“The Fiddle And The Drum” And so once again My dear Johnny my dear friend And so once again you are fightin’ us all And when I ask you why You raise your sticks and cry, and I fall Oh, my friend How did you come To trade the fiddle for the drum You say […]

'Seriously sometimes seems Google's moderators are only optimized to respond to social media outrage'

Three weeks after Google removed 49 Chrome extensions from its browser's software store for stealing crypto-wallet credentials, 11 more password-swiping add-ons have been spotted – and some are still available to download.…

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.…

Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients including those with hereditary and idiopathic CP undergoing total pancreatectomy with islet autotransplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP samples showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor β (TCRβ) repertoire in the CP and control groups. TCRβ sequencing revealed a significant increase in TCRβ repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in Vβ-Jβ gene family usage between hereditary and idiopathic CP and a positive correlation of TCRβ rearrangements with disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreases indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanisms of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis, providing insights into immune responses associated with human CP.

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T cells that persists despite HIV-specific cytotoxic T cell (CTL) responses. Although viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified overexpression of the prosurvival factor B cell lymphoma 2 (BCL-2) as a distinguishing feature of CD4+ T cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2hi subsets in ex vivo CD4+ T cells. Treatment with the BCL-2 antagonist ABT-199 was not sufficient to drive reductions in ex vivo viral reservoirs when tested either alone or with a latency-reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression of the DUX4 gene; however, the DUX4 protein is rare and difficult to detect in human muscle biopsies, and pathological mechanisms are obscure. FSHD is also a chronic disease that progresses slowly over decades. We used the sporadic, low-level, muscle-specific expression of DUX4 enabled by the iDUX4pA-HSA mouse to develop a chronic long-term muscle disease model. After 6 months of extremely low sporadic DUX4 expression, dystrophic muscle presented hallmarks of FSHD histopathology, including muscle degeneration, capillary loss, fibrosis, and atrophy. We investigated the transcriptional profile of whole muscle as well as endothelial cells and fibroadiopogenic progenitors (FAPs). Strikingly, differential gene expression profiles of both whole muscle and, to a lesser extent, FAPs, showed significant overlap with transcriptional profiles of MRI-guided human FSHD muscle biopsies. These results demonstrate a pathophysiological similarity between disease in muscles of iDUX4pA-HSA mice and humans with FSHD, solidifying the value of chronic rare DUX4 expression in mice for modeling pathological mechanisms in FSHD and highlighting the importance FAPs in this disease.

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.

BACKGROUND Mirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODS We treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTS Chronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSION These findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATION Clinicaltrials.gov NCT03049462.FUNDING This work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).

Brown and beige adipose tissues contain thermogenic fat cells that can be activated by β3-adrenergic receptor agonists. In rodents, such drugs both diminish obesity and improve glucose homeostasis. In this issue of the JCI, O’Mara et al. and Finlin and Memetimin et al. report that chronic administration of the approved β3 agonist mirabegron to human subjects was without effect on body weight or fat mass, but improved several measures of glucose homeostasis. Though the mechanisms mediating these metabolic effects are uncertain, the data suggest that β3 agonists could have therapeutic utility in disorders of glucose homeostasis.

BACKGROUND Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.METHODS Before and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.RESULTS The clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).CONCLUSION Mirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.TRIAL REGISTRATION Clinicaltrials.gov NCT02919176.FUNDING NIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.

