Amino acid hydroxylation is a common post-translational modification, which generally regulates protein interactions or adds a functional group that can be further modified. Such hydroxylation is currently considered irreversible, necessitating the degradation and re-synthesis of the entire protein to reset the modification. Here we present evidence that the cellular machinery can reverse FIH-mediated asparagine hydroxylation on intact proteins. These data suggest that asparagine hydroxylation is a flexible and dynamic post-translational modification akin to modifications involved in regulating signaling networks, such as phosphorylation, methylation and ubiquitylation.

High performance liquid chromatography has been employed for decades to enhance detection sensitivity and quantification of complex analytes within biological mixtures. Among these analytes, glycans released from glycoproteins and glycolipids have been characterized as underivatized or fluorescently tagged derivatives by HPLC coupled to various detection methods. These approaches have proven extremely useful for profiling the structural diversity of glycoprotein and glycolipid glycosylation but require the availability of glycan standards and secondary orthogonal degradation strategies to validate structural assignments. A robust method for HPLC separation of glycans as their permethylated derivatives, coupled with in-line MSn fragmentation to assign structural features independent of standards, would significantly enhance the depth of knowledge obtainable from biological samples. Here, we report an optimized workflow for LC-MS analysis of permethylated glycans that includes sample preparation, mobile phase optimization, and MSn method development to resolve structural isomers on-the-fly. We report baseline separation and MSn fragmentation of isomeric N- and O-glycan structures, aided by supplementing mobile phases with Li+, which simplifies adduct heterogeneity and facilitates cross-ring fragmentation to obtain valuable monosaccharide linkage information. Our workflow has been adapted from standard proteomics-based workflows and, therefore, provides opportunities for laboratories with expertise in proteomics to acquire glycomic data with minimal deviation from existing buffer systems, chromatography media, and instrument configurations. Furthermore, our workflow does not require a mass spectrometer with high-resolution/accurate mass capabilities. The rapidly evolving appreciation of the biological significance of glycans for human health and disease requires the implementation of high-throughput methods to identify and quantify glycans harvested from sample sets of sufficient size to achieve appropriately powered statistical significance. The LC-MSn approach we report generates glycan isomeric separations, robust structural characterization, and is amenable to auto-sampling with associated throughput enhancements.

Customers now have access to Google’s homegrown hardware — its Axion CPU and latest Trillium TPU — in its Cloud service.  At the same time, Google gave customers a teaser […]

The post Role Reversal: Google Teases Nvidia’s Blackwell as It Softens TPU Rivalry appeared first on HPCwire.

The principal advice column takes on communicating district decisions you disagree with, optimizing virtual lunch bunches, and more.

The scene at Marjory Stoneman Douglas High School and the surrounding area after the shootings shifted from chaos and panic to grief, anger, and calls for swift and aggressive action to prevent other school attacks.

Scientists converted the patient’s own cells into blood sugar-regulating cell clusters before injecting them back into her abdomen—and one year later, she still doesn't need insulin injections

The votive plaque was found amid the ruins of an ancient Roman fortress. Researchers think a temple dedicated to the mysterious deity may have stood nearby

A new film revisits the 90 minutes before the first episode of "Saturday Night Live" premiered on NBC on October 11, 1975

The last crew of the Logos reunites for a never-to-be-forgotten weekend.

Montevideo, Uruguay :: A Logos Hope crewmember relies on God for strength and the words to say to disruptive inmates at a prison.

A team at the Paul Scherrer Institute (PSI) has achieved a breakthrough with the Kagome superconductor RbV3Sb5, demonstrating time-reversal symmetry (TRS) breaking at 175 Kelvin. This discovery at higher temperatures than typically possible could pave the way for more energy-efficient and practical quantum systems, crucial for quantum computing and storage. The TRS-breaking properties are tunable, offering potential for further advancements in quantum technology, with implications for applications beyond laboratory settings.

