11 February 2020

Delphine Fontaine
Apr 7, 2020; 0:jlr.RA120000634v1-jlr.RA120000634
Research Articles

Inês Magro dos Reis
Apr 14, 2020; 0:jlr.RA120000632v1-jlr.RA120000632
Research Articles

This week host Matt Egan is joined by first time podder and editor of PC Advisor Jim Martin to chat Microsoft Windows 10 anniversary updates and the impact on Microsoft Surface devices. Producer Chris then comes on to chat about Sky's two big NOW TV announcements, and the future of television and broadband (16:00). Finally, UKTW podcast regular David Price chats about the impact technology is having on our holidays (26:30).  

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After indefinite hiatus the gang is back as David Price asks Henry Burrell all about Google I/O. Is it actually going to be called Android Oreo, and should you download the beta? Second up is Tamlin Magee to get to the bottom of WannaCry and the ransomware troubles of the NHS. What is it, should you be worried and will it happen again? May contain terrible jokes.  

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This week we dive into the new Surface Pro with Digital Arts' Neil Bennett. Who is it for and is it that different to the last one? And are 2 in 1 devices really the future of computing? Then Techworld's Scott Carey, fresh back from Cannes, discusses why the French film industry booed at a Netflix film - why was it there in the first place? Is the film industry being that affected by tech giants like Amazon? Tech Advisor's Dom Preston chimes in to let us know. Finally, we all quickly nerded out about Alien: Covenant. Mild spoiler alert!  

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This week it is all about Apple as the company announces its eagerly awaited iPhone X and iPhone 8/8 Plus smartphones, a new Apple watch (yawn) and Apple TV news. Macworld UK editor Karen Haslam is our host this week, as she chats to a distinctly unconvinced Dominic Preston about the latest iPhone, followed by David Price on the Apple Watch Series 3, which he likes but not as much as its predecessor. Then everyone piles in together to discuss the quite-good iPhone 8, the quite-late Apple TV 4K, and all the rest of the evening's festivities.  

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This week on the UK Tech Weekly Podcast our host Scott Carey talks to Macworld editor David Price about the ever-controversial Alex Jones and why the big tech companies are finally stepping up their efforts to ban him from their platforms. Editors note: we recorded this on Thursday before Twitter finally started to take some measures against Jones, without outright banning him.

Next our resident phone nerd and consumer tech editor at Tech Advisor Henry Burrell talks about the upcoming Samsung Galaxy Note 9, the latest iPhone X rumours and how Apple and Google are trying to make you use your phone less.

Lastly Techworld editor Charlotte Jee takes us on a trip down memory lane to talk about the utopian vision of the Millennium Experience, how it reflected the values of a New Labour government and its legacy.

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Ether lipids (ELs) are lipids characterized by the presence of either an ether linkage (alkyl lipids) or a vinyl ether linkage (i.e. plasmalogens [Pls]) at the sn1 position of the glycerol backbone and they are enriched in PUFAs at the sn2 position. In this review, we highlight that ELs have various biological functions, act as a reservoir for second messengers (such as PUFAs), and have roles in many diseases. Some of the biological effects of ELs may be associated with their ability to regulate ion channels that control excitation-contraction/secretion/mobility coupling and therefore cell physiology. These channels are embedded in lipid membranes, and lipids can regulate their activities directly or indirectly as second messengers or by incorporating into membranes. Interestingly, ELs and EL-derived PUFAs have been reported to play a key role in several pathologies, including neurological disorders, cardiovascular diseases, and cancers. Investigations leading to a better understanding of their mechanisms of action in pathologies have opened a new field in cancer research. In summary, newly identified lipid regulators of ion channels, such as ELs and PUFAs, may represent valuable targets to improve disease diagnosis and advance the development of new therapeutic strategies for managing a range of diseases and conditions.

