George C. Linderman and Stefan Steinerberger
Math. Comp. 89 (2020), 1933-1952.
Abstract, references and article information

The London-headquartered fintech startup Soldo has repurposed its spend management tools for local authorities in Italy to support its COVID-19 emergency response measures

Time: 9:00 AM, Location: Senate Chamber

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.

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic regulator that mediates adaptation to nutritional variations to maintain a proper energy balance in cells. We show here that suckling-weaning and fasting-refeeding transitions in rodents are associated with changes in AMPK activation and the cellular energy state in the liver. These nutritional transitions were characterized by a metabolic switch from lipid to glucose utilization, orchestrated by modifications in glucose levels and the glucagon/insulin ratio in the bloodstream. We therefore investigated the respective roles of glucose and pancreatic hormones on AMPK activation in mouse primary hepatocytes. We found that glucose starvation transiently activates AMPK, whereas changes in glucagon and insulin levels had no impact on AMPK. Challenge of hepatocytes with metformin-induced metabolic stress strengthened both AMPK activation and cellular energy depletion under limited-glucose conditions, whereas neither glucagon nor insulin altered AMPK activation. Although both insulin and glucagon induced AMPKα phosphorylation at its Ser485/491 residue, they did not affect its activity. Finally, the decrease in cellular ATP levels in response to an energy stress was additionally exacerbated under fasting conditions and by AMPK deficiency in hepatocytes, revealing metabolic inflexibility and emphasizing the importance of AMPK for maintaining hepatic energy charge. Our results suggest that nutritional changes (i.e. glucose availability), rather than the related hormonal changes (i.e. the glucagon/insulin ratio), sensitize AMPK activation to the energetic stress induced by the dietary transition during fasting. This effect is critical for preserving the cellular energy state in the liver.

Palestinian officials said Friday that Israel is forcing banks in the occupied West Bank to close accounts held by the families of prisoners in Israeli jails to prevent the Palestinian Authority from providing stipends to them. Israel has long objected to the Palestinian Authority's payments to the families of prisoners and those killed in the conflict, including militants, saying it rewards terrorism. The Palestinians view the payments as a social safety net for those living under decades of military occupation.

The presumptive Democratic presidential nominee Joe Biden campaigns virtually in his Delaware home; Fox News correspondent Peter Doocy reports.

Chief Justice Patience Roggensack faced backlash for her comment, with some people calling it "elitist" to separate meatpackers from "regular folks."

Mikheil Saakashvili, the former president of Georgia, vowed on Friday to help his new boss, Ukrainian President Volodymyr Zelenskiy, clean out a political "swamp" of oligarchs' interests that he said were preventing Ukraine prospering. Twice president of Georgia, Saakashvili had a brief but stormy spell in Ukrainian politics five years ago under Zelenskiy's predecessor Petro Poroshenko in which he once clambered onto a roof to avoid law enforcement.

The streets of Chicago may be largely empty as residents hunker down from coronavirus but some of the city's most deprived neighborhoods are still echoing to the sound of deadly gunfire and raucous partying. While significant falls in crime have been one of the few positive side effects of lockdowns in much of the United States and elsewhere, they have barely made a dent in the homicide rate in Chicago, a city that has long recorded the most murders in the country. Chicago police say 56 murders were committed in April despite statewide stay-at-home orders -- only a fraction lower than the 61 for the same month in 2019 -- while last weekend, the first of the new month, four people were killed and 46 others shot and wounded.

