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There’s a very definite Tokyo-area bias in this survey from goo Ranking into which factory tours people would want to go on; the pictured food sample factory is not one of them, though. The only factory tours I’ve been on in Japan were three times to the Yamazaki distillery tour and tasting and once to […]

Two thousand workers from the Amalgamated Transit Union’s Local 1181 voted overwhelmingly to authorize the strike against their employer, which operates about 900 of the city’s more than 8,000 school bus routes.

The versatile actor vaulted to international stardom after playing a police inspector in the 2008 film. Khan, 54, was adored in India despite not being a Bollywood heartthrob.

Indian actor Irrfan Khan, 54, who leaped from small parts in Bollywood films to featured roles in Hollywood blockbusters such as Slumdog Millionaire and Jurassic World, has died after a long illness.

While some people said they were able to file a claim with the state Employment Development Department on Tuesday, many others said they were frustrated that the online portal malfunctioned.

‘Hamilton’ star Renee Elise Goldsberry, Drama Desk Award winner Montego Glover, Thom Sesma, Angel Desai, Kendyl Ito, William Jackson Harper, Tony Award winner Brian Stokes Mitchell will join Uggams in the comedy about a wealthy novelist who invites the eccentric clairvoyant to his home to conduct a séance, hoping to gather material for his next book. And Uggams is playing the medium, named Madame Arcati.

James Lipton, the Emmy-winning drama dean who hosted revealing conversations about the acting craft on "Inside the Actors Studio," has died at age 93.

Known for his rugged roles and handsome charm, Whitman had more than 180 film and TV credits

Mark Blum, who was in several recent episodes of 'You' and was known for his role in 'Crocodile Dundee,' died from coronavirus-related complications.

The drop in foreign orders is devastating workers in the Southeast Asian country, which counts on the garment industry for 40% of its economic output. Those still employed now fear contracting COVID-19 inside cramped factories.

Mexican officials have begun to cave, despite warnings from health authorities

Patricia Bosworth, an actor who went on to chronicle lives including Jane Fonda's, Marlon Brando's and her own, died from coronavirus. She was 86.

What crime novelist Laura Lippman is reading and watching in quarantine

The Times examined the filmographies of the last five years' worth of lead-actor academy award nominees to see how many female filmmakers they've worked with.

"Joker" isn't the movie I'd give Joaquin Phoenix an Oscar for, but his greatness as an actor can't be denied.

Actor Joshua Morrow of "The Young and the Restless" fame has sold his remodeled home in Lake Sherwood for $4.85 million.

Actor Kevin Sorbo, famous for playing Hercules, is asking $3.95 million for his Mediterranean villa in Westlake Village.

Actor Ronen Rubinstein finds that cooking in his light-filled kitchen — and pasta — help him keep a positive attitude as he isolates at home.

Actor Larry Joe Campbell of "According to Jim" has sold his longtime home in Rancho Palos Verdes for $2.138 million.

Oscar-nominated actor Gary Sinise is asking $3.795 million for his two-story farmhouse in the hills of Calabasas after 12 years of ownership.

Tesla's electric car factory was operating as usual Tuesday, despite a San Francisco Bay Area multi-county "shelter in place" lockdown.

A tribute to Tony- and Emmy-winner Shirley Knight, an exemplar of Method who learned from the best of the Actor Studio stars.

A regular in Fox's '9-1-1: Lone Star,' Smith has gotten a lot of reading done as he waits out the pandemic in a friend's guestroom.

For actor Andrew Howard, who played Red Scare in HBO's 'Watchmen,' food is a sense-memory trigger when he prepares for a role.

Sam Lloyd, known for his role as lawyer Ted Buckland in "Scrubs," died April 30 from complications of lung cancer. He was 56.

General Motors' first-quarter net income fell 88 per cent, but it still managed to make US$247 million despite the arrival of the global coronavirus pandemic.

NOT since the final whistle went in Munich at the end of the 2012 Champions League final has John Terry been in such a rush to get his kit on.

The play is the theater program's way of countering anti-drug programs that haven't worked — the kind where adults shake fingers at students.

Australian actor Chris Hemsworth will wield green flag, not Thor's hammer, at 2018 Indianapolis 500.

Purdue, along with Notre Dame, Gonzaga, Louisville and Kentucky are recruiting Dickinson. Duke is also in the mix but has yet to offer Dickinson.

Mike Pence will visit Kokomo Thursday to highlight the administration's response to the novel coronavirus pandemic.

A Bargersville man died in a head-on crash in Johnson County early Saturday morning. Police believe alcohol was a factor in the crash.

Formula 1 almost doubles the shutdown period for teams as the coronavirus crisis continues to play havoc with the 2020 championship.

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Girls who fled Boko Haram attacks are being enslaved and raped by human traffickers who then sell their babies.

• Elon Musk says Tesla may leave its Palo Alto headquarters and Fremont, California factory. 
• In a tweet Saturday morning, the chief executive continued his outrage against shelter-in-place orders that have forced most non-essential businesses to close. 
• Last week, Musk likened the rules to fascism, and urged leaders to "give people their goddamn freedom back." 
• Visit Business Insider's homepage for more stories.

After a week of decrying coronavirus shelter-in-place orders that have left Tesla's main factory shuttered and unable to produce vehicles, Elon Musk says the company may move its factory out of the state.

"Tesla is filing a lawsuit against Alameda County immediately," the chief executive said on Twitter Saturday morning. "The unelected & ignorant 'Interim Health Officer' of Alameda is acting contrary to the Governor, the President, our Constitutional freedoms & just plain common sense!"

That was followed up with a threat to move Tesla's headquarters outside the state.

"Frankly, this is the final straw," he replied. "Tesla will now move its HQ and future programs to Texas/Nevada immediately. If we even retain Fremont manufacturing activity at all, it will be dependent on how Tesla is treated in the future. Tesla is the last carmaker left in CA."

It wasn't immediately clear if a suit had yet been filed, or in which court Tesla will file the lawsuit. Most state and federal courts are closed on weekends and do not allow filing. In a subsequent Tweet, Musk alsourged shareholders to file a class action suit for damages caused by shutdown. 

Tesla's press relations department did not immediately respond to a request for comment. Alameda County did not immediately respond to a request for comment. 

Alameda County — the East Bay locale which includes Fremont, California, and Tesla's gigafactory about 30 miles southeast of San Francisco — extended its shelter-in-place order on April 29 "until further notice." Local authorities have not allowed Tesla to reopen the factory, and all manufacturing remains prohibited under the order.

The San Francisco Chronicle reported that Tesla was planning to resume some manufacturing operations at the factory as soon as last Wednesday, May 6. Local officials said it did not have permission to do so.

"Right now, the same health order is in place so nothing has changed," Fremont Police Department spokeswoman Geneva Bosques told Business Insider at the time. "Operating the assembly line was determined early on to be a violation."

Last week, following Tesla's first-quarter earnings announcement, Musk decried the shutdowns as a substantial risk to the company's financials.

"Frankly, I would call it forcible imprisoning of people in their homes against all of, their constitutional rights, in my opinion," he said on a conference call. "It's breaking people's freedoms in ways that are horrible and wrong and not why they came to America or built this country. What the f---. Excuse me. Outrage. Outrage."

"If somebody wants to stay in their house, that's great and they should be able to," he continued. "But to say they cannot leave their house and that they will be arrested if they do, that's fascist. That is not democratic — this is not freedom. Give people back their goddamn freedom."

Some states, including Texas, Georgia, and others, have begun to slowly allow certain businesses to re-open in recent weeks.

Musk praised counties neighboring Alameda, like San Joaquin for what he said were more "reasonable" responses. In a podcast released May 7, he told Joe Rogan that the company had learned from the coronavirus in China, where it briefly forced Tesla to close its Shanghai factory — a claim he repeated on Twitter Saturday. 

"Our castings foundry and other faculties in San Joaquin have been working 24/7 this entire time with no ill effects. Same with Giga Nevada," Musk said. "Tesla knows far more about what needs to be done to be safe through our Tesla China factory experience than an (unelected) interim junior official in Alameda County." 

As Musk began to complain about factory shutdowns in April, workers at Tesla's Fremont factory told Business Insider that the comments made them anxious.

"I'm for going back to work, but only if it is safe for me, my family, coworkers," said one production employee. "I don't feel like I'm being forced to stay home or that my freedom has been taken away. It's for the good of California."

Join the conversation about this story »

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The actor responded unfavorably to a tweet by McConnell's campaign, and the beef didn't stop there.

Bollywood star, Irrfan Khan, has died after being admitted to the intensive care unit at Mumbai's Kokilaben hospital.

After a long battle with cancer, Bollywood actor Rishi Kapoor has died.

