La máxima competición continental arranca este jueves con hasta 91 jugadores que han pasado por franquicias estadounidenses. Osman, Vezenkov, Fournier, Garuba o Metu, entre los llegados este verano. El Barça es el equipo con más partidos NBA en su plantilla Leer

What is the data strategy for the Defense Information Systems Agency (DISA)? How is DISA leveraging data as a strategic asset? Join host Michael Keegan as he explores these questions and more with Caroline Kuharske, Acting Chief Data Officer, DISA.

The post Data leveraging at the Defense Information Systems Agency: A conversation with Caroline Kuharske first appeared on Federal News Network.

Microlise has Mike Blackburn as its new Chief Revenue Officer. Mike is set to lead the sales and marketing teams in driving revenue generation and accelerating growth.

Microlise Group, the global provider of innovative technology solutions, has announced the adoption of its software by Creed Foodservice, the UK provider of high-quality food & beverage products to the catering industry. 

Newer technologies like automation and AI may offer new solutions to this age-old cybersecurity problem, but they can also be double-edged swords.

The post Endpoint proliferation exacerbates old cybersecurity problem: data integration first appeared on Federal News Network.

"Hurricane Helene caused deadly and destructive flooding when it swept through the Southeast on Sept. 26-29, 2024."

A research facility in Yemassee, S.C., has recovered 25 of the 43 monkeys that escaped from the laboratory last week after a caretaker accidentally left the door to their enclosure unsecured.

(The Center Square) — Several North Carolina cities rank among those with the highest increases in homicide rates in the United States over the last two years, according to a recent analysis.

When conjuring an image of a poet in your mind, you might imagine a brooding, isolated academic type…

En 10AM Hoy por Hoy de Caracol Radio estuvo la representante a la Cámara, Carolina Giraldo, para hablar sobre la prohibición de las terapias de conversión en Colombia.

En 10AM Hoy por Hoy de Caracol Radio estuvo Carolina Corcho, exministra de Salud, para hablar de la polémica ‘red ciudadana solidaria’, que serviría para brindar un apoyo a personas que tienen dificultades para acceder a medicamentos.

La Procuraduría los investigará por presuntas irregularidades en la revocatoria de la concesión del muelle 13 de Buenaventura

Tourists stayed away from western North Carolina this year after Helene swept through the area, and towns that depend on leaf lookers are bracing for big losses.

He says Ray Allen talked to him about enrolling

More than 100 members of the Royal Bermuda Regiment are preparing to travel to the US this weekend for an intense two-week training exercise. A spokesperson said, “The overseas deployment at Marine Corps Base Camp Lejeune, in North Carolina, will allow soldiers and officers to hone skills in larger facilities and more varied environments than […]

Trey Mallory and his UNC Wilmington [UNCW] men’s tennis teammates began competing in the DI 2024 ITA DI men’s Carolina regional championships hosted by Duke University, in Durham, North Carolina. In his round of 64 men’s singles match, Mallory was defeated in straight sets 6-4, 7-5 by Matias Iturbe from UNC Charlotte. Related Stories Photos: […]

Trey Mallory and his UNC Wilmington [UNCW] Men’s Tennis teammate’s returned to action competing in the 2024 ITA DI Men’s Carolina Regional Championships hosted by Duke University, in Durham, North Carolina. In his consolation first round match, Mallory lost in a third set tie-breaker to Johan Van Wijk, from Gardner-Webb University. Gardner-Webb won the first […]

Nisaiah Berkeley and her Lander University women’s rugby teammates defeated Coastal Carolina by a score of 36 – 0. Berkeley and her teammates played their first match in 2024 after they lost in the NIRA national championships in November. The result marked Lander’s sixth overall victory over Coastal Carolina University. Related Stories Jamin Hodgkins Kicks […]

Tyler James earned a first place and a third place finish while competing at the Bruce’s Field II Horse Show in South Carolina. A spokesperson said, “The Bermuda Equestrian Federation extends its congratulations to Tyler James on his recent achievements at the October at Bruce’s Field II Horse Show held from October 24 to October […]

In the wake of the devastation rendered by Hurricane Helene, Carolina Furfare released a newsletter on October 1 stating the cancellation of the event that was to occur this weekend, and indicating that the hotels and facilities were needed in order to assist with rescue and sheltering efforts after the Hurricane hit the mountainous region.

