(American Association for the Advancement of Science) A one-hour exercise designed to increase feelings of social belonging administered during the first year of college appears to significantly improve the lives and careers of black students up to 11 years later, psychologists report.

(Louisiana State University Health Sciences Center) A study conducted at LSU Health New Orleans has shown for the first time that chronic exposure to inhaled nicotine alone increases blood pressure in both the body's general circulation and in the lungs that can lead to pulmonary hypertension. The study also found that nicotine-induced pulmonary hypertension is accompanied by changes in the size, shape and function (remodeling) of the blood vessels in the lung and the right lower chamber of the heart.

(To watch the whole press briefing with sign language interpretation, click here.)

The Agriculture, Fisheries & Conservation Department today said genetic sequencing tests are being carried out on the pet dog of a confirmed COVID-19 patient which could reveal if the virus has mutated or not.

The department's Assistant Director (Inspection & Quarantine) Dr Thomas Sit told a press briefing this afternoon that the coronavirus is what is known as an RNA virus which eventually mutates.

“That is why the University of Hong Kong School of Public Health needs to do a genetic analysis to compare this dog’s genetic sequencing to the virus isolated from the patient so that they can compare. So if it is totally identical, then there is no mutation. The testing is still ongoing.”

Dr Sit reiterated that international experts agreed that the dog has a low level of infection, despite its blood tests not being ready yet.

“From the first sample to our last sample tested, it has already (been) six days. The dog’s nasal or oral mechanism, their secretion they should have - if contaminated - they should have a way to clean the virus, it would not stay for that long if it was just a contamination.

“I think it will take at least five or seven days for the blood results because it is not an easy test, it is not a quick test. We need to grow a virus and then neutralise the serum, so it takes some time.”

He added that it was too early to say whether animal-to-animal transmission was a possibility.

“At this stage, we do not have enough data to have a 100% answer as to whether it is infectious to other dogs or not. But if the dog’s owner is positive, it is better to take precautionary measures to prevent onward transmission.”

Dr Sit also advised dog owners to wash their hands, wear gloves and try to stop their dogs from licking their surroundings to prevent the virus from spreading further.

(Memorial Sloan Kettering Cancer Center) Scientists at the Sloan Kettering Institute have solved the puzzle of how small chromosomes ensure that they aren't skipped over during meiosis, the process that makes sperm and egg.

(Stony Brook University) In evolutionary terms, islands are the stuff of weirdness. It is on islands where animals evolve in isolation, often for millions of years, with different food sources, competitors, predators, and parasites...indeed, different everything compared to mainland species. As a result, they develop into different shapes and sizes and evolve into new species that, given enough time, spawn yet more new species.

(Cell Press) In a study appearing April 30 in the journal Current Biology, scientists tell the story of three 16th century African slaves identified from a mass burial site in Mexico City. Using a combination of genetic, osteological, and isotope analyses, the scientists determined from where in Africa they were likely captured, the physical hardships they experienced as slaves, and what novel pathogens they may have carried with them across the Atlantic.

(American Chemical Society) When a dead body is found, one of the first things a forensic pathologist tries to do is estimate the time of death. There are several ways to do this, including measuring body temperature or observing insect activity, but these methods don't always work for corpses found in water. Now, researchers are reporting a mouse study in ACS' Journal of Proteome Research showing that certain proteins in bones could be used for this determination.

(NOAA Headquarters) While the global average number of tropical cyclones each year has not budged from 86 over the last four decades, climate change has been influencing the locations of where these deadly storms occur, according to new NOAA-led research published in Proceedings of the National Academy of Science.

China reported one new coronavirus case for Friday, unchanged from the day before, data from the national health authority showed on Saturday. One new imported case was recorded on May 8, the National Health Commission said in a statement.

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.

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.

(American Geriatrics Society) The American Geriatrics Society (AGS) today announced that John B. Murphy, MD, a clinician, educator, and administrator working to embed geriatrics education in the fabric of medical curricula and clinical operations will be honored with the 2020 Dennis W. Jahnigen Award celebrating work to train health professionals in the care we all need as we age.

Jan Pearson
Apr 1, 2001; 14:
Articles

Frederick J. Bloom
Jul 1, 2010; 23:165-169
From Research to Practice

Up-and-coming recording artiste Kaay Jones says she did not know she was becoming part of a transformational music project that would connect her to a wide cross section of talent in the Caribbean. Jones carries Jamaica's flag in a unified...

Earthquake: 2020-05-06 21:54HKT M6.7 [7.0S, 130.0E] in Tanimbar Islands Region, Indonesia http://openstreetmap.org/?mlat=-7&mlon=130.