Niemann–Pick type C1 (NPC1) disease is a rare genetic condition in which the function of the lysosomal cholesterol transporter NPC1 protein is impaired. Consequently, sphingolipids and cholesterol accumulate in lysosomes of all tissues, triggering a cascade of pathological events that culminate in severe systemic and neurological symptoms. Lysosomal cholesterol accumulation is also a key-factor in the development of atherosclerosis and non-alcoholic steatohepatitis (NASH). In these two metabolic diseases, the administration of plant stanol esters has been shown to ameliorate cellular cholesterol accumulation and inflammation. Given the overlap of pathological mechanisms among atherosclerosis, NASH and NPC1 disease, we sought to investigate whether dietary supplementation with plant stanol esters improves the peripheral features of NPC1 disease. To this end, we used an NPC1 murine model featuring an Npc1 null allele (Npc1^nih), creating a dysfunctional NPC1 protein. Npc1^nih mice were fed a two or six percent plant stanol esters–enriched diet over the course of 5 weeks. During this period, hepatic and blood lipid and inflammatory profiles were assessed. Npc1^nih mice fed the plant stanol–enriched diet exhibited lower hepatic cholesterol accumulation, damage and inflammation than regular chow–fed Npc1^nih mice. Moreover, plant stanol consumption shifted circulating T-cells and monocytes in particular towards an anti-inflammatory profile. Overall, these effects were stronger following dietary supplementation with 6% stanols, suggesting a dose-dependent effect. The findings of our study highlight the potential use of plant stanols as an affordable complementary means to ameliorate disorders in hepatic and blood lipid metabolism and reduce inflammation in NPC1 disease.

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.

1 February 2008 , Number 5

Niemann-Pick disease type C (NPC) disease is a lipid-storage disorder that is caused by mutations in the genes encoding NPC proteins and results in lysosomal cholesterol accumulation. 2-Hydroxypropyl-β-cyclodextrin (CD) has been shown to reduce lysosomal cholesterol levels and enhance sterol homeostatic responses, but CD’s mechanism of action remains unknown. Recent work provides evidence that CD stimulates lysosomal exocytosis, raising the possibility that lysosomal cholesterol is released in exosomes. However, therapeutic concentrations of CD do not alter total cellular cholesterol, and cholesterol homeostatic responses at the ER are most consistent with increased ER membrane cholesterol. To address these disparate findings, here we used stable isotope labeling to track the movement of lipoprotein cholesterol cargo in response to CD in NPC1-deficient U2OS cells. Although released cholesterol was detectable, it was not associated with extracellular vesicles. Rather, we demonstrate that lysosomal cholesterol trafficks to the plasma membrane (PM), where it exchanges with lipoprotein-bound cholesterol in a CD-dependent manner. We found that in the absence of suitable extracellular cholesterol acceptors, cholesterol exchange is abrogated, cholesterol accumulates in the PM, and reesterification at the ER is increased. These results support a model in which CD promotes intracellular redistribution of lysosomal cholesterol, but not cholesterol exocytosis or efflux, during the restoration of cholesterol homeostatic responses.

When you run the Copy Files task in SAS Enterprise Guide and there is no connection to a SAS server, it fails with the following error: "ERROR: Target folder does not exist or cannot be accessed."

You might see the following error in SAS Workflow Studio when you try to open the CECL_Cycle_AFS workflow template that is shipped with SAS Solution for CECL:

T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (K_ATP channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central K_ATP channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of K_ATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central K_ATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.

S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions.

Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension.

31 May 2019

11 February 2020

This special issue focuses on Diabetes, Covid-19 and managing patient’s diabetes when they are sick.

Recorded April 1, 2020.

This podcast will cover:

1. How do we help our patients with diabetes stay safe
2. Helping patient negotiate safety issues in the workplace
3. Safety Issues when people do not come in for care
4. Managing SGLT-2 inhibitors during the pandemic
5. Home detection and care of DKA
6. Renewing Medications
7. Telemedicine Visits

Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting.

Presented by:

Louis Philipson, MD, PhD, ADA Past President, Medicine & Science, University of Chicago

Anne Peters, MD, Diabetologist, University of Southern California

Additional changes have been made to the operations of the island's courts in light of COVID-19. Changes below: Criminal Cases All hearings in the Home Circuit Court Division of the Gun Court, the High Court Division of the Gun Court, the...

When you are born, You know that you are, Here to change the world, And it is good, And it’s alright, To do your best. Then, You’re checking the curtains, Just in case, You run out of sunshine. -evocative short poetry-

When you are born, You know that you are, Here to change the world, And it is good, And it’s alright, To do your best. Then, You’re checking the curtains, Just in case, You run out of sunshine. -evocative short poetry-

Despite its best efforts, COVID-19 will not be allowed to steal the joy of Mother’s Day this year. An array of the island’s top singers and musicians have pledged to infuse the accustomed specialness into the day dedicated to mothers with a concert...

From formalising her father’s business and taking it to higher and more profitable heights to sitting on the board of EXIM Bank and lecturing in the field of business development, Lacey-Ann Bartley has earned her stripes as the Distinguished Woman...

