Here's how the new Turner Classic Movies "Essentials" guest — the man behind "The Incredibles" and "Ratatouille" — has been influenced by Hitchcock, '50s sci-fi and James Bond.

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 former first lady and her A-list friends triumphed over late-night host James Corden and his squad.

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

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Octoshape announced a partnership with INVISO to deliver Internet TV contribution services throughout Latin America.

"At INVISO, we seek the most innovative and high quality products to serve our customers through the brands we represent,” said Jose Luis Reyes, Vice President for Sales and Operations, INVISO. “In the case of Octoshape, we found a company and a product that bring these qualities to our supply chain, sales and service.”

Octoshape offers an innovative cloud-based solution that provides instant infrastructure for the distribution of both linear and video on demand content. The Octoshape Infinite Uplink service provides point-to-point distribution of TV signals over the Internet for source signal acquisition to traditional IPTV and cable headends as an alternative to traditional methods like satellite and video fiber.

Democratic candidates need to show their math.

Punitive Medicaid work requirements are being rolled back.

Today, the explosion of development in artificial intelligence (AI) and machine learning (ML) technology has created a market for which it appears there’s no limit. No matter the industry, if you name a reasonably-sized (or larger) company, there’s a good chance that they’re investing in AI and ML technology as a cornerstone of their strategic […]

The post 4 High-Potential Sectors for AI and ML Startup Success appeared first on ReadWrite.

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.

Vancouver, Birtish Columbia (plus Victoria, Whistler)

Hear about travel to Victoria Falls as the Amateur Traveler talks to Nir Ben-Dov about his trip to this spectacular falls on the border of Zimbabwe and Zambia. This was Nir’s second trip and his wife’s first trip from their home in Israel to this famed set of falls in southern Africa.

Hear about volunteer travel with the Peace Corps as the Amateur Traveler talks to Peace Corps Director Carrie Hessler-Radelet. Director Hessler-Radelet not only served in the Peace Corps herself in Western Samoa but 4 generations of her family have done so. 

In this special episode of Amateur Traveler, I get to introduce to you some of the wonderful people who joined me in Africa last May. We drove overland from Johannesburg, South Africa to Victoria Falls, Zimbabwe. 

The Protectors (1972) Synopsis The Protectors (1972) was an action thriller television series produced by ITV that premiered in September of 1972. The Protectors (1972) was a British action thriller series created by Gerry Anderson (Thunderbirds) about an international group of rich troubleshooters. Contessa di Contini (played by Nyree Dawn Porter), Paul Buchet (played by […]

Police officers responding to a call about a man with a machete in Oppenheimer Park Friday afternoon found what they were looking for, and then some.

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

Extracytoplasmic sugar decoration of glycopolymer components of the bacterial cell wall contributes to their structural diversity. Typically, the molecular mechanism that underpins such a decoration process involves a three-component glycosylation system (TGS) represented by an undecaprenyl-phosphate (Und-P) sugar-activating glycosyltransferase (Und-P GT), a flippase, and a polytopic glycosyltransferase (PolM GT) dedicated to attaching sugar residues to a specific glycopolymer. Here, using bioinformatic analyses, CRISPR-assisted recombineering, structural analysis of cell wall–associated polysaccharides (CWPS) through MALDI-TOF MS and methylation analysis, we report on three such systems in the bacterium Lactococcus lactis. On the basis of sequence similarities, we first identified three gene pairs, csdAB, csdCD, and csdEF, each encoding an Und-P GT and a PolM GT, as potential TGS component candidates. Our experimental results show that csdAB and csdCD are involved in Glc side-chain addition on the CWPS components rhamnan and polysaccharide pellicle (PSP), respectively, whereas csdEF plays a role in galactosylation of lipoteichoic acid (LTA). We also identified a potential flippase encoded in the L. lactis genome (llnz_02975, cflA) and confirmed that it participates in the glycosylation of the three cell wall glycopolymers rhamnan, PSP, and LTA, thus indicating that its function is shared by the three TGSs. Finally, we observed that glucosylation of both rhamnan and PSP can increase resistance to bacteriophage predation and that LTA galactosylation alters L. lactis resistance to bacteriocin.

