Thi-Thao-Phuong Hoang, Lili Ju, Wei Leng and Zhu Wang
Math. Comp. 89 (2020), 1807-1842.
Abstract, references and article information

Jiangxue Fang
Trans. Amer. Math. Soc. 373 (2020), 3445-3481.
Abstract, references and article information

R. E. Maĭboroda, G. V. Navara and O. V. Sugakova
Theor. Probability and Math. Statist. 99 (2020), 169-188.
Abstract, references and article information

M. M. Kapustei and P. V. Slyusarchuk
Theor. Probability and Math. Statist. 99 (2020), 101-111.
Abstract, references and article information

Time: 9:00 AM, Location: Senate Chamber

Alberto Arenas, Óscar Ciaurri and Edgar Labarga
Proc. Amer. Math. Soc. 148 (2020), 2539-2550.
Abstract, references and article information

Quanlei Fang and Jingbo Xia
Proc. Amer. Math. Soc. 148 (2020), 2497-2507.
Abstract, references and article information

The Immigration Department today announced that aside from its Smart Identity Card Replacement Centres (SIDCC) service and passenger immigration clearance service, it will resume full public services on May 4.

Due to the COVID-19 epidemic, the services of the nine SIDCCs had been suspended earlier.

Around 640,000 people could not replace their Hong Kong identity cards during their specified periods and about 90,000 people are waiting to collect their new identity cards.

To allow affected people to apply for and collect identity cards in an orderly manner, the SIDCCs will first provide identity card collection service and arrange applicants born in 1957 to 1961 who had made appointments before to have their cards replaced once the service resumes.

Other applicants are advised to make appointments to replace their identity cards if they have not done so before.

The department plans to revise designated replacement periods for identity card holders born in 1957 to 1963 and between 1970 and 1976.

Details will be announced later. For enquiries regarding identity cards, call 3521 6565.

Additionally, passenger immigration clearance services at immigration control points except for the Hong Kong International Airport, Shenzhen Bay and Hong Kong-Zhuhai-Macao Bridge Control Points will remain suspended until further notice.

Call 2824 6111 or send an email for enquiries.

The Transport Department today invited tenders for operating six major licensed ferry services for outlying islands for five years from April 1, 2021.

The six routes are between Central to Cheung Chau, Inter-islands between Peng Chau, Mui Wo, Chai Ma Wan and Cheung Chau, Central to Mui Wo, Central to Peng Chau, Central to Yung Shue Wan and Central to Sok Kwu Wan.

The department said that for the purposes of maintaining financial viability of the six major routes, alleviating the burden of fare increases on passengers, enhancing service quality and promoting a green city development, the Government would continue to provide special measures to the routes.

Such measures would include launching a new Vessel Subsidy Scheme to help selected ferry operators replace the fleets of the six major routes and introduce greener vessels in phases, straddling 10 years from 2021.

Having regard to factors such as passenger demand, overall fleet requirements, flexibility in vessel deployment, operational efficiency, and after consulting the Islands District Council, the six major routes are grouped into two packages for tendering.

The first package covers Central-Cheung Chau, Peng Chau-Mui Wo-Chi Ma Wan-Cheung Chau (Inter Islands) and Central-Mui Wo routes.

The other package covers Central-Peng Chau, Central-Yung Shue Wan and Central-Sok Kwu Wan routes.

Tenderers are required to propose a fare for each fare type of each relevant route and it must not exceed the existing fare level of the corresponding route by more than 5%. Tenders should also include in their submissions fare concession proposals that will be considered in the tender evaluation.

In support of the Government's development of a smart city, tenderers should propose measures including dissemination of real-time arrival/departure time of ferry routes, number of remaining seats via mobile phone apps and opening up such data for the public’s use under data.gov.hk.

The tenders must be sealed in envelopes and placed in the Transport Department Tender Box adjacent to the reception counter of the department on the 10th floor of South Tower, West Kowloon Government Offices, 11 Hoi Ting Road, Yau Ma Tei before noon on June 30.

The cover of the tender submission should be marked with tender reference TD 382/2019 and include the subject of the tender. It should also be addressed to the Commissioner for Transport.