Sonali Bendre and Goldie Behl tied the knot in a lavish ceremony on November 12, 2002

The couple's sudden wedding announcement took many by surprise, with fans expressing their shock over the actor's private relationship and quick wedding

Attorney General Jennings today called on U.S. Attorney General William Barr to reverse his abrupt change to a 40-year-old U.S. Department of Justice policy that until this week had kept the department from interfering with election results. In a letter to AG Barr, AG Jennings and 22 other attorneys general strongly objected to a November […]

Consulting firms in the Middle East are likely to take a hit in 2020 due to the coronavirus, after two strong years.

FDI into Brazil has increased by 66.48% in a little under two years. Jonathan Wildsmith reports.

As of Nov. 12, get the JBL Clip 4 for just $39.95 at Walmart, which is $35.04 off its normal price.

The Yamal-Europe pipeline that usually delivers Russian gas to Western Europe was sending the fuel back to Poland for a ninth straight day yesterday, as per data from German network operator Gascade.

The House of Representatives yesterday waded into the ongoing controversy between the Nigeria Ports Authority (NPA) and Intels Nigeria Limited. The House, while adopting a motion by Rep Diri Douye (PDP, Bayelsa), resolved to constitute an ad hoc panel to probe the circumstances that led to NPA’s decision to terminate an existing contract between it […]

Reps ask NPA to reverse termination of agreement with Intels

The Trump administration is attempting to dial down the tension with Iran, lowering the risk of military conflict and pushing for diplomatic negotiations.

Male pattern baldness could soon be a thing of the past, with new hair loss treatments beginning to show tantalising results

A mathematical proof shows that some quantum states can resist nature’s tendency to disorder – but only under very specific conditions

Shapes created by vortices in water often fall apart, but an odd quantum fluid made from ultracold atoms could support vortex knots that never lose their knottiness

Shapes created by vortices in water often fall apart, but an odd quantum fluid made from ultracold atoms could support vortex knots that never lose their knottiness

Title: PFAS 'Forever Chemicals' Linked With Liver Cancer
Category: Health News
Created: 8/10/2022 12:00:00 AM
Last Editorial Review: 8/10/2022 12:00:00 AM

Title: Breakthrough Might Break Down PFAS 'Forever Chemicals'
Category: Health News
Created: 8/19/2022 12:00:00 AM
Last Editorial Review: 8/19/2022 12:00:00 AM

Title: Concussion Recovery Can Reverse After Return to Activity, Study Shows
Category: Health News
Created: 8/28/2014 9:36:00 AM
Last Editorial Review: 8/28/2014 12:00:00 AM

Title: Mouse Study Suggests Stem Cells May Reverse Stroke Damage
Category: Health News
Created: 8/22/2016 12:00:00 AM
Last Editorial Review: 8/23/2016 12:00:00 AM

Mitochondrial dysfunction is a hallmark of many genetic neurodegenerative diseases, but therapeutic options to reverse mitochondrial dysfunction are limited. While recent studies support the possibility of improving mitochondrial fusion/fission dynamics and motility to correct mitochondrial dysfunction and resulting neurodegeneration in Charcot-Marie-Tooth disease (CMT) and other neuropathies, the clinical utility of reported compounds and relevance of preclinical models are uncertain. Here, we describe motor and sensory neuron dysfunction characteristic of clinical CMT type 2 A in a CRISPR/Casp-engineered Mfn2 Thr105Met (T105M) mutant knock-in mouse. We further demonstrate that daily oral treatment with a novel mitofusin activator derived from the natural product piperine can reverse these neurologic phenotypes. Piperine derivative 8015 promoted mitochondrial fusion and motility in Mfn2-deficient cells in a mitofusin-dependent manner and reversed mitochondrial dysfunction in cultured fibroblasts and reprogrammed motor neurons from a human CMT2A patient carrying the MFN2 T105M mutation. Like previous mitofusin activators, 8015 exhibited stereospecific functionality, but the more active stereoisomer, 8015-P2, is unique in that it has subnanomolar potency and undergoes entero-hepatic recirculation which extends its in vivo half-life. Daily administration of 8015-P2 to Mfn2 T105M knock-in mice for 6 weeks normalized neuromuscular and sensory dysfunction and corrected histological/ultrastructural neurodegeneration and neurogenic myoatrophy. These studies describe a more clinically relevant mouse model of CMT2A and an improved mitofusin activator derived from piperine. We posit that 8015-P2 and other piperine derivatives may benefit CMT2A or other neurodegenerative conditions wherein mitochondrial dysdynamism plays a contributory role.