You read that right. Joanne and I visited a Masonic Cemetary. Alone. It was one of the most calming experiences of my life. We were kind of invited, by the town, and when we arrived, we were definitely welcomed by the residents. This all started when, in the brochure listing the “town attractions” that we received in St. Helens, were two cemeteries. The addresses as well as short descriptions were listed, as well as a short missive asking us to please be respectful and not make loud noises. It sounded really creepy and really interesting, so both of us jumped at the chance to drive out there right before sunset. They weren’t what I expected at all… Well, the first one was actually roped off with a “no trespassing” sign hanging from it, so we didn’t go inside. It was right alongside the highway in Oregon, across some old train tracks, visible from the road, and named and marked on a tourist map, yet they didn’t want visitors. I wonder what happened there. In any case, we headed for the other cemetery. This one was removed from the main road, and rumored to be a lot larger. It was also known to be haunted, but visitors were welcome as long as they were respectful. Off the map it was, but when we arrived, it was also gated off. A sad Joanne looks through the gate at the second destination that was cut off from us. Ah, but unlike the other cemetery, this one didn’t have a “no tresspassing” sign. There was a clear path around the sides of the gate, the ground bare of grass and obviously well-traversed. Apparently a lot of people walked around the gate. Maybe they just didn’t want us to drive. We decided to walk. There was even a sign. And a long, winding, steep road through the forest.  It was quite a hike to reach the top of the large hill where the cemetery was supposedly located, but the view was breathtaking. It took us a good ten or fifteen minutes to reach the top, and the road was quite steep. For some reason, to the immediate right of the trail, someone had been excavating land for quite some time, and there was a deep quarry. Why someone would dig a quarry next to a burial ground is beside me. I don’t doubt that the residents were unhappy about it. I wondered if maybe I would feel some spirits, but I didn’t expect what really happened to me. As soon as I stepped off of the road and onto the grass, a calm unlike anything I’ve ever felt descended upon me. It enveloped me in a warm cocoon, and Joanne and I immediately separated and wandered quietly alone between the gravestones. I know, 100%, that not only was I welcomed, but that the residents were happy to have me there. I talked a bit with some of the gravestones, but mostly wandered about, amazed at how much serenity I felt. We must have spent around a half hour wandering quietly alone, together, before we left in order to return to the festivities in town. But I’ll never forget the experience. It was something really, really special. I took some video footage too, but I’m not sure yet whether I want to use it. We’ll see! Someday, I’ll set up a tripod and get a shot of me walking like this. But for now, have Joanne instead. ???? <3

On Wednesday, May 1, 2019, Flayrah contributor 2cross2affliction wrote in the article 'Sonic the Hedgehog' ... the movie ... the trailer:

Fun fact: no movie directly adapted from a video game has ever scored as "fresh" on the review aggregate site Rotten Tomatoes. [...] But, a new challenger approaches! [...] The question of whether this movie is going to be any good, perhaps unfairly, has mostly already been answered by the Internet. The answer so far has been no. No. Just no. Okay, maybe Jim Carrey? But otherwise, why? Why the human teeth? Why ten times?

Whoops. Turns out Sonic the Hedgehog somehow, against the odds, is rated Fresh by Rotten Tomatoes, with a score of 64% positive reviews from 175 professional opinions, as of this writing.

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After the bumper here, the review will get into spoiler territory. I will say that if you are a Sonic fan this movie will give you a sense of pride as it is far better than it should have had any right in being. Taking the franchise’s lore and resetting it to tell its own story, but retaining the strong characterization and quip heavy personalities of Sonic and Robotnik that makes their rivalry such a strong one. It also keeps the first entry simple with the hedgehog and doctor being the only two characters from the universe being in the film. This makes the story stronger since it can develop those two far more and not have to worry about any other kind of side character fan service for now.

Hey, at least now Sonic fans can brag to Mario ones that Mario may still be the king of games, but Sonic blew the plumber’s cinematic pieces out of the water. Not that that was a high bar I suppose. Then again, having better quality games than Sonic these days isn’t one either (the author quips while using a quote from Sonic Forces for his review’s headline).

In the video game Sonic the Hedgehog, timing is everything. While at the heart of the game is a fast paced platformer, its foundation has always been learning the layout of a level and timing your actions appropriately. In a twist, the timing of this film and its release had quite a bit of impact on my view of it.

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NCIS and NCIS: New Orleans will air the first new episodes of 2017 tonight. You can find sneak peeks, tweets and photos...

Criminal Minds has the first new episode of 2017 on the schedule tonight. Here’s a sneak peek from “Profiling 202”, featuring David...

NCIS: Los Angeles will air the first new episode of 2017 tonight. “Kulinda” is scheduled to start at 8:00pm ET/PT. (If anything...

Criminal Minds has a new episode on the schedule tonight. Here’s the first sneak peek from “Seek and Destroy”, featuring Emily Prentiss...

IBM today announced the opening of IBM Studio Groningen, where IBM design, digital and industry experts will work with clients to help them engage with their customers using big data, mobile, cloud and social innovations.

Melbourne, Australia - 18 August 2014: IBM (NYSE: IBM) and the City of Melbourne today launched a new interactive online experience for this year’s Melbourne Spring Fashion Week (MSFW) to enhance the iconic event and help shoppers hunt down the best retail bargains. The launch of the experience signifies the beginning of a three-year partnership between the City of Melbourne and IBM as the Official Innovation and Technology Partner for MSFW.

