Low Temperature Aqueous Electrospray Ionization Mass Spectrometry of Noncovalent Complexes

AbstractIn the present study we describe conditions that permit the characterization of noncovalent protein–substrate complexes in aqueous solution by microspray electrospray ionization-mass spectrometry (ESI-MS), using a heated transfer capillary at low temperature (45 °C). Specifically, we examined the binding of calmodulin to two polypeptides; the calmodulin-binding domain of calmodulin-dependent protein kinase II (CamK-II) and melittin. Calmodulin, a well known calcium-binding protein, binds to a number of small amphipathic peptides in a calcium-dependent manner. Our results directly show that both peptides form equimolar complexes with calmodulin only in the presence of calcium. The stoichiometry necessary for the formation of each complex was 1:1:4 for calmodulin:peptide (melittin or CamK-II):Ca2+, respectively. Furthermore, it is demonstrated that the detection of the complex in ESI-MS is source temperature dependent

An Open-Source Data Manager for Network Models

Developing simulation and optimisation models for resource networks like water or energy systems increasingly involves integrating multiple data sources and software. Connecting multiple models and managing data accessed by different groups of analysts is a software challenge. Many resource systems are represented in computer models as networks of nodes and links, driven by a range of objectives and rules. We present a data storage platform, written in Python, which exploits the commonality of network representations to store data for multiple model types within a single deployment. This open-source platform provides a common source of data to multiple models using consistent data formats, reducing likelihood of error compared to file based data management. When deployed as a web service, it allows data to be shared securely among authorised users over the internet, facilitating collaboration. A case study describes the hosting of a water utility planning model, with an accompanying worked example

The 2020s will be a crunch decade that will determine the UK’s trajectory into the mid-21st century

As vaccines roll out and restrictions are lifted, public debate is turning to the economic recovery from COVID-19 and the deepest annual downturn for 300 years that came in its wake. But viewing the years ahead simply as the post-pandemic period is far too limited a frame, say the authors of the Economy 2020 Inquiry. Instead, the 2020s look set to be the decisive decade during which the UK will need to renew its approach to achieving economic success

A new therapeutic strategy for lung tissue injury induced by influenza with CR2 targeting complement inhibitior

<p>Abstract</p> <p>Background</p> <p>Influenza is a respiratory disease that seriously threatens human health. In fact, influenza virus itself does not make critical contribution to mortality induced by influenza, but "cytokine storm" produced by the excessive immune response triggered by the virus can result in inflammatory reaction of lung tissues and fatal lung tissue injury, and thus increase influenza mortality. Therefore, besides antiviral drugs, immunosuppression drugs should also be included in infection treatment.</p> <p>Presentation of the hypothesis</p> <p>Complement is the center of inflammatory reaction. If complement system is over activated, the body will have strong inflammatory reaction or tissue injury, resulting in pathological process. Many studies have proved that, inflammatory injury of lung tissues caused by influenza virus is closely related to complement activation. Therefore, inhibiting complement activation can significantly reduce inflammatory injury in lung tissues. As complement is both a physiological defense and pathological damage medium, systematic inhibition may result in side effects including infection. Therefore, we design targeting complement inhibitors for complement activation sites, i.e. with CR2 as targeting vector, complement inhibitors like CD59 and Crry are targeted to inflammatory sites to specially inhibit the complement activation in local injury, thus local inflammatory reaction is inhibited.</p> <p>Testing the hypothesis</p> <p>CR2-CD59 and CR2-Crry targeting complement inhibitors are fusion-expressed, and their biological activity is examined via in <it>vivo </it>and in vitro tests. CR2 targeting complement inhibitors are used to treat mouse influenza viral pneumonia model, with PBS treatment group as the control. The survival and lung tissue injury of the mice is observed and the effect of CR2 targeting complement inhibitors on pneumonia induced by influenza virus is evaluated.</p> <p>Implications of the hypothesis</p> <p>CR2 targeting complement inhibitors are expected to be ideal drugs for viral pneumonia.</p

Multimodality imaging for transcatheter tricuspid valve repair and replacement

Transcatheter tricuspid intervention is a rapidly evolving field with multiple classes of therapeutic devices currently in development. Procedural success in tricuspid intervention is predicated on appropriate device selection for patient specific anatomy and satisfactory imaging for intra-procedural guidance. This review will outline protocols and methodology for multi-modality imaging assessment of the tricuspid valve and associated structures, with emphasis on anatomic and functional characteristics that determine suitability for each class of tricuspid intervention. Intra-procedural imaging requirements for each class of device, with design and procedural imaging guidance of specific devices, will also be addressed

Vaccinating adolescents against SARS-CoV-2 in England: a risk-benefit analysis.

