Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both α-cell–intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4–10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mm glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mm. Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mm glucose and did not prevent the suppressive effect of 7 mm glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mm glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion.

β-1,3-d-Glucan is a ubiquitous glucose polymer produced by plants, bacteria, and most fungi. It has been used as a diagnostic tool in patients with invasive mycoses via a highly-sensitive reagent consisting of the blood coagulation system of horseshoe crab. However, no method is currently available for measuring β-1,6-glucan, another primary β-glucan structure of fungal polysaccharides. Herein, we describe the development of an economical and highly-sensitive and specific assay for β-1,6-glucan using a modified recombinant endo-β-1,6-glucanase having diminished glucan hydrolase activity. The purified β-1,6-glucanase derivative bound to the β-1,6-glucan pustulan with a KD of 16.4 nm. We validated the specificity of this β-1,6-glucan probe by demonstrating its ability to detect cell wall β-1,6-glucan from both yeast and hyphal forms of the opportunistic fungal pathogen Candida albicans, without any detectable binding to glucan lacking the long β-1,6-glucan branch. We developed a sandwich ELISA-like assay with a low limit of quantification for pustulan (1.5 pg/ml), and we successfully employed this assay in the quantification of extracellular β-1,6-glucan released by >250 patient-derived strains of different Candida species (including Candida auris) in culture supernatant in vitro. We also used this assay to measure β-1,6-glucan in vivo in the serum and in several organs in a mouse model of systemic candidiasis. Our work describes a reliable method for β-1,6-glucan detection, which may prove useful for the diagnosis of invasive fungal infections.

The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.

Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface availability is dynamically regulated by endocytic trafficking, and direct protein kinase C (PKC) activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. Ex vivo studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic terminals.

The dextransucrase DSR-OK from the Gram-positive bacterium Oenococcus kitaharae DSM17330 produces a dextran of the highest molar mass reported to date (∼109 g/mol). In this study, we selected a recombinant form, DSR-OKΔ1, to identify molecular determinants involved in the sugar polymerization mechanism and that confer its ability to produce a very-high-molar-mass polymer. In domain V of DSR-OK, we identified seven putative sugar-binding pockets characteristic of glycoside hydrolase 70 (GH70) glucansucrases that are known to be involved in glucan binding. We investigated their role in polymer synthesis through several approaches, including monitoring of dextran synthesis, affinity assays, sugar binding pocket deletions, site-directed mutagenesis, and construction of chimeric enzymes. Substitution of only two stacking aromatic residues in two consecutive sugar-binding pockets (variant DSR-OKΔ1-Y1162A-F1228A) induced quasi-complete loss of very-high-molar-mass dextran synthesis, resulting in production of only 10–13 kg/mol polymers. Moreover, the double mutation completely switched the semiprocessive mode of DSR-OKΔ1 toward a distributive one, highlighting the strong influence of these pockets on enzyme processivity. Finally, the position of each pocket relative to the active site also appeared to be important for polymer elongation. We propose that sugar-binding pockets spatially closer to the catalytic domain play a major role in the control of processivity. A deep structural characterization, if possible with large-molar-mass sugar ligands, would allow confirming this hypothesis.

Heterotrimeric G proteins mediate a variety of signaling processes by coupling G protein–coupled receptors to intracellular effector molecules. In Drosophila, the Gαq gene encodes several Gαq splice variants, with the Gαq1 isoform protein playing a major role in fly phototransduction. However, Gαq1 null mutant flies still exhibit a residual light response, indicating that other Gαq splice variants or additional Gq α subunits are involved in phototransduction. Here, we isolated a mutant fly with no detectable light responses, decreased rhodopsin (Rh) levels, and rapid retinal degeneration. Using electrophysiological and genetic studies, biochemical assays, immunoblotting, real-time RT-PCR, and EM analysis, we found that mutations in the Gαq gene disrupt light responses and demonstrate that the Gαq3 isoform protein is responsible for the residual light response in Gαq1 null mutants. Moreover, we report that Gαq3 mediates rhodopsin synthesis. Depletion of all Gαq splice variants led to rapid light-dependent retinal degeneration, due to the formation stable Rh1-arrestin 2 (Arr2) complexes. Our findings clarify essential roles of several different Gαq splice variants in phototransduction and retinal integrity in Drosophila and reveal that Gαq3 functions in rhodopsin synthesis.

