More than 8,200 applications for the Anti-epidemic Support Scheme for Property Management Sector (ASPM) have been received, with over 3,850 approved, the Government announced today.

The approved applications involve subsidies of more than $140 million and will benefit around 22,000 building blocks and about 35,750 frontline property management workers.

Launched under the Anti-epidemic Fund, the ASPM provides subsidies to owners' organisations or property management companies of eligible buildings to provide hardship allowance to frontline property management workers.

It also provides the Anti-epidemic Cleansing Subsidy to owners' organisations or property management companies.

The scheme’s first phase covers private residential and composite buildings, while its second phase covers industrial and commercial buildings.

The ASPM is still open for applications and continues to disburse subsidies.

Contact the Property Management Services Authority at 3696 1156 or 3696 1166, or visit its website for details.

The Centre for Health Protection announced that as of 4pm today, no new COVID-19 cases have been recorded, leaving the number of confirmed cases in Hong Kong at 1,044 so far.

The centre again urged the public to maintain an appropriate social distance with other people to minimise the risk of infection.

It said people should go out less and avoid social activities such as having meals out or other gatherings to minimise the risk of coronavirus clusters emerging in the community.

As the COVID-19 situation remains severe and the number of cases reported around the world continues to rise, people are strongly urged to avoid all non-essential travel outside Hong Kong as well as maintain strict personal and environmental hygiene.

Additionally, the Hospital Authority reported that there are currently 90 patients under isolation and that 967 patients have been discharged upon recovery.

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

IntroductionThe nucleolus is the central organelle within eukaryotic cells whose primary function is to generate ribosomes, the major protein producing machines within all cells. New roles for the nucleolus are continuously emerging as we explore its molecular intricacies. Despite the central and fundamental role of the nucleolus in cell biology, there has previously been no single official meeting that enables the gathering of scientists whose research converges on the nucleolus. As a result, the community of researchers who study this organelle risks fragmentation across disciplines. The Emerging Roles for the Nucleolus Symposium, which has now taken place twice on a biennial basis, first in 2017 (1) and again in 2019, therefore, represents the first of its kind. The overarching goals of this symposium are (a) to convene researchers who study the nucleolus across model systems (yeast, nematodes, fruit flies, mouse, human cell lines) and biological perspectives (structural, biophysical, molecular, cellular, pathophysiology), (b) to share and disseminate the latest research breakthroughs in nucleolar biology, (c) to promote interaction, engagement, and collaboration centered on the nucleolus across disciplines, and (d) to provide trainees and early career investigators with an organelle-specific scientific community of support.The second Emerging Roles for the Nucleolus meeting was sponsored by the American Society for Biochemistry and Molecular Biology and was held at the Stowers Institute for Medical Research in Kansas City, MO, from October 24 to October 27, 2019. It was organized by Jennifer Gerton (Stowers Institute), Francesca Duncan (Northwestern University Feinberg School of Medicine), and Craig Pikaard...

We've all been saying it: These are unprecedented times. The impacts of the COVID-19 pandemic are incredibly wide-ranging and affect all facets of life. One that is hitting the scientific community very hard is the cancellation of meetings, large and small. While we are well-versed in connecting with colleagues and collaborators across a variety of online platforms, these do not replace the immensely gratifying aspects of attending meetings in person: the pleasure of catching up with old friends and making new ones, the insights gained from having real-time conversations with others working on the same topic but with different expertise and perspectives, and the stimulating new scientific ideas we carry home. We have all been feeling the disappointment as we learn that one meeting after another is forced to cancel, from the vibrant ASBMB annual meeting to summer conferences of all types.Another loss from the appropriate but painful decision to cancel the ASBMB annual meeting was the chance to hear from our Herbert Tabor Early Career Investigator Awardees, who represent the best science published in JBC in the preceding year. This year, the competition was particularly fierce. We hope and anticipate that we will be able to hear from the winners at next year's ASBMB annual meeting. But in the meantime, we want to raise a toast to Wenchao Zhao, Yue Yang, Manisha Dagar, Febin Varghese, and Ayumi Nagashima-Kasahara as our 2020 winners. We've captured their award-winning 2019 papers (1–5) on the JBC website (6), and extended profiles of the...

