Episode five of The Last Dance proved to be an emotional watch as a never-before-seen interview with Kobe Bryant was aired.

Mitsubishi Electric Automation, Inc. Equal Opportunity Employer: Mitsubishi Electric Automation, Inc. ("MEAU") is committed to the employment and advancement of minorities, females, individuals with disabilities, and veterans. We are an equal opportunity employer and do not discriminate in hiring or

GTA 6 fans have another date approaching where a reveal is rumoured to be taking place, but don't get your hopes up.

The first round of the FA Cup takes place this weekend.

The summer transfer window is nearly upon us as Manchester United, Chelsea, Liverpool, Arsenal and the rest of the Premier League look to strengthen for whenever the new season starts. Express Sport brings you the latest updates throughout the day.

Intermountain Healthcare is accepting donations of homemade cloth face coverings for visitors and non-frontline caregivers at hospitals and clinics.

A “JAW-DROPPING” 1.6 million lost pension pots worth nearly £20 billion are being left unclaimed, according to estimates from an insurance industry body. Savers are losing track of their pension stash due to job changes or moving house, with future retirees potentially missing out on staggering sums for their golden years.

I'VE BEEN feeling increasingly uncomfortable watching the nightly news on television. We both have. Bulletins - particularly those on the BBC - are increasingly more like a newspaper's obituary page.

Kelly coached at Seymour past three years, formerly was an assistant at Fishers

Through his personal streaming platform, IndyCar veteran Conor Daly's Twitch offers fans a front-row seat to a driver's race-day mind.

The iconic restaurant still conjures up fond memories of the food and the cruising.

Owen Sego's dad died in a plane crash. Avery Whitten's mom died of heart failure. Two tragedies hit two Indian Creek football players in 24 hours.

Indianapolis chefs say Bourdain felt like an old friend, and the day he spent here changed a life.

The iconic restaurant still conjures up fond memories of the food and the cruising.

Indianapolis residents held a vigil for Dreasjon Reed, who was fatally shot by police. At least part of it was captured on a Facebook Live video.

Chelsea in talks over Chilwell, Blues and Manchester United interested in Chiesa, Red Devils ask about Salisu, plus more.

Mark Drakeford said "we should all be anxious" about how long lockdown can be sustained.

The highest mountain in the world will be closed to climbers until at least 30 April.

1. Ahmedabad Police Detain 4 for Spreading Rumours on Amit Shah's Health  The Wire
2. I am healthy, not suffering from any disease, says Amit Shah  Times of India
3. HM Amit Shah silences all the rumour mongers, says 'No need to worry'  TIMES NOW
4. Not Allowing Migrants' Trains "Injustice": Amit Shah To Mamata Banerjee  NDTV
5. 'Not Suffering From Any Disease': Amit Shah Dismisses Rumours About His Health  Outlook India
6. View Full coverage on Google News

The game is a beautiful marriage of aesthetics and gameplay. It has the makings of a minor classic.

Artists are creating social-distancing versions of Vermeer, da Vinci, Michelangelo and more.

Domino's plans to start delivering pizzas using an autonomous, unmanned vehicle. The announcement is the latest example of technology companies using robots to deliver food.

Loon — an Internet-providing balloon service owned by Alphabet, Google’s parent company — will give “mountain villagers” in Kenya the opportunity to purchase 4G service.

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.

After nearly eight months of knowledge-gathering street tests and thousands of successful deliveries, Amazon has announced that its delivery robots have begun delivering packages to customers in Irvine, Calif.

Hyundai, one of the world’s largest automakers, is exploring adding e-scooters to their vehicles. The company has released an e-scooter prototype that is charged using electricity produced while driving.

For months now, Nuro’s robotically piloted vehicles have been quietly delivering groceries to restaurants and homes around Houston, the vehicles’ sensors mapping the city as they go.

Public officials today could take a lesson from the former Federal Reserve chair.

Roy Horn, half of Las Vegas illusionist duo Siegfried and Roy, has died of complications from the coronavirus.