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

The Mycobacterium tuberculosis virulence factor EsxA and its chaperone EsxB are secreted as a heterodimer (EsxA:B) and are crucial for mycobacterial escape from phagosomes and cytosolic translocation. Current findings support the idea that for EsxA to interact with host membranes, EsxA must dissociate from EsxB at low pH. However, the molecular mechanism by which the EsxA:B heterodimer separates is not clear. In the present study, using liposome-leakage and cytotoxicity assays, LC-MS/MS–based proteomics, and CCF-4 FRET analysis, we obtained evidence that the Nα-acetylation of the Thr-2 residue on EsxA, a post-translational modification that is present in mycobacteria but absent in Escherichia coli, is required for the EsxA:B separation. Substitutions at Thr-2 that precluded Nα-acetylation inhibited the heterodimer separation and hence prevented EsxA from interacting with the host membrane, resulting in attenuated mycobacterial cytosolic translocation and virulence. Molecular dynamics simulations revealed that at low pH, the Nα-acetylated Thr-2 makes direct and frequent “bind-and-release” contacts with EsxB, which generates a force that pulls EsxB away from EsxA. In summary, our findings provide evidence that the Nα-acetylation at Thr-2 of EsxA facilitates dissociation of the EsxA:B heterodimer required for EsxA membrane permeabilization and mycobacterial cytosolic translocation and virulence.

Research Event

Event participants

Fadi El-Jardali, Professor of Health Policy and Systems, American University of Beirut
Moderator: Nadim Houry, Executive Director, Arab Reform Initiative

The formation of translationally inactive 70S dimers (called 100S ribosomes) by hibernation-promoting factor is a widespread survival strategy among bacteria. Ribosome dimerization is thought to be reversible, with the dissociation of the 100S complexes enabling ribosome recycling for participation in new rounds of translation. The precise pathway of 100S ribosome recycling has been unclear. We previously found that the heat-shock GTPase HflX in the human pathogen Staphylococcus aureus is a minor disassembly factor. Cells lacking hflX do not accumulate 100S ribosomes unless they are subjected to heat exposure, suggesting the existence of an alternative pathway during nonstressed conditions. Here, we provide biochemical and genetic evidence that two essential translation factors, ribosome-recycling factor (RRF) and GTPase elongation factor G (EF-G), synergistically split 100S ribosomes in a GTP-dependent but tRNA translocation-independent manner. We found that although HflX and the RRF/EF-G pair are functionally interchangeable, HflX is expressed at low levels and is dispensable under normal growth conditions. The bacterial RRF/EF-G pair was previously known to target only the post-termination 70S complexes; our results reveal a new role in the reversal of ribosome hibernation that is intimately linked to bacterial pathogenesis, persister formation, stress responses, and ribosome integrity.

Invitation Only Research Event

Event participants

Megan Greene, Managing Director and Chief Economist, Manulife Asset Management 

Bacterial products such as lipopolysaccharides (or endotoxin) cause systemic inflammation, resulting in a substantial global health burden. The onset, progression, and resolution of the inflammatory response to endotoxin are usually tightly controlled to avoid chronic inflammation. Members of the NF-κB family of transcription factors are key drivers of inflammation that activate sets of genes in response to inflammatory signals. Such responses are typically short-lived and can be suppressed by proteins that act post-translationally, such as the SOCS (suppressor of cytokine signaling) family. Less is known about direct transcriptional regulation of these responses, however. Here, using a combination of in vitro approaches and in vivo animal models, we show that endotoxin treatment induced expression of the well-characterized transcriptional repressor Krüppel-like factor 3 (KLF3), which, in turn, directly repressed the expression of the NF-κB family member RELA/p65. We also observed that KLF3-deficient mice were hypersensitive to endotoxin and exhibited elevated levels of circulating Ly6C+ monocytes and macrophage-derived inflammatory cytokines. These findings reveal that KLF3 is a fundamental suppressor that operates as a feedback inhibitor of RELA/p65 and may be important in facilitating the resolution of inflammation.

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.

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

The formation of translationally inactive 70S dimers (called 100S ribosomes) by hibernation-promoting factor is a widespread survival strategy among bacteria. Ribosome dimerization is thought to be reversible, with the dissociation of the 100S complexes enabling ribosome recycling for participation in new rounds of translation. The precise pathway of 100S ribosome recycling has been unclear. We previously found that the heat-shock GTPase HflX in the human pathogen Staphylococcus aureus is a minor disassembly factor. Cells lacking hflX do not accumulate 100S ribosomes unless they are subjected to heat exposure, suggesting the existence of an alternative pathway during nonstressed conditions. Here, we provide biochemical and genetic evidence that two essential translation factors, ribosome-recycling factor (RRF) and GTPase elongation factor G (EF-G), synergistically split 100S ribosomes in a GTP-dependent but tRNA translocation-independent manner. We found that although HflX and the RRF/EF-G pair are functionally interchangeable, HflX is expressed at low levels and is dispensable under normal growth conditions. The bacterial RRF/EF-G pair was previously known to target only the post-termination 70S complexes; our results reveal a new role in the reversal of ribosome hibernation that is intimately linked to bacterial pathogenesis, persister formation, stress responses, and ribosome integrity.

SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.