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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.

After waiting for what seemed like an eternity, the stewardess announces over the intercom that “we’re just waiting for the pilots.” The passengers look out the window and see two men, dressed as pilots walking towards the plane. Both men are using guide dogs and appear to be blind. There are murmurs among the passengers, […]

The post What A Scary Flight appeared first on Funny & Jokes.

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

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Do you have a fear of standing alone at your company party with nobody to talk to and no way to break the ice? Have no fear, F&J is here! Here’s a quick and dirty arsenal of one-liner jokes that are sure to make you the life of the party. Rest assured that nobody will […]

The post 11 Crappy One-Liners Sure To Leave You A Loser appeared first on Funny & Jokes.

It’s not everyday we regurgitate a few old (and new!) chemistry jokes. How often do we tell them? Periodically. We told one the other day, but there was no reaction. Hahaha! Wait? How come nobody else is laughing? Ehem… well, anyways, here are a few more: When I first heard oxygen and magnesium got together […]

The post Top 20 Chemistry Jokes of Some Time appeared first on Funny & Jokes.

Date: April 23, 2020

Today’s Doodle, illustrated by British guest artist Robin Davey, commemorates St. George’s Day. On the annual celebration of the patron saint, England celebrates St. George and his representation of values like bravery, integrity, and leadership.

According to legend, St. George single-handedly slew a dragon to rescue a city under siege. For centuries, he captured the English imagination; in fact, King Henry V’s veneration for St. George was even immortalized in William Shakespeare’s eponymous play about the monarch.  

St. George was declared England’s patron saint in 1348, and in 1415 St. George’s Day was inaugurated as a national feast day in his honor. Today, the special day lives on as a testament to England’s culture and unique traditions through activities like morris dancing (a rural folk custom) and medieval jousting.

Happy St. George’s Day!

Guest Artist Q&A with Robin Davey

Today’s Doodle was illustrated by British guest artist Robin Davey. Below, he shares his thoughts behind the making of this Doodle:

Q: Why was this topic meaningful to you personally? 

A: As a Briton living abroad, it was nice to make something connected to my home country.

Q: What were your first thoughts when you were approached about the project?

A: My mum, who checks the Doodle daily, will be thrilled :)

Q: Did you draw inspiration from anything in particular for this Doodle? 

A: I wanted to reframe the story of George and the dragon as one of friends, not adversaries.

Q: What message do you hope people take away from your Doodle?

A: That peaceful cooperation with our neighbours is preferable to conflict.

Location: United Kingdom

Tags: national day, National Holiday, history, George, dragon, toast, England

Date: April 25, 2020

As COVID-19 continues to impact communities around the world, people are coming together to help one another now more than ever. We’re launching a Doodle series to recognize and honor many of those on the front lines.

Today, we’d like to say: 

To all coronavirus helpers, thank you.
 

Help stop the spread of COVID-19 by following these steps.  

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags: covid, Current Event, covid-19, appreciation, helpers, coronavirus

Date: April 27, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2017 Doodle game celebrating 50 years of Kids Coding!

Help stop the spread of COVID-19 by following these steps.
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

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: April 28, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2017 Doodle game celebrating Cricket!

Help stop the spread of COVID-19 by following these steps.  
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

Date: April 29, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2017 Doodle game celebrating Oskar Fischinger!
 

Help stop the spread of COVID-19 by following these steps.  
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

Date: April 29, 2020

On the fifth day of the Hebrew month of Iyar, Israeli communities worldwide celebrate their Independence Day, known locally as Yom Ha’atzmaut. Today’s Doodle pays tribute to this annual holiday in recognition of the day in 1948 when the State of Israel declared its independence. 

Depicted in the Doodle artwork, the flag of Israel features two blue stripes running horizontally over the white background with the Star of David at its center. Officially adopted in 1948, the same year as independence, the flag will be waved proudly wherever Israeli’s call home. 

Happy Yom Ha’atzmaut, Israel!​

Location: Israel

Tags: national day, National Holiday, independence, history, Israel

Date: April 30, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2016 Doodle game celebrating Clara Rockmore!
 

Help stop the spread of COVID-19 by following these steps.
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

Date: May 1, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2018 Doodle game celebrating Garden Gnomes!
 

Help stop the spread of COVID-19 by following these steps.  
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

Date: May 1, 2020

Also known as May Day or International Workers’ Day, Labour Day is celebrated on May 1st in many countries around the world. Today’s Doodle celebrates the day by illustrating a handful of the many professions across the labor force.

Recognized around the world, Labour Day originated from the 19th-century labour movement. First declared a holiday by trade unions in 1889, Labour Day commemorates worker’s rights and their fight for weekends, better working conditions, and shorter working days. 

Here’s to everyone contributing to the livelihoods of those around them each and every day. 

Happy Labour Day!