Sulfur is essential for biological processes such as amino acid biogenesis, iron–sulfur cluster formation, and redox homeostasis. To acquire sulfur-containing compounds from the environment, bacteria have evolved high-affinity uptake systems, predominant among which is the ABC transporter family. Theses membrane-embedded enzymes use the energy of ATP hydrolysis for transmembrane transport of a wide range of biomolecules against concentration gradients. Three distinct bacterial ABC import systems of sulfur-containing compounds have been identified, but the molecular details of their transport mechanism remain poorly characterized. Here we provide results from a biochemical analysis of the purified Escherichia coli YecSC-FliY cysteine/cystine import system. We found that the substrate-binding protein FliY binds l-cystine, l-cysteine, and d-cysteine with micromolar affinities. However, binding of the l- and d-enantiomers induced different conformational changes of FliY, where the l- enantiomer–substrate-binding protein complex interacted more efficiently with the YecSC transporter. YecSC had low basal ATPase activity that was moderately stimulated by apo FliY, more strongly by d-cysteine–bound FliY, and maximally by l-cysteine– or l-cystine–bound FliY. However, at high FliY concentrations, YecSC reached maximal ATPase rates independent of the presence or nature of the substrate. These results suggest that FliY exists in a conformational equilibrium between an open, unliganded form that does not bind to the YecSC transporter and closed, unliganded and closed, liganded forms that bind this transporter with variable affinities but equally stimulate its ATPase activity. These findings differ from previous observations for similar ABC transporters, highlighting the extent of mechanistic diversity in this large protein family.

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.

Purinergic signaling by extracellular ATP regulates a variety of cellular events and is implicated in both normal physiology and pathophysiology. Several molecules have been associated with the release of ATP and other small molecules, but their precise contributions have been difficult to assess because of their complexity and heterogeneity. Here, we report on the results of a gain-of-function screen for modulators of hypotonicity-induced ATP release using HEK-293 cells and murine cerebellar granule neurons, along with bioluminescence, calcium FLIPR, and short hairpin RNA–based gene-silencing assays. This screen utilized the most extensive genome-wide ORF collection to date, covering 90% of human, nonredundant, protein-encoding genes. We identified two ABCG1 (ABC subfamily G member 1) variants, which regulate cellular cholesterol, as modulators of hypotonicity-induced ATP release. We found that cholesterol levels control volume-regulated anion channel–dependent ATP release. These findings reveal novel mechanisms for the regulation of ATP release and volume-regulated anion channel activity and provide critical links among cellular status, cholesterol, and purinergic signaling.

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.

Numerous zinc ectoenzymes are metalated by zinc and activated in the compartments of the early secretory pathway before reaching their destination. Zn transporter (ZNT) proteins located in these compartments are essential for ectoenzyme activation. We have previously reported that ZNT proteins, specifically ZNT5–ZNT6 heterodimers and ZNT7 homodimers, play critical roles in the activation of zinc ectoenzymes, such as alkaline phosphatases (ALPs), by mobilizing cytosolic zinc into these compartments. However, this process remains incompletely understood. Here, using genetically-engineered chicken DT40 cells, we first determined that Zrt/Irt-like protein (ZIP) transporters that are localized to the compartments of the early secretory pathway play only a minor role in the ALP activation process. These transporters included ZIP7, ZIP9, and ZIP13, performing pivotal functions in maintaining cellular homeostasis by effluxing zinc out of the compartments. Next, using purified ALP proteins, we showed that zinc metalation on ALP produced in DT40 cells lacking ZNT5–ZNT6 heterodimers and ZNT7 homodimers is impaired. Finally, by genetically disrupting both ZNT5 and ZNT7 in human HAP1 cells, we directly demonstrated that the tissue-nonspecific ALP-activating functions of both ZNT complexes are conserved in human cells. Furthermore, using mutant HAP1 cells, we uncovered a previously-unrecognized and unique spatial regulation of ZNT5–ZNT6 heterodimer formation, wherein ZNT5 recruits ZNT6 to the Golgi apparatus to form the heterodimeric complex. These findings fill in major gaps in our understanding of the molecular mechanisms underlying zinc ectoenzyme activation in the compartments of the early secretory pathway.