Tender documents will be available for collection at the Transport Department’s Ferry & Paratransit Division on the 14th Floor, South Tower, West Kowloon Government Offices, 11 Hoi Ting Road, Yau Ma Tei from April 27 during office hours.

The Transport Department today announced that its driving test (road test) service will resume on May 4 to align with the resumption of public services in phases.

The department said candidates scheduled to take a road test on or after May 4 should take the test according to the test date, time and the driving test centre specified in their appointment letter.

Candidates affected by the suspension of driving test centres will be notified by post of the rescheduled test.

Driving test (written test Part A) and taxi written test services will resume on May 26.

Candidates affected by the suspension of written test services will be rescheduled to take the tests from May 26 and thereafter and notified by post of the rescheduling.

All candidates participating in the driving, road and written tests, must wear surgical masks inside the test centres and throughout the test.

They must also clean their hands with alcohol sanitisers and undergo body temperature screening.

If a candidate does not wear a surgical mask, refuses body temperature screening or has a body temperature higher than 37.5 degrees Celsius, the candidate will not be allowed to enter the venue and the test will be rescheduled.

To improve air circulation inside the vehicle compartment, driving examiners may open vehicle windows during the test.

The department urged candidates not to attend a driving test if they are unwell.

For applicants who are absent from a driving test on medical grounds, they may submit their postponement applications with the original sick leave or medical certificate to the Driving Test Appointment Office within one month from the test date for rescheduling.

Candidates applying for a postponement, temporary cancellation of driving test appointment or change of driving test region may submit signed application letters, copies of identification document and driving test appointment letter via the drop-in box at the Kowloon Licensing Office or post them to the Driving Test Appointment Office on 2/F, Cheung Sha Wan Government Offices, 303 Cheung Sha Wan Road.

Application of driving test appointment services for fresh candidates and repeaters will continue to be suspended until further notice. Call 2771 7723 for enquiries.

Vehicle Examination Centres will resume full services on May 4. The department will continue to process applications for licensing and related services submitted by applicants with scheduled appointments via the drop-in boxes, by post or online except for the direct issue of a full Hong Kong driving licence.

Applications may be submitted via the drop-in boxes at the offices concerned between 9am and 5pm from Monday to Friday except public holidays.

Those who have made online appointments for renewal of a full driving licence, vehicle licence, and transfer of vehicle ownership or international driving permit can visit the Licensing Office concerned at the scheduled time.

To maintain social distancing to reduce the risk of spreading COVID-19, the offices concerned will continue to suspend walk-in counter services.

Meanwhile, the Highways Department's public services will return to normal from May 4.

The department will implement social distancing and precautionary measures, including the introduction of flexible working and lunch hours, meeting adjustments and stepping up the cleansing of its offices.

Members of the public may call the 24-hour hotline 2926 4111 or 1823 for making suggestions, enquiries or complaints. The department can also be contacted by email or fax.

The Education Bureau and the Agriculture, Fisheries & Conservation Department (AFCD) today announced their latest arrangements on public services starting May 4.

All Regional Education Offices, the Joint Office for Kindergartens & Child Care Centres, the School Places Allocation Section, the Qualifications Framework Secretariat and other service units will resume normal opening hours from May 4.

However, the Hong Kong Teachers' Centre, Special Education Resource Centre, Central Resources Centre and Young Achievers' Gallery located at Kowloon Tong Education Services Centre, as well as the Arts & Technology Education Centre will remain closed until further notice.

The AFCD’s licensing services and reception counters at Cheung Sha Wan Government Offices and the Marine Parks Office at CDW Building in Tsuen Wan will resume normal services Monday to Friday from 8.30am to 12.30pm and 1.30pm to 5.45pm.

The anti-rabies dog inoculation and dog licensing services at the animal management centres will also resume as normal from May 4.

Meanwhile, the Hong Kong Wetland Park (except some indoor facilities and play areas), eight Country Park Visitor/Education Centres, seven Hong Kong Geopark Park Visitor Centres and the Endangered Species Resources Centre will reopen from May 4.

However, school and public programmes will remain suspended until further notice.