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.

Chatham House is pleased to announce that Adam Ward will join the institute in a new role as deputy director.

Chatham House is pleased to announce that Professor Tim Benton has been appointed as research director of the Energy, Environment and Resources Department.

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.

Yves André
J. Amer. Math. Soc. 33 (2020), 363-380.
Abstract, references and article information

Mitsunori Fukuda
Jun 1, 2008; 7:1031-1042
Research

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

Sean R. Collins
Mar 1, 2007; 6:439-450
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.

15 October 2019

The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.

6 November 2019 , Volume 96, Number 1

The first issue of International Affairs in 2020 explores the geopolitics of the 'Indo-Pacific' region.

4 March 2020 , Volume 96, Number 2

Corporate Members Event Webinar Partners and Major Corporates

Event participants

Edward Luce, US National Editor and Columnist, Financial Times
Dr Lindsay Newman, Senior Research Fellow, US and the Americas Programme, Chatham House
Chair: Dr Robin Niblett, Director and Chief Executive, Chatham House

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

Members Event Webinar

Event participants

Dr Munzer al-Khalil, Head, Idlib Health Directorate
Raed Al Saleh, Director, Syria Civil Defence (The White Helmets)
Alaa Rajaa Mughrabieh, Child Protection Officer, Hurras Network
Chair: Dr Lina Khatib, Director, Middle East and North Africa Programme, Chatham House

Corporate Members Event Webinar Partners and Major Corporates

Event participants

Luis Almagro, Secretary General, Organization of American States (OAS); Foreign Minister, Uruguay (2010-15)
Respondent: Dr Elena Lazarou, Associate Fellow, US and the Americas Programme, Chatham House
Respondent: Dr Christopher Sabatini, Senior Research Fellow for Latin America, US and the Americas Programme, Chatham House
Chair: Dr Robin Niblett, Director and Chief Executive, Chatham House

Invitation Only Research Event

Corporate Members Event Webinar Partners and Major Corporates

Janet Napolitano, President, University of California; US Secretary of Homeland Security (2009-13)

Chair: Dr Robin Niblett, Director and Chief Executive, Chatham House

Invitation Only Research Event

Event participants

Andrés Velasco, Dean of the School of Public Policy, London School of Economics and Political Science
Robert Funk, Assistant Professor of Political Science, University of Chile; Visiting Senior Fellow at the School of Public Policy, London School of Economics and Political Science
Chair: Melissa MacEwen, Manager, Energy, Environment and Resources Programme 

Invitation Only Research Event

Event participants

John Zogby, Founder and Senior Partner, John Zogby Strategies
Chair: Dr Lindsay Newman, Senior Research Fellow, US and Americas Programme, Chatham House

Corporate Members Event Webinar Partners and Major Corporates

Event participants

Dr Yu Jie, Senior Research Fellow on China, Asia-Pacific Programme, Chatham House
James Kynge, Global China Editor, Financial Times; Editor, Tech Scroll Asia
Chair: Dr Robin Niblett, Director and Chief Executive, Chatham House

Corporate Members Event Webinar Partners and Major Corporates

Event participants

Edward Luce, US National Editor and Columnist, Financial Times
Dr Lindsay Newman, Senior Research Fellow, US and the Americas Programme, Chatham House
Chair: Dr Robin Niblett, Director and Chief Executive, Chatham House

Corporate Members Event Webinar Partners and Major Corporates

Event participants

Luis Almagro, Secretary General, Organization of American States (OAS); Foreign Minister, Uruguay (2010-15)
Respondent: Dr Elena Lazarou, Associate Fellow, US and the Americas Programme, Chatham House
Respondent: Dr Christopher Sabatini, Senior Research Fellow for Latin America, US and the Americas Programme, Chatham House
Chair: Dr Robin Niblett, Director and Chief Executive, Chatham House

Invitation Only Research Event