23 January 2020

Members Event

Event participants

Professor David Heymann CBE, Distinguished Fellow, Global Health Programme, Chatham House; Executive Director, Communicable Diseases Cluster, World Health Organization (1998-03)
Chair: Emma Ross, Senior Consulting Fellow, Global Health Programme, Chatham House

Ludovic C. Gillet
Jun 1, 2012; 11:O111.016717-O111.016717
Research

3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range.

23 January 2020

Publication Date: Apr 10 2020 The SEC will withdraw the existing approval order and the fund will become subject to the requirements of Rule 6c-11 and Nasdaq Rule 5704....

What happens when a service you shared your personal data with is acquired by a giant corporation?

While coordinated action is urgently needed, should we be racing to download everything that promises a solution?

Last month, I paid a visit to Yuen Long where I met a few families at Long Shin Estate. Apart from distributing face masks and anti-epidemic supplies to them, I was also given a better understanding of the impact brought by the epidemic on their daily lives. To show our concerted support in the fight against the disease, the Department of Justice (DoJ) Staff Club organised a volunteer activity on Sunday, which I joined with my fellow colleagues in offering our help to those in need.

To echo the Government's move to stay united, the DoJ Staff Club put forth a cash contribution campaign to buy anti-epidemic supplies for donation. The staff club volunteers acquired face masks and alcohol-based handrub in different ways - some were purchased through online shopping and some were bought at medicine stores. Last Sunday, I joined the volunteers in packing the anti-epidemic supplies, supermarket cash coupons and leaflets with health information. Our volunteers took the care packs in person to a non-governmental organisation a few days ago for passing to the elderly and low-income groups.

The staff club has been participating in volunteer services now and then. Given the overwhelming response this time, I am glad to know that more volunteer activities would be organised in the future. I would definitely be joining as many as I could. Through offering our efforts to help those in need, we hope to show our care for the less privileged in society and contribute to building a caring and inclusive community.

The public services of the DoJ, like all other government departments, have gradually resumed back to normal. I inspected the Justice Place on Monday to learn more about the infection control measures in place, such as the body temperature checking arrangement, provision of hand sanitisers and sanitising mats at building entrances.

We must remain vigilant as the epidemic is still severe, and more importantly, we also need to stand in solidarity in the fight against the disease.

Secretary for Justice Teresa Cheng wrote this article and posted it on her blog on March 5.

Ensemble SU from Korea will stage a concert at Sha Tin Town Hall in December.

The quintet breaks boundaries by merging both traditional Korean musical instruments with Western instruments to bring music to life.

The world touring group plays works ranging from Arirang Rhapsody to Bohemian Rhapsody and from Bul-no-ha to the jazz classic Take Five.

The concert will be held at 8pm on December 6 and tickets are available at URBTIX.

Click here for details.

An extraordinary strings crossover performance by erhu master Xu Ke and the Tokyo String Quintet will be held in December.

Heralded as the Paganini of the erhu world, Mr Xu is currently a guest professor at the Shanghai Conservatory of Music and the Senzoku Gakuen College of Music in Japan.

Presented by the Leisure & Cultural Services Department as part of the Music Delight Series, the concert will be held at Tsuen Wan Town Hall on December 14.

Tickets are available at URBTIX.

Click here for details.

The Housing Authority’s Commercial Properties Committee today approved the extension of rent concessions to over 8,300 non-domestic tenants or licensees for six months from April 1 to September 30.

The authority had earlier granted a 50% rent concession to its eligible retail and factory tenants for six months from April 1.

Under the extension, their rent concession will be increased to 75% over the same period with retrospective effect from April 1. The rent concession does not include rates and air-conditioning charges.

The authority said such further measures are to support the Government's new series of measures announced in early April to relieve the financial burden of individuals and businesses.

A total of 2,450 retail and 3,300 factory tenants will benefit from the approved increase in the rent concession.

The 75% rent concession will also be extended to cover tenants and licensees of bus kiosks and most advertising signboards, as well as car park users for the monthly parking of commercial vehicles.

About 40 tenancies for bus kiosks, 80 advertising signboards and about 2,500 car park users stand to benefit from the concession.

Tenants of premises in the authority's properties which are required to be closed under relevant regulations or the Government's directions, may also apply to the authority for a 100% rent concession for the period during which they are required to be closed.

The authority added that the approved measures will be implemented as soon as possible. For rent and licence fees already paid for the months of April and May, arrangements will be made for offsetting in the payment for subsequent months.

The committee has approved three rounds of rent concessions since last September. Together with this round, the total rent and licence fees foregone by the authority is estimated to reach more than $1 billion.

