Mobile phones have become a must for this generation. They are the devices that are the most helpful for all. You can talk to your loved ones, play music, play videos, play games and do many more other things. In… Continue Reading →

“Even after weeks of staying home, my kids are just not interested in all the stuff we have. Let’s be honest. If a toy isn’t getting any action amid this distraction-free, stuck-at-home living, chances are it’s never getting touched again.” Liz Russell figures out what really engages and changes kids during the quarantine, and will […]

At Let Grow, a wise mom named Kate Sundquist admits that while her kids were already good at playing, they certainly weren’t good at filling hours and hours of free time, playing by themselves. (Read the piece here.) So she her and boys created a schedule. “While these routines might seem restrictive or even the […]

“The most difficult part was persuading our children that they had the freedom to make anything they wanted,” writes mom Anam Ahmed at Let Grow. (Click here!) …Like most kids, my children live prescheduled lives (at least they did in “the time before”). At school, someone tells them when to play outside and when to […]

“When I was 17, I was in a serious accident and had to be home for months. Looking out at our boring backyard, I daydreamed a plan for my life. It became a blueprint.” So writes Holly Korbey in a lovely piece at Let Grow. There are different kinds of daydreaming, of course, and some don’t […]

What expression does — did — your mom use all the time? What skill did you learn from her?  What does (or did) she encourage you to do? These are great questions for any mom and child, whether the kid is 5 or 50. And if you click here, you can print out a very […]

At least for some kids, yes, being flung from the stress of a super-structured, super-supervised existence is having a calming, life-expanding effect. I discuss this amazing phenom in this Big Think article, including six short essays by kids themselves, and also in this interview with Bored Panda,  the  pop culture site, where I note that […]

Parents, kids: Fear not the silica gel pack. Sure it says DO NOT EAT and THROW AWAY. But you should only follow one of those rules.    Instead, save the packs and use them a whole lot of ways: Place them on the car dashboard by the windshield to keep it from fogging up.   […]

These “cards” are really an excuse for kids to interview their moms and shower them with the ultimate gifts: attention to mom’s quirky uniqueness, gratitude, and offers of help! Here you go — click here! (Mother’s Day is SUNDAY!)

The incentive to automate will be enormous for $15 per hour minimum wage. Of America’s nearly 16 million retail workers, the biggest group — 4.6 million — are salespeople. Their average wage is $10.47 an hour. After that, the country has another 3.4 million cashiers, and their average wage is $9.28 an hour. Only a quarter of salespeople earn more than $14 — and only 10 percent earn more than $19. The figures are worse for cashiers. But in the race to automate there will be a clear winner: Amazon. Why: Amazon can automate more easily than can physical stores. It is analogous to why long haul trucking can be automated before taxis: Just as highways are simpler places than...

Daron Acemoglu of MIT and Pascual Restrepo of Boston University find that robots really do decrease human employment. As robots and other computer-assisted technologies take over tasks previously performed by labor, there is increasing concern about the future of jobs and wages. We analyze the effect of the increase in industrial robot usage between 1990 and 2007 on US local labor markets. Using a model in which robots compete against human labor in the production of different tasks, we show that robots may reduce employment and wages, and that the local labor market effects of robots can be estimated by regressing the change in employment and wages on the exposure to robots in each local labor market—defined from the national...

Suppose you randomly go 1 million miles somewhere away from our Sun. What will you find when you get there? With extremely high probability: Nothing! Suppose you go 100 light years in a randomly chosen direction. It is exceedingly likely that once you get there you will find nothing. Space. Vacuum. Rarely any atoms. Nothing, really boring nothing. Space is a dull and boring destination. If we don't take something with us to make our visit to a space destination interesting then it will be boring. Suppose we arrive at some place that is not just space. If some location has lots of mass it begins to have a chance of not being boring. But most pieces of mass out...

Survives another day!

We all have a rope to pull!

Ziggy, is that you?

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 little old lady walks into Bank of America and asks to open a savings account. The new accounts receptionist first thinks this is strange, probably because everyone is leaving them for credit unions now. At any rate, the accounts person asks her how much she wanted to deposit to open the account, and the […]

The post Getting Bank of America By The Balls appeared first on Funny & Jokes.

