The development of the HUPO-PSI's (Proteomics Standards Initiative) standard data formats and MIAPE (Minimum Information About a Proteomics Experiment) guidelines should improve proteomics data sharing within the scientific community. Proteomics journals have encouraged the use of these standards and guidelines to improve the quality of experimental reporting and ease the evaluation and publication of manuscripts. However, there is an evident lack of bioinformatics tools specifically designed to create and edit standard file formats and reports, or embed them within proteomics workflows. In this article, we describe a new web-based software suite (The ProteoRed MIAPE web toolkit) that performs several complementary roles related to proteomic data standards. Firstly, it can verify the reports fulfill the minimum information requirements of the corresponding MIAPE modules, highlighting inconsistencies or missing information. Secondly, the toolkit can convert several XML-based data standards directly into human readable MIAPE reports stored within the ProteoRed MIAPE repository. Finally, it can also perform the reverse operation, allowing users to export from MIAPE reports into XML files for computational processing, data sharing or public database submission. The toolkit is thus the first application capable of automatically linking the PSI's MIAPE modules with the corresponding XML data exchange standards, enabling bidirectional conversions. This toolkit is freely available at http://www.proteored.org/MIAPE/.

Genetic and genomic research has greatly advanced our understanding of heart disease. Yet, comprehensive, in-depth, quantitative maps of protein expression in hearts of living humans are still lacking. Using samples obtained during valve replacement surgery in patients with mitral valve prolapse (MVP), we set out to define inter-chamber differences, the intersect of proteomic data with genetic or genomic datasets, and the impact of left atrial dilation on the proteome of patients with no history of atrial fibrillation (AF).  We collected biopsies from right atria (RA), left atria (LA) and left ventricle (LV) of seven male patients with mitral valve regurgitation with dilated LA but no history of AF. Biopsy samples were analyzed by high-resolution mass spectrometry (MS), where peptides were pre-fractionated by reverse phase high-pressure liquid chromatography prior to MS measurement on a Q-Exactive-HF Orbitrap instrument. We identified 7,314 proteins based on 130,728 peptides. Results were confirmed in an independent set of biopsies collected from three additional individuals. Comparative analysis against data from post-mortem samples showed enhanced quantitative power and confidence level in samples collected from living hearts. Our analysis, combined with data from genome wide association studies suggested candidate gene associations to MVP, identified higher abundance in ventricle for proteins associated with cardiomyopathies and revealed the dilated LA proteome, demonstrating differential representation of molecules previously associated with AF, in non-AF hearts. This is the largest dataset of cardiac protein expression from human samples collected in vivo. It provides a comprehensive resource that allows insight into molecular fingerprints of MVP and facilitates novel inferences between genomic data and disease mechanisms. We propose that over-representation of proteins in ventricle is consequent not to redundancy but to functional need, and conclude that changes in abundance of proteins known to associate with AF are not sufficient for arrhythmogenesis.

7 May 2020 , Volume 96, Number 3

Lipid rafts regulate the initiation of cellular metabolic and signaling pathways by organizing the pathway components in ordered microdomains on the cell surface. Cellular responses regulated by lipid rafts range from physiological to pathological, and the success of a therapeutic approach targeting "pathological" lipid rafts depends on the ability of a remedial agent to recognize them and disrupt pathological lipid rafts without affecting normal raft-dependent cellular functions. In this article, concluding the Thematic Review Series on Biology of Lipid Rafts, we review current experimental therapies targeting pathological lipid rafts, including examples of inflammarafts and clusters of apoptotic signaling molecule-enriched rafts. The corrective approaches include regulation of cholesterol and sphingolipid metabolism and membrane trafficking by using HDL and its mimetics, LXR agonists, ABCA1 overexpression, and cyclodextrins, as well as a more targeted intervention with apoA-I binding protein. Among others, we highlight the design of antagonists that target inflammatory receptors only in their activated form of homo- or heterodimers, when receptor dimerization occurs in pathological lipid rafts. Other therapies aim to promote raft-dependent physiological functions, such as augmenting caveolae-dependent tissue repair. The overview of this highly dynamic field will provide readers with a view on the emerging concept of targeting lipid rafts as a therapeutic strategy.