The barbecue sites and campsites in country parks will also continue to be closed until May 7.

Click here for the latest public service arrangements.

Secretary for the Civil Service Patrick Nip today visited the Transport Department (TD) and the Social Welfare Department (SWD) to learn more about the preparations made by both departments to resume public services.

The Government announced that the resumption of public services will start from May 4 under a phased approach.

While the TD will resume road tests on that day, written tests will resume on May 26.

The SWD will also gradually resume the services of its Integrated Family Service Centres (IFSC).

Mr Nip first visited the driving test centre in Ho Man Tin where he was briefed by the Commissioner for Transport Mable Chan on arrangements for the resumption of road tests and the implementation of infection control measures at driving test centres.

Such measures will require candidates to wear surgical masks and undergo body temperature screening at entrances.

As for the written tests, Mr Nip said he was pleased to learn that the TD will keep seats apart at appropriate distances and step up cleansing of computers at test centres.

Mr Nip then visited the Causeway Bay Integrated Family Service Centre where he was briefed on the plan to gradually resume services at IFSCs and measures to reduce social contact.

Mr Nip also learned that various infection control measures to safeguard the health of colleagues as well as service users will be put in place. For example, group activities will be conducted for no more than four participants and physical partitioning will be erected in meeting rooms for counselling services.

Mr Nip emphasised that many people hope that the Government can provide more public services when the epidemic situation becomes stable.

“I am pleased to learn that the departments have made all the necessary preparations for providing the services needed by the public while striving to safeguard public health.

“Government departments will continue to maintain a high degree of vigilance and adopt all the necessary precautionary measures. The Government will also closely monitor the situation and determine when to embark on a full resumption of normal business.”

Mr Nip expressed hope that the public will continue to fight the virus together with the Government.

He also thanked civil servants for their commitment and dedicated efforts to serve the public during the epidemic.

To align with the phased resumption of public services, various government departments have announced their latest arrangements.

The Department of Justice’s public services will resume normal from May 4. The reception counters of the department’s Prosecutions Division and Civil Division will be open Monday to Friday from 9am to 1pm and 2pm to 6pm.

The Legal Aid Department’s offices will resume normal office hours on May 4 to provide public services including civil and criminal legal aid application and litigation services.

The Government Logistics Department’s collection office will resume normal operation from May 4 and open Monday to Friday from 8.30am to 1pm and 2pm to 5pm.

The Lands Department's offices will resume public counter services and enquiry telephone lines on May 4, providing services such as payment of government rent and premiums, map sales, and collection of compensation for land resumption.

Except for the surveying services to be conducted outside Hong Kong, all services of the Marine Department will resume starting May 4.

The Rating & Valuation Department will resume normal operation of public services from May 4, with its enquiry counters opening from 8.15am to 6pm from Monday to Friday, except on public holidays.

The Civil Engineering & Development Department said office hours for the Civil Engineering Library, applications for dumping licences and sand removal permits, and the Mines Division’s Permit & Licensing Office will return to normal on May 4.

Public services of the Water Supplies Department, the Planning Department, the Drainage Services Department and the Inland Revenue Department will resume normal on May 4.

Starting from May 4, the Registration & Electoral Office’s enquiry counter and offices, the Buildings Department and the Environmental Protection Department’s public counter services and service counters under the Labour Department will reopen.

The Independent Commission Against Corruption's headquarters and regional offices will also resume normal services from May 4.

The Housing Authority's estate management offices, Public Rental Housing Application Office in the Lok Fu Customer Service Centre, the Clearance Housing Office and the Redevelopment Sub-section Offices will reinstate normal services from that date.

Flat selection sessions of the Territory-wide Overcrowding Relief Exercise, the Living Space Improvement Transfer Scheme and Sale of Home Ownership Scheme Flats 2019 will gradually resume from May 8.

Click here for the latest public service arrangements.

To align with the phased resumption of public services, the Information Services Department, Government Records Service and Civil Aviation Department have announced their latest arrangements.

The Information Services Department will resume sales counter services at its Publications Sales Unit and Photo Library at North Point Government Offices from May 4.

The sales office will be open from 9am to 12.30pm and from 2pm to 6pm from Monday to Friday.

