In bottom-up, label-free discovery proteomics, biological samples are acquired in a data-dependent (DDA) or data-independent (DIA) manner, with peptide signals recorded in an intact (MS1) and fragmented (MS2) form. While DDA has only the MS1 space for quantification, DIA contains both MS1 and MS2 at high quantitative quality. DIA profiles of complex biological matrices such as tissues or cells can contain quantitative interferences, and the interferences at the MS1 and the MS2 signals are often independent. When comparing biological conditions, the interferences can compromise the detection of differential peptide or protein abundance and lead to false positive or false negative conclusions.

We hypothesized that the combined use of MS1 and MS2 quantitative signals could improve our ability to detect differentially abundant proteins. Therefore, we developed a statistical procedure incorporating both MS1 and MS2 quantitative information of DIA. We benchmarked the performance of the MS1-MS2-combined method to the individual use of MS1 or MS2 in DIA using four previously published controlled mixtures, as well as in two previously unpublished controlled mixtures. In the majority of the comparisons, the combined method outperformed the individual use of MS1 or MS2. This was particularly true for comparisons with low fold changes, few replicates, and situations where MS1 and MS2 were of similar quality. When applied to a previously unpublished investigation of lung cancer, the MS1-MS2-combined method increased the coverage of known activated pathways.

Since recent technological developments continue to increase the quality of MS1 signals (e.g. using the BoxCar scan mode for Orbitrap instruments), the combination of the MS1 and MS2 information has a high potential for future statistical analysis of DIA data.

Minjuan Ma
Mar 30, 2020; 0:jlr.RA120000664v1-jlr.RA120000664
Research Articles

A double Google header as Henry Burrell leads Scott Carey and Sean Bradley down the tech rabbit hole. Alphabet's most famous outlet has redesigned Gmail for desktop, but what does that mean for businesses and consumers. Will anyone notice?

Then what is Chat? Not Google Chat or Android Chat, mind - just Chat. Will the Google-led initiative really transform text messaging on Android or is it doomed to forever to be a fragmented mess?

Sean then talks us through the latest AMD processors to challenge Intel. Intel hasn't had the best of year's after Apple announced it is going solo. Is there a change afoot?

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Excessive lipid deposition is a hallmark of nonalcoholic fatty liver disease (NAFLD). Although much has been learned about the enzymes and metabolites involved in NAFLD, few studies have focused on the role of long non-coding RNAs (lncRNAs) in hepatic lipid accumulation. Here, using in vitro and in vivo models of NAFLD, we found that the lncRNA Gm15622 is highly expressed in the liver of obese mice fed a high-fat diet (HFD) and in murine liver (AML-12) cells treated with free fatty acids. Investigating the molecular mechanism in the liver-enriched expression of Gm15622 and its effects on lipid accumulation in hepatocytes and on NAFLD pathogenesis, we found that Gm15622 acts as a sponge for the microRNA miR-742-3p. This sponging activity increased the expression of the transcriptional regulator sterol regulatory element–binding transcription factor 1c (SREBP-1c) and promoted lipid accumulation in the liver of the HFD mice and AML-12 cells. Moreover, further results indicated that metformin suppresses Gm15622 and alleviates NAFLD-associated lipid deposition in mice. In conclusion, we have identified an lncRNA Gm15622–miR-742-3p–SREBP-1c regulatory circuit associated with NAFLD in mice, a finding that significantly advances our insight into how lipid metabolism and accumulation are altered in this metabolic disorder. Our results also suggest that Gm15622 may be a potential therapeutic target for managing NAFLD.

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.

Objective:

GPR40 is a G protein-coupled receptor regulating free fatty acid-induced insulin secretion. We have generated transgenic mice overexpressing the human GPR40 gene (hGPR40-Tg) under control of the mouse insulin II promoter and have used them to examine the role of GPR40 in the regulation of insulin secretion and glucose homeostasis.

Cell-surface signaling (CSS) in Gram-negative bacteria involves highly conserved regulatory pathways that optimize gene expression by transducing extracellular environmental signals to the cytoplasm via inner-membrane sigma regulators. The molecular details of ferric siderophore-mediated activation of the iron import machinery through a sigma regulator are unclear. Here, we present the 1.56 Å resolution structure of the periplasmic complex of the C-terminal CSS domain (CCSSD) of PupR, the sigma regulator in the Pseudomonas capeferrum pseudobactin BN7/8 transport system, and the N-terminal signaling domain (NTSD) of PupB, an outer-membrane TonB-dependent transducer. The structure revealed that the CCSSD consists of two subdomains: a juxta-membrane subdomain, which has a novel all-β-fold, followed by a secretin/TonB, short N-terminal subdomain at the C terminus of the CCSSD, a previously unobserved topological arrangement of this domain. Using affinity pulldown assays, isothermal titration calorimetry, and thermal denaturation CD spectroscopy, we show that both subdomains are required for binding the NTSD with micromolar affinity and that NTSD binding improves CCSSD stability. Our findings prompt us to present a revised model of CSS wherein the CCSSD:NTSD complex forms prior to ferric-siderophore binding. Upon siderophore binding, conformational changes in the CCSSD enable regulated intramembrane proteolysis of the sigma regulator, ultimately resulting in transcriptional regulation.

Ralph A. DeFronzo
Apr 1, 2009; 58:773-795
Banting Lecture

Research Event

Event participants

Lord Tu'ivakano, Prime Minister of the Kingdom of Tonga

IN AN effort to alleviate misconceptions and misinterpretations of our current COVID-19 reality, and to create the idea that human beings deserve respect, especially when they are ill, ListenMi News has collaborated with the International...

While playing close to his Alabama home and enjoying a chance to once again work with Atlanta general manager Alex Anthopoulos, the former American League MVP Award winner Josh Donaldson also understands the importance of rejuvenating his career with his deal.

Astros third baseman Alex Bregman continues to progress from the arthroscopic elbow surgery he had a month to remove bone chips.

It took only two words for Alex Bregman to send 9-year-old Jax Nystrom into a frenzy, but this kind of reaction -- young people freaking out at the slightest bit of attention from him -- has become commonplace for the Astros' All-Star third baseman.

Terence Stephenson is a consultant paediatrician who became been chair of the General Medical Council in 2015. His 4 year tenure has now come to an end, but during his time with the regulator the medical profession faced a number of challenges - the case of Hadiza Bawa Garba and a growing recruitment crisis in the NHS - the GMC is the...

Michael West is professor of organisational psychology, at Lancaster University, and co-author of a new GMC report into the wellbeing of NHS staff. The review he led together with the clinical psychiatrist Denise Coia, focused on primary interventions related to workplace factors and the systems that doctors work in, rather than secondary...

Franz M Matschinsky
Feb 1, 1996; 45:223-241
Banting Lecture 1995

Ralph A. DeFronzo
Apr 1, 2009; 58:773-795
Banting Lecture

JW Baynes
Jan 1, 1999; 48:1-9
Articles

THE EDITOR, Madam: The devastating news of Jodian Fearon’s death has resulted in public outrage and concern. The controversy and seemingly negligent actions of the hospitals involved have left many Jamaicans anxious about our health system and...

16 December 2019

Discussion at launch of this MPI-IOM Issue in Brief, Human Rights, Climate Change, Environmental Degradation and Migration: A New Paradigm, which focuses on the vulnerability of environmental migrants and how the international legal framework can better ensure their protection, particularly in the Asia-Pacific region.

This issue brief addresses the rights of migrants whose movement is induced by environmental degradation or climate change, particularly in the highly vulnerable Asia-Pacific region. The brief evaluates the current international legal framework, identifies gaps in the framework and its implementation, and reviews options available to the international community.

This MPI event, in partnership with the International Organization for Migration (IOM), discusses the critical issue of climate-related displacement in the Asia-Pacific region, focusing on the vulnerability of environmental migrants and how the international legal framework can better ensure their protection.

Alison J. Dunkley
Apr 1, 2014; 37:922-933
Current Concepts of Type 2 Diabetes Prevention

Boeing announced Tuesday has presented its first unmanned aircraft to the Royal Australian Air Force.

Boeing was awarded a $128.5 million modification to its Ground-based Midcourse Defense development and sustainment contract Thursday, according to the Pentagon.

Raytheon Missile Systems was awarded a $19 million contract modification to exercise options for Navy Rolling Airframe Missile and Guided Missile Launching Systems, according to the Department of Defense.

Richard M. Bergenstal
Nov 1, 2018; 41:2275-2280
Perspectives in Care

Dr. Rafael "Ray" Bowen, who made significant contributions to dental materials research and retired in 2018 after 62 years at the American Dental Association, has died.

Neurons in the hippocampus categorize what we experience into abstract, discrete events, such as taking a walk versus having lunch

-- Read more on ScientificAmerican.com

Marking the release of an MPI brief that articulates a new adult education program model, this webinar features a discussion among immigration and legal services, adult education, and digital learning experts. The webinar includes a discussion of strategies to implement the English Plus Integration model, which would maintain a central focus on English language acquisition while also building skills necessary for successful immigrant integration.

To successfully integrate, immigrants and refugees need a variety of skills and knowledge—from English proficiency to understanding how school systems and local services work. Yet the adult education programs in place to support them have narrowed in scope. This policy brief proposes a new instructional model, English Plus Integration, to help states more comprehensively meet the diverse needs of their adult immigrant learners.

Taking stock of weaknesses in the WIOA-driven design of most adult basic education programming, MPI analysts draw on research from the integration, adult education, and postsecondary success fields in arguing for the adoption of an “English Plus Integration” (EPI) adult education program model, and discuss strategies for implementation. 

Nancy F. Liu
Jan 1, 2017; 35:27-34
Feature Articles

"The HIV resilience framework will be of relevance to a wide range of people involved at all levels of the HIV response. We hope it provides encouragement for government decision makers and policy developers to pursue consistent and enabling policy and legislative environments and work cooperatively between jurisdictions and across departments to achieve best practice. Our consultation suggests that consistent legislation with the goal of supporting strong health outcomes, making disclosure safe, and eliminating stigmatising laws is crucial to creating environments in which people with HIV feel safe to access testing, treatment, and care. The HIV resilience framework also contains valuable insights for those who have responsibility for HIV health program management and service delivery, providing guidance to help ensure that programs, services, interventions or strategies supporting people living with HIV are developed and delivered in a way that is mindful of the interlinked twin goals of building personal resilience and eliminating stigma and discrimination." --President's message (page 6).

Authors -- Fiction.

UK : Institute of Ophthalmology, 1951.

UK : Institute of Ophthalmology, 1951.

A Paris : Germer-Bailliere ; A Londres : J.-B. Bailliere, 1835.

Wiesbaden : J.F. Bergmann, 1907.

Leipzig : Deuticke, 1898.

Berlin : A. Hirschwald, 1870.

Berlin : A. Hirschwald, 1886.

Paris : Georges Carre, 1896.

Dorpat : H. Laakmann, 1890.

Breslau : A. Gosohorsky, 1876.

London : printed for J. Callow, 1814.