Pathogenic bacteria of the genera Mycobacterium and Corynebacterium cause severe human diseases such as tuberculosis (Mycobacterium tuberculosis) and diphtheria (Corynebacterium diphtheriae). The cells of these species are surrounded by protective cell walls rich in long-chain mycolic acids. These fatty acids are conjugated to the disaccharide trehalose on the cytoplasmic side of the bacterial cell membrane. They are then transported across the membrane to the periplasm where they act as donors for other reactions. We have previously shown that transient acetylation of the glycolipid trehalose monohydroxycorynomycolate (hTMCM) enables its efficient transport to the periplasm in Corynebacterium glutamicum and that acetylation is mediated by the membrane protein TmaT. Here, we show that a putative methyltransferase, encoded at the same genetic locus as TmaT, is also required for optimal hTMCM transport. Deletion of the C. glutamicum gene NCgl2764 (Rv0224c in M. tuberculosis) abolished acetyltrehalose monocorynomycolate (AcTMCM) synthesis, leading to accumulation of hTMCM in the inner membrane and delaying its conversion to trehalose dihydroxycorynomycolate (h2TDCM). Complementation with NCgl2764 normalized turnover of hTMCM to h2TDCM. In contrast, complementation with NCgl2764 derivatives mutated at residues essential for methyltransferase activity failed to rectify the defect, suggesting that NCgl2764/Rv0224c encodes a methyltransferase, designated here as MtrP. Comprehensive analyses of the individual mtrP and tmaT mutants and of a double mutant revealed strikingly similar changes across several lipid classes compared with WT bacteria. These findings indicate that both MtrP and TmaT have nonredundant roles in regulating AcTMCM synthesis, revealing additional complexity in the regulation of trehalose mycolate transport in the Corynebacterineae.

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.

(Flinders University) New physiotherapy guidelines are targeting COVID-19 patient recovery for respiratory management, exercise and mobilisation in acute hospital wards and Intensive Care Units. The new guidelines published in Australian Journal of Physiotherapy aim to prevent complications of the respiratory system and muscle deconditioning, speed up recovery from mechanical ventilation, and improve long-term physical function and recovery.

The Government today announced that applications are open for several support schemes following the funding approval of the second round of the Anti-epidemic Fund and other relief measures by the Legislative Council Finance Committee.

The Club-house Subsidy Scheme, which provides a one-off subsidy of $100,000 to eligible club-houses, is now open for application. The deadline for application is May 18.

Upon submission of the completed application form and supporting documents, the disbursement of subsidies could generally be made in around two weeks.

The Travel Agents & Practitioners Support Scheme and the Hotel Sector Support Scheme are also open for applications, with the deadlines on June 15 and May 18 respectively.

The Subsidy Scheme for the Refuse Transfer Station Account Holders for Transporting Municipal Solid Waste, which offers a one-off subsidy of $8,000 to each of the eligible private municipal solid waste collectors operating in the first quarter, was also endorsed.

To ease the application procedures, the Environmental Protection Department will post cheques to recipients of this special subsidy in about a week after the funding endorsement.

Meanwhile, the total guarantee commitment of the Special 100% Loan Guarantee under the SME Financing Guarantee Scheme has been increased to $50 billion.

The maximum loan amount per enterprise has been increased to $4 million and the principal moratorium arrangement has been extended to the first 12 months.

The Special 100% Loan Guarantee will start receiving applications from April 20 and the application period has been extended to one year.

In March, Hong Kong International Airport (HKIA) became the first in the world to be certified as an International Air Transport Association (IATA) Center of Excellence for Perishable Logistics (CEIV Fresh) Partner Airport.

Two of the airport’s cargo terminal operators, Hong Kong Air Cargo Terminals Limited (HACTL) and Cathay Pacific Services Limited (CPSL) have achieved IATA CEIV Fresh Certification, while Cathay Pacific recently became the world’s first airline to be certified.

IATA created the Centre of Excellence for Independent Validators (CEIV) to help organisations involved in the air cargo supply chain achieve handling excellence.

The certification underscores the speed, consistency and efficiency of all HKIA stakeholders when it comes to the treatment and transportation of perishable products.

It also helps to ensure food safety, and reduce food wastage and loss along the supply chain.

Quality benchmark

Hong Kong Air Cargo Terminals Limited Chief Executive Wilson Kwong said the main value of the accreditation is that it provides a universally recognised standard.