To reduce social contact and avoid people gathering, citizens are encouraged to purchase government publications and photos through the online bookstore and photo store.

The Government Records Service's Public Records Office will provide search room services, including onsite loan and circulation services, from Monday to Friday, 9am to 5.45pm, for people who have made reservations through the online catalogue.

The office will also resume search room services from 9am to 1pm on Saturdays for people to inspect holdings which have been reserved online. 

Requests by up to 15 users will be accepted for search room services for each open day on a first-come, first-served basis. Users will be notified of the reservation results by email.

Visitor and public education programmes will continue to be suspended, while the Exhibition Hall at the Public Records Building will be temporarily closed for preparation of the new thematic exhibition until further notice.

Enquiries can be made to 2195 7700 or via email.

The Civil Aviation Department’s Personnel Licensing Office will continue to provide counter services from next Monday and resume relevant licensing examinations.

The office's opening hours are 8.45am to 12.45pm and 1.45pm to 5pm, Monday to Friday. Enquiries can be made to 2910 6046 or via email.

Click here for the latest public service arrangements.

Hong Kong’s foreign currency reserve assets rose to US$441.2 billion in April from March’s US$437.6 billion, the Monetary Authority announced today.

The reserve assets represent over six times the currency in circulation or about 46% of Hong Kong dollar M3.

Including unsettled foreign exchange contracts, the foreign currency reserve assets at the end of April increased to US$440.7 billion from March’s US$437.6 billion.

(Arizona State University) Cun-Zheng Ning, a professor of electrical engineering in the Ira A. Fulton Schools of Engineering at Arizona State University, and collaborators from Tsinghua University in China discovered a process of physics that enables low-power nanolasers to be produced in 2D semiconductor materials. Understanding the physics behind lasers at nanoscale and how they interact with semiconductors can have major implications for high-speed communication channels for supercomputers and data centers.

"[W]hen the editors at Quanta Magazine invited me to host a podcast for them, I jumped at the chance...Through this podcast, I've been learning about the inner lives of some of the most intriguing mathematicians and scientists working today. [I]n every case, I wanted to know what makes them tick. I wanted to know why they do what they do, what they’ve discovered, and why it matters to them and to the world." Read "Why I'm Hosting The Joy of x Podcast," by Steven Strogatz, Quanta Magazine, January 14, 2020.

Cell-surface signaling (CSS) in Gram-negative bacteria involves highly conserved regulatory pathways that optimize gene expression by transducing extracellular environmental signals to the cytoplasm via inner-membrane sigma regulators. The molecular details of ferric siderophore-mediated activation of the iron import machinery through a sigma regulator are unclear. Here, we present the 1.56 Å resolution structure of the periplasmic complex of the C-terminal CSS domain (CCSSD) of PupR, the sigma regulator in the Pseudomonas capeferrum pseudobactin BN7/8 transport system, and the N-terminal signaling domain (NTSD) of PupB, an outer-membrane TonB-dependent transducer. The structure revealed that the CCSSD consists of two subdomains: a juxta-membrane subdomain, which has a novel all-β-fold, followed by a secretin/TonB, short N-terminal subdomain at the C terminus of the CCSSD, a previously unobserved topological arrangement of this domain. Using affinity pulldown assays, isothermal titration calorimetry, and thermal denaturation CD spectroscopy, we show that both subdomains are required for binding the NTSD with micromolar affinity and that NTSD binding improves CCSSD stability. Our findings prompt us to present a revised model of CSS wherein the CCSSD:NTSD complex forms prior to ferric-siderophore binding. Upon siderophore binding, conformational changes in the CCSSD enable regulated intramembrane proteolysis of the sigma regulator, ultimately resulting in transcriptional regulation.

