A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis

Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.</p

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Controls on gut phosphatisation : the trilobites from the Weeks Formation Lagerstätte (Cambrian; Utah)

Despite being internal organs, digestive structures are frequently preserved in Cambrian Lagerstätten. However, the reasons for their fossilisation and their biological implications remain to be thoroughly explored. This is particularly true with arthropods--typically the most diverse fossilised organisms in Cambrian ecosystems--where digestive structures represent an as-yet underexploited alternative to appendage morphology for inferences on their biology. Here we describe the phosphatised digestive structures of three trilobite species from the Cambrian Weeks Formation Lagerstätte (Utah). Their exquisite, three-dimensional preservation reveals unique details on trilobite internal anatomy, such as the position of the mouth and the absence of a differentiated crop. In addition, the presence of paired pygidial organs of an unknown function is reported for the first time. This exceptional material enables exploration of the relationships between gut phosphatisation and the biology of organisms. Indeed, soft-tissue preservation is unusual in these fossils as it is restricted to the digestive structures, which indicates that the gut played a central role in its own phosphatisation. We hypothesize that the gut provided a microenvironment where special conditions could develop and harboured a source of phosphorus. The fact that gut phosphatization has almost exclusively been observed in arthropods could be explained by their uncommon ability to store ions (including phosphorous) in their digestive tissues. However, in some specimens from the Weeks Formation, the phosphatisation extends to the entire digestive system, suggesting that trilobites might have had some biological particularities not observed in modern arthropods. We speculate that one of them might have been an increased capacity for ion storage in the gut tissues, related to the moulting of their heavily-mineralised carapace

Electrophysiological Heterogeneity of Fast-Spiking Interneurons: Chandelier versus Basket Cells

In the prefrontal cortex, parvalbumin-positive inhibitory neurons play a prominent role in the neural circuitry that subserves working memory, and alterations in these neurons contribute to the pathophysiology of schizophrenia. Two morphologically distinct classes of parvalbumin neurons that target the perisomatic region of pyramidal neurons, chandelier cells (ChCs) and basket cells (BCs), are generally thought to have the same "fast-spiking" phenotype, which is characterized by a short action potential and high frequency firing without adaptation. However, findings from studies in different species suggest that certain electrophysiological membrane properties might differ between these two cell classes. In this study, we assessed the physiological heterogeneity of fast-spiking interneurons as a function of two factors: species (macaque monkey vs. rat) and morphology (chandelier vs. basket). We showed previously that electrophysiological membrane properties of BCs differ between these two species. Here, for the first time, we report differences in ChCs membrane properties between monkey and rat. We also found that a number of membrane properties differentiate ChCs from BCs. Some of these differences were species-independent (e.g., fast and medium afterhyperpolarization, firing frequency, and depolarizing sag), whereas the differences in the first spike latency between ChCs and BCs were species-specific. Our findings indicate that different combinations of electrophysiological membrane properties distinguish ChCs from BCs in rodents and primates. Such electrophysiological differences between ChCs and BCs likely contribute to their distinctive roles in cortical circuitry in each species. © 2013 Povysheva et al

Implementing complete smokefree policies in mental health inpatient settings Results from a before and after mixed-methods evaluation : results from a before and after mixed-methods evaluation

Abstract Background Tobacco smoking is extremely prevalent in people with severe mental illness (SMI) and has been recognised as the main contributor to widening health inequalities in this population. Historically, smoking has been deeply entrenched in the culture of mental health settings in the UK, and until recently, smokefree policies tended to be only partially implemented. However, recent national guidance and the government’s tobacco control plan now call for the implementation of complete smokefree policies. Many mental health Trusts across the UK are currently in the process of implementing the new guidance, but little is known about the impact of and experience with policy implementation. Methods This paper reports findings from a mixed-methods evaluation of policy implementation across 12 wards in a large mental health Trust in England. Quantitative data were collected and compared before and after implementation of NICE guidance PH48 and referred to 1) identification and treatment of tobacco dependence, 2) smoking-related incident reporting, and 3) prescribing of psychotropic medication. A qualitative exploration of the experience of inpatients was also carried out. Descriptive statistical analyses were performed, and the feasibility of collecting relevant and complete data for each quantitative component was assessed. Qualitative data were analysed using thematic framework analysis. Results Following implementation of the complete smokefree policy, increases in the numbers of patients offered smoking cessation advice (72% compared to 38%) were identified. While incident reports demonstrated a decrease in challenging behaviour during the post-PH48 period (6% compared to 23%), incidents relating to the concealment of smoking materials increased (10% compared to 2%). Patients reported encouraging changes in smoking behaviour and motivation to maintain change after discharge. However, implementation issues challenging full policy implementation, including covert facilitation of smoking by staff, were reported, and difficulties in collecting relevant and complete data for comprehensive evaluation purposes identified. Conclusions Overall, the implementation of complete smokefree policies in mental health settings may currently be undermined by partial support. Strategies to enhance support and the establishment of suitable data collection pathways to monitor progress are required