Date: April 27, 2020

Today’s Doodle commemorates what is widely revered as the Netherlands’ most popular holiday, King’s Day. Known as Koningsdag in Dutch, today honors the birthday of the first Dutch king in 123 years, His Royal Highness Willem-Alexander.

Depicted in the Doodle artwork, the red, white, and blue tricolor Dutch flag was affirmed in its current form by a royal decree in 1937. With orange as the official color of the day, the flag is often seen with a small orange stripe, or a wimpel, hovering on the top for King’s Day.

Fijne Koningsdag! (Happy King’s Day!)

Location: Netherlands

Tags: national day, National Holiday, independence, history, Netherlands, King's Day

Date: May 3, 2020

Location: Hungary, Lithuania, Portugal, Romania, Spain

Tags:

Date: May 10, 2020

All that glitters is not gold, but sometimes it comes in handy.

Whether they're near or far, make Mom a little piece of art from your heart in today’s interactive, digital card-maker Doodle.

Learn more about the inspiration that led to the creation of this Doodle on our official Google Blog.

Happy Mother’s Day!

Cut out some time to send a mom some love today! Search for ”GoogleDoodles” in Gboard, GIF Keyboard by Tenor, or the GIF search in your favorite social apps.

Below, the Doodlers behind today’s Doodle share their own MOM-umental creations:
 

Anthony Irwin, UX Designer

Collin Irwin, Engineer

Grace Chen, Marketing

Perla Campos, Marketing

Tom Tabanao, Engineer

More behind-the-scenes of the making of today’s Doodle:
 

It begins! Special thanks to the Takara and McGupta Families for materials.

Early Bead Tests

Angle Reference for the Doodle G

Turtle In-Progress

Glitter Star Animation Frames

❤️ MOTHER’S DAY 2020 TEAM ❤️

Lead Artist | Alyssa Winans

Engineering | Brian Murray, Collin Irwin, Tom Tabanao, Jacob Howcroft, Nicole Patten, Yumi Kim

Producer | Gregory Capuano, Colin Duffy

UX Design | Anthony Irwin, Diana Tran

Sound Design | Jacob Howcroft

Marketing | Perla Campos, Grace Chen

Business Affairs Lead & Partnerships | Madeline Belliveau

Doodle Team Lead | Jessica Yu, Brian Kaas

Location: Global

Tags: Interactive, National Holiday, greeting card, turtles, macaroni, buttons, sequins, hearts, dragonflies, giraffes, seashells, stars, glitter

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Живущий в России американский журналист пишет своего рода хроники из коронавирусной Москвы накануне Дня Победы. Несмотря на необходимый для западных СМИ скепсис, даже он признает, что дела здесь идут неплохо: какие бы кризисы ни сотрясали Россию, она находит силы выстоять.

Королева Великобритании Елизавета II — единственная из действующих глав государств, служившая в вооруженных силах во время Второй мировой войны, — произнесла речь в честь Дня победы в Европе, который отмечается 8 мая. В своем выступлении она воздала дань памяти погибших и подчеркнула, что они гордились бы потомками.

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.

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.

Organ shortage continues to limit the lives of patients who require liver transplantation. While extending criteria for liver organs provides a needed resource, tissue damage from prolonged ischemic injury can result in early allograft dysfunction and consequent rejection. In this issue of the JCI, Nakamura et al. used a mouse transplantation model with prolonged ex vivo cold storage to explore liver graft protection. The authors found that liver grafts with absent carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) exhibited increased ischemia-reperfusion injury inflammation and decreased function in wild-type recipients. The authors went on to correlate CEACAM1 levels with postreperfusion damage in human liver transplant recipients. Notably, this study identified a potential biomarker for liver transplant donor graft quality.

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.

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.

Lymph node stromal cells (LNSCs) regulate immunity through constructing lymphocyte niches. LNSC-produced laminin α5 (Lama5) regulates CD4+ T cells but the underlying mechanisms of its functions are poorly understood. Here we show that depleting Lama5 in LNSCs resulted in decreased Lama5 protein in the LN cortical ridge (CR) and around high endothelial venules (HEVs). Lama5 depletion affected LN structure with increased HEVs, upregulated chemokines, and cell adhesion molecules, and led to greater numbers of Tregs in the T cell zone. Mouse and human T cell transendothelial migration and T cell entry into LNs were suppressed by Lama5 through the receptors α6 integrin and α-dystroglycan. During immune responses and allograft transplantation, depleting Lama5 promoted antigen-specific CD4+ T cell entry into the CR through HEVs, suppressed T cell activation, and altered T cell differentiation to suppressive regulatory phenotypes. Enhanced allograft acceptance resulted from depleting Lama5 or blockade of T cell Lama5 receptors. Lama5 and Lama4/Lama5 ratios in allografts were associated with the rejection severity. Overall, our results demonstrated that stromal Lama5 regulated immune responses through altering LN structures and T cell behaviors. This study delineated a stromal Lama5–T cell receptor axis that can be targeted for immune tolerance modulation.