VOLUME 295 (2020) PAGES 1898–1914Yichen Zhong's name was misspelled. The correct spelling is shown above.

VOLUME 292 (2017) PAGES 3531–3540This article has been withdrawn by Shuofeng Hu, Xiaomin Ying, Xiangming Zhang, and Ya Wang. Baocheng Hu, Xiang Wang, Ping Wang, Jian Wang, and Hongyan Wang could not be reached. In Fig. 1C, the DAPI and merged images for the no IR control were switched. The DNA-PKcs and actin immunoblots on the left appear to have been spliced. In Fig. 4C, the DNA-PKcs immunoblot appears to have been spliced. In Fig. 4D, lanes 1 and 5; lanes 2, 6, and 8; and lanes 3 and 7 of the DNA-PKcs immunoblot are the same. In the p-DNA-PKcs immunoblot, lanes 1 and 8, lanes 2 and 6, and lanes 3 and 7 are the same. In the CRY2 immunoblot, lanes 5 and 7 are the same. In the CDC25A immunoblot, lanes 3 and 8 are the same. In the GSK3B immunoblot, lanes 1 and 5 and lanes 3 and 7 are the same. Also in the GSK3B immunoblot, the upper GSK3B bands in lanes 6 and 8 are the same. Lanes 4 and 8 of the cyclin D1 immunoblot are the same. In Fig. 5A, the CDC25A immunoblot appears to have been spliced. Also in Fig. 5A, lanes 2–4 and lanes 6–8 of the CDC25A immunoblot are the same. Lanes 4–6 and 7–9 of the actin immunoblot are the same. In Fig. 5C, lane 1 of the CDC25A immunoblot was reused in lane 5, and lanes 3 and 4 were reused in lanes 7 and 8. In the...

Hippo pathway signaling limits cell growth and proliferation and maintains the stem-cell niche. These cellular events result from the coordinated activity of a core kinase cassette that is regulated, in part, by interactions involving Hippo, Salvador, and dRassF. These interactions are mediated by a conserved coiled-coil domain, termed SARAH, in each of these proteins. SARAH domain–mediated homodimerization of Hippo kinase leads to autophosphorylation and activation. Paradoxically, SARAH domain–mediated heterodimerization between Hippo and Salvador enhances Hippo kinase activity in cells, whereas complex formation with dRassF inhibits it. To better understand the mechanism by which each complex distinctly modulates Hippo kinase and pathway activity, here we biophysically characterized the entire suite of SARAH domain–mediated complexes. We purified the three SARAH domains from Drosophila melanogaster and performed an unbiased pulldown assay to identify all possible interactions, revealing that isolated SARAH domains are sufficient to recapitulate the cellular assemblies and that Hippo is a universal binding partner. Additionally, we found that the Salvador SARAH domain homodimerizes and demonstrate that this interaction is conserved in Salvador's mammalian homolog. Using native MS, we show that each of these complexes is dimeric in solution. We also measured the stability of each SARAH domain complex, finding that despite similarities at both the sequence and structural levels, SARAH domain complexes differ in stability. The identity, stoichiometry, and stability of these interactions characterized here comprehensively reveal the nature of SARAH domain–mediated complex formation and provide mechanistic insights into how SARAH domain–mediated interactions influence Hippo pathway activity.

T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.

Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion of autophagy-related 5 (ATG5), results in accumulation of intracellular VEGFA, indicating that VEGFA is a basal autophagic substrate. Mechanistically, decorin increased the VEGFA clearance rate by augmenting autophagic flux, a process that required RAB24 member RAS oncogene family (RAB24), a small GTPase that facilitates the disposal of autophagic compartments. We validated these findings by demonstrating the physiological relevance of this process in vivo. Mice starved for 48 h exhibited a sharp decrease in overall cardiac and aortic VEGFA that could be blocked by systemic chloroquine treatment. Thus, our findings reveal a unified mechanism for the metabolic control of endothelial VEGFA for autophagic clearance in response to decorin and canonical pro-autophagic stimuli. We posit that the VEGFR2/AMPK/PEG3 axis integrates the anti-angiogenic and pro-autophagic bioactivities of decorin as the molecular basis for tumorigenic suppression. These results support future therapeutic use of decorin as a next-generation protein therapy to combat cancer.

Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin–Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor–like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS–based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9th carbon due to decreased FAHFA hydrolysis activity. The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, which is active in vivo. Acute treatment of WT mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on extent of upregulation of FAHFA levels, glucose tolerance, or insulin sensitivity in mice, indicating that therapeutic strategies should weigh more on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease.

The ribosome biogenesis factor Las1 is an essential endoribonuclease that is well-conserved across eukaryotes and a newly established member of the higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain-containing nuclease family. HEPN nucleases participate in diverse RNA cleavage pathways and share a short HEPN nuclease motif (RφXXXH) important for RNA cleavage. Most HEPN nucleases participate in stress-activated RNA cleavage pathways; Las1 plays a fundamental role in processing pre-rRNA. Underscoring the significance of Las1 function in the cell, mutations in the human LAS1L (LAS1-like) gene have been associated with neurological dysfunction. Two juxtaposed HEPN nuclease motifs create Las1's composite nuclease active site, but the roles of the individual HEPN motif residues are poorly defined. Here using a combination of in vivo experiments in Saccharomyces cerevisiae and in vitro assays, we show that both HEPN nuclease motifs are required for Las1 nuclease activity and fidelity. Through in-depth sequence analysis and systematic mutagenesis, we determined the consensus HEPN motif in the Las1 subfamily and uncovered its canonical and specialized elements. Using reconstituted Las1 HEPN-HEPN' chimeras, we defined the molecular requirements for RNA cleavage. Intriguingly, both copies of the Las1 HEPN motif were important for nuclease function, revealing that both HEPN motifs participate in coordinating the RNA within the Las1 active site. We also established that conformational flexibility of the two HEPN domains is important for proper nuclease function. The results of our work reveal critical information about how dual HEPN domains come together to drive Las1-mediated RNA cleavage.

(Elsevier) Children looking for health information online could end up more prone to obesity. A new study in the Journal of Nutrition Education and Behavior, published by Elsevier, shows a lack of digital health literacy can lead children to misinterpret portions, adopt recommendations intended for adults, or take guidance from noncredible sources.

A pet dog repeatedly tested weak positive for the COVID-19 virus, indicating a low-level of infection with the virus, the Agriculture, Fisheries & Conservation Department said today.

The department first collected test samples from the dog on February 26. It detected low levels of COVID-19 virus from its nasal and oral cavity samples on February 27.

The dog also tested weak positive for the virus when the department repeated the test on February 28 and March 2.

Experts from Hong Kong University’s School of Public Health, City University’s College of Veterinary Medicine & Life Sciences and the World Organisation for Animal Health have been consulted, and unanimously agreed that these results suggest that the dog has a low-level of infection and it is likely to be a case of human-to-animal transmission, the department noted.

The dog has not shown any signs of disease related to COVID-19. It is currently under quarantine at the animal keeping facility at the Hong Kong Port of Hong Kong-Zhuhai-Macao Bridge. The department will closely monitor the dog and repeat the test later.

To ensure public and animal health, the department strongly advises that mammalian pets from households with COVID-19 infected people, or close contacts of infected individuals, should be put under quarantine in the department’s facilities.

The department emphasised that there is currently no evidence that pets can be a source of infection of COVID-19 and under no circumstances should people abandon their pets.

(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.

The Agriculture, Fisheries & Conservation Department (AFCD) today said a pet dog has tested positive for the COVID-19 virus. 

The case involves a German Shepherd dog whose owners live in Pok Fu Lam. This follows an earlier case in which a 17-year-old Pomeranian dog tested weak positive during repeated tests for the virus.

When the German Shepherd's owner was confirmed with COVID-19, it was sent for quarantine with another mixed breed dog from the same residence to the animal keeping facility at the Hong Kong-Zhuhai-Macao Bridge's Hong Kong Port yesterday.

No positive results were obtained from the mixed breed dog and neither dog has shown any signs of the disease.

The department will continue to closely monitor both dogs and conduct repeated tests on them.

It strongly advises that mammalian pet animals including dogs and cats from households with people confirmed as infected with COVID-19, or close contacts of COVID-19 infected people, should be put under quarantine in AFCD facilities.

The department emphasised that there is currently no evidence pet animals can be a source of COVID-19 for humans or that this virus can cause the disease in dogs.

Pet owners are reminded to maintain good hygiene practices and under no circumstances should they abandon their pets.

