Two’s a crowd for this week’s games and Christmas pod with Consumer Tech Editor Henry Burrell and Games Editor Lewis Painter. Lewis lines up reviews of the awful Fallout 76 and the excellent online mode of Red Dead Redemption 2 – two polar opposites in how to make a decent online multiplayer game.

We also discuss smartwatches we’ve recently reviewed that left us feeling cold and why Apple is still king of the hill.

And to get into the festive vibe, interspersed throughout as we enter December are our top tech Christmas gift picks, both cheap and indulgent.

Everything we recommend is linked below:

Google Home Hub

Tile Bluetooth tracker

Red Dead Redemption 2 (PS4)

Super Smash Bros – Ultimate (Switch)

Pokémon: Let’s Go, Pikachu! (Switch)

Turtle Beach Elite Pro 2 + Superamp

Amazon Kindle Paperwhite

PlayStation Classic

PlayStation VR Starter Pack

The best budget smartphones

See acast.com/privacy for privacy and opt-out information.

Niemann-Pick disease, type C1 (NPC1) is a lipid storage disorder in which cholesterol and glycosphingolipids accumulate in late endosomal/lysosomal compartments because of mutations in the NPC1 gene. A hallmark of NPC1 is progressive neurodegeneration of the cerebellum as well as visceral organ damage; however, the mechanisms driving this disease pathology are not fully understood. Phosphoinositides are phospholipids that play distinct roles in signal transduction and vesicle trafficking. Here, we utilized consensus spectra analysis of MS imaging datasets and orthogonal LC–MS analyses to evaluate the spatial distribution of phosphoinositides and quantify them in cerebellar tissue from Npc1-null mice. Our results suggest significant depletion of multiple phosphoinositide species, including phosphatidylinositol (PI), phosphatidylinositol monophosphate (PIP), and bisphosphate (PIP2), in the cerebellum of the Npc1-null mice in both whole-tissue lysates and myelin-enriched fractions. Additionally, we observed altered levels of the regulatory enzyme phosphatidylinositol 4-kinase type 2 α (PI4K2A) in Npc1-null mice. In contrast, the levels of related kinases, phosphatases, and transfer proteins were unaltered in the Npc1-null mouse model as observed by Western blot analysis. Our discovery of phosphoinositide lipid biomarkers for NPC1 opens new perspectives on the pathophysiology underlying this fatal neurodegenerative disease.

This article provides an introduction to Fourier transform-based mass spectrometry (FTMS). The key performance characteristics of FTMS, mass accuracy and resolution, are presented in the view of how they impact the interpretation of measurements in proteomic applications. The theory and principles of operation of two types of mass analyzer, Fourier transform ion cyclotron resonance and Orbitrap, are described. Major benefits as well as limitations of FTMS technology are discussed in the context of practical sample analysis, and illustrated with examples included as figures in this text and in the accompanying slide set. Comparisons highlighting the performance differences between the two mass analyzers are made where deemed useful in assisting the user with choosing the most appropriate technology for his/her application. Recent developments of these high-performing mass spectrometers are mentioned to provide a future outlook.

This article has been withdrawn by the authors. We discovered an error after this manuscript was published as a Paper in Press. Specifically, we learned that the structures of glycans presented for the PD-L1 peptide were drawn and labeled incorrectly. We wish to withdraw this article and submit a corrected version for review.

In bottom-up mass spectrometry-based proteomics, relative protein quantification is often achieved with data-dependent acquisition (DDA), data-independent acquisition (DIA), or selected reaction monitoring (SRM). These workflows quantify proteins by summarizing the abundances of all the spectral features of the protein (e.g., precursor ions, transitions or fragments) in a single value per protein per run. When abundances of some features are inconsistent with the overall protein profile (for technological reasons such as interferences, or for biological reasons such as post-translational modifications), the protein-level summaries and the downstream conclusions are undermined. We propose a statistical approach that automatically detects spectral features with such inconsistent patterns. The detected features can be separately investigated, and if necessary removed from the dataset. We evaluated the proposed approach on a series of benchmark controlled mixtures and biological investigations with DDA, DIA and SRM data acquisitions. The results demonstrated that it can facilitate and complement manual curation of the data. Moreover, it can improve the estimation accuracy, sensitivity and specificity of detecting differentially abundant proteins, and reproducibility of conclusions across different data processing tools. The approach is implemented as an option in the open-source R-based software MSstats.