6 April 2018

17 April 2014

As part of a roundtable series, Chatham House and China University of Political Science and Law (CUPL) jointly organized this four-day meeting at Chatham House for international lawyers to discuss a wide range of issues related to public international law and the rights of individuals.

Invitation Only Research Event

Coenzyme Q (Qn) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1–coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6. The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in respiration and as an antioxidant and is believed to chaperone Q6 from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q6 biosynthesis. Because “fused” proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q6 biosynthesis of the coq10Δ mutant. Additionally, immunoblotting indicated that yeast coq11Δ mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q6 biosynthesis and that its absence increases mitochondrial Q6 content in the coq10Δcoq11Δ double mutant. This augmented mitochondrial Q6 content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10Δ mutant. This study further clarifies the intricate connection between Q6 biosynthesis, trafficking, and function in mitochondrial metabolism.

Sperm head shaping is a key event in spermiogenesis and is tightly controlled via the acrosome–manchette network. Linker of nucleoskeleton and cytoskeleton (LINC) complexes consist of Sad1 and UNC84 domain–containing (SUN) and Klarsicht/ANC-1/Syne-1 homology (KASH) domain proteins and form conserved nuclear envelope bridges implicated in transducing mechanical forces from the manchette to sculpt sperm nuclei into a hook-like shape. However, the role of LINC complexes in sperm head shaping is still poorly understood. Here we assessed the role of SUN3, a testis-specific LINC component harboring a conserved SUN domain, in spermiogenesis. We show that CRISPR/Cas9-generated Sun3 knockout male mice are infertile, displaying drastically reduced sperm counts and a globozoospermia-like phenotype, including a missing, mislocalized, or fragmented acrosome, as well as multiple defects in sperm flagella. Further examination revealed that the sperm head abnormalities are apparent at step 9 and that the sperm nuclei fail to elongate because of the absence of manchette microtubules and perinuclear rings. These observations indicate that Sun3 deletion likely impairs the ability of the LINC complex to transduce the cytoskeletal force to the nuclear envelope, required for sperm head elongation. We also found that SUN3 interacts with SUN4 in mouse testes and that the level of SUN4 proteins is drastically reduced in Sun3-null mice. Altogether, our results indicate that SUN3 is essential for sperm head shaping and male fertility, providing molecular clues regarding the underlying pathology of the globozoospermia-like phenotype.

Cryptocurrency profits from sextortion spam funneled into wallets tied to other cybercrime and dark web market activity.

Invitation Only Research Event

Invitation Only Research Event

This project brings together experts on the use of armed drones, including current and former military officials, academia, think-tanks and NGOs, to discuss and exchange perspectives based on their different experiences, with the aim of sharing knowledge and increasing understanding on these issues, and to inform and provide input into the European debate.

More on Policy Implications of Armed Drone Use

Invitation Only Research Event

Research Event

Event participants

Konstantinos Komaitis, Senior Director, Policy Development & Strategy, Internet Society
Gregory Asmolov, Leverhulme Early Career Fellow Russia Institute, King’s College London
Further speakers to be announced.
Chair: Joyce Hakmeh, Senior Research Fellow, International Security Programme, Chatham House and Co-Editor of the Journal of Cyber Policy.

Members Event Screening Room

Event participants

Nigol Bezjian, Director, Broken Dinners, Postponed Kisses
Chair: Rima Maktabi, Bureau Chief, Al Arabiya (UK)

Members Event

Event participants

Dr Wolfram Lacher, Senior Associate, German Institute for International and Security Affairs; Author, Libya's Fragmentation: Structure and Process in Violent Conflict
Chair: Maryam Nemazee, Anchor, Al Jazeera

Further speakers to be announced.

Invitation Only Research Event

Event participants

Abdul Rahman Alageli, Associate Fellow, MENA Programme, Chatham House
Emaddedin Badi, Non-Resident Scholar, Middle East Institute
Tim Eaton, Senior Research Fellow, MENA Programme Chatham House
Valerie Stocker, Independent Researcher

Invitation Only Research Event

Event participants

Nikolay Kozhanov, Research Associate Professor, Gulf Studies Center, Qatar University; Consulting Fellow, Russia and Eurasia Programme, Chatham House 
Chair: Sanam Vakil, Senior Research Fellow, Project Director, Future Dynamics of the Gulf, Middle East & North Africa Programme, Chatham House

