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Processivity of dextransucrases synthesizing very-high-molar-mass dextran is mediated by sugar-binding pockets in domain V [Glycobiology and Extracellular Matrices]

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.




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Withdrawal: miR-21-mediated radioresistance occurs via promoting repair of DNA double strand breaks. [Withdrawals/Retractions]

VOLUME 292 (2017) PAGES 3531–3540This article has been withdrawn by Shuofeng Hu, Xiaomin Ying, Xiangming Zhang, and Ya Wang.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...




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A Legionella effector kinase is activated by host inositol hexakisphosphate [Enzymology]

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




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Biophysical characterization of SARAH domain-mediated multimerization of Hippo pathway complexes in Drosophila [Signal Transduction]

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.




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Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes [Cell Biology]

The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.




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The mRNA levels of heat shock factor 1 are regulated by thermogenic signals via the cAMP-dependent transcription factor ATF3 [Metabolism]

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.




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DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels [Cell Biology]

Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension.




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5-Ethynyl-2'-deoxycytidine and 5-ethynyl-2'-deoxyuridine are differentially incorporated in cells infected with HSV-1, HCMV, and KSHV viruses [Microbiology]

Nucleoside analogues are a valuable experimental tool. Incorporation of these molecules into newly synthesized DNA (i.e. pulse-labeling) is used to monitor cell proliferation or to isolate nascent DNA. Some of the most common nucleoside analogues used for pulse-labeling of DNA in cells are the deoxypyrimidine analogues 5-ethynyl-2'-deoxyuridine (EdU) and 5-ethynyl-2'-deoxycytidine (EdC). Click chemistry enables conjugation of an azide molecule tagged with a fluorescent dye or biotin to the alkyne of the analog, which can then be used to detect incorporation of EdU and EdC into DNA. The use of EdC is often recommended because of the potential cytotoxicity associated with EdU during longer incubations. Here, by comparing the relative incorporation efficiencies of EdU and EdC during short 30-min pulses, we demonstrate significantly lower incorporation of EdC than of EdU in noninfected human fibroblast cells or in cells infected with either human cytomegalovirus or Kaposi's sarcoma-associated herpesvirus. Interestingly, cells infected with herpes simplex virus type-1 (HSV-1) incorporated EdC and EdU at similar levels during short pulses. Of note, exogenous expression of HSV-1 thymidine kinase increased the incorporation efficiency of EdC. These results highlight the limitations when using substituted pyrimidine analogues in pulse-labeling and suggest that EdU is the preferable nucleoside analogue for short pulse-labeling experiments, resulting in increased recovery and sensitivity for downstream applications. This is an important discovery that may help to better characterize the biochemical properties of different nucleoside analogues with a given kinase, ultimately leading to significant differences in labeling efficiency of nascent DNA.




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Profiles of kindergartens posted online




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Government announces Study Subsidy Scheme for Designated Professions/Sectors for 2020/21 cohort - sub-degree programmes




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Subsidy amount for Non-means-tested Subsidy Scheme for Self-financing Undergraduate Studies in Hong Kong in 2020/21 academic year announced




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Appointment of new member to Advisory Committee on Gifted Education




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EDB provides more relief grants to affected sectors




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Primary One Central Allocation results to be posted to parents in early June




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Heng Tai Hse partially evacuated

People living in units 13 and 14 of the top six floors of Heng Tai House in Fu Heng Estate, Tai Po need to be quarantined as a precaution.

 

Hong Kong University Chair of Infectious Disease Prof Yuen Kwok-yung made the statement at a media briefing today after an expert team conducted initial epidemiological investigations in the building to find the cause of a new COVID-19 infection.

 

The new case announced this afternoon involves a 59-year-old man who lives on the 34th floor of the building.

 

Prof Yuen said: “There is a possibility that when the patients on the 32nd floor are defecating - we know now that the fecal material actually contains the virus - while they’re defecating the fecal material goes into the sewer system.

 

“There is a vent of air that comes through the venting pipe, which goes to the top floor and maybe aerosolised in the air and then the droplets try to settle but, while at the same time, when there’s a light wind blowing, in which the air current going over the rooftop carries the particles back into the top floors.

 

“And of course, the 34th floor is the top floor. That is the most dangerous, followed by the 33rd and 32nd floors.”

 

Prof Yuen added he is uncertain if the venting pipe will continue to produce more infected aerosolised particles.

