Calling all idle Hollywood creative types and wannabe filmmakers. Roger Corman, 94, challenges you to make a short film for his Quarantine Film Festival.

Rogosin's longest-running success was the classic TV western 'The Virginian'

Celtic legend Chris Sutton has bitten back Robbie Savage on Twitter, as the Hoops finished the week top of the Scottish Premiership table, after Rangers’ 1-1 draw against Hearts.

Novak Djokovic has reduced the gap to Roger Federer's record significantly over the past two years.

Roger Federer and Rafael Nadal are both waiting for the signal to resume action.

There is an ongoing debate to crown a member of the 'Big Three' as the greatest of all time.

Todd Martin coached Novak Djokovic in his formative years on the ATP Tour and knows what makes him special.

Ivan Lendl has weighed in on the ongoing GOAT debate.

Rangers boss Steven Gerrard has admitted that he's pleased with the "definite progress" the team is making at Ibrox, ahead of the Gers Scottish Premiership tie against St Johnstone, with the manager explaining one key Celtic comparison in the title race.

Ivan Lendl has weighed in on the ongoing GOAT debate.

MICROSOFT CORPORATION seeks a Senior Program Manager in Redmond, WA: Coordinate program dev. of comp. softw. applications, sys. or services, working with dev. and prod. planning teams. Write functional specs and apply principles and tech. of comp. sci., eng., or math analysis. Areas of resp. sp

Woolpert, Inc. is a cutting-edge national architecture, engineering and geospatial (AEG) firm that delivers value to clients by blending engineering excellence with innovative technology and geospatial applications. Woolpert was recently certified as an Employer of Choice by Great Place To Work

Woolpert, Inc. is a cutting-edge national architecture, engineering and geospatial (AEG) firm that delivers value to clients by blending engineering excellence with innovative technology and geospatial applications. Woolpert was recently certified as an Employer of Choice by Great Place To Work

DUTIES: **All applications must be submitted by January 31, 2018, at http://www.mdc.mo.gov/about/jobs. **Any applications submitted through external sources will not be reviewed. Works as a member of the Infrastructure Asset Management Program Team and supports the Design and Development Divisi

DUTIES: **All applications must be submitted by January 31, 2018, at http://www.mdc.mo.gov/about/jobs. **Any applications submitted through external sources will not be reviewed. Works as a member of the Infrastructure Asset Management Program Team and supports the Design and Development Divisi

Mission: Engineer responsible for performing structure inspections in accordance with MetroLink's Structures Inspection Program, structural review of design calculations, plans, and specifications, design and construction oversight of structural repairs, providing engineering support as re

Structural Engineer/Programmer SDS/2 (d.b.a., "Design Data Corporation") is seeking two (2) civil engineers, for their Lincoln, Nebraska, location, with knowledge of structural steel and computer programming who can analyze, develop, modify, enhance, and/or write computer code while incorporatin

Microsoft Corporation seeks a Program Manager II in Redmond, WA: Resp for coordinating prgm dvlpmt of computer SW apps, sys/services, wrkng with dev and prod planning teams. Write funct specs & apply principles & technqs of CS/Engg/Math. Resp. for prod life cycle & owning/contrib to vision & strateg

BARNES AND NOBLE has a regular summer reading programme every year - but will they launch the same thing this year amid the coronavirus outbreak?

Kurt Koehler, founder and president of AlGalCo, shows his HOT (Hydrogen on Tap) system.

Penske has seen his company's stock price fall by 40%, his new racing series suspended and the Indy 500 scheduled outside of May for the first time

This week, PrepVolleyball.com released its Class of 2020 recruiting rankings. The Hoosiers came in at No. 15 — a program best.

This week, PrepVolleyball.com released its Class of 2020 recruiting rankings. The Hoosiers came in at No. 15 — a program best.

This week, PrepVolleyball.com released its Class of 2020 recruiting rankings. The Hoosiers came in at No. 15 — a program best.

Three boys grew up knowing someone named Roger Brown was their grandfather. Then, one day, they began to understand the legacy of the Pacers legend.

The Pacers didn't have their starting point guard for the last three games before the NBA went on hiatus, but he's able to play if/when it restarts.

The Pacers didn't have their starting point guard for the last three games before the NBA went on hiatus, but he's able to play if/when it restarts.

This week, PrepVolleyball.com released its Class of 2020 recruiting rankings. The Hoosiers came in at No. 15 — a program best.

How best for the party to get its message across to voters.

velocityconf: New #velocityconf CA program preview is up: http://t.co/rKjf91RXdD @ariyahidayat on End-to-End JS Quality Analysis.

If you’re a big business and you abused the Small Business Association’s new Paycheck Protection Program, you’re getting very close to the deadline for you to pay the government back. If you don’t, that means the government is going to be coming after you — and you can definitely be ready for an audit. That’s…

The post Big Businesses That Abused Paycheck Protection Program Should Get Ready for an Audit appeared first on The Western Journal.

Joshua Summers, CEO of linear television supply-side platform clypd, discusses the major advanced targeting trends expected to infiltrate traditional TV ad buying within the next year.

There’s no perfect process for hiring great programmers, but there are plenty of terrible ways to screw it up. We’ve rejected the industry stables of grilling candidates in front of a whiteboard or needling them with brain teasers since the start at Basecamp. But you’re not getting around showing real code when applying for a… keep reading

Part of the They've got the look promo for the BBC UK Homepage

Part of the Food for thought promo for the BBC UK Homepage

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.

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.

Chatham House is pleased to announce that Dr Lina Khatib has joined the institute as head of the Middle East and North Africa Programme.

Creon Butler has been appointed to lead the Global Economy and Finance programme at Chatham House, joining the institute at the beginning of December. He will also form part of the institute’s senior leadership team.

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.

Formate oxidation to carbon dioxide is a key reaction in one-carbon compound metabolism, and its reverse reaction represents the first step in carbon assimilation in the acetogenic and methanogenic branches of many anaerobic organisms. The molybdenum-containing dehydrogenase FdsABG is a soluble NAD+-dependent formate dehydrogenase and a member of the NADH dehydrogenase superfamily. Here, we present the first structure of the FdsBG subcomplex of the cytosolic FdsABG formate dehydrogenase from the hydrogen-oxidizing bacterium Cupriavidus necator H16 both with and without bound NADH. The structures revealed that the two iron-sulfur clusters, Fe4S4 in FdsB and Fe2S2 in FdsG, are closer to the FMN than they are in other NADH dehydrogenases. Rapid kinetic studies and EPR measurements of rapid freeze-quenched samples of the NADH reduction of FdsBG identified a neutral flavin semiquinone, FMNH•, not previously observed to participate in NADH-mediated reduction of the FdsABG holoenzyme. We found that this semiquinone forms through the transfer of one electron from the fully reduced FMNH−, initially formed via NADH-mediated reduction, to the Fe2S2 cluster. This Fe2S2 cluster is not part of the on-path chain of iron-sulfur clusters connecting the FMN of FdsB with the active-site molybdenum center of FdsA. According to the NADH-bound structure, the nicotinamide ring stacks onto the re-face of the FMN. However, NADH binding significantly reduced the electron density for the isoalloxazine ring of FMN and induced a conformational change in residues of the FMN-binding pocket that display peptide-bond flipping upon NAD+ binding in proper NADH dehydrogenases.

Mohamad Navab
Jun 1, 2004; 45:993-1007
Thematic Reviews

IJ Goldberg
Apr 1, 1996; 37:693-707
Reviews