Protein cross-linking and the analysis of cross-linked peptides by mass spectrometry is currently receiving much attention. Not only is this approach applied to isolated complexes to provide information about spatial arrangements of proteins but it is also increasingly applied to entire cells and their organelles. As in quantitative proteomics, the application of isotopic labelling further makes it possible to monitor quantitative changes in the protein-protein interactions between different states of a system. Here, we cross-linked mitochondria from Saccharomyces cerevisiae grown on either glycerol- or glucose-containing medium to monitor protein-protein interactions under non-fermentative and fermentative conditions. We investigated qualitatively the protein-protein interactions of the 400 most abundant proteins applying stringent data-filtering criteria, i.e. a minimum of two cross-linked peptide spectrum matches and a cut-off in the spectrum scoring of the used search engine. The cross-linker BS3 proved to be equally suited for connecting proteins in all compartments of mitochondria when compared with its water-insoluble but membrane-permeable derivative DSS. We also applied quantitative cross-linking to mitochondria of both the growth conditions using stable-isotope labelled BS3. Significant differences of cross-linked proteins under glycerol and glucose conditions were detected, however, mainly due to the different copy numbers of these proteins in mitochondria under both the conditions. Results obtained from the glycerol condition indicate that the internal NADH:ubiquinone oxidoreductase Ndi1 is part of an electron transport chain supercomplex. We have also detected several hitherto uncharacterized proteins and identified their interaction partners. Among those, Min8 was found to be associated with cytochrome c oxidase. BN-PAGE analyses of min8 mitochondria suggest that Min8 promotes the incorporation of Cox12 into cytochrome c oxidase.

7 May 2020 , Volume 96, Number 3

Bile acids (BAs) serve multiple biological functions, ranging from the absorption of lipids and fat-soluble vitamins to serving as signaling molecules through the direct activation of dedicated cellular receptors. Synthesized by both host and microbial pathways, BAs are increasingly understood as participating in the regulation of numerous pathways relevant to metabolic diseases, including lipid and glucose metabolism, energy expenditure, and inflammation. Quantitative analyses of BAs in biological matrices can be problematic due to their unusual and diverse physicochemical properties, making optimization of a method that shows good accuracy, precision, efficiency of extraction, and minimized matrix effects across structurally distinct human and murine BAs challenging. Herein we develop and clinically validate a stable-isotope-dilution LC/MS/MS method for the quantitative analysis of numerous primary and secondary BAs in both human and mouse biological matrices. We also utilize this tool to investigate gut microbiota participation in the generation of structurally specific BAs in both humans and mice. We examine circulating levels of specific BAs and in a clinical case-control study of age- and gender-matched type 2 diabetes mellitus (T2DM) versus nondiabetics. BAs whose circulating levels are associated with T2DM include numerous 12α-hydroxyl BAs (taurocholic acid, taurodeoxycholic acid, glycodeoxycholic acid, deoxycholic acid, and 3-ketodeoxycholic acid), while taurohyodeoxycholic acid was negatively associated with diabetes. The LC/MS/MS-based platform described should serve as a robust, high-throughput investigative tool for studying the potential involvement of structurally specific BAs and the gut microbiome on both physiological and disease processes.

Invitation Only Research Event

Event participants

Anita Isaacs, Professor of Political Science, Haverford College; Co-Director, Migration Encounters Project
Juan Ricardo Ortega, Principal Advisor for Central America, Inter-American Development Bank
Chair: Amy Pope, Associate Fellow, Chatham House; US Deputy Homeland Security Adviser for the Obama Administration (2015-17)

The National Works Agency (NWA) has given the assurance that the recent outbreak of the COVID-19 pandemic will not affect the roll-out of the highly anticipated Southern Coastal Highway Improvement Project in St Thomas and Portland. In fact, the...