Carlos Gustavo T. Moreira, Maria José Pacifico and Sergio Romaña Ibarra
Bull. Amer. Math. Soc. 57 (2018), 269-292.
Abstract, references and article information

The Hong Kong Special Administrative Region (HKSAR) Government welcomes the promulgation of the Meteorological Development Plan ...

(American Marketing Association) Nonprofits may better meet their missions by learning to effectively employ the entirety of the marketing mix to attract individuals to available donation opportunities.

(Queensland University of Technology) Your house number could be the key to the safe relaxation of COVID-19-related restrictions if governments follow a new exit strategy proposal published today in the British Medical Journal. Co-authored by QUT statistician Professor Adrian Barnett, the paper proposes the use of an 'odds-and-evens' approach to allowing people to head back to work and enjoy other activities after weeks of lockdown.

(Kudos Innovations Ltd) Kudos helps researchers maximize reach and visibility of research by opening up Kudos Pro. The platform helps showcase work to a range of target audiences, supporting researchers in fields where conferences have been cancelled -- and those with COVID-19-relevant work that needs rapid communication. Over 2,000 researchers have already signed up.

(American Association for the Advancement of Science) High-resolution images and video were taken by the Japanese space agency's Hayabusa2 spacecraft as it briefly landed to collect samples from Ryugu -- a nearby asteroid that orbits mostly between Earth and Mars -- allowing researchers to get an up-close look at its rocky surface, according to a new report.

(University of Maryland) Many historians have claimed the Justinianic Plague (c. 541-750 CE) killed half of the population of Byzantine (Eastern Roman) Empire. New historical research and mathematical modeling challenge the death rate and severity of this first plague pandemic, named for Emperor Justinian I.

(Marine Biological Laboratory) Microbial life is bubbling up to the ocean floor along with fluids from deeply buried petroleum reservoirs, reports a team of scientists from the University of Calgary and the Marine Biological Laboratory, Woods Hole.

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.

