A. V. Ivanov and I. K. Matsak
Theor. Probability and Math. Statist. 99 (2020), 91-99.
Abstract, references and article information

Applications for the $1.3 billion in subsidies earmarked for registered owners of goods vehicles and green minibus operators under the Anti-epidemic Fund opened today, the Transport Department announced.

A one-off non-accountable subsidy of $10,000 will be provided to each registered goods vehicle owner for each goods vehicle.

From today until September 30, registered owners of goods vehicles who have received the department's letters must use the registration PIN provided in the letters for submission of registrations through GovHK.

After successful completion of registration, the subsidy will be disbursed to the designated local bank account provided in the registration through autopay in about two to three weeks.

Cross-boundary goods vehicle drivers who conduct nucleic acid tests in Hong Kong can apply for the subsidy on an accountable basis, with the maximum amount being $350 per test.

A one-off non-accountable subsidy of $30,000 per green minibus will be provided to each holder of a Passenger Service Licence-Public Light Bus (Scheduled) Service who has been approved to operate a relevant green minibus route package.

The department briefed the green minibus trade today on the subsidy arrangement and application details with the distribution of the application forms.

Green minibus operators are required to send the completed application forms to the department by post on or before September 30.

After the department has verified their submissions, the subsidy will be disbursed through autopay in about one month.

To assist the transport trades to cope with operational demands in the prevailing economic environment, the Government has rolled out the fuel subsidy and one-off subsidy measures under the first round of the Anti-epidemic Fund progressively.

As of mid-April, the department has received applications for subsidies from three franchised bus companies, 10 franchised and licensed ferry operators, Hong Kong Tramways Limited, registrations from 1,700 registered owners of non-franchised public buses, school private light buses and hire cars. Over $100 million of the subsidies have been disbursed.

Click here for details.

The Minimum Wage Commission today launched an eight-week public consultation to review the statutory minimum wage rate.

The commission said it adopts an evidence-based approach in conducting the minimum wage rate review and will consider the community's views.

Views can be sent by email before June 16.

Click here for information.

The Minimum Wage Commission will submit to the Chief Executive in Council its recommendation report on the statutory minimum wage rate by the end of October at the latest.

In accordance with the Minimum Wage Ordinance, the Chief Executive has required the commission to submit its recommendation report on or before October 31.

Pursuant to the ordinance, the commission must maintain an appropriate balance between the objectives of forestalling excessively low wages and minimising the loss of low-paid jobs as well as the need to sustain the city's economic growth and competitiveness.

The commission is conducting a public consultation on the statutory minimum wage rate review.

Views can be sent by email before June 16.

Click here for the consultation details.

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

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

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

(Bentham Science Publishers) Using a nationally representative sample, the researchers explored racial/ethnic variation in the link between educational attainment and heart disease among American adults.

(University of Chicago Press Journals) A recent study confirms that Mesoamerican priests ripped the hearts out of their still-living victims in three different ways. New forensic evidence, historic witness accounts and native representations now show that the most common form of native heart extraction was from beneath the rib cage, second was forceful chest penetration between two ribs and at mid-chest level between the nipples, and thirdly, a mid-chest opening of one single blow, extracting the heart from the front.

(Bentham Science Publishers) Two authors representing environmental geomorphology and historical archaeology collaborated in an investigation that aimed to examine the material culture still evident in urban burial sites with dated, upstanding headstone memorials.

(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.

13 April 2018

Eelke P. Béguin
Apr 24, 2020; 0:RA120.001964v1-mcp.RA120.001964
Research

Invitation Only Research Event

Event participants

Beyza Unal, Senior Research Fellow, International Security Department, Chatham House
Patricia Lewis, Research Director, International Security Department, Chatham House

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

We back. Google and Amazon introduced a raft of new products for us to drool over and, of course, apply a degree of scepticism. Jim Martin was on the ground to use all the new Google stuff and has the latest. Scott then talks us through Uber's mishaps, this time its London licence has been revoked. Will the company go public when it wants to? Finally we discuss the SNES Mini which we managed to get our hands on and why Nintendo has such low stock of all its great products.  

See acast.com/privacy for privacy and opt-out information.

Join host Scott Carey as the team dissects Tory meltdown and what it means for tech and the ministers we haven't heard of. What can they actually do to help the country? Charlotte Jee explains.

Then Henry Burrell chats on the new Microsoft Surface Go, an 'affordable' Surface tablet that actually still breaks the bank. Who is it for, and is Microsoft really chasing the iPad market?

David Price rounds up the pod with Musk Corner as everyone's favourite Twitter megalomaniac flies off to Thailand to help with a cave rescue - but should he stay out of it?

