---------------------------------------------------[Sat Nov 26 15:25:44 2016]--
From: (S) ease of well-being  (steph)

Subject: Optimism or denial as mental self-defence

A few things recently have given me cause to consider my response to bad things
happening, and my reactions to other people's responses.  First, there's
Trump's election in the US which is undesirable and directly or indirectly
likely to cause some people harm (although I doubt it'll have any effect on me
personally).  I agree that he's not the best or even a good candidate and I
agree that he has incited prejudiced people to show and act on their
prejudices: people are being hurt.  However, I do not like the stream of
articles saying he's a white supremacist or a Nazi or California should secede
or the Electoral College should choose Clinton, or whatever.  Part of this is
doubtless my contrary streak, but part of it is something different.  I observe
that I am semi-consciously adopting a position that `things will turn out all
right' or `it won't be that bad' because countenancing the opposite is not good
for my mental health.

The other thing is some changes in the wider organisation for which I work;
basically there has been a botched reorganisation which has left most people
unhappy and from what I hear from numerous sources with good reason.  This
doesn't currently affect me much and I don't expect it to because of political
realities.  However, even just having the argument with someone closer to the
failing department (and more likely to feel its direct effects) seems to be
followed by my feeling anxious and depressed.  Again, adopting a constructive
positive attitude (which may appear to others pollyannaish, naive, optimistic,
or just in denial) seems to be a defence I've learned here and I suspect it
helps.  But there's more obviously a risk when I'm more involved than I am in
the US case, namely that my optimism will blind me to dangers that will be to
my detriment.

Does my ornery nature come to the rescue, though?  Perhaps because I'm at heart
a bit of a grumpy sod and only respect authorities when I think they deserve it
my tendency to want to probe and prod and query and dig my heels in may
counteract the defensive optimism.  Or alternatively, I'm optimistic in a
different sense: perhaps I just have confidence that I'll win?

LJDW

Hearing loss caused by the death of sensory hair cells of the inner ear is an unfortunate side effect for many patients treated with aminoglycoside antibiotics or platinum-containing chemotherapy agents. In animal models, induction of heat shock confers substantial otoprotection against aminoglycoside- and cisplatin-induced hair cell death. In this issue of the JCI, Breglio et al. demonstrate that inner ear tissue released exosomes carrying heat shock protein 70 (HSP70) in response to heat stress. HSP70 acted by a paracrine mechanism that engaged the Toll-like receptor 4 (TLR4) on hair cells to protect them from death. Exosomes and the HSP70/TLR4 pathway could thus provide treatment targets for the protection of hair cells from chemically induced death or from other insults, such as noise.

Levodopa-induced dyskinesia (LID) poses a significant health care challenge for Parkinson’s disease (PD) patients. Amantadine is currently the only drug proven to alleviate LID. Although its efficacy in treating LID is widely assumed to be mediated by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, our experiments demonstrate that at therapeutically relevant concentrations, amantadine preferentially blocks inward-rectifying K+ channel type 2 (Kir2) channels in striatal spiny projection neurons (SPNs) — not NMDA receptors. In so doing, amantadine enhances dendritic integration of excitatory synaptic potentials in SPNs and enhances — not antagonizes — the induction of long-term potentiation (LTP) at excitatory, axospinous synapses. Taken together, our studies suggest that the alleviation of LID in PD patients is mediated by diminishing the disparity in the excitability of direct- and indirect-pathway SPNs in the on state, rather than by disrupting LTP induction. This insight points to a pharmacological approach that could be used to effectively ameliorate LID and improve the quality of life for PD patients.

Hair cells, the mechanosensory receptors of the inner ear, are responsible for hearing and balance. Hair cell death and consequent hearing loss are common results of treatment with ototoxic drugs, including the widely used aminoglycoside antibiotics. Induction of heat shock proteins (HSPs) confers protection against aminoglycoside-induced hair cell death via paracrine signaling that requires extracellular heat shock 70-kDa protein (HSP70). We investigated the mechanisms underlying this non–cell-autonomous protective signaling in the inner ear. In response to heat stress, inner ear tissue releases exosomes that carry HSP70 in addition to canonical exosome markers and other proteins. Isolated exosomes from heat-shocked utricles were sufficient to improve survival of hair cells exposed to the aminoglycoside antibiotic neomycin, whereas inhibition or depletion of exosomes from the extracellular environment abolished the protective effect of heat shock. Hair cell–specific expression of the known HSP70 receptor TLR4 was required for the protective effect of exosomes, and exosomal HSP70 interacted with TLR4 on hair cells. Our results indicate that exosomes are a previously undescribed mechanism of intercellular communication in the inner ear that can mediate nonautonomous hair cell survival. Exosomes may hold potential as nanocarriers for delivery of therapeutics against hearing loss.

