Protein phosphatase 2A (PP2A) is a large enzyme family responsible for most cellular Ser/Thr dephosphorylation events. PP2A substrate specificity, localization, and regulation by second messengers rely on more than a dozen regulatory subunits (including B/R2, B'/R5, and B″/R3), which form the PP2A heterotrimeric holoenzyme by associating with a dimer comprising scaffolding (A) and catalytic (C) subunits. Because of partial redundancy and high endogenous expression of PP2A holoenzymes, traditional approaches of overexpressing, knocking down, or knocking out PP2A regulatory subunits have yielded only limited insights into their biological roles and substrates. To this end, here we sought to reduce the complexity of cellular PP2A holoenzymes. We used tetracycline-inducible expression of pairs of scaffolding and regulatory subunits with complementary charge-reversal substitutions in their interaction interfaces. For each of the three regulatory subunit families, we engineered A/B charge–swap variants that could bind to one another, but not to endogenous A and B subunits. Because endogenous Aα was targeted by a co-induced shRNA, endogenous B subunits were rapidly degraded, resulting in expression of predominantly a single PP2A heterotrimer composed of the A/B charge–swap pair and the endogenous catalytic subunit. Using B'δ/PPP2R5D, we show that PP2A complexity reduction, but not PP2A overexpression, reveals a role of this holoenzyme in suppression of extracellular signal–regulated kinase signaling and protein kinase A substrate dephosphorylation. When combined with global phosphoproteomics, the PP2A/B'δ reduction approach identified consensus dephosphorylation motifs in its substrates and suggested that residues surrounding the phosphorylation site play roles in PP2A substrate specificity.

16 January 2020

Background: Functional magnetic resonance imaging (fMRI) studies have reported altered integrity of large-scale neurocognitive networks (NCNs) in dementing disorders. However, findings on specificity of these alterations in patients with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are still very limited. Recently, NCNs have been successfully captured using positron emission tomography (PET) with F18-fluordesoxyglucose (FDG). Methods: Network integrity was measured in 72 individuals (38 male) with mild AD, bvFTD, and healthy controls using a simultaneous resting state fMRI and FDG-PET. Indices of network integrity were calculated for each subject, network, and imaging modality. Results: In either modality, independent component analysis revealed four major NCNs: anterior default mode network (DMN), posterior DMN, salience network, and right central executive network (CEN). In fMRI data, integrity of posterior DMN was found to be significantly reduced in both patient groups relative to controls. In the AD group anterior DMN and CEN appeared to be additionally affected. In PET data, only integrity of posterior DMN in patients with AD was reduced, while three remaining networks appeared to be affected only in patients with bvFTD. In a logistic regression analysis, integrity of anterior DMN as measured with PET alone accurately differentiated between the patient groups. A correlation between indices of two imaging modalities was overall low. Conclusion: FMRI and FDG-PET capture partly different aspects of network integrity. A higher disease specificity of NCNs as derived from PET data supports metabolic connectivity imaging as a promising diagnostic tool.

The value of interim ¹⁸F-fluorodeoxyglucose positron emission tomography (iPET) guided treatment decisions in patients with diffuse large B-cell lymphoma (DLBCL) has been the subject of much debate. This investigation focuses on a comparison of the Deauville score and the deltaSUV_max (SUV_max) approach – two methods to assess early metabolic response to standard chemotherapy in DLBCL. Methods: Of 609 DLBCL patients participating in the Positron Emission Tomography-guided Therapy of Aggressive non-Hodgkin Lymphomas (PETAL) trial, iPET scans of 596 patients originally evaluated using the SUV_max method were available for post-hoc assessment of the Deauville score. A commonly used definition of an unfavorable iPET result according to the Deauville score is an uptake greater than that of the liver, whereas an unfavorable iPET scan with regard to the SUV_max approach is characterized as a relative reduction of the maximum standardized uptake value between baseline and iPET staging of less than or equal to 66%. We investigated the two methods’ correlation and concordance by Spearman’s rank correlation coefficient and the agreement in classification, respectively. We further used Kaplan-Meier curves and Cox regression to assess differences in survival between patient subgroups defined by the pre-specified cut-offs. Time-dependent receiver operating curve analysis provided information on the methods’ respective discrimination performance. Results: Deauville score and SUV_max approach differed in their iPET-based prognosis. The SUV_max approach outperformed the Deauville score in terms of discrimination performance – most likely due to a high number of false-positive decisions by the Deauville score. Cut-off-independent discrimination performance remained low for both methods, but cut-off-related analyses showed promising results. Both favored the SUV_max approach, e.g. for the segregation by iPET response, where the event-free survival hazard ratio was 3.14 (95% confidence interval (CI): 2.22 – 4.46) for SUV_max and 1.70 (95% CI: 1.29 – 2.24) for the Deauville score. Conclusion: When considering treatment intensification, the currently used Deauville score cut-off of an uptake above that of the liver seems to be inappropriate and associated with potential harm for DLBCL patients. The SUV_max criterion of a relative reduction of the maximum standardized uptake value of less than or equal to 66% should be considered as an alternative.