 

“So it is just a precautionary measure that we must remove the residents from the top six floors in units 13 and 14 for a period of time.”

 

For information and health advice on COVID-19, visit the Government's dedicated webpage.




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Shoreline clean-up conducted

Various government departments, together with volunteers today conducted a shoreline clean-up along the remote rocky beach in Kung Pui Wan, Tap Mun to remove two tonnes of refuse.

 

The Environmental Protection Department, the Food & Environmental Hygiene Department (FEHD) and the Marine Department participated in the operation.

     

The Inter-departmental Working Group on Marine Environmental Management said the beach, facing the windy and wavy sea, is not easily accessible by working vessels and the rough terrain connecting the rocky beach also increases the difficulty of routine cleaning work.

 

FEHD cleaners along with the volunteers packed the refuse and delivered it on foot to a nearby pier for temporary storage. FEHD staff then took the refuse to the Marine Department's collection vessel in batches for onward delivery to a rubbish collection point for centralised handling.

     

To minimise the risk of spreading COVID-19, the operation was carried out in groups of no more than four participants each. They maintained an appropriate distance from each other and paid heed to personal protection, including wearing masks.

     

The working group thanked the volunteers for taking part and called on the public to keep the countryside and shoreline clean during outings.

     

For information on clean shorelines, visit the Clean Shorelines facebook and Instagram pages.




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Researchers Answer a Diversity Puzzle: Why Chinese Americans but not Indian Americans are Underrepresented in Leadership Positions

Thursday, February 20, 2020 - 11:15

New studies identify the boundary and causes of the “Bamboo Ceiling”




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How to Make Sound Decisions with Limited Data During the Coronavirus Pandemic

Thursday, April 2, 2020 - 13:00

Coronavirus presents an unprecedented predicament: Everyday, leaders must make momentous decisions with life or death consequences for many—but there is a dearth of data. Oded Netzer is a Columbia Business School professor and Data Science Institute affiliate who builds statistical and econometric models to measure consumer behavior that help business leaders make data-driven decisions. Here, he discusses how leaders from all fields can make sound decisions with scarce data to guide them.




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Oncotarget: Loss of p16 and high Ki67 labeling index is associated with poor outcome

(Impact Journals LLC) Oncotarget Volume 11, Issue 12 reported that the p16 tumor suppressor is coded by CDKN2A and plays an important role during carcinogenesis and tumor progression in numerous tumor entities.




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Comparing opioid-related deaths among cancer survivors, general population

(JAMA Network) Death certificate data were used to compare the rate of opioid-related deaths in the US among cancer survivors with that of the general population from 2006 through 2016. Whether opioid-associated deaths in cancer survivors, who are often prescribed opioids for cancer-related pain, are rising at the same rate as in the general population is unknown.




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CT scan database of 1000 sets was created for teaching AI to diagnose COVID-19

(Moscow Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies) Researchers of the Moscow Diagnostics and Telemedicine Center collected a dataset that includes more than a thousand sets of chest CT scans of patients with imaging finding of COVID-19. As of today, it is the largest completely anonymized database of CT studies, which has no analogues in Russia or in the world. It is available for download and can be used for developing services based on artificial intelligence technologies.




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Software flaws often first reported on social media networks, PNNL researchers find

(DOE/Pacific Northwest National Laboratory) Software vulnerabilities are more likely to be discussed on social media before they're revealed on a government reporting site, a practice that could pose a national security threat, according to computer scientists at Pacific Northwest National Laboratory.




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Rutgers' Greg Moore elected to National Academy of Sciences

(Rutgers University) Rutgers Professor Gregory W. Moore, a renowned physicist who seeks a unified understanding of the basic forces and fundamental particles in the universe, has been elected to the prestigious National Academy of Sciences.




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Evidence of Late Pleistocene human colonization of isolated islands beyond Wallace's Line

(Max Planck Institute for the Science of Human History) What makes our species unique compared to other hominins? High profile genetic, fossil and material culture discoveries present scientists working in the Late Pleistocene with an ever-more complex picture of interactions between early hominin populations. One distinctive characteristic of Homo sapiens, however, appears to be its global distribution. Exploring how Homo sapiens colonized most of the world's continents in a relatively short period could reveal the exceptional capacities of humans relative to other hominins.