OBJECTIVE: To offer a quantitative risk-benefit analysis of two doses of SARS-CoV-2 vaccination among adolescents in England. SETTING: England. DESIGN: Following the risk-benefit analysis methodology carried out by the US Centers for Disease Control, we calculated historical rates of hospital admission, Intensive Care Unit admission and death for ascertained SARS-CoV-2 cases in children aged 12-17 in England. We then used these rates alongside a range of estimates for incidence of long COVID, vaccine efficacy and vaccine-induced myocarditis, to estimate hospital and Intensive Care Unit admissions, deaths and cases of long COVID over a period of 16 weeks under assumptions of high and low case incidence. PARTICIPANTS: All 12-17 year olds with a record of confirmed SARS-CoV-2 infection in England between 1 July 2020 and 31 March 2021 using national linked electronic health records, accessed through the British Heart Foundation Data Science Centre. MAIN OUTCOME MEASURES: Hospitalisations, Intensive Care Unit admissions, deaths and cases of long COVID averted by vaccinating all 12-17 year olds in England over a 16-week period under different estimates of future case incidence. RESULTS: At high future case incidence of 1000/100,000 population/week over 16 weeks, vaccination could avert 4430 hospital admissions and 36 deaths over 16 weeks. At the low incidence of 50/100,000/week, vaccination could avert 70 hospital admissions and two deaths over 16 weeks. The benefit of vaccination in terms of hospitalisations in adolescents outweighs risks unless case rates are sustainably very low (below 30/100,000 teenagers/week). Benefit of vaccination exists at any case rate for the outcomes of death and long COVID, since neither have been associated with vaccination to date. CONCLUSIONS: Given the current (as at 15 September 2021) high case rates (680/100,000 population/week in 10-19 year olds) in England, our findings support vaccination of adolescents against SARS-CoV2

Oslo government district bombing and Utøya island shooting July 22, 2011: The immediate prehospital emergency medical service response

<p>Abstract</p> <p>Background</p> <p>On July 22, 2011, a single perpetrator killed 77 people in a car bomb attack and a shooting spree incident in Norway. This article describes the emergency medical service (EMS) response elicited by the two incidents.</p> <p>Methods</p> <p>A retrospective and observational study was conducted based on data from the EMS systems involved and the public domain. The study was approved by the Data Protection Official and was defined as a quality improvement project.</p> <p>Results</p> <p>We describe the timeline and logistics of the EMS response, focusing on alarm, dispatch, initial response, triage and evacuation. The scenes in the Oslo government district and at Utøya island are described separately.</p> <p>Conclusions</p> <p>Many EMS units were activated and effectively used despite the occurrence of two geographically separate incidents within a short time frame. Important lessons were learned regarding triage and evacuation, patient flow and communication, the use of and need for emergency equipment and the coordination of helicopter EMS.</p

The clinical features of polymerase proof-reading associated polyposis (PPAP) and recommendations for patient management

Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype–phenotype associations, these recommendations should apply to all PPAP patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10689-021-00256-y

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis

OBJECTIVE: Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.DESIGN: 14 patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.RESULTS: Liraglutide reduced BMI (-1.9 vs. +0.04 kg/m2;p&lt;0.001), HbA1c (-0.3 vs. +0.3%;p&lt;0.01), cholesterol-LDL (-0.7 vs. +0.05 mmol/L;p&lt;0.01), ALT (-54 vs -4.0 IU/L;p&lt;0.01) and serum leptin, adiponectin, and CCL-2 (all p&lt;0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin;p&lt;0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8 pmol/L insulin required to ½ maximally suppress serum NEFA; p&lt;0.05), and specifically within subcutaneous adipose tissue (p&lt;0.05). In addition, liraglutide decreased hepatic DNL in-vivo (-1.26 vs. +1.30%; p&lt;0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p&lt;0.01).CONCLUSIONS: Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.</p

Education Can Compensate for Society - a Bit

In this paper I reflect on the findings of a number of loosely related research projects undertaken with colleagues over the last ten years. Their common theme is equity, in formal education and beyond, in wider family and social settings, and with inequity expressed as the stratification of a variety of educational outcomes. The projects are based on a standard mixture of pre-existing records, official documents, large-scale surveys, observations, interviews and focus groups. The numeric data were largely used to create biographical models of educational experiences, and the in-depth data were used to try to explain individual decisions and disparities at each stage of the model. Data have been collected for England and Wales, in five other countries of the European Union and for Japan. A meta-view of these various findings suggests that national school intakes tend to be at least moderately segregated by prior attainment and socio-economic factors, and that learning outcomes as assessed by formal means, such as examinations, are heavily stratified by these same factors. There is no convincing evidence that compulsory schooling does very much to overcome the initial disparity in the resources and attainment of school intakes. On the other hand, there are indications that the nature of a national school system and the social experiences of young people in schools can begin to equalise educational outcomes as more widely envisaged, including learning to trust and willingness to help others, aspirations, and attitudes to continuing in education and training. The cost-free implications of the argument in this paper, if accepted, are that everything possible should be done to make school intakes comprehensive, and that explicit consideration, by teachers and leaders, of the applied principles of equity could reduce potentially harmful misunderstandings in educational contexts