16 January 2020

Katherine Henderson is the clinical lead of the emergency department at St Thomas's hospital in London. She worries that lack of ward space is having a domino effect throughout A and E and is the cause of increased waiting time for both patients and ambulances. If you would like to contribute to this collection, please email a brief audio...

If you're a patient in the UK, increasingly, your first interaction with the healthcare system won't be the traditional face to fact chat with your doctor - instead you'll have a telephone consultation. The prevalence of these telephone consultations is increasing, and being promoted by CCGs and private companies who administer them - usually as...

The first digital banking in the UK was launched in 1983, Skype turns 15 this year, but 2017 finally saw panic over the impact that online consultations may have on general practices. In this podcast Martin Marshall, professor of healthcare improvement at University College London joins us to discuss whether video conference actually is a...

Helen talks about new research on prevention of recurrent VTE - and Carl things the evidence goes further, and we can extend prophylaxis for a year. 13.00 - CRP testing for antibiotic prescription in COPD exacerbations, should we start doing it in primary care settings - and what will that mean. We also hear from Chris Butler, one of the...

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110 activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110 inactivation was found to attenuate pathological retinal angiogenesis. p110 inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110 constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.

Research Event

OBJECTIVE

In patients with type 1 diabetes and end-stage renal disease, it is controversial whether a simultaneous pancreas-kidney (SPK) transplantation improves survival compared with kidney transplantation alone. We compared long-term survival in SPK and living- or deceased-donor kidney transplant recipients.

The ADA is calling on third-party payers to support dental practices in the midst of the COVID-19 pandemic.

Two additional Delta Dental member companies announced details April 27-28 of programs that will provide economic assistance and post-COVID-19 pandemic relief for members of its independent provider networks across 16 states and the District of Columbia.

The NCAA is expected to formally approve rules changes that will allow athletes to get endorsement income in 2021.

Feminism and art.

Londres : Paris, 1860.

Berlin : J.W. Boike, 1828-49.

Ming Yu, Varun Gupta, Mladen Kolar.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 413--457.

Abstract:
We study the problem of recovery of matrices that are simultaneously low rank and row and/or column sparse. Such matrices appear in recent applications in cognitive neuroscience, imaging, computer vision, macroeconomics, and genetics. We propose a GDT (Gradient Descent with hard Thresholding) algorithm to efficiently recover matrices with such structure, by minimizing a bi-convex function over a nonconvex set of constraints. We show linear convergence of the iterates obtained by GDT to a region within statistical error of an optimal solution. As an application of our method, we consider multi-task learning problems and show that the statistical error rate obtained by GDT is near optimal compared to minimax rate. Experiments demonstrate competitive performance and much faster running speed compared to existing methods, on both simulations and real data sets.

Sihai Dave Zhao, Yet Tien Nguyen.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 110--142.