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Minimum energy requirements for microbial communities to live predicted

(University of Warwick) A microbial community is a complex, dynamic system composed of hundreds of species and their interactions, they are found in oceans, soil, animal guts and plant roots. Each system feeds the Earth's ecosystem and their own growth, as they each have their own metabolism that underpin biogeochemical cycles. Researchers from the School of Life Sciences at the University of Warwick have produced an extendable thermodynamic model for simulating the dynamics of microbial communities.




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New technique delivers complete DNA sequences of chromosomes inherited from mother and father

(University of Adelaide) An international team of scientists led by the University of Adelaide's Davies Research Centre has shown that it is possible to disentangle the DNA sequences of the chromosomes inherited from the mother and the father, to create true diploid genomes from a single individual.




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Modeling gas diffusion in aggregated soils

(American Society of Agronomy) Researchers develop soil-gas diffusivity model based on two agricultural soils.




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Gregory McMichael worked in local law enforcement for over 30 years and previously investigated Ahmaud Arbery

Gregory McMichael and his son, Travis, were charged with murder and aggravated assault in relation to the shooting death of Ahmaud Arbery in February.





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A standard for real-time calculation of pollutant emissions allocated to the use of ICT

(École de technologie supérieure) The first ever standard for real-time calculation of pollutant emissions allocated to the use of information and communication technologies (ICT) was recently introduced, thanks to the work of the IEEE ICT Emissions Working Group Committe, chaired by Mohamed Cheriet, a Professor in the Systems Engineering Department at École de technologie supérieure. Under the auspices of the IEEE Standards Association, the Working Group Committee is made up of researchers from diverse backgrounds and many different countries.




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A High Level of Patient Activation Is Observed But Unrelated to Glycemic Control Among Adults With Type 2 Diabetes

Robert Mayberry
Jul 1, 2010; 23:171-176
Feature Articles




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Improving Diabetes Care in the Hospital Using Guideline-Directed Orders

Stephen F. Quevedo
Oct 1, 2001; 14:
Feature Articles




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Insulin-Related Knowledge Among Health Care Professionals in Internal Medicine

Rachel L. Derr
Jul 1, 2007; 20:177-185
Feature Articles




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What about entertainment? - Industry insider feels sector under-represented in COVID recovery task force

Last month, Prime Minister Andrew Holness announced the establishment of an Economic Recovery Task Force, chaired by Finance Minister Dr Nigel Clarke. The multisectoral task force, which is mandated to oversee Jamaica's economic recovery from...




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Man arrested in connection with West Kingston shooting

A man has been arrested in connection with the “vile and brutal” murders of 8-year-old Toya Brown and 15-year-old Nyron Taylor, who were shot and killed last evening, revealed Minister of National Security, Dr. Horace Chang. Chang says...




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J’can healthcare worker dies from COVID-19-related complications

Antoniette Bryden has fond memories of her mother, Arlene Reid, 51, a healthcare worker originally from Yallahs, St Thomas, who died of COVID-19 in Brampton, Ontario, Canada, on April 27. Reid, a personal support worker (PSW) who worked part-time...




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COVID-19: Economic Implications for Japan and the United States

Exploring the economic implications of COVID-19 on Japan and the US.




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Leading Through a Protracted Crisis: How to Drive, Survive, and Thrive in a Crisis

Management professors Adam Galinksy and Paul Ingram, together with Jonathan Laor ’21, CEO of Applicaster, advise on leadership during a crisis.




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Bulletin updated at 19:45 HKT - 03/05/2020

There is no warning in force.




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12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2{gamma} knockout [Signal Transduction]

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.




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Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol [Glycobiology and Extracellular Matrices]

β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro. β-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation. Liquid chromatography–tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain. We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination. We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes. In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain.




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Deletion of fatty acid transport protein 2 (FATP2) in the mouse liver changes the metabolic landscape by increasing the expression of PPAR{alpha}-regulated genes [Lipids]

Fatty acid transport protein 2 (FATP2) is highly expressed in the liver, small intestine, and kidney, where it functions in both the transport of exogenous long-chain fatty acids and the activation of very-long-chain fatty acids. Here, using a murine model, we investigated the phenotypic impacts of deleting FATP2, followed by a transcriptomic analysis using unbiased RNA-Seq to identify concomitant changes in the liver transcriptome. WT and FATP2-null (Fatp2−/−) mice (5 weeks) were maintained on a standard chow diet for 6 weeks. The Fatp2−/− mice had reduced weight gain, lowered serum triglyceride, and increased serum cholesterol levels and attenuated dietary fatty acid absorption. Transcriptomic analysis of the liver revealed 258 differentially expressed genes in male Fatp2−/− mice and a total of 91 in female Fatp2−/− mice. These genes mapped to the following gene ontology categories: fatty acid degradation, peroxisome biogenesis, fatty acid synthesis, and retinol and arachidonic acid metabolism. Targeted RT-quantitative PCR verified the altered expression of selected genes. Of note, most of the genes with increased expression were known to be regulated by peroxisome proliferator–activated receptor α (PPARα), suggesting that FATP2 activity is linked to a PPARα-specific proximal ligand. Targeted metabolomic experiments in the Fatp2−/− liver revealed increases of total C16:0, C16:1, and C18:1 fatty acids; increases in lipoxin A4 and prostaglandin J2; and a decrease in 20-hydroxyeicosatetraenoic acid. We conclude that the expression of FATP2 in the liver broadly affects the metabolic landscape through PPARα, indicating that FATP2 provides an important role in liver lipid metabolism through its transport or activation activities.




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Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes [Cell Biology]

The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.




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Bulletin updated at 00:00 HKT 10/May/2020

General Situation:
A trough of low pressure will edge towards the coast of Guangdong today and linger over the region in the following couple of days. There will be thundery showers over Guangdong. With the anticyclone aloft strengthening in the middle and latter parts of this week, the weather over southern China will improve and it will be hot.

Date/Month: 10/05 (Sunday)
Wind: South force 3.
Weather: Sunny intervals and a few showers. Isolated thunderstorms later.
Temp range: 28 - 32 C
R.H. range: 65 - 95 per Cent

Date/Month: 11/05 (Monday)
Wind: South force 2 to 3.
Weather: Mainly cloudy with occasional showers and a few squally thunderstorms.
Temp range: 26 - 30 C
R.H. range: 70 - 95 per Cent

Date/Month: 12/05 (Tuesday)
Wind: Light winds force 2.
Weather: Mainly cloudy with a few showers and thunderstorms.
Temp range: 25 - 29 C
R.H. range: 70 - 95 per Cent

Date/Month: 13/05 (Wednesday)
Wind: Southeast force 3.
Weather: Sunny intervals and one or two showers.
Temp range: 26 - 30 C
R.H. range: 65 - 90 per Cent

Date/Month: 14/05 (Thursday)
Wind: Southeast force 3.
Weather: Sunny periods.
Temp range: 26 - 31 C
R.H. range: 60 - 85 per Cent

Date/Month: 15/05 (Friday)
Wind: South to southeast force 3.
Weather: Sunny periods.
Temp range: 27 - 32 C
R.H. range: 60 - 85 per Cent

Date/Month: 16/05 (Saturday)
Wind: South force 3.
Weather: Sunny periods.
Temp range: 27 - 32 C
R.H. range: 60 - 85 per Cent

Date/Month: 17/05 (Sunday)
Wind: South force 3 to 4.
Weather: Sunny periods.
Temp range: 28 - 32 C
R.H. range: 70 - 90 per Cent

Date/Month: 18/05 (Monday)
Wind: South force 3 to 4.
Weather: Sunny periods and isolated showers.
Temp range: 28 - 32 C
R.H. range: 70 - 90 per Cent

Sea surface temperature at 2 P.M. 09/05/2020 at North Point was 25 degrees C.
Soil temperatures at 7 A.M. 09/05/2020 at Hong Kong Observatory :
0.5 M below surface was 27.6 degrees C
1.0 M below surface was 26.4 degrees C




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Bulletin updated at 00:45 HKT 10/05/2020

An anticyclone aloft brought hot weather to southern China yesterday. Locally, it was hot with sunny periods and isolated showers. A trough of low pressure will edge towards the coast of Guangdong today and linger over the region in the following couple of days. There will be thundery showers over Guangdong.

Weather forecast for Hong Kong:
Mainly cloudy with a few showers. Sunny intervals during the day. There will be isolated thunderstorms later. Hot with temperatures ranging between 28 and 32 degrees. Moderate southerly winds.

Outlook: There will be showers and thunderstorms on Monday and Tuesday. The weather will improve gradually in the following couple of days.




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The DNA sensor cGAS is decorated by acetylation and phosphorylation modifications in the context of immune signaling

Bokai Song
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Modulation of natural HLA-B*27:05 ligandome by ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 2 (ERAP2)

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