Actinobacillus pleuropneumoniae (App) is the etiological agent of acute porcine pneumonia and responsible for severe economic losses worldwide. The capsule polymer of App serotype 1 (App1) consists of [4)-GlcNAc-β(1,6)-Gal-α-1-(PO4-] repeating units that are O-acetylated at O-6 of the GlcNAc. It is a major virulence factor and was used in previous studies in the successful generation of an experimental glycoconjugate vaccine. However, the application of glycoconjugate vaccines in the animal health sector is limited, presumably because of the high costs associated with harvesting the polymer from pathogen culture. Consequently, here we exploited the capsule polymerase Cps1B of App1 as an in vitro synthesis tool and an alternative for capsule polymer provision. Cps1B consists of two catalytic domains, as well as a domain rich in tetratricopeptide repeats (TPRs). We compared the elongation mechanism of Cps1B with that of a ΔTPR truncation (Cps1B-ΔTPR). Interestingly, the product profiles displayed by Cps1B suggested processive elongation of the nascent polymer, whereas Cps1B-ΔTPR appeared to work in a more distributive manner. The dispersity of the synthesized products could be reduced by generating single-action transferases and immobilizing them on individual columns, separating the two catalytic activities. Furthermore, we identified the O-acetyltransferase Cps1D of App1 and used it to modify the polymers produced by Cps1B. Two-dimensional NMR analyses of the products revealed O-acetylation levels identical to those of polymer harvested from App1 culture supernatants. In conclusion, we have established a protocol for the pathogen-free in vitro synthesis of tailored, nature-identical App1 capsule polymers.

The SAS Stored Process Server does not create a detailed log file by default. However, you can create a detailed SAS Stored Process Server log file (that will contain information about all of the code that was executed) by using this approach. AUTO

The "Online Video Course on Weather Observation" will explain concisely the basic weather observation methods and techniques, such...

(NASA/Goddard Space Flight Center) A bustling stellar nursery in the picturesque Orion Nebula will be a subject of study for NASA's James Webb Space Telescope, scheduled to launch in 2021. A team led by Mark McCaughrean, the Webb Interdisciplinary Scientist for Star Formation, will survey an inner region of the nebula called the Trapezium Cluster. This cluster is home to a thousand or so young stars, all crammed into a space only 4 light-years across -- about the distance from our Sun to Alpha Centauri.

(University of Warwick) 21st century X-ray technology has allowed University of Warwick scientists to peer back through time at the production of the armour worn by the crew of Henry VIII's favoured warship, the Mary Rose.

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

(Queensland University of Technology) Robots that fly, swim and drive are being designed and built by internationally renowned Australian scientists from QUT.

(American Association for the Advancement of Science) Ice sheet losses from Greenland and Antarctica have outpaced snow accumulation and contributed approximately 14 millimeters to sea level rise over 16 years (2003 to 2019), a new analysis of data from NASA's laser-shooting satellites has revealed.

The U.S. Navy is in “rough waters” and suffering from leadership failures, the diplomat tapped to be the next Navy secretary told a Senate committee Thursday. Kenneth J. Braithwaite, the ambassador to Norway and a retired Navy rear admiral, faced repeated questions about recent crises that have rocked the service, including the firing of an aircraft carrier captain who urged faster action to fight a coronavirus outbreak on his ship and the subsequent resignation of the acting secretary who fired him. Braithwaite said that Navy culture has been tarnished and trust in the service's leaders has broken down.

(University of Surrey) A new research study, investigating how service robots in hotels could help redefine leadership and boost the hospitality industry, has taken on new significance in the light of the seismic impact of the Covid-19 outbreak on tourism and business travel. The study by academics at The University of Surrey and MODUL University Vienna focuses on how HR experts perceive service robots and their impact on leadership and HR management in the hotel industry.

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

Apr 1, 2004; 17:97-101
Articles

Qingbo Shu
Apr 1, 2020; 19:672-689
Research

Eva Griesser
May 1, 2020; 19:839-851
Research

How to create secure access to services hosted in AWS with Sophos XG Firewall.