Chữa đau nhức chân với bồn ngâm massage chân là một phương pháp được đánh giá rất cao hiện nay. Tuy nhiên thông tin về phương pháp này không phải ai cũng...

23 February 2017

Although most renewable energy policy frameworks treat biomass as carbon-neutral at the point of combustion, biomass emits more carbon per unit of energy than most fossil fuels. 

IF MIXOLOGY is artistry in motion, then consider the instruments as the canvas, the ingredients as the paint, and Randeen Thomas as the Pablo Picasso of his time, giving spirits new life. Some might be familiar with ‘The Big Belly Bartender’,...

A few days ago as the lady and I drove out, headed to the hardware store to purchase one piece of lumber, she was wearing a face mask, and I had mine on the seat behind me. “So, what’s the point of you wearing the mask in the car and me without...

Michelle Thomas has joined the ranks of society’s young movers and shakers in her capacity as a lawyer. The work truly began after she was crowned Miss Kingston and St Andrew Festival Queen in 2015. Since then, she has been pushing for more female...

A sufficient β-cell mass is crucial for preventing diabetes, and perinatal β-cell proliferation is important in determining the adult β-cell mass. However, it is not yet known how perinatal β-cell proliferation is regulated. Here, we report that serotonin regulates β-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In β-cell–specific Tph1 knockout (Tph1 βKO) mice, perinatal β-cell proliferation was reduced along with the loss of serotonin production in β-cells. Adult Tph1 βKO mice exhibited glucose intolerance with decreased β-cell mass. Disruption of Htr2b in β-cells also resulted in decreased perinatal β-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in β-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the β-cell mass by regulating perinatal β-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.

Those hoping to watch Ronald Acuna Jr. extend last season's incredible post-All-Star break production should remember that his pace would have equated to 45 homers and 33 stolen bases over 162 games.

WASHINGTON (AP) — Federal health officials have revoked US authorisation for masks made by more than 60 Chinese manufacturers after they failed to meet standards needed to protect health care workers. The Food and Drug Administration had...

In an ideal world, policies would be evidence based - but governments are made of humans, who have positions and ideologies and moral bases. In this podcast Anthony Painter, from the RSA will be talking about why universal basic income may work, but who’s proponents cross ideological barriers, and writer and philosopher AC Grayling explains how...

Underneath all of our civilisation and science, we’re still primates - and the connection between patient and doctor can be reinforced by simply taking a hand. Robin Youngson, cofounder of hearts in healthcare, and Mitzi Blennerhassett, who has written extensively on patient engagement, have co-authored an editorial calling for the humanisation...

the Christmas BMJ season is upon us - if you’re to go to our website now, you’ll see that it’s been a bumper year. In the podcast, we’re going to be bringing you a select few - we’ll be looking at motherhood. Trying to figure out what 17th Century causes of death were, and - as it’s christmas - in this pod we’ll be looking at food. We talk to...

2018 will go down in history as a year of reckoning as the year that that some men’s behaviour came back to bite them. The continuing impact of #MeToo across the world has prompted another round of thinking about women’s experiences in medicine, which can be seen this year’s christmas journal In this podcast, Esther Choo and Eleni Lenos, join us...

For many of you Christmas is over and, you’re back to work. Admin piled up over christmas? Feeling resentful for all those forms, and the weird codes they make you put in them? In this podcast I hope we can explain why that’s important, with 17th century death, the esoteria of reed codes, and why the WHO cares about spaceship...

Welcome to the festive talk evidence, giving you a little EBM to take you into the new year. As always Duncan Jarvies is joined by Helen Macdonald (resting GP and editor at The BMJ) and Carl Heneghan (active GP, director of Oxford University’s CEBM and editor of BMJ Evidence) This month: (2.00) Helen look back at a Christmas article, which...

For the next few months Talk Evidence is going to focus on the new corona virus pandemic. There is an enormous amount of uncertainty about the disease, what the symptoms are, fatality rate, treatment options, things we shouldn't be doing. We're going to try to get away from the headlines and talk about what we need to know - to hopefully give...