Do you know which main gases are contained in the composition of air? Under climate change and global warming, carbon dioxide ...

(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.

The Lady of Dancehall, D'Angel, says although her COVID-19 Relief Concert did not meet its US$200,000 target, she is overwhelmed by the support. The event, held via Instagram Live last Friday, saw performances from the likes of Beenie Man, G...

Georg H H Borner
Apr 28, 2020; 0:R120.001971v1-mcp.R120.001971
Review

9 September 2019

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.

The accuracy of lutetium-177 (¹⁷⁷Lu) radiotracer concentration measurements using quantitative clinical software was determined by comparing in vivo results for a digital solid-state cadmium-zinc-telluride SPECT/CT (single photon emission computed tomography / x-ray computed tomography) system to in vitro sampling. First, image acquisition parameters were assessed for an International Electrotechnical Commission (IEC) body phantom emulating clinical count rates loaded with a "lung" insert and 6 hot spheres with a 12:1 target-to-background ratio of ¹⁷⁷Lu solution. Then, the data of 28 whole-body SPECT/CT scans of 7 patients who underwent ¹⁷⁷Lu prostate membrane antigen (¹⁷⁷Lu-PSMA) radioligand therapy was retrospectively analyzed. Three users analyzed SPECT/CT images for in vivo urinary bladder radiotracer uptake using quantitative software (Q.Metrix, GE Healthcare). In vitro radiopharmaceutical concentrations were calculated using urine sampling obtained immediately after each scan, scaled to standardized uptake values (SUVs). Any in vivo/in vitro identity relations were determined by linear regression (ideally slope=1, intercept=0), within a 95 % confidence interval (CI). Phantom results demonstrated lower quantitative error for acquisitions using the 113 keV ¹⁷⁷Lu energy peak rather than including the 208 keV peak, given that only low-energy collimation was available in this camera configuration. In the clinical study, 24 in vivo/in vitro pairs were eligible for further analysis, having rejected 4 as outliers (via Cook’s distance calculations). All linear regressions (R2 ≥ 0.92, P<0.0001) provided identity in vivo/in vitro relations (95 % CI), with SUV averages from all users giving a slope of 1.03±0.09, an intercept of –0.25±0.64 g/mL, and an average residual difference of 20.4 %. Acquiring with the lower energy ¹⁷⁷Lu energy peak, solid-state SPECT/CT imaging provides an accuracy to within ~20 % for in vivo urinary bladder radiotracer concentrations. This non-invasive in vivo quantitation method can potentially improve diagnosis, improve patient management and treatment response assessment, and provide data essential to ¹⁷⁷Lu dosimetry.

The use of protein biomarkers as surrogates for clinical endpoints requires extensive multilevel validation including development of robust and sensitive assays for precise measurement of protein concentration. Multiple reaction monitoring (MRM) is a well-established mass-spectrometric method that can be used for reproducible protein-concentration measurements in biological specimens collected via microsampling. The dried blood spot (DBS) microsampling technique can be performed non-invasively without the expertise of a phlebotomist, and can enhance analyte stability which facilitate the application of this technique in retrospective studies while providing lower storage and shipping costs, because cold-chain logistics can be eliminated. Thus, precise, sensitive, and multiplexed methods for measuring protein concentrations in DBSs can be used for de novo biomarker discovery and for biomarker quantification or verification experiments. To achieve this goal, MRM assays were developed for multiplexed concentration measurement of proteins in DBSs.

The lower limit of quantification (LLOQ) was found to have a median total coefficient of variation (CV) of 18% for 245 proteins, whereas the median LLOQ was 5 fmol of peptide injected on column, and the median inter-day CV over 4 days for measuring endogenous protein concentration was 8%. The majority (88%) of the assays displayed parallelism, whereas the peptide standards remained stable throughout the assay workflow and after exposure to multiple freeze-thaw cycles. For 190 proteins, the measured protein concentrations remained stable in DBS stored at ambient laboratory temperature for up to 2 months. Finally, the developed assays were used to measure the concentration ranges for 200 proteins in twenty same sex, same race and age matched individuals.

Protein subcellular localization is an essential and highly regulated determinant of protein function. Major advances in mass spectrometry and imaging have allowed the development of powerful spatial proteomics approaches for determining protein localization at the whole cell scale. Here, a brief overview of current methods is presented, followed by a detailed discussion of organellar mapping through proteomic profiling. This relatively simple yet flexible approach is rapidly gaining popularity, due to its ability to capture the localizations of thousands of proteins in a single experiment. It can be used to generate high-resolution cell maps, and as a tool for monitoring protein localization dynamics. This review highlights the strengths and limitations of the approach, and provides guidance to designing and interpreting profiling experiments. 

APOA5 is a low-abundance exchangeable apolipoprotein that plays critical roles in human triglyceride (TG) metabolism. Indeed, aberrations in the plasma concentration or structure of APOA5 are linked to hypertriglyceridemia, hyperchylomicronemia, myocardial infarction risk, obesity, and coronary artery disease. While it has been successfully produced at low yield in bacteria, the resulting protein had limitations for structure-function studies due to its low solubility under physiological buffer conditions. We hypothesized that the yield and solubility of recombinant APOA5 could be increased by: i) engineering a fusion protein construct in a codon optimized expression vector, ii) optimizing an efficient refolding protocol, and iii) screening buffer systems at physiological pH. The result was a high-yield (25 mg/l) bacterial expression system that produces lipid-free APOA5 soluble at concentrations of up to 10 mg/ml at a pH of 7.8 in bicarbonate buffers. Physical characterization of lipid-free APOA5 indicated that it exists as an array of multimers in solution, and far UV circular dichroism analyses show differences in total α-helicity between acidic and neutral pH buffering conditions. The protein was functional in that it bound and emulsified multilamellar dimyristoyl-phosphatidylcholine vesicles and could inhibit postprandial plasma TG accumulation when injected into C57BL/6J mice orally gavaged with Intralipid.

Ceramides (Cers) with ultralong (~32-carbon) chains and -esterified linoleic acid, composing a subclass called omega-O-acylceramides (acylCers), are indispensable components of the skin barrier. Normal barriers typically contain acylCer concentrations of ~10 mol%; diminished concentrations, along with altered or missing long periodicity lamellar phase (LPP), and increased permeability accompany an array of skin disorders, including atopic dermatitis, psoriasis, and ichthyoses. We developed model membranes to investigate the effects of the acylCer structure and concentration on skin lipid organization and permeability. The model membrane systems contained six to nine Cer subclasses as well as fatty acids, cholesterol, and cholesterol sulfate; acylCer content—namely, acylCers containing sphingosine (Cer EOS), dihydrosphingosine (Cer EOdS), and phytosphingosine (Cer EOP) ranged from zero to 30 mol%. Systems with normal physiologic concentrations of acylCer mixture mimicked the permeability and nanostructure of human skin lipids (with regard to LPP, chain order, and lateral packing). The models also showed that the sphingoid base in acylCer significantly affects the membrane architecture and permeability and that Cer EOP, notably, is a weaker barrier component than Cer EOS and Cer EOdS. Membranes with diminished or missing acylCers displayed some of the hallmarks of diseased skin lipid barriers (i.e., lack of LPP, less ordered lipids, less orthorhombic chain packing, and increased permeability). These results could inform the rational design of new and improved strategies for the barrier-targeted treatment of skin diseases.

To ensure fetal lipid supply, maternal blood triglyceride (TG) concentrations are robustly elevated during pregnancy. Interestingly, a lower increase in maternal blood TG concentrations has been observed in some obese mothers. We have shown that high-fat (HF) feeding during pregnancy significantly reduces maternal blood TG levels. Therefore, we performed this study to investigate if and how obesity alters maternal blood TG levels. Maternal obesity was established by prepregnant HF feeding (ppHF), which avoided the dietary effect during pregnancy. We found that maternal blood TG concentrations in ppHF dams were not only remarkably lower than control dams, but the TG peak occurred earlier during gestation. Hepatic TG production and intestinal TG absorption were unchanged in ppHF dams, but systemic lipoprotein lipase (LPL) activity was increased, suggesting that increased blood TG clearance contributes to the decreased blood TG concentrations in ppHF dams. Although significantly higher levels of UCP1 protein were observed in iBAT of ppHF dams, Ucp1 gene deletion did not restore blood TG concentrations in ppHF dams. Expression of the angiopoietin-like protein 4 (ANGPTL4), a potent endogenous LPL inhibitor, was significantly increased during pregnancy. However, the pregnancy-induced elevation of blood TG was almost abolished in Angptl4^-/- dams. Compared with control dams, Angptl4 mRNA levels were significantly lower in iBAT, gWAT and livers of ppHF dams. Importantly, ectopic overexpression of ANGPTL4 restored maternal blood TG concentrations in ppHF dams. Together, these results indicate that ANGPTL4 plays a vital role in increasing maternal blood TG concentrations during pregnancy. Obesity impairs the rise of maternal blood TG concentrations by reducing ANGPTL4 expression in mice.

