precursors of colorectal cancer (CRC) including cancers harbouring somatic BRAF (V600E) mutations. While the morphological diagnostic criteria of SSA/P have been established, distinguishing between small/early SSA/P and microvesicular hyperplastic polyps (MVHP) is challenging and may not be possible in routine practice.

Methods: Gene expression profiling of MVHP (n=5, all BRAF V600E wild-type) and SSA/P (n=5, all BRAF V600E mutant) samples was performed.

Psychological advocacy toward healing (PATH): study protocol for a randomized controlled trial.

Background: Domestic violence and abuse (DVA), defined as threatening behavior or abuse by adults who are intimate partners or family members, is a key public health and clinical priority. The prevalence of DVA in the United Kingdom and worldwide is high, and its impact on physical and mental health is detrimental and persistent. There is currently little support within healthcare settings for women experiencing DVA.