Invitation Only Research Event

Purpose: To investigate differences between positron emission tomography/magnetic resonance imaging (PET/MRI) and PET/computed tomography (PET/CT) in lesion detection and classification in oncological whole-body examinations and to investigate radiation exposure differences between both modalities. Material and Methods: In this prospective, single-center, observational study 1003 oncological examinations (918 patients, mean age 57.8±14.4y) were included. Patients underwent PET/CT and subsequent PET/MRI (149.8±49.7min after tracer administration). Examinations were reviewed by radiologists and nuclear medicine physicians in consensus. Additional findings, characterization of indetermiante findings in PETCT, missed findings in PET/MRI including their clinical relevance and effective dose of both modalities were investigated. McNemar’s test was used to compare lesion detection between both hybrid imaging modalities (p<0.001 indicating statistical significance). Results: Additional information in PET/MRI was reported in 26.3% (264/1003) of examinations compared to PET/CT (p<0.001). Of these, additional malignant findings were detected in 5.3% (53/1003), leading to a change in TNM-staging in 2.9% (29/1003) due to PET/MRI. Definite lesion classification of indeterminate PET/CT findings was possible in 11.1% (111/1003) with PET/MRI. In 2.9% (29/1003), lesions detected in PET/CT were not visible in PET/MRI. Malignant lesions were missed in 1.2% (12/1003) by PET/MRI leading to a change in TNM-staging in 0.5% (5/1003). The estimated mean effective-dose for whole-body PET/CT amounted to 17.6±8.7mSv in comparison to 3.6±1.4mSv in PET/MRI, resulting in a potential dose reduction of 79.6% (p<0.001). Conclusion: PET/MRI improves lesion detection and potentially reduces additional examinations in tumor staging. Especially younger patients may benefit from the clinically relevant dose reduction of PET/MRI compared to PET/CT.

Purpose: To evaluate ¹¹C-choline PET/CT detection performance for biochemically recurrent prostate cancer (PCa) in a large non-European cohort in the context of emerging evidence for PSMA PET in this setting, and to map patterns of PCa recurrence. Methods: We retrospectively analyzed ¹¹C-choline PET/CT scans from 287 patients who were enrolled onto an imaging protocol based on rising prostate-specific antigen (PSA) levels (mean:3.43 ng/mL, median:0.94 ng/mL, range:0.15–89.91) and suspected recurrent PCa. A total of 187 patients had undergone primary radical prostatectomy (RP; 79/187 had secondary radiotherapy), 30 had undergone primary radiotherapy (RT), and 70 had persistent PSA elevation after receiving initial treatment (69 post-RP, 1 post-RT). The level of suspicion for recurrence on ¹¹C-choline PET/CT was scored (0:negative, 1:equivocal, 2:positive) by two readers. The correlation between ¹¹C-choline PET/CT positivity and initial treatment, Gleason score, NCCN stage, PSA level, PSA doubling time, PSA velocity, and time between initial treatment and PET imaging was evaluated. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were used to map ¹¹C-choline recurrence patterns. Results: Considering scores 1 and 2 as positives, consensus between the two readers deemed 66% of the ¹¹C-choline PET/CT scans as positive. When sorted by PSA level, 45% of patients with PSA<0.5 ng/mL, 56% of patients with PSA 0.5–0.99 ng/mL, 70% of patients with PSA 1.0–1.99 ng/mL, and 90% of patients with PSA ≥2.0 ng/mL scored either 1 or 2 on ¹¹C-choline PET/CT scans. When considering scores of 2 only, ¹¹C-choline PET/CT positivity was 54% (28%, 46%, 62%, and 81%, respectively, for patients with PSA <0.5 ng/mL, 0.5–0.99 ng/mL, 1.0–1.99 ng/mL, and ≥2.0 ng/mL). In multivariate analysis, only the PSA level was significantly associated with scan positivity. Pattern analysis showed that pelvic lymph nodes were the most common site of recurrence, and 28% of patients had ¹¹C-choline-positive suspected recurrences outside the initial treatment field. Conclusion: ¹¹C-choline PET/CT can detect PCa recurrence even among patients with low PSA levels when interpretation accounts for the clinical context, providing a certain pre-test probability. Until PSMA agents are fully approved for PCa, choline PET/CT may provide clinical utility.