The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.

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.

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain–containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti–PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti–PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

IL-17–producing RORγt+ γδ T cells (γδT17 cells) are innate lymphocytes that participate in type 3 immune responses during infection and inflammation. Herein, we show that γδT17 cells rapidly proliferate within neonatal lymph nodes and gut, where, upon entry, they upregulate T-bet and coexpress IL-17, IL-22, and IFN-γ in a STAT3- and retinoic acid–dependent manner. Neonatal expansion was halted in mice conditionally deficient in STAT5, and its loss resulted in γδT17 cell depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A homolog had a dominant role over STAT5B in promoting γδT17 cell expansion and downregulating gut-associated T-bet. In contrast, STAT5B preferentially expanded IFN-γ–producing γδ populations, implying a previously unknown differential role of STAT5 gene products in lymphocyte lineage regulation. Importantly, mice lacking γδT17 cells as a result of STAT5 deficiency displayed a profound resistance to experimental autoimmune encephalomyelitis. Our data identify that the neonatal microenvironment in combination with STAT5 is critical for post-thymic γδT17 development and tissue-specific imprinting, which is essential for infection and autoimmunity.

Regenerative pain medicine, which seeks to harness the body’s own reparative capacity, is rapidly emerging as a field within pain medicine and orthopedics. It is increasingly appreciated that common analgesic mechanisms for these treatments depend on neuroimmune modulation. In this Review, we discuss recent progress in mechanistic understanding of nociceptive sensitization in chronic pain with a focus on neuroimmune modulation. We also examine the spectrum of regenerative outcomes, including preclinical and clinical outcomes. We further distinguish the analgesic mechanisms of regenerative therapies from those of cellular replacement, creating a conceptual and mechanistic framework to evaluate future research on regenerative medicine.

Facioscapulohumeral muscular dystrophy (FSHD) results from expression of the full-length double homeobox 4 (DUX4-FL) retrogene in skeletal muscle. However, even in cases of severe FSHD the presence of DUX4 is barely detectable. In this issue of the JCI, Bosnakovski et al. used an inducible, muscle-specific human DUX4 to reproduce the low-level, sporadic DUX4 expression of human FSHD muscle as well the myopathology seen in human FSHD disease. Notably, dysregulated fibroadipogenic progenitors accumulated in affected muscles, thus providing a mechanism for the replacement of muscle by fibrosis and fat.

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.

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.

Immunosuppression continues to be a necessary component of transplantation, despite its association with a multitude of adverse effects. Numerous efforts have been made to circumvent the need for immunosuppression by using various techniques to achieve donor hyporesponsiveness. In this issue of the JCI, Morath et al. take this endeavor forward. Prior to transplantation, the researchers infused recipients with donor-modified immune cells and achieved immunologic hyporesponsiveness. This successful phase I trial also provides a possible avenue for achieving transplantation without the requisite immunosuppression.

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).

Prenatal alcohol exposure (PAE) affects at least 10% of newborns globally and leads to the development of fetal alcohol spectrum disorders (FASDs). Despite its high incidence, there is no consensus on the implications of PAE on metabolic disease risk in adults. Here, we describe a cohort of adults with FASDs that had an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity. Using a zebrafish model for PAE, we performed population studies to elucidate the metabolic disease seen in the clinical cohort. Embryonic alcohol exposure (EAE) in male zebrafish increased the propensity for diet-induced obesity and fasting hyperglycemia in adulthood. We identified several consequences of EAE that may contribute to these phenotypes, including a reduction in adult locomotor activity, alterations in visceral adipose tissue and hepatic development, and persistent diet-responsive transcriptional changes. Taken together, our findings define metabolic vulnerabilities due to EAE and provide evidence that behavioral changes and primary organ dysfunction contribute to resultant metabolic abnormalities.

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.