This weather event hit the top ten most fatal and costly hurricanes in the United States even before full recovery efforts could be finalized. People who pre-registered have been given the option to roll over to next year, or to Bewhiskered 2025; due to the cancellation being so close to event day they cannot guarantee refunds for now.

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The FEMA official who was just fired for telling workers to avoid homes impacted by the hurricanes in Florida if they had Trump signs says that it was not “isolated” and that FEMA workers were instructed to do it in the Carolinas too. (X) The American people must get justice. Indict and convict. So, apparently this …

Nuclear proliferation in a fragmenting world 13 September 2022 — 1:00PM TO 2:00PM Anonymous (not verified) 5 September 2022 Online

Where does the Treaty on the Non-Proliferation of Nuclear Weapons (NPT) stand in 2022?

With the war in Ukraine and China–US tensions rising, the threat of a nuclear arms race has never been as high since the Cold War.

Global efforts to control the appropriation and use of nuclear weapons are strained with the war in Ukraine, US–Russia and US–China tension, Iran on the nuclear threshold, instability in Pakistan and the ongoing threat from North Korea.

The Review Conference of the NPT that took place in New York this August sought to deal with the multiple nuclear threats, but new missile technology such as hypersonic glide vehicles and torpedoes are not covered by a treaty.

Russia and the US are in a development phase for a host of new technologies and delivery systems, especially after both withdrew from various arms-control treaties in the 2000s and 2010s. Now the nuclear stockpile is growing again and major superpowers are adopting confrontational geostrategic positions.

As the world’s established orders and system fragment, there is a possibility the nine countries with confirmed nuclear weapons could grow. Events in Ukraine highlight the need for a new, modern agreement on nuclear weapons control, needed today more than ever.

The panel of experts discuss key questions including:

• What did ‘RevCon’ in New York tell us about the adoption or update to the NPT?

• Will the war in Ukraine deter or prevent any agreement between nations or does nuclear weapons control represent an area of potential multilateral harmony?

• Are we likely to see a new arms race akin to the Cold War? Where does China fit into this race?

• How has technology changed the arms control landscape?

 As with all Chatham House member events, questions from members drive the conversation.

World in brief: Ukraine and nuclear proliferation to dominate G7 The World Today mhiggins.drupal 28 March 2023

Following Russia’s ongoing intimidation, Japan will use its presidency of the G7 – and its history – to prioritize the dangers of nuclear threats, writes James Orr.

Two issues are expected to dominate the agenda as Japan hosts the G7 summit in Hiroshima from May 19-21. Central to talks will be the conflict in Ukraine, with member states eager to highlight a message of unity and resolve in the face of Russia’s continuing aggression.

Fumio Kishida, Japan’s prime minister, made an unannounced visit to Kyiv on March 21, meeting the Ukrainian president Volodymyr Zelenskyy.  This coincided with a visit to Moscow by China’s leader Xi Jinping, who described Russian president Vladimir Putin as a friend and partner.

‘Absolutely unacceptable’

Hosting the G7 summit in Hiroshima is significant, too, with Kishida expected to emphasize the ‘absolutely unacceptable’ threat of nuclear proliferation. Ongoing tensions between China and Taiwan, together with recent North Korean ballistic missile tests, have heightened fears of a breakdown in security in the region.

Meanwhile, President Vladimir Putin’s menacing references to the use of nuclear weapons in Ukraine has raised the prospect of a potentially devastating conflict with NATO. ‘Kishida’s principal goal for the presidency of the G7 is to try to draw the world away from the path of destruction that is another nuclear conflict,’ said Duncan Bartlett, a research associate at SOAS, the School of Oriental and African Studies, in London.

‘Early last year, Putin warned of terrible consequences if NATO and the West interfered in the Ukraine conflict, and that was widely seen as being a nuclear threat. North Korea is also pursuing its nuclear weapons programme, and in February an intercontinental ballistic missile went into the sea just near the northern Japanese island of Hokkaido,’ said Bartlett.

After Russia invaded Ukraine in February 2022, Kishida has taken a firm position on Putin, in line with his G7 peers. President Zelenskyy has addressed the Japanese parliament via video link and Dmytro Kuleba, Ukraine’s minister of foreign affairs, was invited by his Japanese counterpart to a G7 meeting held during the Munich Security Conference earlier this year.

Kishida committed $600 million in financial support to Ukraine and his government may well announce the provision of further non-lethal assistance to Zelenskyy at the summit. The country’s constitution effectively outlaws the export of deadly weapons to foreign forces. On his visit to Kyiv, Kishida promised a further $30 million to Ukraine.

‘Kishida has revised key defence documents and is pursuing a radical and controversial expansion of Japan’s defence budget and capabilities,’ said Hugo Dobson, Professor of Japan’s International Relations at the University of Sheffield.

‘He and his G7 partners have signed historic defence agreements, pledged to strengthen ties or declared the inseparability of their security in light of actual conflict in Ukraine and potential conflict in East Asia. Kishida has linked the two by emphasizing that Ukraine today may be East Asia tomorrow,’ said Dobson.

Aside from security matters, Kishida will at the summit address issues on clean energy, climate change, global health and boosting multilateral cooperation to drive post-pandemic economic recovery.

Invitation to Nagasaki

He is understood to have invited President Joe Biden to visit Nagasaki, where the second of America’s two atomic bombs is estimated to have killed 60,000 people in August 1945. No sitting US president has ever visited the city, and Kishida, who grew up in Hiroshima, may see the visit as an opportunity to boost his flagging domestic approval ratings. It may also serve as a timely reminder to Russia and others that the G7 opposes any future nuclear weapon use.

Chi-Liang Eric Yen
Nov 1, 2008; 49:2283-2301
Thematic Reviews

K Schoonjans
May 1, 1996; 37:907-925
Reviews

Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element–binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing Δ1-pyrroline-5-carboxylate (P5C) to proline through the oxidation of NAD(P)H. Many cancers alter their proline metabolism by up-regulating the proline cycle and proline biosynthesis, and knockdowns of PYCR1 lead to decreased cell proliferation. Thus, evidence is growing for PYCR1 as a potential cancer therapy target. Inhibitors of cancer targets are useful as chemical probes for studying cancer mechanisms and starting compounds for drug discovery; however, there is a notable lack of validated inhibitors for PYCR1. To fill this gap, we performed a small-scale focused screen of proline analogs using X-ray crystallography. Five inhibitors of human PYCR1 were discovered: l-tetrahydro-2-furoic acid, cyclopentanecarboxylate, l-thiazolidine-4-carboxylate, l-thiazolidine-2-carboxylate, and N-formyl l-proline (NFLP). The most potent inhibitor was NFLP, which had a competitive (with P5C) inhibition constant of 100 μm. The structure of PYCR1 complexed with NFLP shows that inhibitor binding is accompanied by conformational changes in the active site, including the translation of an α-helix by 1 Å. These changes are unique to NFLP and enable additional hydrogen bonds with the enzyme. NFLP was also shown to phenocopy the PYCR1 knockdown in MCF10A H-RASV12 breast cancer cells by inhibiting de novo proline biosynthesis and impairing spheroidal growth. In summary, we generated the first validated chemical probe of PYCR1 and demonstrated proof-of-concept for screening proline analogs to discover inhibitors of the proline cycle.

Xinting Zhang
Dec 8, 2020; 0:RA120.002306v1-mcp.RA120.002306
Research

RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer.

The assembly of the postsynaptic transmitter sensing machinery at inhibitory nerve cell synapses requires the intimate interplay between cell adhesion proteins, scaffold and adaptor proteins, and γ-aminobutyric acid (GABA) or glycine receptors. We developed an in vitro membrane system to reconstitute this process, to identify the essential protein components, and to define their mechanism of action, with a specific focus on the mechanism by which the cytosolic C terminus of the synaptic cell adhesion protein Neuroligin-2 alters the conformation of the adaptor protein Collybistin-2 and thereby controls Collybistin-2-interactions with phosphoinositides (PtdInsPs) in the plasma membrane. Supported hybrid membranes doped with different PtdInsPs and 1,2-dioleoyl-sn-glycero-3-{[N-(5-amino-1-carboxypentyl)iminodiacetic acid]succinyl} nickel salt (DGS-NTA(Ni)) to allow for the specific adsorption of the His6-tagged intracellular domain of Neuroligin-2 (His-cytNL2) were prepared on hydrophobically functionalized silicon dioxide substrates via vesicle spreading. Two different collybistin variants, the WT protein (CB2SH3) and a mutant that adopts an intrinsically 'open' and activated conformation (CB2SH3/W24A-E262A), were bound to supported membranes in the absence or presence of His-cytNL2. The corresponding binding data, obtained by reflectometric interference spectroscopy, show that the interaction of the C terminus of Neuroligin-2 with Collybistin-2 induces a conformational change in Collybistin-2 that promotes its interaction with distinct membrane PtdInsPs.