“It gives assurance to the various stakeholders that we have, and we are adhering to the highest possible standards.”

Both accredited cargo terminal operators HACTL and CPSL have set up perishable cargo handling areas with truck docks next to the apron.

As soon as the perishable goods are unloaded from the aircraft, they are immediately transported to the handling area.

The clearance and sampling checks have been streamlined to minimise the time taken to unload the goods. There are cold rooms set at tailored temperatures for various kinds of perishable cargo.

Their staff training and handling process have also been assessed and certified for their compliance with the global industry standards.

Cathay Pacific Services Limited Chief Executive Officer Jenny Lam noted that one of the challenges in meeting the certification standard is training its 2,000 employees in handling and storing perishable goods.

“They first have to identify what types of perishables they are, such as are they flowers, are they fruits, are they meat, so that they know how to segregate the storage.

“Secondly, they gain knowledge about certain fruits that cannot be put close to each other such as bananas and apples.”

Growth opportunities

In 2018, the airport handled about 380,000 tonnes of perishable cargo - a rise of 12% on 2017, with perishables accounting for about 8% of total air cargo volume.

Airport Authority Commercial Executive Director Cissy Chan explained that temperature-controlled air freight is one of the fastest growing segments in the air cargo market.

She believes with the new certification, the airport is well-placed to capture the increasing growth opportunities in the market for fresh and perishable goods.

“With the opening of the Hong Kong-Zhuhai-Macao Bridge, the transport time between the airport and the Greater Bay Area, notably the western part of the Pearl River Delta, will be further cut down.

“So this will put us in an even better position to become the transhipment hub for these perishables for the entire bay area.”

Extra backing

To support the growing demand for perishables, the Airport Authority has provided additional cool dollies, so there are now more than 30 for use by the whole airport community. It is also building apron shelters to protect the perishables from ambient weather elements.

Cathay Pacific Cargo Service Delivery General Manager Frosti Lau said they would work closely with the authority and its cargo terminal to see what new investments are required to handle the increasing demand.

The Airport Authority expanded the scope of its food waste recycling programme in 2011 to cover Hong Kong International Airport business partners, including restaurants and lounges operating in terminal buildings, as well as airline catering companies, hotels and cargo terminals.

In 2017-18, over 2,000 tonnes of food waste from 17 airport business partners were collected for recycling.

Rainie Ho, the supervisor of one participating restaurant, said staff make every effort to collect food waste on a constant basis.

“We have three bins of recycled food waste, including eggs, toast, bread, chicken, meat, pork bones, tea and coffee every day.”

Ms Ho gave kudos to the Airport Authority for making the process simple.

“The Airport Authority provides us with garbage bags every month. We explain to our staff that the red bags are for food waste, while the black ones are for general rubbish. This makes it easier for them to remember and handle.”

Airport Authority Assistant General Manager (Sustainability) Mike Kilburn is the facilitator of the food waste recycling programme. He hoped to encourage more business partners to join by making the scheme as trouble-free as possible.

“This is an example of an easy, useful and free programme because the contractor comes to collect from each company and the contractor provides a clean rubbish bin for the food waste, they take the food waste away, they wash the bin and then they bring it back clean.

“And it is useful because the food waste is not just sent to the landfill, but it is turned into fish meal so it goes back into the food chain because the fish meal is fed to the fish and the people can eat the fish, so it is a very complete system.”

Surplus food collection

In addition to food waste recycling, the authority promotes the Food Rescue Programme in co-operation with a local non-governmental organisation called Food Angel.

In 2013, the authority helped Food Angel to purchase a refrigerated truck and covered the cost of collecting surplus food from business partners on the airport island.

By 2014, a central storage room was set up in the terminal building to collect even more surplus food from catering outlets.

By proving it can reduce its environmental impact by working closely with the entire airport community, the authority was recognised at the 2018 Hong Kong Awards for Environmental Excellence where it won the Gold Award for the Public & Community Services Sector.

Future prep

In 2018, the authority launched a voluntary municipal solid waste charging pilot scheme to achieve waste reduction.

It has assisted more than 200 tenants with measuring their waste generation and calculating what it would cost to dump it in the future.

Another participating restaurant manager Alfred Lau explained that the pilot scheme helps restaurants gear up for the polluter-pays principle.