In the latest episode of their thoroughly vetted podcast, Ken and Robin talk converting standard GUMSHOE scenarios to QuickShock, a Ukraine mole, QuestWorlds with Ian Cooper, and moving Lovecraft to Chicago.

U.S. Financial System “Monitor” Failed to Flash Warning as Fed Pumped $6 Trillion Emergency Liquidity into Wall Street

By Pam Martens and Russ Martens: May 8, 2020 ~  The Office of Financial Research (OFR) was created under the Dodd-Frank financial reform legislation of 2010 to keep the Financial Stability Oversight Council (F-SOC) informed on emerging threats that have the potential to implode the financial system — as occurred in 2008 in the worst financial crash since the Great Depression. The Trump administration has gutted both its funding and staff. One of the early warning systems of an impending financial crisis that OFR was supposed to have created is the heat map above. Green means low risk; yellow tones mean moderate risk; while red tones flash a warning of a serious problem. On September 17, 2019, liquidity was so strained on Wall Street that the Federal Reserve had to step in and began providing hundreds of billions of dollars per week in repo loans. By January 27, 2020 (before … Continue reading →

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Zájem o nákup rekreačních nemovitostí je letos výrazně vyšší než v posledních letech. Objektů, které se dostávají do prodeje, je naopak tento rok méně. Viníkem je v obou případech epidemie koronaviru a s ní spojená nejistota kolem letních dovolených. To se podepisuje na cenách, často se dostanou výš, než byly inzerované.

1. Pionier van de rockmuziek Little Richard (87) overleden  De Morgen
2. Rock-n'-rollpionier Little 'Tutti Frutti' Richard (87) overleden  Het Laatste Nieuws
3. Rock 'n' roll-pionier Little Richard is overleden, herontdek zijn grootste hits  VRT NWS
4. Grondlegger rock-'n-roll Little Richard (87) overleden | Show  AD.nl
5. Muzieklegendes over Little Richard: “Als ik zijn muziek beluisterde, kon ik God horen”  Het Laatste Nieuws
6. Hele verhaal bekijken via Google Nieuws

1. Samsonite Oudenaarde stevent af op collectief ontslag  De Standaard
2. Samsonite plant ontslagronde in Oudenaarde  De Tijd
3. Corona kost banen bij reiskofferfabrikant Samsonite: “Het gi... (Oudenaarde)  Het Nieuwsblad
4. Mogelijke ontslagen bij Samsonite Oudenaarde door coronacrisis: “Niemand wil een reiskoffer kopen”  VRT NWS
5. Samsonite Oudenaarde kondigt ontslagen aan (Oudenaarde)  Het Nieuwsblad
6. Hele verhaal bekijken via Google Nieuws

This article with drawings is in these links https://www.academia.edu/40876793/Synchronizing_moving_GPS_clocks Word, PDF https://pengkuanonphysics.blogspot.com/2019/11/synchronizing-moving-gps-clocks.html PDF 1. Light pulse synchronization Can we synchronize clocks of a moving frame? Let us see Figure 1 where we have stationary frame F1 and moving frame F’2. The 2 clocks in the frame F1 are synchronized with the master clock through a...

Dunfermline,15th September. An event encouraging more people to consider working in social care and support.

The moon isn't "dead" after all: Newly discovered ridges on the moon's surface are leading scientists to think that the moon might have an active tectonic system.

The Eta Aquarid meteor shower peaks overnight tonight (May 4), with the best views arriving before dawn on Tuesday (May 5).

Nickelodeon used its Kids' Choice Awards show broadcast to premiere the first footage of its trademark green slime floating on board the International Space Station.