Abstract:
It is frequently of interest to identify simultaneous signals, defined as features that exhibit statistical significance across each of several independent experiments. For example, genes that are consistently differentially expressed across experiments in different animal species can reveal evolutionarily conserved biological mechanisms. However, in some problems the test statistics corresponding to these features can have complicated or unknown null distributions. This paper proposes a novel nonparametric false discovery rate control procedure that can identify simultaneous signals even without knowing these null distributions. The method is shown, theoretically and in simulations, to asymptotically control the false discovery rate. It was also used to identify genes that were both differentially expressed and proximal to differentially accessible chromatin in the brains of mice exposed to a conspecific intruder. The proposed method is available in the R package github.com/sdzhao/ssa.

Daniel R. Kowal, Antonio Canale.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1744--1772.

Abstract:
We propose a simple yet powerful framework for modeling integer-valued data, such as counts, scores, and rounded data. The data-generating process is defined by Simultaneously Transforming and Rounding (STAR) a continuous-valued process, which produces a flexible family of integer-valued distributions capable of modeling zero-inflation, bounded or censored data, and over- or underdispersion. The transformation is modeled as unknown for greater distributional flexibility, while the rounding operation ensures a coherent integer-valued data-generating process. An efficient MCMC algorithm is developed for posterior inference and provides a mechanism for adaptation of successful Bayesian models and algorithms for continuous data to the integer-valued data setting. Using the STAR framework, we design a new Bayesian Additive Regression Tree model for integer-valued data, which demonstrates impressive predictive distribution accuracy for both synthetic data and a large healthcare utilization dataset. For interpretable regression-based inference, we develop a STAR additive model, which offers greater flexibility and scalability than existing integer-valued models. The STAR additive model is applied to study the recent decline in Amazon river dolphins.

Victor Coscrato, Rafael Izbicki, Rafael B. Stern.

Source: Brazilian Journal of Probability and Statistics, Volume 34, Number 2, 230--250.

Abstract:
Despite its common practice, statistical hypothesis testing presents challenges in interpretation. For instance, in the standard frequentist framework there is no control of the type II error. As a result, the non-rejection of the null hypothesis $(H_{0})$ cannot reasonably be interpreted as its acceptance. We propose that this dilemma can be overcome by using agnostic hypothesis tests, since they can control the type I and II errors simultaneously. In order to make this idea operational, we show how to obtain agnostic hypothesis in typical models. For instance, we show how to build (unbiased) uniformly most powerful agnostic tests and how to obtain agnostic tests from standard p-values. Also, we present conditions such that the above tests can be made logically coherent. Finally, we present examples of consistent agnostic hypothesis tests.

Andreas Anastasiou, Robert E. Gaunt.

Source: Brazilian Journal of Probability and Statistics, Volume 34, Number 1, 136--149.

Abstract:
We use the delta method and Stein’s method to derive, under regularity conditions, explicit upper bounds for the distributional distance between the distribution of the maximum likelihood estimator (MLE) of a $d$-dimensional parameter and its asymptotic multivariate normal distribution. Our bounds apply in situations in which the MLE can be written as a function of a sum of i.i.d. $t$-dimensional random vectors. We apply our general bound to establish a bound for the multivariate normal approximation of the MLE of the normal distribution with unknown mean and variance.

Klemm (Family)

Delta said it is making the move to protect employees amid the coronavirus pandemic, but planes have been flying near empty

Peter M. Zygmunt
Jun 1, 2002; 22:4720-4727
Behavioral

To determine whether Cav1.2 voltage-gated Ca²⁺ channels contribute to astrocyte activation, we generated an inducible conditional knock-out mouse in which the Cav1.2 α subunit was deleted in GFAP-positive astrocytes. This astrocytic Cav1.2 knock-out mouse was tested in the cuprizone model of myelin injury and repair which causes astrocyte and microglia activation in the absence of a lymphocytic response. Deletion of Cav1.2 channels in GFAP-positive astrocytes during cuprizone-induced demyelination leads to a significant reduction in the degree of astrocyte and microglia activation and proliferation in mice of either sex. Concomitantly, the production of proinflammatory factors such as TNFα, IL1β and TGFβ1 was significantly decreased in the corpus callosum and cortex of Cav1.2 knock-out mice through demyelination. Furthermore, this mild inflammatory environment promotes oligodendrocyte progenitor cells maturation and myelin regeneration across the remyelination phase of the cuprizone model. Similar results were found in animals treated with nimodipine, a Cav1.2 Ca²⁺ channel inhibitor with high affinity to the CNS. Mice of either sex injected with nimodipine during the demyelination stage of the cuprizone treatment displayed a reduced number of reactive astrocytes and showed a faster and more efficient brain remyelination. Together, these results indicate that Cav1.2 Ca²⁺ channels play a crucial role in the induction and proliferation of reactive astrocytes during demyelination; and that attenuation of astrocytic voltage-gated Ca²⁺ influx may be an effective therapy to reduce brain inflammation and promote myelin recovery in demyelinating diseases.

