Pixie, you came to us beaten, starved, scared and lonely. No one wanted to take on a rescue Staffordshire Bull Terrier, but we did as company for our

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Easy 2 ingredients spinach dip

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Secarma may be next for Inflexion buyout

Cloud hosting biz UKFast's founders, Laurence and Gail Jones, have "exited the business" as a private equity firm ups its stake – all as UKFast itself starts eyeing up Jones-owned infosec biz Secarma.…

High-frequency audio could be used to stealthily track netizens

Technical folks looking to improve web privacy haven't been able to decide whether sound beyond the range of human hearing poses enough of a privacy risk to merit restriction.…

Schneider Electric patches vulns after Trustwave raises alarm

Two Schneider Electric SCADA products had vulnerabilities similar to the ones exploited in the Iran-bothering Stuxnet worm, an infosec outfit has claimed.…

Every cricket follower fervently needs to watch real-time cricket suit. Nothing can change the excitement, delights and excitement of real-time cricket suit. Live cricket suit is of much worry for a fan during any recurring series or competitions. Every cricket… Continue Reading →

Spiegel has a piece Inside the Desperate Battle against Sports Doping. Lots of athletes get away with it. Pretty unfair for the ones who do not cheat. I've made this argument many times: anti-doping efforts are a losing cause. Doping techniques will become harder to detect. They will also become more powerful. But there is hope of a sort on the horizon: In 10 years time we have orders of magnitude more understanding of how genetic variants cause differences in human performance. This is inevitable due to the plunging costs of DNA sequencing. As a result it will become possible to measure a person's genetic potential to perform in various sports. Test the genetic potential. Then report for each athlete...

The National Highway Traffic Safety Administration (NHTSA) finds Tesla's Autopilot cuts crashes by 40%. How cool is that? Autonomous vehicles are going to cause a huge decline in accidents and deaths. Even short of autonomous vehicles, when you get your next car try to get one that supports automatic braking on imminent collision detection. You could get a large fraction of the collision avoidance benefit at a much lower cost today. Check out Insurance Institute for Highway Safety ratings of collision avoidance systems in current cars. Watch a Tesla react to a crash in front of it: Watch a Tesla avoid hitting a reckless driver: A recent analysis finds that autonomous vehicles will allow 2 million disabled people to get...

Contes de fées aux enfants - Octo-Puce la pieuvre et Craby-la-Pince le crabe.

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De très petit à 76 x 102 centimètres, c'est à 30 x 40 pouces.
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Affiches.
Vous pouvez commander des affiches de cette image en ligne.
De très petit à 76 x 102 centimètres, c'est à 30 x 40 pouces.
Prix d'USS 1.95 vers les USA $79.95.

A man walks in a bar with his pet monkey. He sits down and orders a drink, meanwhile the monkey is running around all over the place and jumps up on a pool table. He grabs the 8 ball, shoves it into his mouth and swallows it hole. “Holy crap!” says the bartender, completely livid. […]

The post The Not So Stupid Monkey appeared first on Funny & Jokes.

A pirate is starting his first day aboard his new ship and the captain is giving him the tour. ”There’s the plank for trouble makers, there’s the deck that needs swabbing everyday and there’s the barrel for all you sexual needs.” ”Whatcha mean? my sexual needs?” ”Well, you stick your willy in the hole and […]

The post Those Dirty Pirates appeared first on Funny & Jokes.

The post Fishing Footwear Basics: Keeping Your Feet Neat and Safe appeared first on Ocean Blue Fishing Adventures.

Whether mutations in cancer driver genes directly affect cancer immune phenotype and T cell immunity remains a standing question. ARID1A is a core member of the polymorphic BRG/BRM-associated factor chromatin remodeling complex. ARID1A mutations occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A aberrations on cancer immunity. We demonstrated that ARID1A aberrations resulted in limited chromatin accessibility to IFN-responsive genes, impaired IFN gene expression, anemic T cell tumor infiltration, poor tumor immunity, and shortened host survival in many human cancer histologies and in murine cancer models. Impaired IFN signaling was associated with poor immunotherapy response. Mechanistically, ARID1A interacted with EZH2 via its carboxyl terminal and antagonized EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.

Alterations in calcium signaling in pancreatic acinar cells can result in pancreatitis. Although pressure changes in the pancreas can elevate cytosolic calcium (Ca2+) levels, it is not known how transient pressure-activated elevations in calcium can cause prolonged calcium changes and consequent pancreatitis. In this issue of the JCI, Swain et al. describe roles for the mechanically activated plasma membrane calcium channels Piezo1 and transient receptor potential vanilloid subfamily 4 (TRPV4) in acinar cells. The authors used genetic deletion models and cell culture systems to investigate calcium signaling. Notably, activation of the Piezo1-dependent TRPV4 pathway was independent of the cholecystokinin (CCK) stimulation pathway. These results elegantly resolve an apparent discrepancy in calcium signaling and the pathogenesis of pancreatitis in pancreatic acinar cells.