As businesses slowly reopen, experts warn that social distancing may need to be dialed back up: ‘It’s not an on-off switch’ * Coronavirus – latest US updates * Coronavirus – latest global updatesSome California businesses on Friday began opening their doors for business – at least partially.As states and counties across the nation contend with pressure to lift the stay-at-home measures that have destroyed local economies, California is taking an especially cautious approach, walking a fine line between political and economic pressure to reopen and the public health imperative to stop the spread of disease.Public health experts told the Guardian that while no US state was equipped with enough coronavirus testing and surveillance to feel fully confident reopening, California’s slow, piecemeal recovery plan – though far from perfect – seemed like the least risky option. The planSeven weeks after the governor, Gavin Newsom, ordered his 40 million constituents to shelter in place and all non-essential businesses to close, California on Friday entered phase two of its grand reopening plan.Some retail stores, including bookshops, florists, music stores, clothing and sporting goods retailers, can reopen if they organize curbside pickup. Some manufacturing and logistics in the retail supply chain can restart as well, as long as they follow safety and hygiene protocols. And local authorities are allowed to ease regulations further than the state guidelines if they meet certain testing and sanitation requirements.Phase three of the plan – potentially months away – could see salons, gyms, movie theaters and in-person church services resume. Phase four would end all restrictions. The timingFriday’s reopenings come as California has avoided the surge of infections states like New York have seen. And although California has seen more than 61,000 cases and 2,500 deaths, its hospitals have not been overwhelmed.Last week, state officials reported the first week-over-week decline in Covid-19 deaths.The new guidelines also follow small but sustained protests across the state to demand a relaxation of regulations to revive the state’s crippled economy, and some rural counties have partially reopened in defiance of the lockdown measures. The caveatsHowever, California still hasn’t seen the two weeks of declining cases that the White House suggested as a criterion for easing restrictions and that several European countries have used as a benchmark.The state also lacks the robust testing and tracking systems that countries such as Germany and South Korea have used.The state has ramped up its ability to administer and process tests, although for now, its rate of 29,414 tests a day is below the figure required by some analyses.Authorities are working to put a robust contact tracing effort in place to make sure those who test positive get the care they need and are able to isolate themselves until they recover. Although some counties and communities have spearheaded community-wide testing and tracing programs, overall, the state isn’t at the point where its system is as widespread or efficient as a country like Germany’s.Experts say California should also have a system in place to make sure vulnerable, unhoused populations have access to shelter and medical care – to prevent infection flare-ups in homeless shelters and encampments. Progress on those measures heavily varies county by county.And ideally, there would be a treatment or a vaccine before reopening, said Dr Richard Jackson, a professor emeritus at the UCLA Fielding School of Public Health and the former head of the California department of public health. While we await a cure, Jackson cautioned, “no one should feel completely safe as we remove restrictions.” The trade-offsCalifornia’s reopening strategy stands in sharp contrast to the approach of states like Georgia, which suddenly allowed gyms, barber shops, hair salons, tattoo parlors and bowling alleys to welcome customers last week.“What certain places have done, where they’ve just thrown open the doors and said, ‘OK, we don’t have to keep our distance any more,’ is a colossal mistake,” Jackson said. Reopening businesses that put lots of people into close contact and speed the spread of disease will reverse the success of shelter-in-place rules, he noted, and overwhelm hospitals as cases surge. “Doing it very cautiously and carefully does make sense at this point in time,” he said.“I get that governors have to balance the public health goals with the economic goals,” said Dr Robert Tsai, surgeon and health policy researcher at Brigham and Women’s hospital in Boston and the Harvard TH Chan School of Public Health. “But this stage of the pandemic is really all about trade-offs,” he noted. The weeks aheadIn the coming weeks, state and local leaders will have to watch closely and prepare to dial the distancing back up if the number of cases surges, said Tsai.“Social distancing isn’t an on-off switch. What it needs to be is a dial, which can be turned up or down depending on what the data show on the ground in terms of how the Covid-19 epidemic is progressing.“Reopening is going to be a very complicated process, and it should be complicated,” he added. “Because this is about making sure that people don’t end up in the hospital or dying.”That California’s plan allows for counties to maintain stricter distancing guidelines or ease up measures could be both a strength and a liability.The flexibility has allowed hotspots like the Bay Area and Los Angeles to take a more cautious approach, but it has also already caused confusion. In San Diego, where curbside shopping has already begun, business owners were unsure what, if anything, would change on Friday. In Bakersfield, restaurants allowed patrons to dine in on Monday and Tuesday, in defiance of the state’s guidelines.A hodgepodge reopening could cause surges in cases; Californians who travel between more lax and more strict counties could spread infections. Moreover, a rush to reopen fast in some areas could be counterproductive to economic recovery, said Alessandro Rebucci, an economist at the Johns Hopkins Carey School of Business.“If you reopen when the pandemic is still out there, people and businesses will not just go back to normal,” Rebucci noted. Based on research from China, it seems clear that fear of contracting the illness will keep businesses owners and patrons home until they feel it’s safe enough, he said.

Restaurant workers in a reopened Dallas eatery say they are being asked to weigh their safety against their jobs.

Russia's GRU military intelligence service appears to have got hold of many emails from Chancellor Angela Merkel's constituency office in a 2015 hack attack on Germany's parliament, Der Spiegel magazine reported on Friday, without citing its sources. A spokesman for the German government had no immediate comment. Der Spiegel said federal criminal police and the federal cyber agency had been able to partially reconstruct the attack and found that two email inboxes from Merkel's office had been targeted.