Transient activation of dopaminergic neurons during development modulates visual responsiveness, locomotion and brain activity in a dopamine ontogeny model of schizophrenia

It has been observed that certain developmental environmental risk factors for schizophrenia when modeled in rodents alter the trajectory of dopaminergic development, leading to persistent behavioural changes in adults. This has recently been articulated as the "dopamine ontogeny hypothesis of schizophrenia". To test one aspect of this hypothesis, namely that transient dopaminergic effects during development modulate attention-like behavior and arousal in adults, we turned to a small-brain model, Drosophila melanogaster. By applying genetic tools allowing transient activation or silencing of dopaminergic neurons in the fly brain, we investigated whether a critical window exists during development when altered dopamine (DA) activity levels could lead to impairments in arousal states in adult animals. We found that increased activity in dopaminergic neurons in later stages of development significantly increased visual responsiveness and locomotion, especially in adult males. This misallocation of visual salience and hyperactivity mimicked the effect of acute methamphetamine feeding to adult flies, suggesting up-regulated DA signaling could result from developmental manipulations. Finally, brain recordings revealed significantly reduced gamma-band activity in adult animals exposed to the transient developmental insult. Together, these data support the idea that transient alterations in DA signaling during development can permanently alter behavior in adults, and that a reductionist model such as Drosophila can be used to investigate potential mechanisms underlying complex cognitive disorders such as schizophrenia

Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin.

The in situ hybridization Allen Mouse Brain Atlas was mined for proteases expressed in the somatosensory cerebral cortex. Among the 480 genes coding for protease/peptidases, only four were found enriched in cortical interneurons: Reln coding for reelin; Adamts8 and Adamts15 belonging to the class of metzincin proteases involved in reshaping the perineuronal net (PNN) and Mme encoding for Neprilysin, the enzyme degrading amyloid β-peptides. The pattern of expression of metalloproteases (MPs) was analyzed by single-cell reverse transcriptase multiplex PCR after patch clamp and was compared with the expression of 10 canonical interneurons markers and 12 additional genes from the Allen Atlas. Clustering of these genes by K-means algorithm displays five distinct clusters. Among these five clusters, two fast-spiking interneuron clusters expressing the calcium-binding protein Pvalb were identified, one co-expressing Pvalb with Sst (PV-Sst) and another co-expressing Pvalb with three metallopeptidases Adamts8, Adamts15 and Mme (PV-MP). By using Wisteria floribunda agglutinin, a specific marker for PNN, PV-MP interneurons were found surrounded by PNN, whereas the ones expressing Sst, PV-Sst, were not

Feasibility study of hospital antimicrobial stewardship analytics using electronic health records

Background: Hospital antimicrobial stewardship (AMS) programmes are multidisciplinary initiatives to optimise the use of antimicrobials. Most hospitals depend on time-consuming manual audits to monitor clinicians’ prescribing. But much of the information needed could be sourced from electronic health records (EHRs). Objectives: To develop an informatics methodology to analyse characteristics of hospital AMS practice using routine electronic prescribing and laboratory records. Methods: Feasibility study using electronic prescribing, laboratory and clinical coding records from adult patients admitted to six specialties at Queen Elizabeth Hospital, Birmingham, UK (September 2017–August 2018). The study involved: (1) a review of antimicrobial stewardship standards of care; (2) their translation into concepts measurable from commonly available EHRs; (3) pilot application in an EHR cohort study (n=61,679 admissions). Results: We developed data modelling methods to characterise the use of antimicrobials (antimicrobial therapy episode linkage methods, therapy table, therapy changes). Prescriptions were linked into antimicrobial therapy episodes (mean 2.4 prescriptions/episode; mean length of therapy of 5.8 days) enabling production of several actionable findings. For example, 22% of therapy episodes for low-severity community acquired pneumonia were congruent with prescribing guidelines, with a tendency to use antibiotics with a broader spectrum. Analysis of therapy changes revealed a delay in switching from intravenous to oral therapy by an average 3.6 days [95% CI: 3.4; 3.7]. Performance of microbial cultures prior to treatment initiation occurred in just 22% of antibacterial prescriptions. The proposed methods enabled fine-grained monitoring of AMS practice all the way down to specialties, wards, and individual clinical teams by case mix, enabling more meaningful peer comparison. Conclusions: It is feasible to use hospital EHRs to construct rapid, meaningful measures of prescribing quality with potential to support quality improvement interventions (audit/feedback to prescribers), engagement with front-line clinicians on optimising prescribing, and AMS impact evaluation studies

De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability