An integrated native mass spectrometry and top-down proteomics method that connects sequence to structure and function of macromolecular complexes.

Mass spectrometry (MS) has become a crucial technique for the analysis of protein complexes. Native MS has traditionally examined protein subunit arrangements, while proteomics MS has focused on sequence identification. These two techniques are usually performed separately without taking advantage of the synergies between them. Here we describe the development of an integrated native MS and top-down proteomics method using Fourier-transform ion cyclotron resonance (FTICR) to analyse macromolecular protein complexes in a single experiment. We address previous concerns of employing FTICR MS to measure large macromolecular complexes by demonstrating the detection of complexes up to 1.8 MDa, and we demonstrate the efficacy of this technique for direct acquirement of sequence to higher-order structural information with several large complexes. We then summarize the unique functionalities of different activation/dissociation techniques. The platform expands the ability of MS to integrate proteomics and structural biology to provide insights into protein structure, function and regulation

Characterizing mixed mode oscillations shaped by noise and bifurcation structure

Many neuronal systems and models display a certain class of mixed mode oscillations (MMOs) consisting of periods of small amplitude oscillations interspersed with spikes. Various models with different underlying mechanisms have been proposed to generate this type of behavior. Stochastic versions of these models can produce similarly looking time series, often with noise-driven mechanisms different from those of the deterministic models. We present a suite of measures which, when applied to the time series, serves to distinguish models and classify routes to producing MMOs, such as noise-induced oscillations or delay bifurcation. By focusing on the subthreshold oscillations, we analyze the interspike interval density, trends in the amplitude and a coherence measure. We develop these measures on a biophysical model for stellate cells and a phenomenological FitzHugh-Nagumo-type model and apply them on related models. The analysis highlights the influence of model parameters and reset and return mechanisms in the context of a novel approach using noise level to distinguish model types and MMO mechanisms. Ultimately, we indicate how the suite of measures can be applied to experimental time series to reveal the underlying dynamical structure, while exploiting either the intrinsic noise of the system or tunable extrinsic noise.Comment: 22 page

Clinical and economic implications of therapeutic switching of Angiotensin receptor blockers to Angiotensin-converting enzyme inhibitors : a population-based study

OBJECTIVE: To evaluate the clinical and cost impact of switching angiotensin receptor blockers (ARBs) to angiotensin-converting enzyme inhibitors (ACEIs) in patients with hypertension. METHODS: This study used the UK Clinical Practice Research Datalink, linking with the Hospital Episode Statistics (April 2006 to March 2012). Adults with hypertension (n = 470) were followed from the first ARB prescription date to the switching date (preswitching period); then from the switching date to the date when study ended, patient left the dataset or died (postswitching period). Patients were divided into ACEIs-combined (n = 369) and ACEIs-monotherapy (n = 101) groups by whether additional antihypertensive drugs were prescribed with ACEIs in the postswitching period. Proportion of days covered (PDC), clinical outcomes and costs were compared between the preswitching and postswitching periods using a multilevel regression. RESULTS: Overall, in the postswitching period, there was a significant increase in the proportion of nonadherence (PDC < 80%) (OR: 2.4; 95% CI: 1.6-3.7), but a significant reduction in mean SBP (mean difference: -2.3; 95 CI: -3.4 to 1.2 mmHg) and mean DBP (mean difference: -1.9; 95% CI: -2.6 to -1.2 mmHg). However, these results were only observed in the ACEIs-combined group. There was no postswitching significant difference in either the incidence of individual or composite hypertension-related complications (OR: 0.9; 95% CI: 0.4-2.0). There was a significant reduction in the overall annual medical cost per patient by £329 (95% CI: -534 to -205). CONCLUSION: Switching of ARBs to ACEIs monotherapy appeared to be clinically effective and a cost-saving strategy. The observed changes in the ACEIs-combined group are assumed to be related to factors other than the ARBs switching

The Landscape of Long Non-Coding RNA Dysregulation and Clinical Relevance in Muscle Invasive Bladder Urothelial Carcinoma.

Bladder cancer is one of the most common cancers in the United States, but few advancements in treatment options have occurred in the past few decades. This study aims to identify the most clinically relevant long non-coding RNAs (lncRNAs) to serve as potential biomarkers and treatment targets for muscle invasive bladder cancer (MIBC). Using RNA-sequencing data from 406 patients in The Cancer Genome Atlas (TCGA) database, we identified differentially expressed lncRNAs in MIBC vs. normal tissues. We then associated lncRNA expression with patient survival, clinical variables, oncogenic signatures, cancer- and immune-associated pathways, and genomic alterations. We identified a panel of 20 key lncRNAs that were most implicated in MIBC prognosis after differential expression analysis and prognostic correlations. Almost all lncRNAs we identified are correlated significantly with oncogenic processes. In conclusion, we discovered previously undescribed lncRNAs strongly implicated in the MIBC disease course that may be leveraged for diagnostic and treatment purposes in the future. Functional analysis of these lncRNAs may also reveal distinct mechanisms of bladder cancer carcinogenesis

The impact of the ‘Better Care Better Value’ prescribing policy on the utilisation of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for treating hypertension in the UK primary care setting: longitudinal quasi-experimental design

In April/2009, the UK National Health Service initiated four Better Care Better Value (BCBV) prescribing indicators, one of which encouraged the prescribing of cheaper angiotensin-converting enzyme inhibitors (ACEIs) instead of expensive angiotensin receptor blockers (ARBs), with 80 % ACEIs/20 % ARBs as a proposed, and achievable target. The policy was intended to save costs without affecting patient outcomes. However, little is known about the actual impact of the BCBV indicator on ACEIs/ARBs utilisation and cost-savings. Therefore, this study aimed to evaluate the impact of BCBV policy on ACEIs/ARBs utilisation and cost-savings, including exploration of regional variations of the policy’s impact

A full free spectral range tuning of p-i-n doped Gallium Nitride microdisk cavity

Effective, permanent tuning of the whispering gallery modes (WGMs) of p-i-n doped GaN microdisk cavity with embedded InGaN quantum dots over one free spectral range is successfully demonstrated by irradiating the microdisks with a ultraviolet laser (380nm) in DI water. For incident laser powers between 150 and 960 nW, the tuning rate varies linearly. Etching of the top surface of the cavity is proposed as the driving force for the observed shift in WGMs, and is supported by experiments. The tuning for GaN/InGaN microdisk cavities is an important step for deterministically realizing novel nanophotonic devices for studying cavity quantum electrodynamics

Extracellular domain of CD98hc is required for early murine development

<p>Abstract</p> <p>Background</p> <p>The multifunctional protein CD98 heavy chain (CD98hc, Slc3a2) associates with integrin β1 through its cytoplasmic and transmembrane domains and the CD98hc-mediated integrin signaling is required for maintenance of ES cell proliferation. CD98hc-null mice exhibit early post-implantation lethality similar to integrin β1-null mice, supporting the importance of its interaction with integrin β1. On the other hand, the extracellular domain of CD98hc interacts with L-type amino acid transporters (LATs) and is essential for appropriate cell surface distribution of LATs. LATs mediate the transport of amino acids and other molecules such as thyroid hormone. In this respect, CD98hc may also affect development via these transporters.</p> <p>Results</p> <p>In this study, mice were generated from embryonic stem (ES) cell line (PST080) harboring a mutant CD98hc allele (CD98hc^Δ/+). Expression of the CD98hc mutant allele results in ΔCD98hc-β geo fusion protein where extracellular C-terminal 102 amino acids of CD98hc are replaced with β geo. Analyses of PST080 ES cells as well as reconstituted frog oocytes demonstrated that ΔCD98hc-β geo fusion protein preserved its ability to interact with integrin β1 although this mutant protein was hardly localized on the cell surface. These findings suggest that ΔCD98hc-β geo protein can mediate integrin signaling but cannot support amino acid transport through LATs. CD98hc^Δ/+mice were normal. Although some of the implantation sites lacked embryonic component at E9.5, all the implantation sites contained embryonic component at E7.5. Thus, CD98hc^Δ/Δembryos are likely to die between E7.5 and E9.5.</p> <p>Conclusions</p> <p>Considering that CD98hc complete knockout (CD98hc^-/-) embryos are reported to die shortly after implantation, our findings suggest potential stage-specific roles of CD98hc in murine embryonic development. CD98hc may be essential for early post-implantation development by regulating integrin-dependent signaling, while the other function of CD98hc as a component of amino acid transporters may be required for embryonic development at later stages.</p

Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination nanochemotherapy for treating patients with MPNSTs

The development of a national salt reduction strategy for Australia

Excess dietary salt is a well established cause of high blood pressure and vascular disease. National and international bodies recommend a significant reduction in population salt intakes on the basis of strong evidence for health gains that population salt reduction strategies could achieve. The Australian Division of World Action on Salt and Health (AWASH) coordinates the Drop the Salt! campaign in Australia. This aims to reduce the average amount of salt consumed by Australians to six grams per day over five years through three main implementation strategies targeting the food industry, the media and government. This strategy has the potential to achieve a rapid and significant reduction in dietary salt consumption in Australia. With industry and government engagement, this promises to be a highly effective, low cost option for preventing chronic disease.<br /

Regional Transport – a supply chain mapping exercise and Brexit exposure check of automotive, aerospace and rail value dependency in the WMCA region

This report presents the findings and key policy recommendations of a combined supply chain mapping exercise and Brexit exposure check of the transport manufacturing sector in the Midlands,funded by the West Midlands Combined Authority. These sectors consisted of automotive, rail and aerospace manufacturers and suppliers, for which 234 firms were surveyed between November 2019 and January 2020. Of these, 25 were exclusively involved in aerospace manufacture; 59 were exclusively involved in automotive manufacture; 3 were exclusively involved in non-auto road vehicles; 32 were exclusively involved in rail manufacture; 27 were mixed manufacturers and; 87 were freight/logistics firms. Key aspects examined in the mapping exercise included: value of automotive businesses in the West Midlands split by vehicle company clients and local authorities; divisions between tiers one and two, and logistics and suppliers, employment mix (UK/EU), major challenges faced by supply chain e.g.transport infrastructure and paperwork; import/export ratios, transport route dependency, and ‘Brexit readiness’