“A mock monthly invoice was issued to us, showing the quantity of waste disposed and the estimated disposal charge. Now we understand that by reducing our waste, we will pay less in the end.”

Mr Lau believes the pilot scheme encourages eateries to alter their disposal behaviour by recycling as much food waste as possible.

“Our disposed waste amount fell sharply once we learnt useful ways to recycle. Our restaurant is located in the restricted area of the airport where drinks are not allowed to be brought inside. So many passengers buy bottled drinks and create a large amount of plastic waste. Just by recycling plastic bottles, our waste decreased significantly.”

The authority said it is proud to be the driving force behind waste reduction.

“We make it easy for them because we do all the organisation, we make it useful because they can help them to prepare, and it is free for them to join the programme. This is very important for us because as the Airport Authority, our job is to create a concept that other people can follow and if you address those three criteria, you make it very hard for them to say no to you. We take away their reasons to say no, so it is easy for them to join our scheme,” said Mr Kilburn.

The Hong Kong Awards for Environmental Excellence is led by the Environmental Campaign Committee alongside the Environmental Protection Department and in conjunction with nine organisations. The objective is to reduce Hong Kong’s environmental impact by promoting environmental management.

The Airport Authority’s current target is to reduce, recycle and recover 50% of all its waste by 2021.

SAS Visual Analytics can be configured to send a notification to specific users when report objects contain data that meets certain criteria. This SAS note contains frequently asked questions about setting up alerts.

(American Association for Cancer Research) Combining intratumoral electroporation of interleukin-12 (IL-12) DNA (tavokinogene telseplasmid, or TAVO) with the immune checkpoint inhibitor pembrolizumab (Keytruda) led to clinical responses in patients with immunologically quiescent advanced melanoma, according to results from a phase II trial.

(George Mason University) The team's work supports evidence-based decision making, informed by models, to rethink and facilitate hospital operations during the pandemic.

(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.

(University of Michigan) The coronavirus pandemic has highlighted just how reliant the United States and other countries are on Chinese manufacturing, with widespread shortages of protective medical gear produced there.

(American Society of Agronomy) Study shows which desert soils better recover from disturbance.

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.

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

(Kessler Foundation) Andrew Houtenville, Ph.D., research director of the University of New Hampshire's Institute on Disability: 'Unlike the Great Recession and the Great Depression, many workers in the COVID Recession may be 'on temporary layoff' (aka furloughed) and may be recalled, rather than losing their jobs completely. To further investigate this issue, we plan to release a Special nTIDE Report on May 15.'

(University of Portsmouth) The first major UK study into victims of computer misuse crime has exposed the serious harm some victim's experience, as well as barriers to reporting such offences, receiving support, achieving justice and the precarious resources dedicated by the police to cybercrime.

Linda J. Piccinino
May 1, 2017; 30:95-100
From Research to Practice

Korey Capozza
May 1, 2015; 28:83-91
Feature Articles

Martha Mitchell Funnell
Oct 1, 2007; 20:221-226
Articles

Tricia S. Tang
May 1, 2011; 24:85-98
From Research to Practice/Behavioral Interventions for Diabetes Self-Management

Michele Heisler
Oct 1, 2007; 20:214-221
Articles

10 December 2018

Clarification of international humanitarian law is important in ensuring compliance with the rule of proportionality, but a culture of compliance within armed forces and groups is also crucial.

Invitation Only Research Event

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.

Pathogenic bacteria of the genera Mycobacterium and Corynebacterium cause severe human diseases such as tuberculosis (Mycobacterium tuberculosis) and diphtheria (Corynebacterium diphtheriae). The cells of these species are surrounded by protective cell walls rich in long-chain mycolic acids. These fatty acids are conjugated to the disaccharide trehalose on the cytoplasmic side of the bacterial cell membrane. They are then transported across the membrane to the periplasm where they act as donors for other reactions. We have previously shown that transient acetylation of the glycolipid trehalose monohydroxycorynomycolate (hTMCM) enables its efficient transport to the periplasm in Corynebacterium glutamicum and that acetylation is mediated by the membrane protein TmaT. Here, we show that a putative methyltransferase, encoded at the same genetic locus as TmaT, is also required for optimal hTMCM transport. Deletion of the C. glutamicum gene NCgl2764 (Rv0224c in M. tuberculosis) abolished acetyltrehalose monocorynomycolate (AcTMCM) synthesis, leading to accumulation of hTMCM in the inner membrane and delaying its conversion to trehalose dihydroxycorynomycolate (h2TDCM). Complementation with NCgl2764 normalized turnover of hTMCM to h2TDCM. In contrast, complementation with NCgl2764 derivatives mutated at residues essential for methyltransferase activity failed to rectify the defect, suggesting that NCgl2764/Rv0224c encodes a methyltransferase, designated here as MtrP. Comprehensive analyses of the individual mtrP and tmaT mutants and of a double mutant revealed strikingly similar changes across several lipid classes compared with WT bacteria. These findings indicate that both MtrP and TmaT have nonredundant roles in regulating AcTMCM synthesis, revealing additional complexity in the regulation of trehalose mycolate transport in the Corynebacterineae.