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton magnetic resonance spectroscopy (MRS), we measured glutamate concentrations in ACC and occipital cortex (OCC) in 13 T1D without major depression (HbA1c=7.1±0.7% [54±7mmol/mol]) and 11 healthy non-diabetic controls (HbA1c=5.5±0.2% [37±3mmol/mol]) during fasting euglycemia (EU) followed by a 60-minute +5.5mmol/l hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level dependent functional MRI to measure the fractional amplitude of low frequency fluctuations in slow-band 4 (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (Emotional-Stroop, Self-Referent-Encoding-Task SRET) and clinical ratings (HAM-D, SCL-90-R), respectively. During HG, ACC glutamate increased (1.2mmol/kg, +10%, p=0.014) while ACC fALFF4 was unchanged (-0.007, -2%, p=0.449) in T1D; in contrast, glutamate was unchanged (-0.2mmol/kg, -2%, p=0.578) while fALFF4 decreased (-0.05, -13%, p=0.002) in controls. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative-word response-times (p=0.017) and higher depression-rating scores (HAM-D p=0.020; SCL-90-R-depression p=0.008). Higher glutamate change tended to associate with longer Emotional-Stroop response-times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia due to the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations between chronic hyperglycemia, cortical thinning and depressive symptoms in T1D.

A greater decrease in 24-h energy expenditure (24EE) during 24h fasting defines a thriftier metabolic phenotype prone to weight gain during overfeeding and resistant to weight loss during caloric restriction. As the thermogenic response to mild cold exposure (COLD) may similarly characterize this human phenotype identified by acute fasting conditions, we analyzed changes in 24EE and sleeping metabolic rate (SLEEP) in a whole-room indirect calorimeter during 24h fasting at thermoneutrality (24°C) and during energy balance both at thermoneutrality (24°C) and mild cold (19°C) in 20 healthy volunteers (80% male, age: 36.6±11.4y, percentage body fat: 34.8±10.5%). Greater decrease in 24EE during fasting (thriftier phenotype) was associated with less increase in 24EE during COLD, i.e. less cold-induced thermogenesis. Greater decreases in plasma fibroblast growth factor 21 (FGF21) after 24h fasting and after COLD were highly correlated and associated with greater decreases in SLEEP in both conditions. We conclude that the metabolic responses to short-term fasting and COLD are associated and mediated by the liver-derived hormone FGF21. Thus, the 24EE response to COLD further identifies the thrifty versus spendthrift phenotype, providing an additional setting to investigate the physiological mechanisms underlying the human metabolic phenotype and characterizing the individual susceptibility to weight change.

Mandeep Bajaj
Nov 1, 2005; 54:3148-3153
Metabolism

Mariam Alatrach
Apr 1, 2020; 69:681-688
Pathophysiology

This special issue focuses on Cardiovascular Concerns with Diabetes an COVID-19. 

Recorded April 19, 2020.

This is a part of the American Diabetes Associations ongoing project providing resources for practicing clinicians on the care of Diabetes during the Covid-19 pandemic.  Todays discussion is an audio version of a webinar recorded on April 19, 2020.

Presented by:

Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health

John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health

Despite its best efforts, COVID-19 will not be allowed to steal the joy of Mother’s Day this year. An array of the island’s top singers and musicians have pledged to infuse the accustomed specialness into the day dedicated to mothers with a concert...

Gerrit Cole and Justin Verlander are not fans of the "opener" and explained why it's not a long-term option.

Reverse innovation may sound like some attempt to return to the dark ages - but it has a specific meaning, especially when it comes to med-tech. It’s about where we look for innovation - and overturning our preconceived ideas of where new ideas come from. Mark Skopec, and Matthew Harris - both from Imperial College London are two of the authors...

Cindy J.M. Loomans
Jan 1, 2004; 53:195-199
Complications

Norikazu Maeda
Sep 1, 2001; 50:2094-2099
Pathophysiology

Invitation Only Research Event

When you think of the D-backs, what players spring to mind? Luis Gonzalez, Randy Johnson, Paul Goldschmidt and Matt Williams are probably some of the names that arise. But what names are familiar to baseball fans but might have even some D-backs fans saying, "He was a Diamondback?"

Noncitizens have long served in the U.S. military, often encouraged by the promise of a fast track to U.S. citizenship. In recent years, however, Congress and the Defense Department have made it more difficult for noncitizens to enlist. This brief give context to these policy changes and explores ways the military could better balance concerns about national security and the need for recruits with key cultural and professional skills.