Objectives: Esthesioneuroblastoma (ENB) is rare with limited therapeutic options when unresectable or metastatic; however, expression of somatostatin receptors qualifies it for peptide receptor radionuclide therapy (PRRT). We report outcomes of PRRT in ENB from two referral centers. Methods: Using PRRT databases at two European Neuroendocrine Tumour Society Centers of Excellence, case finding was undertaken between 2004-2018 for patients who had PRRT with recurrent/metastatic ENB deemed unsuitable for further conventional therapies. Evaluations of response using a composite reference standard and for survival were performed. Results: Of seven patients, four had partial response, two had disease stabilization and one had early progression. Possible side effects include worsening CSF-leaks. Median progression-free survival was 17 months (range, 0-30), and median overall survival was 32 months (range, 4–53). Conclusion: PRRT shows promising efficacy and moderate survival duration in unresectable locally advanced or metastatic ENB warranting larger cohort studies incorporating measures of quality of life.

For individual treatment decisions in patients with metastatic prostate cancer (mPC), molecular diagnostics are increasingly used. Bone metastases are frequently the only source for obtaining metastatic tumor tissue. However, the success rate of computed tomography (CT)-guided bone biopsies for molecular analyses in mPC patients is only ~40%. Positron emission tomography (PET) using Gallium-68 prostate specific membrane antigen (⁶⁸Ga-PSMA) is a promising tool to improve the harvest rate of bone biopsies for molecular analyses. Aim of this study was to determine the success rate of ⁶⁸Ga-PSMA guided bone biopsies for molecular diagnostics in mPC patients. Methods: Within a prospective multicenter whole-genome sequencing trial (NCT01855477), 69 mPC patients underwent ⁶⁸Ga-PSMA PET/CT prior to bone biopsy. Primary endpoint was success rate (tumor percentage ≥30%) of ⁶⁸Ga-PSMA guided bone biopsies. At biopsy sites, ⁶⁸Ga-PSMA uptake was quantified using rigid body image registration of ⁶⁸Ga-PSMA PET/CT and interventional CT. Actionable somatic alterations were identified. Results: Success rate of ⁶⁸Ga-PSMA guided biopsies for molecular analyses was 70%. At biopsy sites categorized as positive, inconclusive, or negative for ⁶⁸Ga-PSMA uptake, 70%, 64%, and 36% of biopsies were tumor positive (≥30%), respectively (P = 0.0610). In tumor positive biopsies, ⁶⁸Ga-PSMA uptake was significantly higher (P = 0.008), whereas radiodensity was significantly lower (P = 0.006). With an area under the curve of 0.84 and 0.70, both ⁶⁸Ga-PSMA uptake (maximum standardized uptake value) and radiodensity (mean Hounsfield Units) were strong predictors for a positive biopsy. Actionable somatic alterations were detected in 73% of the sequenced biopsies. Conclusion: In patients with mPC, ⁶⁸Ga-PSMA PET/CT improves the success rate of CT-guided bone biopsies for molecular analyses, thereby identifying actionable somatic alterations in more patients. Therefore, ⁶⁸Ga-PSMA PET/CT may be considered for guidance of bone biopsies in both clinical practice and clinical trials.

Bone metastases are common, especially in more prevalent malignancies such as breast and prostate cancer. They cause significant morbidity and draw on healthcare resources. Molecular and hybrid imaging techniques, including single photon emission computed tomography with computed tomography (SPECT/CT), positron emission tomography / CT and whole-body MRI with diffusion-weighted imaging (WB-MRI), have improved diagnostic accuracy in staging the skeleton compared to previous standard imaging methods, allowing earlier tailored treatment. With the introduction of several effective treatment options, it is now even more important to detect and monitor response in bone metastases accurately. Conventional imaging, including radiographs, CT, MRI and bone scintigraphy, are recognized as being insensitive and non-specific for response monitoring in a clinically relevant time frame. Early reports of molecular and hybrid imaging techniques, as well as WB-MRI, promise earlier and more accurate prediction of response vs non-response but have yet to be adopted routinely in clinical practice. We summarize the role of new molecular and hybrid imaging methods including SPECT/CT, PET/CT and WB-MRI. These modalities are associated with improvements in diagnostic accuracy for staging and response assessment of skeletal metastases over standard imaging methods, being able to quantify biological processes related to the bone microenvironment as well as tumor cells. The described improvements in the imaging of bone metastases and their response to therapy have led to some being adopted into routine clinical practice in some centers and at the same time provide better methods to assess treatment response of bone metastases in clinical trials.