Empathetic, God-fearing, humanitarian, motivated, and optimistic – these are just a few words that come to mind when one thinks of Dr Kazi-Ann Kasimbie. Dr Kasimbie is the CEO and founder of Psychfactor Consulting Services, a psychological...

Brian McCann still laughs about what transpired as he learned the Braves were calling him up to the Majors during the 2005 season. He remembers being summoned to Brian Snitker's room, where he found the then Double-A manager eating pizza while wearing nothing more than his underwear.

WASHINGTON (AP) — President Donald Trump, who’s taken to calling the US the “king” of ventilators, is making plans to ship 8,000 of the breathing machines to foreign countries by the end of July to help in their fight...

KINGSTON COLLEGE (KC) principal Dave Myrie has refuted claims that St Jago High School sprint hurdler Vashaun Vascianna will be joining the school this September. The Gleaner understands that Vascianna, who broke the Class Two boys’ 110m hurdles...

State regulation is necessary for safety, says Simon Capewell, professor of public health and policy at the University of Liverpool. Richard Lilford, professor of public health at the University of Warwick, argues that restricting adults’ choice can undermine such aims. Read the debate: http://www.bmj.com/content/355/bmj.i6341

Earlier this year, the WannaCry ransomeware attack took control of computers in 40 NHS trusts, blocking access to the data held on them. This wasn’t the first time that NHS computers had been infected by malware, but it brought the danger of cyber attack into the consciousness of doctors and patients. In this podcast we hear from two people who...

Series two of The Recommended Dose kicks off with polymath and poet, Dr John Ioannidis. Recognised by The Atlantic as one the most influential scientists alive today, he’s a global authority on genetics, medical research and the nature of scientific inquiry itself – among many other things. A professor at Stanford University, John has authored...

Hi impact, low probability events are a planners nightmare. You know that you need to think about them, but how can you prioritise which event - terrorist attack, natural disaster, disease outbreak, deserves attention - and how can you sell the risks of that, but not oversell them? Risky business is a conference where some of these kind of things...

Cannabinoid hyperemesis syndrome is a relatively newly recognised condition - but, according to one study, can account for up to 6% of patients presenting to emergency departments. The causal mechanism is as yet unclear - but currently the only known way to prevent the syndrome is for the patient to stop their cannabis use. Yaniv Chocron, chief...

Brexit. Who knows what’s going to happen in the next few weeks, months, years - the uncertainty is high. In the face of that, you’d hope that the government was doing all it could to plan for any eventuality - let alone for a massive, country altering one like suddenly crashing out without a deal - but Martin McKee, professor of public health at...

This week we saw the release of the much awaited Yellowhammer documents from the government, documents which outline some of the risks involved with Britain’s sudden departure from the EU. The documents themselves outline that there are risks to the supply of medicines - but do not set out the detail of how those risks have been mitigated, and...

Our latest series kicks off with Australia’s multi-award-winning health and science reporter, Liam Mannix. He joins Ray to share his insights into the role and impact of evidence, advocacy and investigative reporting in today’s ever-changing media landscape.

HE Hohmeier
Mar 1, 2000; 49:424-430
Articles

Days after The Gleaner reported a clarion call from Port Maria Mayor Richard Creary for the quarantine of St Mary communities owing to growing concerns about the spread of COVID-19 in the parish, the Government responded with the lockdown of three...

Schwann cell–derived exosomes communicate with dorsal root ganglia (DRG) neurons. The current study investigated the therapeutic effect of exosomes derived from healthy Schwann cells (SC-Exos) on diabetic peripheral neuropathy (DPN). We found that intravenous administration of SC-Exos to type 2 diabetic db/db mice with peripheral neuropathy remarkably ameliorated DPN by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. These functional improvements were associated with the augmentation of epidermal nerve fibers and remyelination of sciatic nerves. Quantitative RT-PCR and Western blot analysis of sciatic nerve tissues showed that SC-Exo treatment reversed diabetes-reduced mature form of miRNA (miR)-21, -27a, and -146a and diabetes-increased semaphorin 6A (SEMA6A); Ras homolog gene family, member A (RhoA); phosphatase and tensin homolog (PTEN); and nuclear factor-B (NF-B). In vitro data showed that SC-Exos promoted neurite outgrowth of diabetic DRG neurons and migration of Schwann cells challenged by high glucose. Collectively, these novel data provide evidence that SC-Exos have a therapeutic effect on DPN in mice and suggest that SC-Exo modulation of miRs contributes to this therapy.

Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)–producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.