G Xu
Dec 1, 1999; 48:2270-2276
Articles

Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of β-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and β-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive β-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing β-cell mass during obesity-related insulin resistance.

As the D-backs went through fielding drills Tuesday, Yasmany Tomas spent his time at first base rather than in the outfield.

We aimed to assess the value of ¹¹C-choline PET in patients with primary hyperparathyroidism and negative or discordant results on ^99mTc-sestamibi imaging and neck ultrasound. Methods: Eighty-seven such patients were assessed and subsequently underwent parathyroidectomy. PET/CT image data were analyzed semiquantitatively using SUV_max and SUV ratios (target to contralateral thyroid gland and carotid artery). A positive PET/CT result was defined as focal uptake significantly higher than regular thyroid tissue. Ectopic foci were also considered positive. Inconclusive PET/CT cases were defined as a lesion with uptake equal to normal thyroid tissue. If no prominent or ectopic uptake was detectable, the PET/CT result was considered negative. Results: When dichotomizing the ¹¹C-choline PET/CT imaging results by defining lesions with both positive and inconclusive uptake as positive, we found 84 of 92 lesions (91.3%) to have true-positive uptake whereas 8 lesions (8.7%) had false-positive uptake. One lesion showed false-negative uptake; the sensitivity was 98.8%. The corresponding positive predictive value for lesions was 91.3%. The mean SUV_max was 6.15 ± 4.92 in 72 lesions with positive uptake (70 patients) and 2.96 ± 2.32 in 20 lesions with inconclusive uptake (18 patients). Conclusion: These results in a large group of patients indicate that ¹¹C-choline PET/CT is a promising tool for parathyroid adenoma localization when ultrasound and ^99mTc-sestamibi imaging yield negative or discordant results.

An MPI Leadership Visions discussion with the Foreign Minister of Mexico, Claudia Ruiz-Massieu, for her first public appearance in Washington, DC. 

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

Robert A. Ritzel
Mar 1, 2006; 29:717-718
BR Pathophysiology/Complications

3M has signed a $126 million deal with the Pentagon to increase its production of N95 masks to 26 million per month beginning in October 2020.

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 American Dental Association has created a tip sheet with guidance from the National Institute for Occupational Safety and Health group at the Centers for Disease Control and Prevention to help health care professionals avoid buying or using counterfeit N95 respirators, which are often simply referred to as masks.

Test results suggest N95 masks can be safely disinfected through heating 50 times before their filtration efficiency begins to decline.

Engineers in China have developed a fossil fuel-free jet propulsion prototype design that uses microwave air plasmas.

An MPI Leadership Visions discussion with the Foreign Minister of Mexico, Claudia Ruiz-Massieu, for her first public appearance in Washington, DC. 

For Stephen we'd  use the nickname "Stevie" and for Thomas we'd use the nickname "Tommy" if that helps.

Social psychologist William B. Swann once had a group of married people evaluate their spouses even as their spouses evaluated them. People with high self-esteem, the psychologist found, felt closer to their partners when they received positive evaluations. People with low self-esteem, however, felt...

Take a step back from the Republican and Democratic presidential primary races and you will see a sharp difference between the two.

When President-elect Barack Obama, an early opponent of the Iraq war, asked Sen. Hillary Rodham Clinton -- who helped to authorize the war -- to be his secretary of state, many liberals scratched their heads.

This recipe was featured on Foodie Tuesday, a weekly segment with Raf Epstein on Drive, 774 ABC Melbourne, 3:30 PM, courtesy of Phillippa Grogan. Her new book is 'Phillippa's Home Baking.'

I love Christmas my all time favourite time of year. It's also a great time for awesome summer sweet produce. Muscovado brown sugar is a treacle like flavour and makes a welcome texture to a traditional pavlova.

I absolutely adore a rich moist fruit cake laced with brandy. We love this cake in our house and will stay fresh in a airtight tin for months.

This recipe featured on Foodie Tuesday, a weekly segment on 774 Drive with Raf Epstein, 3.30PM, shared by Jad Choucair of Mankoushe.