He's celebrating 10 years of dancing both competitively and in the street, and the co-founder of Unruly Skankaz, Devon Brown, says he is looking to expand the brand. The once three-member male dance group has grown to five, he told THE WEEKEND...

The Sanford C. Bernstein & Co. Center for Leadership and Ethics spoke with Anna Houseman '21 about her daily routine, personal ethics, and staying productive during the pandemic. 

Nora Linscheid
Apr 14, 2020; 0:RA119.001878v1-mcp.RA119.001878
Research

Samuel W Entwisle
Apr 6, 2020; 0:RA120.001946v2-mcp.RA120.001946
Research

Chia-Feng Tsai
May 1, 2020; 19:828-838
Research

Research Event

Adenosine monophosphate-activated protein kinase (AMPK) is an obligate heterotrimer that consists of a catalytic subunit (α) and two regulatory subunits (β and ). AMPK is a key enzyme in the regulation of cellular energy homeostasis. It has been well studied and is known to function in many cellular pathways. However, the interactome of AMPK has not yet been systematically established, although protein-protein interaction is critically important for protein function and regulation. Here, we used tandem-affinity purification, coupled with mass spectrometry (TAP-MS) analysis, to determine the interactome of AMPK and its functions. We conducted a TAP-MS analysis of all seven AMPK subunits. We identified 138 candidate high-confidence interacting proteins (HCIPs) of AMPK, which allowed us to build an interaction network of AMPK complexes. Five candidate AMPK-binding proteins were experimentally validated, underlining the reliability of our data set. Furthermore, we demonstrated that AMPK acts with a strong AMPK-binding protein, Artemis, in non-homologous end joining. Collectively, our study established the first AMPK interactome and uncovered a new function of AMPK in DNA repair.

Mass spectrometry (MS)-based proteomics has great potential for overcoming the limitations of antibody-based immunoassays for antibody-independent, comprehensive, and quantitative proteomic analysis of single cells. Indeed, recent advances in nanoscale sample preparation have enabled effective processing of single cells. In particular, the concept of using boosting/carrier channels in isobaric labeling to increase the sensitivity in MS detection has also been increasingly used for quantitative proteomic analysis of small-sized samples including single cells. However, the full potential of such boosting/carrier approaches has not been significantly explored, nor has the resulting quantitation quality been carefully evaluated. Herein, we have further evaluated and optimized our recent boosting to amplify signal with isobaric labeling (BASIL) approach, originally developed for quantifying phosphorylation in small number of cells, for highly effective analysis of proteins in single cells. This improved BASIL (iBASIL) approach enables reliable quantitative single-cell proteomics analysis with greater proteome coverage by carefully controlling the boosting-to-sample ratio (e.g. in general <100x) and optimizing MS automatic gain control (AGC) and ion injection time settings in MS/MS analysis (e.g. 5E5 and 300 ms, respectively, which is significantly higher than that used in typical bulk analysis). By coupling with a nanodroplet-based single cell preparation (nanoPOTS) platform, iBASIL enabled identification of ~2500 proteins and precise quantification of ~1500 proteins in the analysis of 104 FACS-isolated single cells, with the resulting protein profiles robustly clustering the cells from three different acute myeloid leukemia cell lines. This study highlights the importance of carefully evaluating and optimizing the boosting ratios and MS data acquisition conditions for achieving robust, comprehensive proteomic analysis of single cells.

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.

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic regulator that mediates adaptation to nutritional variations to maintain a proper energy balance in cells. We show here that suckling-weaning and fasting-refeeding transitions in rodents are associated with changes in AMPK activation and the cellular energy state in the liver. These nutritional transitions were characterized by a metabolic switch from lipid to glucose utilization, orchestrated by modifications in glucose levels and the glucagon/insulin ratio in the bloodstream. We therefore investigated the respective roles of glucose and pancreatic hormones on AMPK activation in mouse primary hepatocytes. We found that glucose starvation transiently activates AMPK, whereas changes in glucagon and insulin levels had no impact on AMPK. Challenge of hepatocytes with metformin-induced metabolic stress strengthened both AMPK activation and cellular energy depletion under limited-glucose conditions, whereas neither glucagon nor insulin altered AMPK activation. Although both insulin and glucagon induced AMPKα phosphorylation at its Ser485/491 residue, they did not affect its activity. Finally, the decrease in cellular ATP levels in response to an energy stress was additionally exacerbated under fasting conditions and by AMPK deficiency in hepatocytes, revealing metabolic inflexibility and emphasizing the importance of AMPK for maintaining hepatic energy charge. Our results suggest that nutritional changes (i.e. glucose availability), rather than the related hormonal changes (i.e. the glucagon/insulin ratio), sensitize AMPK activation to the energetic stress induced by the dietary transition during fasting. This effect is critical for preserving the cellular energy state in the liver.