Elevated pressure in the pancreatic gland is the central cause of pancreatitis following abdominal trauma, surgery, endoscopic retrograde cholangiopancreatography, and gallstones. In the pancreas, excessive intracellular calcium causes mitochondrial dysfunction, premature zymogen activation, and necrosis, ultimately leading to pancreatitis. Although stimulation of the mechanically activated, calcium-permeable ion channel Piezo1 in the pancreatic acinar cell is the initial step in pressure-induced pancreatitis, activation of Piezo1 produces only transient elevation in intracellular calcium that is insufficient to cause pancreatitis. Therefore, how pressure produces a prolonged calcium elevation necessary to induce pancreatitis is unknown. We demonstrate that Piezo1 activation in pancreatic acinar cells caused a prolonged elevation in intracellular calcium levels, mitochondrial depolarization, intracellular trypsin activation, and cell death. Notably, these effects were dependent on the degree and duration of force applied to the cell. Low or transient force was insufficient to activate these pathological changes, whereas higher and prolonged application of force triggered sustained elevation in intracellular calcium, leading to enzyme activation and cell death. All of these pathological events were rescued in acinar cells treated with a Piezo1 antagonist and in acinar cells from mice with genetic deletion of Piezo1. We discovered that Piezo1 stimulation triggered transient receptor potential vanilloid subfamily 4 (TRPV4) channel opening, which was responsible for the sustained elevation in intracellular calcium that caused intracellular organelle dysfunction. Moreover, TRPV4 gene–KO mice were protected from Piezo1 agonist– and pressure-induced pancreatitis. These studies unveil a calcium signaling pathway in which a Piezo1-induced TRPV4 channel opening causes pancreatitis.

Nerve growth factor (NGF) regulates many aspects of neuronal biology by retrogradely propagating signals along axons to the targets of those axons. How this occurs when axons contain a plethora of proteins that can silence those signals has long perplexed the neurotrophin field. In this issue of the JCI, Li et al. suggest an answer to this vexing problem, while exploring why the Elp1 gene that is mutated in familial dysautonomia (FD) causes peripheral neuropathy. They describe a distinctive function of Elp1 as a protein that is required to sustain NGF signaling by blocking the activity of its phosphatase that shuts off those signals. This finding helps explain the innervation deficits prominent in FD and reveals a unique role for Elp1 in the regulation of NGF-dependent TrkA activity.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Although gene-environment interactions have been implicated in the etiology of several disorders, the impact of paternal and/or maternal metabolic syndrome on the clinical phenotypes of offspring and the underlying genetic and epigenetic contributors of NAFLD have not been fully explored. To this end, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique nondietary model manifesting 3 hallmarks that confer high risk for the development of NAFLD: hyperglycemia, insulin resistance, and dyslipidemia. We report that parental metabolic syndrome epigenetically reprograms members of the TGF-β family, including neuronal regeneration–related protein (NREP) and growth differentiation factor 15 (GDF15). NREP and GDF15 modulate the expression of several genes involved in the regulation of hepatic lipid metabolism. In particular, NREP downregulation increases the protein abundance of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-citrate lyase (ACLY) in a TGF-β receptor/PI3K/protein kinase B–dependent manner, to regulate hepatic acetyl-CoA and cholesterol synthesis. Reduced hepatic expression of NREP in patients with NAFLD and substantial correlations between low serum NREP levels and the presence of steatosis and nonalcoholic steatohepatitis highlight the clinical translational relevance of our findings in the context of recent preclinical trials implicating ACLY in NAFLD progression.

Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an “autonomous,” self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β–dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.

Approximately half of the world’s population is infected with the stomach pathogen Helicobacter pylori. Infection with H. pylori is the main risk factor for distal gastric cancer. Bacterial virulence factors, such as the oncoprotein CagA, augment cancer risk. Yet despite high infection rates, only a fraction of H. pylori–infected individuals develop gastric cancer. This raises the question of defining the specific host and bacterial factors responsible for gastric tumorigenesis. To investigate the tumorigenic determinants, we analyzed gastric tissues from human subjects and animals infected with H. pylori bacteria harboring different CagA status. For laboratory studies, well-defined H. pylori strain B128 and its cancerogenic derivative strain 7.13, as well as various bacterial isogenic mutants were employed. We found that H. pylori compromises key tumor suppressor mechanisms: the host stress and apoptotic responses. Our studies showed that CagA induces phosphorylation of XIAP E3 ubiquitin ligase, which enhances ubiquitination and proteasomal degradation of the host proapoptotic factor Siva1. This process is mediated by the PI3K/Akt pathway. Inhibition of Siva1 by H. pylori increases survival of human cells with damaged DNA. It occurs in a strain-specific manner and is associated with the ability to induce gastric tumor.

Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer, and there is great interest in applying inhibitors of HIF as anticancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2α. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors affect physiological responses to hypoxia at relevant doses. Here, we show that pharmacological HIF-2α inhibition with PT2385, at doses similar to those reported to inhibit tumor growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatization and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2α PAS-B S305M mutation that disrupts PT2385 binding, but not dimerization with HIF-1β, did not respond to PT2385, indicating that these effects are on-target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2α S305M mutant mice suggests a function for the HIF-2α PAS-B domain beyond heterodimerization with HIF-1β. Although PT2385 was well tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive.

Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.

Apple has launched a new web page that brings together links and information about its online services for customers shopping from home during the global health crisis.


Titled "Everything you love about our stores is online," the new catch-all page links from the Apple.com home page and includes details about no-contact delivery options, Apple Specialist help, financing and credit options, Apple Trade In, Apple Card, order status checking, service and support.

The page also links out to "Today at Apple - At home," a series of fun how-to videos to help users get creative during the ongoing stay-at-home measures, and there's a series of category links for customers to explore products on Apple's online store.

Apple has been gradually re-opening its retail stores in countries where lockdowns have eased, although some are operating on limited hours.

Apple CEO Tim Cook last week said that Apple was going to reopen stores in Austria and Australia this week, and Apple's sole Apple Store in Vienna will be reopening on Tuesday, May 5.

We're still waiting to hear exactly when stores in North America will reopen, but Cook also said that Apple is planning to reopen a few stores in the U.S. starting in May. Store openings will be staggered, with Apple evaluating data that includes local guidelines and recommendations before reopening.
This article, "New Apple Web Page Directs Customers to Its Online Shopping Services" first appeared on MacRumors.com

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For this week's giveaway, we've once again teamed up with Throwboy to offer MacRumors readers a chance to win one of Throwboy's plushes modeled after classic Apple products and icons.


Throwboy makes a whole range of different plush pillow options priced at $30 to $40, with each one designed to look like an Apple product of some kind, including classic Macs, the iPod, the iPhone, and more. Each pillow features detailed embroidery and careful construction to highlight each component and to accurately represent Apple's designs.

The 1998 pillow, for example, is modeled after Apple's original iMac with its bright Bondi Blue design, while the 2001 pillow modeled after the original iPod comes complete with a screen and click wheel embroidery.


The 2007 pillow looks like the original ‌iPhone‌ with black bezels and a silver backing, and the Icon Pillow looks like Apple's classic happy Finder icon.


There's even a rainbow-colored Spinning Wheel Pillow that's designed to look like the dreaded spinning pinwheel that the cursor morphs into when an application is busy.


All of Throwboy's plushes are soft, squishy, huggable, and the perfect accent piece for an Apple fan. Each pillow is the ideal size to be used as a comfortable throw pillow for a couch or a chair. Photos of the pillows in action can be seen on Throwboy's Instagram account.


We have 10 of Throwboy's pillows to give away to MacRumors readers, and each winner will be able to pick their favorite pillow: ‌iMac‌, iPod, classic ‌iPhone‌, Finder Icon, or Spinning Wheel.

To enter to win our ‌giveaway‌, use the Gleam.io widget below and enter an email address. Email addresses will be used solely for contact purposes to reach the winners and send the prizes. You can earn additional entries by subscribing to our weekly newsletter, subscribing to our YouTube channel, following us on Twitter, following us on Instagram, or visiting the MacRumors Facebook page.

Due to the complexities of international laws regarding giveaways, only U.S. residents who are 18 years or older and Canadian residents (excluding Quebec) who have reached the age of majority in their province or territory are eligible to enter. To offer feedback or get more information on the ‌giveaway‌ restrictions, please refer to our Site Feedback section, as that is where discussion of the rules will be redirected.

….for the three of you who still read blogs! Album of the Year: Janelle Monae, Dirty Computer. Really no question about this one. I enjoyed her previous albums, but this one is really a whole additional quantum level of amazing. Honorable Mentions: K.I.D, Tired All the Time — the early contender before Janelle’s album came … Continue reading Music Picks for 2018

Tough choices this year! Charly Bliss got surprisingly (and impressively) sophisticated on their sophomore effort, K.Flay took one step further away from indie-rap towards indie-rock, and her girlfriend Miya Folick put forth a deeply rich and powerful album. Album of the Year: Maddie Ross, Never Have I Ever. I was already digging this a lot … Continue reading Music Picks for 2019