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

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.
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We're still waiting to hear news about Apple Card's performance relative to the major card issuers, but that hasn't stopped Samsung from announcing plans to launch an "innovative" debit card as part of a new mobile-first money management platform the company has been developing over the last year.


Announced on Thursday in a blog post by Samsung Pay vice-president Sang Ahn, the forthcoming debit card is in partnership with finance company SoFi and will be backed by a cash management account.

"In 2020, Samsung Pay will be expanding our service from being a rewarding way to shop and pay, to also being a rewarding way to manage money," writes Ahn. "Over the past year we have been busy developing a mobile-first money management platform. Our vision is to help consumers better manage their money so that they can achieve their dreams and goals. Now more than ever, mobile financial services and money management tools will play an even bigger role in our daily lives while also opening up new possibilities."

The debit card is scheduled to launch this summer. Other than that, Samsung hasn't offered any details on how it will work, but expect it to integrate with Samsung's existing mobile payment system.

Launched in August 2019, ‌Apple Card‌ is a credit card linked to Apple Pay and built into the Wallet app on iPhone. Apple partnered with Goldman Sachs to launch the card, and in October the investment bank hailed it as "the most successful credit-card launch ever." Nine months later, neither Apple nor Goldman Sachs has offered any concrete details on its performance.

During the global health crisis, Apple has introduced an ‌Apple Card‌ Assistance Program that allows ‌‌Apple Card‌‌ holders to skip their March and April payments without incurring interest charges for that billing cycle. For more details on how the card works, check out our comprehensive Apple Card guide.
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Apple today announced that it will begin reopening its retail stores in Germany on May 11, nearly two months after they were closed due to the global health crisis.


In a statement shared with German website Macerkopf, Apple said the stores will initially be focusing on Genius Bar service and support. Enhanced health and safety measures will be implemented, such as body temperature checks prior to entry, limits on how many customers can be in the store at once, social distancing, and reduced hours of operation.

Apple operates 15 retail stores in Germany and will be posting specific hours of operation for each location on its website.

Apple closed all of its retail stores outside of the Greater China region in mid-March. The company has since started to reopen some locations, including in South Korea, Austria, and Australia. All locations in the United States remain closed.

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The Label's "The_Otherside" is this week's addition to Apple Arcade on the iPhone, iPad, and Apple TV. The game is described as both a turn-based RPG and a strategy board game:

Otherside is a turn based RPG and strategy board game where you will control four survivors who hope to push back the shadowy threat. Make your way through each level solving puzzles, fighting monsters, and destroying the spirit anchors that threaten our dimension.

Do you have what it takes to restore the town back to normal and save the day?

"The_Otherside" is available on the App Store with an Apple Arcade subscription. The service provides iPhone, iPad, Apple TV, and Mac users with access to over 100 games with no in-app purchases or ads for $4.99 per month.
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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.

Throwboy GiveawayThe contest will run from today (May 8) at 11:00 a.m. Pacific Time through 11:00 a.m. Pacific Time on May 15. The winners will be chosen randomly on May 15 and will be contacted by email. The winners will have 48 hours to respond and provide a shipping address before new winners are chosen.
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Apple's next-generation Apple Watch and watchOS 7 will focus on new mental health capabilities, according to leaker Jon Prosser who recently spoke on the Geared Up podcast. The mention of new ‌Apple Watch‌ features comes towards the end of the podcast.


The next-generation version of the ‌Apple Watch‌, the ‌Apple Watch‌ Series 6, has been rumored to include a blood oxygen sensor, which Prosser says Apple will take advantage of to implement new mental health-related features, such as detecting panic attacks.

What their biggest focus on is right now and I hope it comes this year, it might come next year, but I hope it's coming to WWDC is mental health capabilities. Where they can take the oxygen levels in your blood with your heart rate and determine if you're hyperventilating.

They can identify a panic attack before it happens and warn you on your watch. Especially if you're driving, they'll ask you to pull over and they'll offer breathing exercises once you get pulled over.

Prosser says that while he hopes the feature is released this year, "it might come next year." He also says he hopes for a WWDC unveiling, but if the new feature relies on a blood oxygen sensor in an unreleased version of the ‌Apple Watch‌, it's not likely Apple will unveil the capability until the fall when new ‌Apple Watch‌ models that support it are released.

There is, however, a possibility that it will be revealed at WWDC if older ‌Apple Watch‌ models have a latent ability to detect blood oxygen level, which is not clear at this time, or if the feature does not involve blood oxygen monitoring.