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.

Teng-Fei Yuan
Apr 1, 2020; 61:580-586
Methods

In this week's UK Tech Weekly Podcast host Matt Egan is joined by first time podder Tamlin Magee (1:50), online editor at ComputerworldUK.com, to discuss the UK tech implications of this year's Budget, including rural broadband and driverless cars. Then Christina Mercer, assistant online editor at Techworld.com, chats AlphaGo (10:00) and board games following the AI's historic win over world Go champion Lee Sedol. Later, resident Virtual Reality (VR) enthusiast and PCAdvisor.co.uk staff writer Lewis Painter discussed "the big three" VR headset release dates, pricing and features from HTC, Sony Playstation and Oculus Rift (19:00). Finally, UKTW Podcast regular David Price, acting editor at Macworld.co.uk chats about Apple's big upcoming event (28:45).  

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In this week's UK Tech Weekly Podcast host Matt Egan is joined by acting editor at Macworld.co.uk David Price to discuss this week's Apple event announcements, from the iPhone SE to the iPad Pro and iOS 9.3. Then first time podder and staff writer at Macworld.co.uk Henry Burrell wades in to discuss Facebook dropping its support for Blackberry and the future of the under-fire mobile phone maker (19:45). Finally, online editor at Techworld.com Scott Carey chats coding in schools following the BBC micro:bit news and how it differs from the Raspberry Pi (27:40).  

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Producer Chris dives in this week to discuss the HTC 10 release, and why it's difficult to get excited about good mobile phones. Then Techworld.com editor Charlotte Jee chats Facebook chatbots and other F8 news (12:30). Finally, editor at Digitalartsonline.co.uk Neil Bennett jumps in to discuss the new Amazon e-reader (31:00) Kindle Oasis and why everyone is kicking off about the price.  

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This week host Matt Egan is rejoined by Macworld.co.uk acting editor David Price to chat about Apple's latest Macbook announcements. Then online editor at ComputerworldUK Christina Mercer jumps in to give a break down of Google's fight with the EU over antitrust infringements (13:00). Finally, ex-dating app user Scott Carey, online editor at Techworld.com gives a state of the union on dating apps, from Tinder to Bumble to Happn, if they are good for society and which one is set to corner the market (27:00).  

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This week host Matt Egan is joined by regular podder David Price, acting editor of Macworld.co.uk, to discuss Apple's not so awesome results and stalling iPhone sales. Then online editor Scott Carey jumps in to discuss Facebook's far better results and how it has come to dominate the mobile advertising market (15:00) Finally, producer Chris comes out from behind the glass to discuss Nintendo's secretive NX console and having to wait for the new Zelda game (28:00).  

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This week host Matt Egan is joined by PC Advisor staff writer Chris Minasians to chat about the AMD Radeon RX 480 graphics card and what this could mean for the future of virtual reality games. Fellow staff writer at PC Advisor Henry Burrell jumps in to talk about the "not terrible" Windows 10 phone as he starts using the Microsoft Lumia 950 and can't see what everyone's beef with it is (13:00). Finally Ashleigh Allsopp, engagement editor at Macworld UK chats about using your technology at concerts (24:30).  

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Host Matt Egan is joined this week by Henry Burrell, staff writer at Macworld UK to talk about the EU referendum website crashing Lewis Painter, staff writer at PC Advisor, jumps in to chat about Oculus Rift games and how immersive they are. Finally regular David Price comes on to talk about Apple's upcoming WWDC software developer conference and what we can (and cannot) expect.  

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Host Matt Egan is joined by Online Editor at Techworld.com Scott Carey to break down Microsoft's mega acquisition of LinkedIn. Staff Writer at PC Advisor Chris joins in to discuss all of the news coming out of E3 and how Xbox and Playstation are set to battle it out again this summer, or will Nintendo and Zelda steal the show? (13:00). Finally, David Price comes on to talk about all of the news coming out of Apple's WWDC developer conference this week, from Hair Force One to watchOS, tvOS, macOS and iOS (26:30) And please do share, rate and review the UK Tech Weekly Podcast.  

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