Location: Global

Tags:

Date: May 3, 2020

Location: Hungary, Lithuania, Portugal, Romania, Spain

Tags:

Date: May 4, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2016 Doodle game celebrating Wilbur Scoville!
 

Help stop the spread of COVID-19 by following these steps.  
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

Date: May 5, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2019 Doodle game celebrating Lotería!
 

Help stop the spread of COVID-19 by following these steps.  
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

Date: May 6, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2016 Doodle game celebrating Halloween!
 

Help stop the spread of COVID-19 by following these steps.  
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

Date: May 7, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2017 Doodle game celebrating the birth of Hip Hop!
 

Help stop the spread of COVID-19 by following these steps.  
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

Date: May 8, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2010 Doodle game celebrating PAC-MAN!
 

Help stop the spread of COVID-19 by following these steps.  
 

Learn more here about the latest ways we’re responding, and how our products can help people stay connected during this time.

Location: Global

Tags:

Date: May 8, 2020

Location: South Korea

Tags: Parents' Day, carnations, flowers, stop-motion, Animation

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

The post New Arrivals: Top Fishing Sunglasses You Can Try this 2020 appeared first on Ocean Blue Fishing Adventures.

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The post Unpacking After a Fishing Trip: Why is it so Important? appeared first on Ocean Blue Fishing Adventures.

Посол Алексей Ерхов в статье, опубликованной в турецком издании по случаю Дня Победы, призвал тех, кто пытается переписывать историческую правду, извлечь правильные уроки из истории Второй мировой войны. В противном случае, по его мнению, мы можем столкнуться с риском снова пережить эту катастрофу.

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.

Две недели назад финские СМИ сообщили, что в России возбуждено уголовное дело о действиях финнов на территории оккупированной ими с 1941 по 1944 год Карелии. События того времени будут рассмотрены на предмет геноцида. Руководитель Национального архива Финляндии сделал по этому поводу заявление.

Ничто так не подчёркивает важность достоверных новостей, как кризис. Однако пандемия сovid-19 переворачивает вверх дном журналистику и меняет условия труда. Нельзя недооценивать возникающий в результате стресс для психического здоровья работников СМИ.

We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells’ inflammatory phenotype may impact obesity and its complications.

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.

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.

Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow–derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress–triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

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.

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents.

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.

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.

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.

Hepatocellular carcinoma (HCC) is clearly age-related and represents one of the deadliest cancer types worldwide. As a result of globally increasing risk factors including metabolic disorders, the incidence rates of HCC are still rising. However, the molecular hallmarks of HCC remain poorly understood. Neuropeptide Y (NPY) and NPY receptors represent a highly conserved, stress-activated system involved in diverse cancer-related hallmarks including aging and metabolic alterations, but its impact on liver cancer had been unclear. Here, we observed increased expression of NPY5 receptor (Y5R) in HCC, which correlated with tumor growth and survival. Furthermore, we found that its ligand NPY was secreted by peritumorous hepatocytes. Hepatocyte-derived NPY promoted HCC progression by Y5R activation. TGF-β1 was identified as a regulator of NPY in hepatocytes and induced Y5R in invasive cancer cells. Moreover, NPY conversion by dipeptidylpeptidase 4 (DPP4) augmented Y5R activation and function in liver cancer. The TGF-β/NPY/Y5R axis and DPP4 represent attractive therapeutic targets for controlling liver cancer progression.

BACKGROUND Neurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNSTs is challenging, especially for large tumors, and established systemic treatments are lacking.METHODS We used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs.RESULTS Whole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns.CONCLUSION These findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications.FUNDING This work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program.

Familial dysautonomia (FD) is the most prevalent form of hereditary sensory and autonomic neuropathy (HSAN). In FD, a germline mutation in the Elp1 gene leads to Elp1 protein decrease that causes sympathetic neuron death and sympathetic nervous system dysfunction (dysautonomia). Elp1 is best known as a scaffolding protein within the nuclear hetero-hexameric transcriptional Elongator protein complex, but how it functions in sympathetic neuron survival is very poorly understood. Here, we identified a cytoplasmic function for Elp1 in sympathetic neurons that was essential for retrograde nerve growth factor (NGF) signaling and neuron target tissue innervation and survival. Elp1 was found to bind to internalized TrkA receptors in an NGF-dependent manner, where it was essential for maintaining TrkA receptor phosphorylation (activation) by regulating PTPN6 (Shp1) phosphatase activity within the signaling complex. In the absence of Elp1, Shp1 was hyperactivated, leading to premature TrkA receptor dephosphorylation, which resulted in retrograde signaling failure and neuron death. Inhibiting Shp1 phosphatase activity in the absence of Elp1 rescued NGF-dependent retrograde signaling, and in an animal model of FD it rescued abnormal sympathetic target tissue innervation. These results suggest that regulation of retrograde NGF signaling in sympathetic neurons by Elp1 may explain sympathetic neuron loss and physiologic dysautonomia in patients with FD.

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.