Lens proteins become increasingly cross-linked through nondisulfide linkages during aging and cataract formation. One mechanism that has been implicated in this cross-linking is glycation through formation of advanced glycation end products (AGEs). Here, we found an age-associated increase in stiffness in human lenses that was directly correlated with levels of protein–cross-linking AGEs. α-Crystallin in the lens binds to other proteins and prevents their denaturation and aggregation through its chaperone-like activity. Using a FRET-based assay, we examined the stability of the αA-crystallin–γD-crystallin complex for up to 12 days and observed that this complex is stable in PBS and upon incubation with human lens–epithelial cell lysate or lens homogenate. Addition of 2 mm ATP to the lysate or homogenate did not decrease the stability of the complex. We also generated complexes of human αA-crystallin or αB-crystallin with alcohol dehydrogenase or citrate synthase by applying thermal stress. Upon glycation under physiological conditions, the chaperone–client complexes underwent greater extents of cross-linking than did uncomplexed protein mixtures. LC-MS/MS analyses revealed that the levels of cross-linking AGEs were significantly higher in the glycated chaperone–client complexes than in glycated but uncomplexed protein mixtures. Mouse lenses subjected to thermal stress followed by glycation lost resilience more extensively than lenses subjected to thermal stress or glycation alone, and this loss was accompanied by higher protein cross-linking and higher cross-linking AGE levels. These results uncover a protein cross-linking mechanism in the lens and suggest that AGE-mediated cross-linking of α-crystallin–client complexes could contribute to lens aging and presbyopia.

Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.

16 March 2020

In this first episode of a three-part series on “Disrupting Therapeutic Inertia in Diabetes Management,” Drs. John Russell and Neil Skolnik examine a case study of a 55-year-old man with type 2 diabetes (3 years duration, A1C 8.2%). In so doing, they review six articles that define achievement gaps in reaching A1C goals and the reasons for why those gaps exist. In episodes 2 and 3 of this series, Drs. Russell and Skolnik we will look at additional causes of therapeutic inertia and solutions for overcoming it. This special three-part series on therapeutic inertia is supported by independent educational grant from Sanofi (https://www.sanofi.com).

This issue will review:

1. Achievement of target therapeutic goals in persons with T2DM
2. Achievement of therapeutic goals from 2005 – 2015
3. Clinical Inertia in Newly Diagnosed Type 2 DM
4. Clinical Inertia over Time in Type 2 DM
5. Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use
6. Difference between Clinical Trial and Real-World Studies Achievement of Target A1C <7.0% in Patients Treated with Basal Insulin in RCTs and Clinical Practice

For more information about each of ADA’s science and medical journals, please visit www.diabetesjournals.org.

Presented by:

Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health

John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health

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Sue Farrington is chair of the Patient Information Forum, a member organisation which promotes best practice in anyone who produces information for patients. In this podcast, she discusses what makes good patient information, why doctors should be pleased when patients arrive at an appointment with a long list of questions, and why patients are...

There is very little guidance on withdrawing or tapering opioids in chronic pain (not caused by cancer). People can fear pain, withdrawal symptoms, a lack of social and healthcare support, and they may also distrust non-opioid methods of pain management. This can mean that patients receive repeat opioid prescriptions for extended periods of...

Susan Greenhalg is a research professor of chinese society in Harvard’s department of anthropology - not a natural fit for a medical journal you may think, but recently she has been looking at the influence of Coca Cola on obesity policy in China. She has written up her investigation in an article published on bmj.com this week, and joins us in...

Jönköping has been at the centre of the healthcare quality improvement movement for years - but how did a forested region of Sweden, situated between it's main cities, come to embrace the philosophy of improvement so fervently? Goran Henriks, chief executive of learning and innovation at Qulturum in Jönköping joins us to explain. He also tells...

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.

25 November 2014

This paper accompanies a series of assessments on China, France, Japan, the Netherlands, the UK, the US and Vietnam, providing details on how the estimates of the level of illegality of imports of wood-based products into those countries were derived.

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

Discussion at this event focused on findings from MPI's report examining the interior immigration enforcement system in the United States, including ICE data on deportations and arrests, and the responses of state and local governments, civil society, and consulates.  

Marking the release of an MPI study, this discussion examines the operation of today’s interior enforcement system and how state and local governments, civil society, and consulates are responding.    

The recent rise in xenophobia in Hungary stands in marked contrast with the country's rich migration history. After 390,000 migrants and asylum seekers arrived in 2015, the government of Viktor Orbán issued policies to significantly limit migration and enacted a law criminalizing humanitarian assistance to migrants. This country profile examines Hungary’s migration past and present, tracing the country’s multicultural heritage to the current wave of anti-immigrant sentiment.