As part of Barcelona’s efforts to reclaim its car-congested streets for pedestrians, the city has tapped architects to create "superblocks” — groups of streets transformed into car-free public plazas. One such project was completed in 2019 by Leku Studio in the trendy neighborhood of Sant Antoni. Redesigned with attractive way-finding elements and street furniture, the Superblock of Sant Antoni is the second of six superblocks completed to date.[...]

https://t.co/BoAi0VA5gR

Robert Smith of The Cure's 'Schecter Signature UltraCure' Guitar, Played at Pasadena Daydream Festival on August 31st

Your bid supports: Free Arts For Abused Children, Mr. Holland's Opus Foundation, Little Kids Rock, Inner-City Arts, The Painted Turtle pic.twitter.com/skBiHZslmy

— The Cure (@thecure) August 29, 2019

Robert Smith is donating the guitar he will be playing this weekend at Pasadena Daydream Festival to be auctioned off to benefit @FreeArtsLA, @InnerCityArts, @littlekidsrock, @HollandsOpusFdn and @PaintedTurtleCA! ????

bid here????https://t.co/eZ9QdO3lgt

— goldenvoice (@goldenvoice) August 27, 2019

October 12th, 2019
Austin City Limits Festival in Austin, Texas
Cure are scheduled to play from 8 - 10 pm central.

Setlist: Plainsong, Pictures of You, A Night Like This, Just One Kiss, Lovesong, Last Dance, Burn, Fascination Street, Never Enough, Push, In Between Days, Just Like Heaven, From the Edge of the Deep Green Sea, Play For Today, A Forest, Shake Dog Shake, Disintegration

Encore: Lullaby, The Caterpillar, The Walk, Friday I'm in Love, Close to Me, Why Can't I Be You?, Boys Don't Cry.

Note: Eden Gallup is playing bass in place of Simon.

Tweets by CraigatCoF 

Andrea Goldsmith, a global leader in the development of wireless systems, has been awarded the Marconi Prize, the highest honor in telecommunications research. She is the first woman to win the prize, now in its 45th year.

Paula Kahumbu, CEO of WildlifeDirect who leads the campaign “Hands Off Our Elephants,” speaks on the “All for Earth” podcast about building a conservation movement in Kenya.

It was quite an early start as a I retraced my steps from the previous day to Serdika Bus Station. As I got there far too early I headed over to the other bus terminal for a bit of a mooch around. This one was much better and had shops places to get food

It is dark when I wake . It is Day 48 of the lockdown . The sun has not risen and the birds have not woken. It is Thursday . Sage are meeting today with our government . Sage used to be that herb that you stuffed up a chicken together with onion . Now it i

In den Vorständen deutscher Firmen sitzen kaum Frauen - und deshalb fehle "eine Instanz für Zweifel", sagt die neue Wirtschaftsweise Monika Schnitzer. Männer unter sich einigten sich leichter auf "eine genehme Sicht der Dinge".

On Thursday, European leaders will discuss how to navigate the block through the economic crisis triggered by the novel coronavirus. In a DER SPIEGEL interview, European Commissioner Paolo Gentiloni talks about what is at stake and the need to find at least 1 trillion euros.

We study a novel policy tool—interest rate uncertainty—that can be used to discourage inefficient capital inflows and to adjust the composition of external accounts between short-term securities and foreign direct investment (FDI). We identify the trade-offs faced in navigating between external balance and price stability. The interest rate uncertainty policy discourages short-term inflows mainly through portfolio risk and precautionary saving channels. A markup channel generates net FDI inflows under imperfect exchange rate pass-through. We further investigate new channels under different assumptions about the irreversibility of FDI, the currency of export invoicing, risk aversion of outside agents, and effective lower bound in the rest of the world. Under every scenario, uncertainty policy is inflationary.

Banks usually hold large amounts of domestic public debt which makes them vulnerable to their own sovereign’s default risk. At the same time, governments often resort to costly public bailouts when their domestic banking sector is in trouble. We investigate how the interbank network structure and the distribution of sovereign debt holdings jointly affect the optimal bailout policy in the presence of this "doom loop". Rescuing banks with high domestic sovereign exposure is optimal if these banks are sufficiently central in the network, even though that requires larger bailout expenditures than rescuing low-exposure banks. Our findings imply that highly central banks can use exposure to their own government as a strategic tool to increase the likelihood of being bailed out. Our model thus illustrates how the "doom loop" exacerbates the "too interconnected to fail" problem in banking.

By the time in 2015 when prosecutors indicted Chris Christie flunkies Bridget Kelly and Bill Baroni for shutting down Fort Lee’s George Washington Bridge lanes for four days in 2013 to punish the mayor for failing to endorse the big man in Trenton’s reelection, the two sick sycophants had long lost their stupid sinecures in the State House and Port Authority. And Christie had already rightly lost the trust of Jerseyans for building the hothouse in which the lichens could grow.