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The vessel wall is continuously exposed to hemodynamic forces generated by blood flow. Endothelial mechanosensors perceive and translate mechanical signals via cellular signaling pathways into biological processes that control endothelial development, phenotype and function. To assess the hemodynamic effects on the endothelium on a system-wide level, we applied a quantitative mass spectrometry approach combined with cell surface chemical footprinting. SILAC-labeled endothelial cells were subjected to flow-induced shear stress for 0, 24 or 48 hours, followed by chemical labeling of surface proteins using a non-membrane permeable biotin label, and analysis of the whole proteome and the cell surface proteome by LC-MS/MS analysis. These studies revealed that of the >5000 quantified proteins 104 were altered, which were highly enriched for extracellular matrix proteins and proteins involved in cell-matrix adhesion. Cell surface proteomics indicated that LAMA4 was proteolytically processed upon flow-exposure, which corresponded to the decreased LAMA4 mass observed on immunoblot. Immunofluorescence microscopy studies highlighted that the endothelial basement membrane was drastically remodeled upon flow exposure. We observed a network-like pattern of LAMA4 and LAMA5, which corresponded to the localization of laminin-adhesion molecules ITGA6 and ITGB4. Furthermore, the adaptation to flow-exposure did not affect the inflammatory response to tumor necrosis factor α, indicating that inflammation and flow trigger fundamentally distinct endothelial signaling pathways with limited reciprocity and synergy. Taken together, this study uncovers the blood flow-induced remodeling of the basement membrane and stresses the importance of the subendothelial basement membrane in vascular homeostasis.

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

6 November 2019 , Volume 95, Number 6

Just the mention of the name Marvia Providence sends a tingle to the toes and, immediately, feet start tapping and bodies begin swaying. Before you know it, all the ‘warriors’ – prayer and otherwise – are in full flight. That’s the effect of the...

On the 1st of May, 2018 Scotland was the first country to try a new way of reducing alcohol consumption in its population. It introduced a minimum unit prices for alcohol. Now new research just published on BMJ.com is looking at the effect of that price increase - and measuring how well it has achieved the goal of reducing drinking in...

For the next few months Talk Evidence is going to focus on the new corona virus pandemic. There is an enormous amount of uncertainty about the disease, what the symptoms are, fatality rate, treatment options, things we shouldn't be doing. We're going to try to get away from the headlines and talk about what we need to know - to hopefully give...

ROSEAU, Dominica, CMC –A senior education official Thursday said students would sit the Grade Six National Assessment examinations later this year, despite the disruption caused to the education system by the coronavirus (COVID-19). Dominica...

Invitation Only Research Event

Research Event

Event participants

Tom Butler, Chief Executive Officer, International Council for Mining and Metals (ICMM)
Evelyn Dietsche, Associate Fellow, Energy, Environment and Resources, Chatham House
Chair: Bernice Lee, Executive Director, Hoffman Centre, Chatham House 

Intravenous access is difficult in some patients referred for ¹⁸F-FDG PET imaging. Extravasation at the injection site and accumulation in central catheters can lead to limited tumor ¹⁸F-FDG uptake, erroneous quantitation, and significant image artifacts. In this study, we compared the human biodistribution and dosimetry for ¹⁸F-FDG after oral and intravenous administrations sequentially in the same subjects to ascertain the dosimetry and potential suitability of orally administered ¹⁸F-FDG as an alternative to intravenous administration. We also compared our detailed intravenous ¹⁸F-FDG dosimetry with older dosimetry data. Methods: Nine healthy volunteers (6 male and 3 female; aged 19–32 y) underwent PET/CT imaging after oral and intravenous administration of ¹⁸F-FDG. Identical preparation and imaging protocols (except administration route) were used for oral and intravenous studies. During each imaging session, 9 whole-body PET scans were obtained at 5, 10, 20, 30, 40, 50, 60, 120, and 240 min after ¹⁸F-FDG administration (370 ± 16 MBq). Source organ contours drawn using CT were overlaid onto registered PET images to extract time–activity curves. Time-integrated activity coefficients derived from time–activity curves were given as input to OLINDA/EXM for dose calculations. Results: Blood uptake after orally administered ¹⁸F-FDG peaked at 45–50 min after ingestion. The oral-to-intravenous ratios of ¹⁸F-FDG uptake for major organs at 45 min were 1.07 ± 0.24 for blood, 0.94 ± 0.39 for heart wall, 0.47 ± 0.12 for brain, 1.25 ± 0.18 for liver, and 0.84 ± 0.24 for kidneys. The highest organ-absorbed doses (μGy/MBq) after oral ¹⁸F-FDG administration were observed for urinary bladder (75.9 ± 17.2), stomach (48.4 ± 14.3), and brain (29.4 ± 5.1), and the effective dose was significantly higher (20%) than after intravenous administration (P = 0.002). Conclusion: ¹⁸F-FDG has excellent bioavailability after oral administration, but peak organ activities occur later than after intravenous injection. These data suggest PET at 2 h after oral ¹⁸F-FDG administration should yield images that are comparable in biodistribution to conventional clinical images acquired 1 h after injection. Oral ¹⁸F-FDG is a palatable alternative to intravenous ¹⁸F-FDG when venous access is problematic.

Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of ⁸⁹Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of ⁸⁹Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1–2, 6–8, 24, 48, and 96–144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results: ⁸⁹Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time–activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24–48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most ⁸⁹Zr-IAB22M2C–positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion: ⁸⁹Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell–rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.