Glutathionylation is an important posttranslational modification that protects proteins from further oxidative damage as well as influencing protein structure and activity. In the present study, we demonstrate that the cysteine-42 residue in protein arginine N-methyltransferase 5 (PRMT5) is glutathionylated in aged mice or in cells that have been exposed to oxidative stress. Deglutathionylation of this protein is catalyzed by glutaredoxin-1 (Grx1). Using mutagenesis and subsequent biochemical analyses, we show that glutathionylation decreased the binding affinity of PRMT5 with methylosome protein-50 (MEP50) and reduced the methyltransferase activity of PRMT5. Furthermore, overexpression of PRMT5-C42A mutant caused a significant increase in histone methylation in HEK293T and A549 cells and promoted cell growth, whereas overexpression of the PRMT5-C42D mutant, a mimic of glutathionylated PRMT5, inhibited cell proliferation. Taken together, our results demonstrate a new mechanism of regulation of PRMT5 methyltransferases activity and suggest that PRMT5 glutathionylation is partly responsible for reactive oxygen species-mediated cell growth inhibition.

Gonadal soma-derived factor (gsdf) has been demonstrated to be essential for testicular differentiation in medaka (Oryzias latipes). To understand the protein dynamics of Gsdf in spermatogenesis regulation, we used a His-tag "pull-down" assay coupled with shotgun LC-MS/MS to identify a group of potential interacting partners for Gsdf, which included cytoplasmic dynein light chain 2, eukaryotic polypeptide elongation factor 1 alpha (eEF1α), and actin filaments in mature medaka testis. As for the interaction with TGFβ-dynein being critical for spermatogonial division in Drosophila melanogaster, the physical interactions of Gsdf-dynein and Gsdf-eEF1α were identified through a yeast 2-hybrid (Y2H) screening of an adult testis cDNA library using Gsdf as bait, which were verified by a paired Y2H assay. Co-immunoprecipitation of Gsdf and eEF1α was defined in adult testes as supporting the requirement of a Gsdf and eEF1α interaction in testis development. Proteomics analysis (data are available via ProteomeXchange with identifier PXD022153) and ultrastrutural observations showed that Gsdf deficiency activated eEF1α-mediated protein synthesis and ribosomal biogenesis, which in turn led to the differentiation of undifferentiated germ cells. Thus, our results provide a framework and new insight into the coordination of a Gsdf (TGFβ and eEF1α complex in the basic processes of germ cell proliferation, transcriptional and translational control of sexual RNA which may be fundamentally conserved across phyla during sexual differentiation.

The Dallas Cowboys agreed to trade a fourth-round pick in the 2025 NFL Draft to the Carolina Panthers in exchange for wide receiver Jonathan Mingo and a seventh-round pick, a league source told UPI on Tuesday.

The Carolina Panthers signed running back Chuba Hubbard to a four-year contract extension worth $33.2 million, a league source told UPI on Thursday.

A South Carolina woman ended up calling the police for help after she walked into her apartment's bathroom and found a large ball python behind her toilet.

Police in a small South Carolina town are warning residents to keep their doors and windows locked after 43 monkeys escaped from a research facility.

A North Carolina man's age turned out to be a lucky number when it inspired him to buy a scratch-off lottery ticket worth $200,000.

The state's two virtual charter schools have earned poor marks from the state's accountability system in the few years they've been operating.

U.S. Ed Secretary DeVos has approved plans for 46 states, plus the District of Columbia and Puerto Rico. Still waiting: California, Florida, Oklahoma, and Utah.

A sea of red-clad teachers took to the streets around North Carolina's legislative building in Raleigh to fight for higher pay and more school funding. See photos from the event.

Cursive writing is experiencing a resurgence of sorts in North Carolina elementary schools thanks to a state law that was passed in 2013.

Thousands of North Carolina teachers will take leave on May 16 to protest at the state capitol, forcing some school districts to close.