SIGNIFICANCE STATEMENT Reducing voltage-gated Ca²⁺ influx in astrocytes during brain demyelination significantly attenuates brain inflammation and astrocyte reactivity. Furthermore, these changes promote myelin restoration and oligodendrocyte maturation throughout remyelination.

Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2-1–GluN1 complexes in the spinal cord and the level of α2-1–bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2-1 with gabapentin or disrupting the α2-1–NMDAR interaction with α2-1Tat peptide completely reversed the effects of FK506. In α2-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2-1–bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.

SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2-1 and NMDARs and their synaptic trafficking in the spinal cord. α2-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2-1 or disrupting α2-1–NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.

Press release about the Basel Committee publishing consultation paper on revisions to the credit valuation adjustment risk framework, 28 November 2019.

Michell Jesse said the personal care home operators she represents have been frustrated trying to keep up with the government's direction during an already stressful time.

God is using the Mission Extreme programme in Panama to shape lives, starting with the participants and extending out to the local pastors they meet.

THE LTA has today announced a multi-million pound package of additional funding and measures to support those involved in tennis in Britain through the impact of the ongoing COVID-19 crisis.

We check out the UEFA Grassroots Day activities that took place at the Malta Football Association national training centre in Ta'Qali.

A new youth academy in Ta' Qali for the island's outstanding talents has sharpened the focus of the Malta Football Association as it envisions a bright future for the game.

A few days after a majority of Britons backed Brexit in June 2016, this newspaper reported that Nicola Sturgeon had been in talks with London Mayor Sadiq Khan and the Chief Minister of Gibraltar, Fabian Picardo.

THE Herald has reported (May 6) on another economically and socially “lost generation” of children and young people due to Covid-19.

Functional somatic symptoms (FSS) in children account for 10% to 15% of visits in medical services. Few studies have investigated the full range of pediatric FSS and factors linked to the medical help-seeking for young children with these symptoms.

More parental worries, higher symptom severity and impact, and previous contact to medical services are found among the children with FSS who seek medical consultation. Putative risk mechanisms include the early pattern of health care use and parental worries. (Read the full article)

Medication errors occur frequently among pediatric patients, particularly those treated in rural emergency departments (EDs). Although telemedicine has been proposed as a potential solution, there are few data supporting its clinical effectiveness and its effect on medication errors.

The use of telemedicine to provide pediatric critical care consultations to rural EDs is associated with less frequent physician-related ED medication errors among seriously ill and injured children. Therefore, this model of care may improve patient safety in rural hospital EDs. (Read the full article)

Handheld echocardiography is a more portable and lower-cost alternative to standard echocardiography for rheumatic heart disease screening. Direct comparison of handheld echocardiography and auscultation for the detection of rheumatic heart disease has not been done previously.

Handheld echocardiography significantly improves detection of rheumatic heart disease compared with auscultation alone and may be a cost-effective screening strategy in developing countries. (Read the full article)

• Free pizza for health workers
• Men’s and women’s national teams appear in StaySafeHome video
• Teaming up with mental health charities to help people cope with self-isolation

Minister of Public Enterprises Pravin Gordhan briefed a joint meeting of Parliament's Portfolio and Standing Committees on Public Enterprises on Wednesday evening.

Success in today’s digital-first world depends on a marketing organisation’s ability to create and activate hyper-relevant, data-driven and omnichannel customer experiences, says Nikki Mendonca.

Agency: GSS Closing Date: 6/4/2020