The panic attack detecting rumor was first shared by EverythingApplePro and leaker Max Weinbach back in April, who said that the ‌Apple Watch‌ will also be able to determine when a user is experiencing high levels of stress. Weinbach and EverythingApplePro did not suggest the feature would rely on blood oxygen monitoring, however, and said that it would be available on the ‌Apple Watch‌ Series 4 or later.

Hints that blood oxygen tracking capabilities are coming to a future version of the ‌Apple Watch‌ were found in a leaked version of iOS 14. Blood oxygen monitoring is an important feature because a drop in blood oxygen levels can suggest a serious respiratory or cardiac problem that requires immediate medical attention.

Multiple prior rumors from Bloomberg and other sources have also indicated that the next-generation ‌Apple Watch‌ and watchOS 7 will include sleep tracking features, allowing the ‌Apple Watch‌ to measure sleep quality, length, and other metrics.
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Dan Avidan, after years of dancing around topic of being a furry and which he would be, seems to have settled on his fursona of a cyberpunk wolf in a recently released music video. The video features animal characters with trans-humanist enhancements. The coloration has a signature bleed of 80s style animation.

The story portrays a pack of wolves seeking vengeance against a stag mogul after having their kin slaughtered at his hand. The style of animation and situation has some striking similarities to that of Caravan Palace's music video for Lone Digger.

This was brought to my attention by Majira Strawberry who asked why know one was talking about it. The answer to that in my case is object pertinence.

For those who are fans of cyberpunk and animation this is certainly worth the watch.

If you were to Google the definition of a comedian you would see it defined by Dictionary.com as an entertainer whose act is designed to make an audience laugh. Likewise the New York Times has a comedy critic, Jason Zinoman, who defines comedy in a moment of reflecting on his own career of analyzing them.

This often dictates the form of my column, since while the goal of comedy is to make you laugh, what’s fascinating about the art form — especially these days, when it’s so fragmented and aesthetically diverse — is that there are many ways artists accomplish that goal.

However, if you were to ask one furry who considers himself one, 2 Gryphon, you’d find an entirely different etymology of the word, and what the job of a comic is.

It's the JOB of the comic to bring forth uncomfortable things and question them in a way that makes people think about them.Since that has become "wrong", expect that the Western world will not be laughing as much. https://t.co/EIExUX5W2h— 2, The Ranting Gryphon (@2_gryphon) June 9, 2019

It is this quote that we are going to be over-analysing today. I have broken this down into three main points as to why this definition of the job of a comedian is not only a fundamental misunderstanding of the role, but also a resignation of the foundational principles of comedy.

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Mele was my buddy. Mele was a very good dog. I love you, buddy. You run on ahead. We’ll be there to throw the ball for you soon enough.

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On the Young Turks, Cenk Uygur quotes passages from Bob Woodward's book, "The Price of Politics", quoting statements made by President Obama proving that he intends to cut entitlements like social security, medicare, and medicaid. Continue reading →

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Is your standard charge for a speech $300,000?  According to an article appearing on the website of the Las Vegas Review-Journal, and a May 31, 2013 email, Clinton’s standard contract usually includes: Round-trip transportation on a chartered private jet “e.g., a Gulfstream … Continue reading →

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Are you as an employer having trouble paying online your unemployment compensationtaxes with the Connecticut Department of Labor? SNAFU. Continue reading →

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Video and transcript of Farron Cousins' discussion of Hillary Clinton's fake populism on Ring of Fire TV, May 18, 2015. Continue reading →

SANDERS: ... there is more coverage about the political gossip of a campaign, about raising money, about polling, about somebody saying something dumb, or some kid works for a campaign sends out something stupid on Facebook, right? We can expect that to be a major story. But what your job is, what the media's job is, is to say, look, these are the major issues facing the country. We're a democracy. People have different points of view. Let's argue it. Continue reading →

Chuck Todd tells Andrea Mitchell that Hillary Clinton will win the African-American and Hispanic vote in spite of the intellectual appeal of Bernie Sanders to liberal white voters Continue reading →

Bernie Sanders calls out Hillary Clinton to announce her position on the Trans-Pacific Partnership (TPP) agreement; however, Hillary Clinton refuses to reveal her position, hoping that the agreement will be passed and she won't have to take a position. Continue reading →