8 May 2019

This paper sets out a roadmap for how organizations in the civil nuclear sector can explore their options and review their cyber risk exposure.

Invitation Only Research Event

2 April 2020

4 March 2020 , Volume 96, Number 2

29 April 2020

Sodium–glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-³H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n = 26) or placebo (n = 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (+0.66 ± 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (+0.71 ± 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.

Purpose: Although the incidence of de novo neuroendocrine prostate cancer (NEPC) is rare, recent data suggests that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine (NE) hallmarks and androgen receptor (AR)-suppression in prostate cancer (PC). Previous clinical reports indicate that PCs with a phenotype similar to NE tumors can be more amenable to imaging by ¹⁸F-Fluorodeoxyglucose (FDG) rather than PSMA-targeting radioligands. In this study, we evaluated the association between NE gene signature and FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported FDG-avidity of PSMA-suppressed tumors. Methods: Data mining approaches, cell lines and patient-derived xenograft (PDX) models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes: HK1 to 3 and GCK) and PSMA (FOLH1 gene) following AR-inhibition and in correlation with NE hallmarks. Also, we characterize a NE-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no NE histopathology. We measured glucose uptake in a NE-induced in vitro model and a zebrafish model by non-radioactive imaging of glucose uptake using fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrates that a NE gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR-inhibitors, high expression of GCK and low expression of SLC2A12 correlated with NE histopathology and PSMA gene suppression. GLUT12-suppression and amplification of glucokinase was observed in NE-induced PC cell lines and PDX models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: NE gene signature in NEPC and NELPC associates with a distinct transcriptional profile of GLUTs and HKs. PSMA-suppression correlates with GLUT12-suppression and glucokinase-amplification. Alteration of FDG uptake-associated genes correlated positively with higher glucose uptake in AR and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient pre-clinical method for monitoring non-radioactive glucose uptake.

Background: Accurate definition of the extent and severity of left-ventricular assist device (LVAD) infection may facilitate therapeutic decision making and targeted surgical intervention. Here, we explore the value of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for guidance of patient management. Methods: Fifty-seven LVAD-carrying patients received 85 whole-body ¹⁸F-FDG PET/CT scans for the work-up of device infection. Clinical follow-up was obtained over a period of up to two years. Results: PET/CT showed various patterns of infectious involvement of the 4 LVAD components: driveline entry point (77% of cases), subcutaneous driveline path (87%), pump pocket (49%) and outflow tract (58%). Driveline smears revealed staphylococcus or pseudomonas strains as the underlying pathogen in a majority of cases (48 and 34%, respectively). At receiver-operating characteristics analysis, an ¹⁸F-FDG standardized uptake value (SUV) >2.5 was most accurate to identify smear-positive driveline infection. Infection of 3 or all 4 LVAD components showed a trend towards lower survival vs infection of 2 or less components (P = 0.089), while involvement of thoracic lymph nodes was significantly associated with adverse outcome (P = 0.001 for nodal SUV above vs below median). Finally, patients that underwent early surgical revision within 3 months after PET/CT (n = 21) required significantly less inpatient hospital care during follow-up when compared to those receiving delayed surgical revision (n = 11; p<0.05). Conclusion: Whole-body ¹⁸F-FDG PET/CT identifies the extent of LVAD infection and predicts adverse outcome. Initial experience suggests that early image-guided surgical intervention may facilitate a less complicated subsequent course.