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7–10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain.

Reverb features new works by Es Devlin and Theaster Gates, plus Devon Turnbull's Listening Room.

The post The Vinyl Factory: Reverb exhibition extended until 22 December appeared first on Fact Magazine.

When nightmarish sci-fi extraction shooter The Forever Winter launched into early access in September it was somewhat messy. Bugs and maddening enemy spawns diminished the tension of being a fleshy human scavenger in a mech battlefield. But one feature annoyed some players much more - fresh water. See, you need to keep your headquarters stocked with water, as it gets steadily used by your settlement's inhabitants. The catch being that this water diminishes even while you're not playing the game. If it runs out completely, then everything you've collected gets wiped. The developers have listened to complaints about this most Farmville of mechanics, and they've answered in an interesting way. Water thieves! Now, on top of the usual downward trickle, burglars will come to steal your H2O as well.

It's not as bad as it sounds.

Read more

Donald Trump will embrace the truth Joe Biden has refused to countenance: Israel's enemies are America's enemies. And when Israel defeats its enemies, America wins.

It’s become a joke to talk about Cave Story and Dark Souls when describing other games, but in the case of Momodora: Reverie Under the Moonlight, I’d be remiss not to: the series has never been shy about its influences. In Reverie, the fourth game of the Momodora series, rdein has done a fantastic job […]

Male pattern baldness could soon be a thing of the past, with new hair loss treatments beginning to show tantalising results

We spoke to Dr Ian Paul, who is a reverend and member of General Synod and the Archbishops’ Council.

On May 13, 1985, after a long standoff, Philadelphia municipal authorities dropped a bomb on the headquarters of the African-American radical group MOVE. In the documentary Let the Fire Burn, director Jason Osder uses archival footage to chronicle the years of tension that ended in tragedy.

The new president-elect can go beyond just pulling out of the Paris Agreement. But it may be more difficult to roll back clean energy policies

Forever Youth Liberator Serum Video

Jon recently started a new project. When setting up his dev environment, one of his peers told him, "You can disable verbose logging by setting DEBUG_LOG=false in your config file."

Well, when Jon did that, the verbose logging remained on. When he asked his peers, they were all surprised to see that the flag wasn't turning off debug logging. "Hunh, that used to work. Someone must have changed something…" Everyone had enough new development to do that tracking down a low priority bug fell to Jon. It didn't take long.

const DEBUG_LOG = process.env.DEBUG_LOG || true

According to the blame, the code had been like this for a year, the commit crammed with half a dozen features, was made by a developer who was no longer with the company, and the message was simply "Debugging". Presumably, this was intended to be a temporary change that accidentally got committed and no one noticed or cared.

Jon fixed it, and moved on. There was likely going to be plenty more to find.

Shapes created by vortices in water often fall apart, but an odd quantum fluid made from ultracold atoms could support vortex knots that never lose their knottiness

Switzerland has proposed introducing the value-added tax reverse charge mechanism for domestic transactions in emission allowances.

The Irish headline rate of VAT will return to 23 percent from March, having been temporarily reduced in response to the COVID-19 pandemic.

On September 24, 2020, HM Revenue and Customs released in-depth guidance on the introduction of the VAT reverse charge mechanism on the supply of building or construction services.

A new peer-reviewed study published today in the journal Environmental Health Perspectives reveals that per- and polyfluoroalkyl substances (PFAS), often

Researchers in Australia have identified a previously unknown population of stem cells fibroblast growth factor 18 (FGF18) stimulated Gremlin 1 cells,

I was literally confused to deployment testing services and testing scenarios, but thank to my one friend who advised me to use the computaris “top testing suite”. It was the...