Infection with the Gram-negative bacterium Helicobacter pylori remains the most important modifiable risk factor for the development of gastric cancer, a leading cause of cancer-related deaths worldwide. How the interactions between H. pylori and its host shape the gastric environment during chronic infection warrants further investigation. In this issue of the JCI, Palrasu et al. used human cell lines and mouse models to provide mechanistic insight into H. pylori’s ability to delay apoptosis in gastric epithelial cells by actively driving the degradation of a proapoptotic factor, SIVA1. Their findings suggest that promoting the survival of gastric epithelial cells has implications not only for H. pylori pathogenesis but for host tumorigenesis.

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.

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR–expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.

The editors of JCI and JCI Insight are revisiting our editorial processes in light of the strain that the COVID-19 pandemic places on the worldwide scientific community. Here, we discuss adjustments to our decision framework in light of restrictions placed on laboratory working conditions for many of our authors.

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.

I’ve been to Forks and La Push, where the Twilight book series takes place, but I’ve never been to the actual filming locations from the movies! That’s because while the director wanted to film in Forks, when he came to scout the town he realized there was just not enough infrastructure to support an entire film crew– there were literally not enough places to house and feed all of the people who would be working on the movie, and there was no other large town within driving distance! (Yeah, Forks is really far out there) Enter Halloweento— I mean, St. Helens, Oregon! St. Helens stands in for most of Forks in the movies, and a few places in nearby Portland, Oregon make up most of the rest. I ended up nearby by complete accident, as it was only when I picked up a brochure at Halloweentown that I learned that Bella’s house was just on the other side of town! LUCKY!!!  So, we took a short break to drive over to the locations that were still standing, and made a special detour to Portland because how could we leave the Cullen house behind?! I WANTED TO GO INSIDE SO BADLY! It is a real house with real people that live there, and although they encouraged taking photos from outside (according both to a brochure from City Hall and a sign in front of the house), the inside was off-limits. Honestly, it’s not Bella that I particularly love. I didn’t care for her portrayal by Kristen Stewart (sorry!), or her melancholy, passive attitude in the book. Actually, I didn’t care for Edward, either. It was the idea of a love so strong that forces of  nature were pulling you together. It’s the idea of fitting together so perfectly that you can’t do anything without the other that I am a complete sucker for! I said it on my old Livejournal years ago, but Twilight is just a big Mary Sue anyway, so I like to imagine myself as Bella, with a gorgeous (female) Edward out there waiting for me. ???? Like I said, it’s the love, not the characters themselves. I’ll fight you on this (just kidding). ???? Here is where Edward rescued Bella from some catcallers, complete with the mural that the movie crew painted (!) on the building. And the theater that they drove past, that you can’t really see well in the movie but hey, it was on the map!! This is Jilly’s, which supplied all of the dresses in the shop when Bella went to pick out something with her friends for prom. Oddly enough, they had this sign outside but no actual merchandise inside. Go figure. ???? This place, which is a private house now, was the bookstore where Bella went to find out more information about the Quileute myths. And then, though we only had a little bit of time, we drove over to Portland and checked out Edward’s house. I have to say…. THIS HOUSE WAS GORGEOUS. Whew! I would LOVE to live there. LOVE LOVE LOVE! I would also have loved a tour, but it is a private residence, and therefore we kept our distance. Mmm, but it sure is gorgeous! Twilight brings back a lot of memories for me, and it’s special because I grew up (mostly) in Washington. It’s also not the only book series to claim that there are werewolves living amongst the local residents. The town that I spent most of my childhood in also has a series revolving around it! I’m planning to take a trip over there to see my old friends and photograph all of the wolfy places of interest, so I’ll post about it then! Love ya, and see ya tomorrow!