It may not be a pardon. But the Justice Department has dropped charges against Donald Trump’s former national security adviser Michael Flynn, who pleaded guilty to lying to the FBI.Retired Army Lt. Gen. Flynn, an important figure in the war on terror who gave Trump’s 2016 run military validation, will avoid prison time after the Justice Department provided a deliverance on Thursday that Flynn had long sought. It is also the second redemption that Trump has provided the general, who served as his first national security adviser for less than a month. “The Government has determined, pursuant to the Principles of Federal Prosecution and based on an extensive review and careful consideration of the circumstances, that continued prosecution of this case would not serve the interests of justice,” wrote Timothy Shea, the interim U.S. attorney for the District of Columbia and a former senior aide to Attorney General William Barr. Shortly before the filing, lead prosecutor Brandon Von Grack abruptly withdrew from the case.The Justice Department filing, in essence, portrays Flynn as the victim of an FBI frame-up job, and his lies to the FBI as legally marginal. Shea wrote that Flynn’s lies needed to have been “not simply false, but ‘materially’ false with respect to a matter under investigation.” Later in the filing, Shea referred to those lies as “gaps in [Flynn’s] memory,” rather than deliberate falsehoods Flynn conceded. “Even if he told the truth, Mr. Flynn’s statements could not have conceivably ‘influenced’ an investigation that had neither a legitimate counterintelligence nor criminal purpose,” Shea wrote.It was an astonishing turnaround since 2018, when a federal judge said to Flynn in a sentencing hearing, “arguably, you sold your country out.” That judge, Emmet Sullivan, could still decide to reject Shea’s filing and continue with Flynn’ sentencing. Michael Bromwich, a former federal prosecutor and Justice Department inspector general, tweeted that the extraordinary move represented “a pardon by another name” and called it a “black day in DOJ history.”Rep. Jerrold Nadler (D-NY), chairman of the House Judiciary Committee, said the decision to drop charges was “outrageous” and revealed “a politicized and thoroughly corrupt Department of Justice.” Sen. Ron Wyden (D-OR) added, “If Barr’s Justice Department will drop charges against someone who twice pleaded guilty to lying to the FBI and who the White House publicly fired for lying to the vice president, there’s nothing it won’t do, no investigation it won’t taint.”Neither Flynn nor his attorney, Sidney Powell, responded immediately to requests for comment.Speaking to reports on Thursday afternoon, Trump said he had no prior knowledge of the Justice Department’s decision. “He was an innocent man,” Trump said, of Flynn. “Now in my book he’s an even greater warrior.”The dropped charges follow a years-long groundswell from Trump’s base, and particularly Fox News, to clear Flynn. His advocates claim that Flynn was set up by the same disreputable FBI figures who they believe persecuted Trump over phantom collusion with Russia.Flynn’s guilty plea, in December, 2017, has been no obstacle to the narrative, particularly since Flynn sought afterwards, unsuccessfully, to withdraw his plea. His sentencing, initially set for February, had also been delayed.Last month, agitation for a Flynn pardon intensified after documents emerged from two of Trump’s most hated ex-FBI figures, counterintelligence official Peter Strzok and attorney Lisa Page, discussing Flynn’s fateful January 2017 interview with the FBI. Page asked when and how to “slip it in” to Flynn that lying to an FBI agent is a crime, something that Flynn’s advocates believed showed the general being railroaded from the start. But veteran FBI agents and prosecutors have pointed out that the FBI is not legally obligated to inform an interview subject that lying to them is illegal. “Michael Flynn was very familiar with the FBI,” said Stephanie Douglas, a former executive assistant director of the FBI’s National Security Branch. “He would certainly have been aware of his obligation to provide candid and truthful information. His claim he was tricked and manipulated doesn’t sound valid to me.” Shea, in his Thursday court filing, suggested the FBI officials were “fishing for falsehoods merely to manufacture jurisdiction over any statement.” In Shea’s view, Flynn’s lies were less germane to the prosecution than the FBI “lack[ing] sufficient basis to sustain its initial counterintelligence investigation,” and its pre-interview position that it ought to close the investigation before speaking with the then national security adviser.Former FBI deputy head Andrew McCabe said on Thursday that the suggestion there was no reason to interview Flynn was “patently false, and ignores the considerable national security risk his contacts raised.” He said Flynn’s lies added to the FBI’s concerns about his relationship with Russia. “Today’s move... is pure politics designed to please the president,” he added.U.S. Attorney Jeff Jensen, who was appointed by Barr to review Flynn’s and other high-profile cases, said on Thursday that he concluded “the proper and just course” was to dismiss the case. “I briefed Attorney General Barr on my findings, advised him on these conclusions, and he agreed,” he said.The FBI Didn’t Frame Michael Flynn. That’s Just Trump’s Excuse for a Prospective Pardon.While serving as national security adviser, Flynn misled FBI interviewers about conversations he had with the then-Russian ambassador, Sergei Kislyak. In one of those late 2016 conversations, according to court filings, Flynn asked the Russians to avoid escalatory actions in response to sanctions and diplomatic expulsions then President Barack Obama enacted as reprisal for Russian electoral interference. Shea, in his filing, called Flynn’s Kislyak calls “entirely appropriate on their face.”The national security adviser’s lies prompted the holdover attorney general, Sally Yates, to warn the White House that Flynn had given the Russians leverage to blackmail him. But it would take weeks before Trump fired Flynn over “an eroding level of trust” concerning misleading Vice President Mike Pence on the Kislyak contacts. By May, Trump was said to have regretted dismissing the general.  Flynn in 2017 agreed to cooperate with Special Counsel Robert Mueller’s investigation. The general avoided charges for taking $530,000 in unregistered money from interests connected to the Turkish government—something he only declared with the Justice Department after his downfall as national security adviser. During a sentencing hearing in 2018, a federal judge castigated Flynn for disgracing the uniform Flynn wore for three decades. “Arguably, you sold your country out,” Judge Emmet Sullivan said. Two years earlier, on stage at the Republican national convention, Flynn had led a chant of “lock her up” about Hillary Clinton. Protesters outside Flynn’s courtroom did not let the general forget it. Trump’s enduring bond with Flynn is a testament to the importance of the role the general played in 2016.A host of national security officials, many aligned with the Republican Party, rejected Trump in 2016 as unfit to be president owing to his nativism, his penchant for brutality and his benign view of dictators like Russia’s Vladimir Putin. Flynn was the exception. And the general was an exceptional figure. As the intelligence chief for the Joint Special Operations Command during the mid-2000s, Flynn is one of a select few people who can be said to have personally prosecuted the most sensitive missions of the war on terror. Michael Flynn Putting Mueller Deal at Risk in ‘Dangerous’ New TrialIt was a pivotal credential in another way. Flynn emerged from the war on terror endorsing Trump’s view that the security apparatus, abetted by hidebound liberals and cowardly conservatives, had neutered the war on terror by refusing to see it was a civilizational conflict with Islam. “Islam is a political ideology” that “hides behind this notion of being a religion,” Flynn told the Islamophobic group ACT for America shortly after the 2016 convention. His hostility to Islam informed his sanguine view of Russia, which both Flynn and Trump saw as naturally aligned with the U.S. against what they called “Radical Islamic Terror.”It also meant that Trump and Flynn shared a common bureaucratic enemy. James Clapper, then the director of national intelligence, was a lead architect of an intelligence assessment finding Russia intervened in the election on Trump’s behalf. In 2014, Clapper fired Flynn as director of the Defense Intelligence Agency. It was deeply embittering. Just four years earlier, Flynn had been hailed as an innovator after claiming U.S. military intelligence had misunderstood the Afghanistan war. While Flynn portrayed himself as a martyr, victimized by the ‘Deep State’ for daring to warn about radical Islam, Clapper and other intelligence leaders had fallen out with Flynn over what they considered an incompetent management style and an iffy relationship with the truth. Reportedly, Flynn believed Iran was involved in the 2012 assault on a CIA compound in Benghazi that killed four Americans, and claimed incorrectly that Iran was responsible for more American deaths than al-Qaeda. Aides referred to such untruths as “Flynn facts.” Flynn facts did not disturb Trump. They validated his instincts on national security. Trump rewarded Flynn by making him national security adviser, one of the most important positions in the U.S. security apparatus. It was the first time Trump redeemed Flynn. Thursday’s dropped charges represent the second. Read more at The Daily Beast.Get our top stories in your inbox every day. Sign up now!Daily Beast Membership: Beast Inside goes deeper on the stories that matter to you. Learn more.

Now Swain, 40, spends her evenings having dinner with her girls, age 5 and 8, and studying for her real-estate license, which she hopes will provide more long-term stability for her family after the coronavirus crisis upended her livelihood. "I can't be put in a position like this again," said Swain, a bartender for 20 years. American women are taking an outsized hit from the early wave of unemployment caused by the pandemic, due to the nature of the jobs that were lost in the business shutdowns to control the spread of the coronavirus.

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

(Oregon State University) Clinical trial data behind drug dose recommendations for elevated cholesterol and chronic obstructive pulmonary disease illustrate how larger doses may not be worth the extra costs for many types of patients.

(Institute of Atmospheric Physics, Chinese Academy of Sciences) Scientists investigate how nitrogen dynamics affects carbon and water budgets in China by incorporating the terrestrial nitrogen cycle into the Noah Land Surface Model.

(Crime and Justice Research Alliance) A new study evaluated the effects of legalizing cannabis on police officers' law enforcement efforts in Washington. The study found that officers in that state, although not supportive of recriminalization, had a variety of concerns, from worries about the effect on youth to increases in impaired driving. The study can inform other states' efforts to address legalization.

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Hours after he was released from police lock-up last week, dancehall artiste Dexta Daps dropped some new music on his eager fans. The track, Breaking News, explores an all-too-familiar domestic violence storyline, but incorporates a controversial...

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

As the pandemic ebbed in China, alumni from the region raised more than $2.1 million to send crucial protective gear to New York healthcare workers.

6 April 2018

Research Event

Event participants

Professor Dapo Akande, Co-Director, Oxford Institute for Ethics, Law and Armed Conflict 
Emanuela-Chiara Gillard, Associate Fellow, International Law Programme, Chatham House
Ahila Sornarajah, Senior Lawyer, International and EU Law
Chair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House

Research Event

Event participants

Emanuela-Chiara Gillard, Associate Fellow, International Law Programme, Chatham House
Ezequiel Heffes, Thematic Legal Adviser, Geneva Call
Sigrid Redse Johansen, Judge Advocate General, Norwegian Armed Forces
Andrew Murdoch, Legal Director, UK Foreign & Commonwealth Office
Chair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House

The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS–based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9th carbon due to decreased FAHFA hydrolysis activity. The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, which is active in vivo. Acute treatment of WT mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on extent of upregulation of FAHFA levels, glucose tolerance, or insulin sensitivity in mice, indicating that therapeutic strategies should weigh more on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease.