Marcello Lippi resigns as Italy coach after leading the nation to World Cup glory.

Sunderland complete the signing of defender Sotirios Kyrgiakos on loan from VfL Wolfsburg until the end of the season.

West Ham United sign Manchester United's Ravel Morrison for an undisclosed fee.

Everton sign Croatian international striker Nikica Jelavic from Rangers.

Chilean midfielder David Pizarro joins Manchester City on loan from Roma for the rest of the season.

Funerals have been banned in Italy - robbing many families of the chance to say a final goodbye.

PM Scott Morrison said wide usage would be the "ticket" to normal life resuming as soon as possible.

Facts, figures and dates on the organisation committed to representing the political, economic and cultural interests of the developing world.

An Ontario judge has dispensed with the need for a signature on a probation order due to the risks of COVID-19.

We here at Patriot Depot have mastered the art of creating the perfect cup o' joe: no cream, no sugar, and one Donald. (You can alter the first two according to taste.)

You will brew the perfect cup of coffee with..

Price: $14.95

5 Things I Learned From Being an HGTV Designer

From the adorable to the powerful, here's what the sequel delivers that's new, and eye-popping, to fans.

The true star of “Resident Evil 3” is its supurb graphics engine.

In Ann Arbor, Mich., the creators of a new autonomous vehicle have designed their robot to operate on local streets — but more so like a bicycle than a car.

The Members team ultimately fell 10-4 to the press team, despite valiant efforts from players such as 2020 presidential hopeful and team pitcher Kirsten Gillibrand.

Low-key no longer: The presidential candidate and his actress girlfriend appeared together at public events over the holiday weekend.

The rapper has been a supporter of the Democratic presidential candidate, and says she wants to help "a movement of young people to transform this country."

Whatever meager gains Trump’s trade deals represent hardly look worth the pain we endured getting here.

In the past five years, mobile games have exploded in popularity. With the advent of Apple’s App Store, mobile app developers have jumped on the opportunity to create mobile games from scratch on the most popular devices in the world. What Makes a Mobile Game Go Viral? Why is it that some mobile games become […]

The post From Concept to Design: How Developers Create Today’s Most Popular Mobile Games appeared first on SpyreStudios.

Staying fit these days is now more important than ever with the global pandemic having no cure or vaccine yet other than a healthy body. It just so happens that being active is also more difficult because gyms are closed in affected areas. Home workouts like yoga, in that regard, are golden and yoga website […]

The post 12 Yoga Website Designs for Inspiration appeared first on SpyreStudios.

Coffee, music, YouTube channels, and procrastination— only a handful of things can make your day when it comes to increasing productivity but none of them are as complete as having a home office setup. It makes a world of difference where and how you work especially if you work from home. Hence, some home office […]

The post 12 Home Office Setup Ideas for Web Designers and Developers appeared first on SpyreStudios.

One of the biggest mistakes a business owner can make today is ignoring social media marketing or treating it as an afterthought. This is even more so in an increasingly competitive space like the web design niche where small businesses have to strive to leave the shadows of more established brands with years of history […]

The post How to Use Instagram To Grow Your Web Design Business appeared first on SpyreStudios.

With the lockdown across nations, you are probably spending more time reading. Whether it’s for pleasure or for work, we’re here to help you fill your time with some reading material. These web design articles are not only about best practices, deals, and trends in the niche but also include feel-good stories that we all […]

The post Roundup: Web Design Articles May 8, 2020 appeared first on SpyreStudios.

oscon: Mobile UX Design & Development for Apps - learn to craft an app that’s functional and fun to use http://t.co/L8kTLaxbYH #oscon #tutorial

Despite numerous unknowns and continued challenges, many agencies and advertisers say they have shifted gears for the next phase.

Please visit Search Engine Land for the full article.

As US states reopen, White House keeps CDC guidance on the shelf | Trump tests negative after valet contracts virus; here are the top world news videos for today. WATCH.

velocityconf: Who's up for a 5 minute lightning talk. Last day to get your #Ignite proposal in for #velocityconf CA. http://t.co/pzL0WJtQH5

The health expert who helped shaped Britain’s lockdown policies in response to the coronavirus has resigned after admitting he broke his own rules by having his married lover visit him at his home. Professor Neil Ferguson, 51, of Imperial College in London was a prominent member of the Scientific Advisory Group for Emergencies. The Telegraph…

The post Scientist Behind Social Distancing Breaks Own Rules To Cheat with Married Woman, Resigns appeared first on The Western Journal.

When jokes are so horrible, so obvious, so corny that they make your eyes roll, it’s a good chance that they’re what many call “dad jokes.” Bordering on lame, and all the more hilarious because of it, these jokes are so bad and yet fathers seem to get such joy from trotting out the perfect…

The post Man Posts Hilarious ‘Bad Dad Jokes’ Daily on Sign in Front Lawn To Spread Cheer to Neighbors appeared first on The Western Journal.

The Assad government sought to promote regime-sponsored cultural events through a marketing campaign called "Summer in Syria," but the effort didn't exactly go as planned.

At least 65,116 individuals have been "forcibly disappeared" by the Syrian government, according to a new report by Amnesty International.

Just days after the attack in Paris, America’s top intelligence official suggested that recent leaks about classified surveillance programs were partially responsible.

Signs of Slowing Unemployment

Signs of Slowing Unemployment

Travel is fun, when you plan things properly. If you have visited many countries, then surely you have made many mistakes such as booking resorts at wrong places or buying costly souvenirs which are easily available in your country. We all make silly mistakes when we visit a new country and there is no need to feel ashamed. What you need to do is make sure that you don’t repeat those mistakes.

When it comes to mistakes, I am not talking about flight or hotel ticket booking blunders. There are many more small oversights that can ruin your vacation. Let’s explore some of the common mistakes that tourists make every year.

No research about the place: You may know the name of the country, its capital and its currency exchange rate, but do you really know the place you are visiting? For example, in India, there are many prepaid taxi booths that charge right amount for a trip, but if you just pick any cab from the road, the driver may charge you double because you don’t know the route to your destination. Similarly, it is important to know the things you can and can’t do in the place you are visiting. For example, taking pictures is prohibited in many religious places.

Over-packing: Never carry too many clothes, because you are going to carry your bags, and if those are too heavy, you will curse yourself. Besides, the airlines charge hefty amount if your luggage crosses the weight limit. Always pack only those things that are necessary for the place you are visiting. For example, if you are going to Tadoba tiger reserve forest and staying at Tadoba tiger resort, then you don’t need to pack a cocktail party dress. It is better to pack a few jeans and t-shirts.

Speaking English only: Try to learn a few sentences in the local language. For example, words of greetings, how to ask for road directions and how to ask the price of something. The more you communicate with the locals in their own language, the more confident you will feel.

Disrespecting the customs: India is a conservative county, and the culture of Indians is very different from Americans. However, that does not mean you can mock or disrespect their culture. For example, Americans enter churches wearing shoes, but in India, you can’t wear shoes in a temple. Respect the rule while visiting any temple in India. After all, you are visiting a new country to understand its culture.

Reading guidebooks only: Guidebooks are for references and they can’t give you all the information about the place. For example, a guidebook may tell you that Taj Mahal is wonderful, but unless you raise your face from the book, can you truly appreciate its beauty?

Booking hotels and flights separately: Take a look at the famous travel portals and you will find that they are offering great hotel + airplane deals. When you book return tickets and also hotel rooms, you can save a few hundred dollars. Besides, it is a hassle free process as you are getting everything from one site.

Interrupting the guide: You can be the history professor in a college, but if you interrupt the guide when he is talking about a historical place, then you are being rude. All the other tourists have paid for the guided tour and by interrupting the guide frequently you are making everyone angry.

So, when you visit a foreign country this year, make sure that you don’t make the mistakes mentioned above. Enjoy nature, history and culture of the place you are visiting and you will feel rejuvenated by the end of your vacation.

If you like traveling to exotic places, check out our Machu Picchu Tours page

Part of the Sport Relief promo for the BBC UK Homepage

11 February 2020

The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.

NAD+ is a central metabolite participating in core metabolic redox reactions. The prokaryotic NAD synthetase enzyme NadE catalyzes the last step of NAD+ biosynthesis, converting nicotinic acid adenine dinucleotide (NaAD) to NAD+. Some members of the NadE family use l-glutamine as a nitrogen donor and are named NadEGln. Previous gene neighborhood analysis has indicated that the bacterial nadE gene is frequently clustered with the gene encoding the regulatory signal transduction protein PII, suggesting a functional relationship between these proteins in response to the nutritional status and the carbon/nitrogen ratio of the bacterial cell. Here, using affinity chromatography, bioinformatics analyses, NAD synthetase activity, and biolayer interferometry assays, we show that PII and NadEGln physically interact in vitro, that this complex relieves NadEGln negative feedback inhibition by NAD+. This mechanism is conserved in distantly related bacteria. Of note, the PII protein allosteric effector and cellular nitrogen level indicator 2-oxoglutarate (2-OG) inhibited the formation of the PII-NadEGln complex within a physiological range. These results indicate an interplay between the levels of ATP, ADP, 2-OG, PII-sensed glutamine, and NAD+, representing a metabolic hub that may balance the levels of core nitrogen and carbon metabolites. Our findings support the notion that PII proteins act as a dissociable regulatory subunit of NadEGln, thereby enabling the control of NAD+ biosynthesis according to the nutritional status of the bacterial cell.

Invitation Only Research Event

Event participants

Myron Brilliant, Executive Vice President and Head of International Affairs, US Chamber of Commerce
Chair: James Nixey, Head, Russia and Eurasia Programme, Chatham House

Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.

Yi Zhang
Sep 1, 2005; 4:1240-1250
Research

Joris J. Benschop
Jul 1, 2007; 6:1198-1214
Research

Albrecht Gruhler
Mar 1, 2005; 4:310-327
Research

Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both α-cell–intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4–10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mm glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mm. Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mm glucose and did not prevent the suppressive effect of 7 mm glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mm glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion.

The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.