A young bull went wandering on a Massachusetts highway after escaping from a trailer and was captured without causing any incidents, police said.

A Michigan family said their 6-foot-tall emu was found playing in another resident's sprinkler about a mile from home one day after escaping.

Police in Britain said a surprised jogger tipped officers off to the location of a wallaby that escaped from a zoo and went hopping through the countryside.

Police in the Netherlands said officers responding to reports of a loose camel ended up capturing an emu running wild through the city of Rotterdam.

Mexicans migrate to Canada in much smaller numbers than to the United States, yet over the last 30 years the country has become an increasingly attractive destination. Canada prioritizes highly skilled, educated Mexicans for permanent residency, but also attracts temporary workers from Mexico. This article examines Mexican migration to Canada and how it has been shaped by visa requirements, trade policy, and more.

Gujarat university, second MBBS examination, forensic medicine question papers, January 2015

Gujarat university, second MBBS examination, microbiology question papers, January 2015

Gujarat university, second MBBS examination, pathology question papers, January 2015

Gujarat university, second MBBS examination, pharmacology question papers (2010-2014)

Gujarat university, second MBBS examination, pharmacology question papers, January 2015

MD pharmacology examination, question papers, Gujarat university, April 2012

MD pharmacology examination, question papers, Gujarat university, October 2012

MD pharmacology examination, question papers, Gujarat university, April 2013

Here’s my Q&A column from the WSJ this week — and if you have any questions for me, you can tweet them to @danariely with the hashtag #askariely, post a comment on my Ask Ariely Facebook page, or email them to AskAriely@wsj.com. ___________________________________________________ Dear Dan, I shop at two different grocery...

The failure of Geert Wilders’ right-wing, anti-Islam Freedom Party (PVV) to become the top vote-getter in the Dutch parliamentary elections is being hailed as proof of the limits of anti-Muslim rhetoric and even the “waning” of the appeal of right-wing populism. But as this commentary explores, a closer reading leads one to a more nuanced interpretation of the results and the recognition that Wilders will remain a major force.

The Houston metro area, home to 1.6 million immigrants, is diverse and rapidly growing. This report sketches the area's immigrant population, examining top origin countries, key socioeconomic measures, and more. It also explores how Hurricane Harvey affected the immigrant population, and how national policy changes under the Trump administration are being felt locally, including by DACA recipients and asylum seekers.

Experts share how states have approached Every Student Succeeds Act (ESSA) implementation, and areas where the law and state efforts to support English Learners can be improved.

All 50 states, the District of Columbia, and Puerto Rico have developed blueprints to meet their commitments under the Every Student Succeeds Act—including requirements that aim to raise the profile of English Learners (EL) in state accountability systems. This report breaks these plans down, comparing the significant diversity of approaches taken on everything from EL identification to tracking academic achievement.

Cabbage at its best.

A simple summer seafood dish!

Salmon and fennel at its best.

Experts share how states have approached Every Student Succeeds Act (ESSA) implementation, areas where the law and state efforts to support English Learners can be improved, and findings from the compendium, The Patchy Landscape of State English Learner Policies under ESSA. 

The public-charge rule issued by the Trump administration in August 2019 will have profound effects on future immigration and on use of public benefits by millions of legal noncitizens and their U.S.-citizen family members. Complex standards for determining when an immigrant is likely to become a public charge could cause a significant share of the nearly 23 million noncitizens and U.S. citizens in benefits-using immigrant families to disenroll, as this commentary explains.

Stephen Brunton
Apr 1, 2019; 37:105-106
Editorials

Jane K. Dickinson
Jan 1, 2017; 35:51-54
Commentary

Heroism Science: Call for Papers, Special Issue The Heroism of Whistleblowers Edited by Ari Kohen, Brian Riches, and Matt Langdon Whistleblowers speak up with “concerns or information about wrongdoing inside organizations and institutions.” As such, whistleblowing “can be one of the most important and difficult forms of heroism in modern society” (Brown, 2016 p. 1). … Continue reading Heroism Science: Call for Papers, Special Issue: The Heroism of Whistleblowers →

To combat COVID-19, countries have enforced city-wide shutdowns, stay-at-home orders and mask mandates -- but the reaction (and adherence) to these rules has differed markedly in the East and West. In conversation with TED's head of curation Helen Walters, writer and publisher Huang Hung sheds light on how Chinese and American cultural values shaped their responses to the outbreak -- and provides perspective on why everyone needs to come together to end the pandemic. (Recorded April 16, 2020)