McCune-Albright syndrome (MAS) is a mosaic disorder arising from gain-of-function mutations in the GNAS gene, which encodes the 3', 5'-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gsα. Clinical manifestations of MAS in a given individual, including fibrous dysplasia, are determined by the timing and location of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gsα in the affected tissues. The Gsα mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), which catalyzes the hydrolysis of cAMP. Increased cAMP levels have been found in vitro in both animal models of fibrous dysplasia and in cultured cells from individuals with MAS, but not in humans with fibrous dysplasia. Positron emission tomography (PET) imaging of PDE4 with ¹¹C-(R)-rolipram has been used successfully to study the in vivo activity of the cAMP cascade. To date, it remains unknown whether fibrous dysplasia and other symptoms of MAS, including neuropsychiatric impairments, are associated with increased PDE4 activity in humans. Methods: ¹¹C-(R)-rolipram whole-body and brain PET scans were performed in six individuals with MAS (three for brain scans and six for whole-body scans) and nine healthy controls (seven for brain scans and six for whole-body scans). Results: ¹¹C-(R)-rolipram binding correlated with known locations of fibrous dysplasia in the periphery of individuals with MAS; no uptake was observed in the bones of healthy controls. In peripheral organs and the brain, no difference in ¹¹C-(R)-rolipram uptake was noted between participants with MAS and healthy controls. Conclusion: This study is the first to find evidence for increased cAMP activity in areas of fibrous dysplasia in vivo. No differences in brain uptake between MAS participants and controls were detected, which could be due to several reasons, including the limited anatomic resolution of PET. Nevertheless, the results confirm the usefulness of PET scans with ¹¹C-(R)-rolipram to indirectly measure increased cAMP pathway activation in human disease.

Research Event

Event participants

Hon Bruno Nabagné Kone, Minister of Construction, Housing and Urban Planning, Republic of Côte d'Ivoire

Research Event

Event participants

Alan Doss, President, Kofi Annan Foundation
 

Research Event

Event participants

HE Nabil Ben Khedher, Ambassador of Tunisia to the United Kingdom
Professor Naohiro Kitano, Visiting Fellow, Japan International Cooperation Agency Research Institute (JICA-RI); Professor, Waseda University
Taku Miyazaki, Deputy Director General, Japan External Trade Organisation (JETRO) London
Serge Mouangue, Founder and Art Director, WAfrica
Norio Suzuki, Senior Strategist, BBOXX
HE Professor Mohammed Gana Yisa, Ambassador of the Federal Republic of Nigeria to Japan; Chairman, African Diplomatic Corps in Tokyo (ADC) TICAD Committee

Chairs:
Dr Champa Patel, Director, Asia-Pacific Programme, Chatham House
Dr Alex Vines OBE, Managing Director, Ethics, Risk & Resilience; Director, Africa Programme

Research Event

Event participants

Paul Mashatile, Treasurer General, African National Congress (ANC)

Systemic infection and proliferation of intracellular pathogens require the biogenesis of a growth-stimulating compartment. The gastrointestinal pathogen Salmonella enterica commonly forms highly dynamic and extensive tubular membrane compartments built from Salmonella-modified membranes (SMMs) in diverse host cells. Although the general mechanism involved in the formation of replication-permissive compartments of S. enterica is well researched, much less is known regarding specific adaptations to different host cell types. Using an affinity-based proteome approach, we explored the composition of SMMs in murine macrophages. The systematic characterization provides a broader landscape of host players to the maturation of Salmonella-containing compartments and reveals core host elements targeted by Salmonella in macrophages as well as epithelial cells. However, we also identified subtle host specific adaptations. Some of these observations, such as the differential involvement of the COPII system, Rab GTPases 2A, 8B, 11 and ER transport proteins Sec61 and Sec22B may explain cell line-dependent variations in the pathophysiology of Salmonella infections. In summary, our system-wide approach demonstrates a hitherto underappreciated impact of the host cell type in the formation of intracellular compartments by Salmonella.

Coenzyme Q (Qn) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1–coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6. The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in respiration and as an antioxidant and is believed to chaperone Q6 from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q6 biosynthesis. Because “fused” proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q6 biosynthesis of the coq10Δ mutant. Additionally, immunoblotting indicated that yeast coq11Δ mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q6 biosynthesis and that its absence increases mitochondrial Q6 content in the coq10Δcoq11Δ double mutant. This augmented mitochondrial Q6 content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10Δ mutant. This study further clarifies the intricate connection between Q6 biosynthesis, trafficking, and function in mitochondrial metabolism.

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.

11 February 2020

Chelsea DeLeon
May 1, 2020; 61:767-777
Research Articles