Acidosis is a key driver for many diseases, including cancer, sepsis, and stroke. The spatiotemporal dynamics of dysregulated pH across disease remains elusive and current diagnostic strategies do not provide localization of pH alterations. We sought to explore if PET imaging using hydrophobic cyclic peptides that partition into the cellular membrane at low extracellular pH (denoted as "pHLIC") can permit accurate in vivo visualization of acidosis. Methods: Acid-sensitive cyclic peptide c[E4W5C] pHLIC was conjugated to bifunctional maleimide-NO2A and radiolabeled with copper-64 (t1/2 = 12.7 h). C57BL/6J mice were administered LPS (15 mg/kg) or saline (vehicle) and serially imaged with [⁶⁴Cu]Cu-c[E4W5C] over 24 h. Ex vivo autoradiography was performed on resected brain slices and subsequently stained with cresyl violet to enable high-resolution spatial analysis of tracer accumulation. A non- pH-sensitive cell-penetrating control peptide (c[R4W5C]) was used to confirm specificity of [⁶⁴Cu]Cu-c[E4W5C]. CD11b (macrophage/microglia) and TMEM119 (microglia) immunostaining was performed to correlate extent of neuroinflammation with [⁶⁴Cu]Cu-c[E4W5C] PET signal. Results: [⁶⁴Cu]Cu-c[E4W5C] radiochemical yield and purity was >95% and >99% respectively, with molar activity >0.925 MBq/nmol. Significantly increased [⁶⁴Cu]Cu-c[E4W5C] uptake was observed in LPS-treated mice (vs. vehicle) within peripheral tissues including blood, lungs, liver, and small intestines (P < 0.001-0.05). Additionally, there was significantly increased [⁶⁴Cu]Cu-c[E4W5C] uptake in the brains of LPS-treated animals. Autoradiography confirmed increased uptake in the cerebellum, cortex, hippocampus, striatum, and hypothalamus of LPS-treated mice (vs. vehicle). Immunohistochemical (IHC) analysis revealed microglial/macrophage infiltrate, suggesting activation in brain regions containing increased tracer uptake. [⁶⁴Cu]Cu-c[R4W5C] demonstrated significantly reduced uptake in the brain and periphery of LPS mice compared to the acid-mediated [⁶⁴Cu]Cu-c[E4W5C] tracer. Conclusion: Here, we demonstrate that a pH-sensitive PET tracer specifically detects acidosis in regions associated with sepsis-driven pro-inflammatory responses. This study suggests that [⁶⁴Cu]Cu-pHLIC is a valuable tool to noninvasively assess acidosis associated with both central and peripheral innate immune activation.

10 October 2019

This briefing note is the result of a collaborative research process with the Zimbabwean private sector, government representatives, industry organizations and experts, drawing on best practice and senior-level insights to identify policy options for long-term economic revival and expansion in Zimbabwe, and pathways for inclusive development.

6 November 2019 , Volume 95, Number 6

Mycobacterial Ser/Thr protein kinases (STPKs) play a critical role in signal transduction pathways that ultimately determine mycobacterial growth and metabolic adaptation. Identification of key physiological substrates of these protein kinases is, therefore, crucial to better understand how Ser/Thr phosphorylation contributes to mycobacterial environmental adaptation, including response to stress, cell division, and host-pathogen interactions. Various substrate detection methods have been employed with limited success, with direct targets of STPKs remaining elusive. Recently developed mass spectrometry (MS)-based phosphoproteomic approaches have expanded the list of potential STPK substrate identifications, yet further investigation is required to define the most functionally significant phosphosites and their physiological importance. Prior to the application of MS workflows, for instance, GarA was the only known and validated physiological substrate for protein kinase G (PknG) from pathogenic mycobacteria. A subsequent list of at least 28 candidate PknG substrates has since been reported with the use of MS-based analyses. Herein, we integrate and critically review MS-generated datasets available on novel STPK substrates and report new functional and subcellular localization enrichment analyses on novel candidate protein kinase A (PknA), protein kinase B (PknB) and PknG substrates to deduce the possible physiological roles of these kinases. In addition, we assess substrate specificity patterns across different mycobacterial STPKs by analyzing reported sets of phosphopeptides, in order to determine whether novel motifs or consensus regions exist for mycobacterial Ser/Thr phosphorylation sites. This review focuses on MS-based techniques employed for STPK substrate identification in mycobacteria, while highlighting the advantages and challenges of the various applications.