Mountain Gorillas in Uganda and Rwanda

The Amateur Traveler talks to Doug McConnell of OpenRoad.tv about his love for the Eastern Sierra Nevada mountains. Doug has been going to this rugged, stark and beautiful area of California and Nevada since he was a kid. He tells us about Hollywood's love of this area, the oldest trees on the planet, the water wars of California, the tufa fields of Mono Lake, the ghost town of Bodie and more. He also tells of his friends Galen and Barbara Rowell who called this area their home until their deaths in 2002. Galen was a renowned nature photographer and Barbara was his partner and pilot.

The Amateur Traveler talks to Nathan from Wand’rly Magazine about Great Smoky Mountains National Park and about his current home of Western North Carolina. The Great Smoky Mountains National Park is the most visited U.S. National Park.

Hear about climbing Mount Kilimanjaro as the Amateur Traveler talks to Kylie Chenn from Acanela Expeditions about what you should know about climbing the tallest mountain in Africa. 

A powerful player on Facebook’s new content oversight board infamously mocked Barron Trump during last year’s impeachment hearings, sowing doubt in the social media platform’s promises of unbiased moderation. The selection of Pamela Karlan, a professor at Stanford Law School, was announced Wednesday by Facebook, according to CNBC. Karlan will sit alongside 19 other experts…

The post Academic Who Infamously Mocked Barron Trump Gets Censorship Gig from Facebook appeared first on The Western Journal.

Celebrity Deaths in April 2020 Here’s a look at some of the famous faces we lost in the month of April. Ellis Marsalis Jr. Ellis Marsalis, 1934 – 2020 He went out the way he lived: embracing reality pic.twitter.com/sPyYUuBoIG — Wynton Marsalis (@wyntonmarsalis) April 2, 2020 New Orleans jazz legend Ellis Marsalis Jr., 85, died on…

The post Famous Faces Who Passed Away in April 2020 appeared first on The Western Journal.

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.

The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.

Qin Liu
Aug 1, 2007; 6:1299-1317
Research

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. Whereas most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that 1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, 2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, 3) MyD88 splicing is regulated by the NF-κB transcription factor, and 4) NF-κB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled.

W Gamble
Nov 1, 1978; 19:1068-1070
Articles

The DOCK-D (dedicator of cytokinesis D) family proteins are atypical guanine nucleotide exchange factors that regulate Rho GTPase activity. The family consists of Zizimin1 (DOCK9), Zizimin2 (DOCK11), and Zizimin3 (DOCK10). Functions of the DOCK-D family proteins are presently not well-explored, and the role of the DOCK-D family in neuroinflammation is unknown. In this study, we generated three mouse lines in which DOCK9 (DOCK9−/−), DOCK10 (DOCK10−/−), or DOCK11 (DOCK11−/−) had been deleted and examined the phenotypic effects of these gene deletions in MOG35–55 peptide-induced experimental autoimmune encephalomyelitis, an animal model of the neuroinflammatory disorder multiple sclerosis. We found that all the gene knockout lines were healthy and viable. The only phenotype observed under normal conditions was a slightly smaller proportion of B cells in splenocytes in DOCK10−/− mice than in the other mouse lines. We also found that the migration ability of macrophages is impaired in DOCK10−/− and DOCK11−/− mice and that the severity of experimental autoimmune encephalomyelitis was ameliorated only in DOCK10−/− mice. No apparent phenotype was observed for DOCK9−/− mice. Further investigations indicated that lipopolysaccharide stimulation up-regulates DOCK10 expression in microglia and that microglial migration is decreased in DOCK10−/− mice. Up-regulation of C–C motif chemokine ligand 2 (CCL2) expression induced by activation of Toll-like receptor 4 or 9 signaling was reduced in DOCK10−/− astrocytes compared with WT astrocytes. Taken together, our findings suggest that DOCK10 plays a role in innate immunity and neuroinflammation and might represent a potential therapeutic target for managing multiple sclerosis.

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.

The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.