The action mechanisms revealed by the biochemical and structural analyses of replicative and translesion synthesis (TLS) DNA polymerases (Pols) are retained in their cellular roles. In this regard, DNA polymerase θ differs from other Pols in that whereas purified Polθ misincorporates an A opposite 1,N6-ethenodeoxyadenosine (ϵdA) using an abasic-like mode, Polθ performs predominantly error-free TLS in human cells. To test the hypothesis that Polθ adopts a different mechanism for replicating through ϵdA in human cells than in the purified Pol, here we analyze the effects of mutations in the two highly conserved tyrosine residues, Tyr-2387 and Tyr-2391, in the Polθ active site. Our findings that these residues are indispensable for TLS by the purified Pol but are not required in human cells, as well as other findings, provide strong evidence that the Polθ active site is reconfigured in human cells to stabilize ϵdA in the syn conformation for Hoogsteen base pairing with the correct nucleotide. The evidence that a DNA polymerase can configure its active site entirely differently in human cells than in the purified Pol establishes a new paradigm for DNA polymerase function.

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.

The ribosome biogenesis factor Las1 is an essential endoribonuclease that is well-conserved across eukaryotes and a newly established member of the higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain-containing nuclease family. HEPN nucleases participate in diverse RNA cleavage pathways and share a short HEPN nuclease motif (RφXXXH) important for RNA cleavage. Most HEPN nucleases participate in stress-activated RNA cleavage pathways; Las1 plays a fundamental role in processing pre-rRNA. Underscoring the significance of Las1 function in the cell, mutations in the human LAS1L (LAS1-like) gene have been associated with neurological dysfunction. Two juxtaposed HEPN nuclease motifs create Las1's composite nuclease active site, but the roles of the individual HEPN motif residues are poorly defined. Here using a combination of in vivo experiments in Saccharomyces cerevisiae and in vitro assays, we show that both HEPN nuclease motifs are required for Las1 nuclease activity and fidelity. Through in-depth sequence analysis and systematic mutagenesis, we determined the consensus HEPN motif in the Las1 subfamily and uncovered its canonical and specialized elements. Using reconstituted Las1 HEPN-HEPN' chimeras, we defined the molecular requirements for RNA cleavage. Intriguingly, both copies of the Las1 HEPN motif were important for nuclease function, revealing that both HEPN motifs participate in coordinating the RNA within the Las1 active site. We also established that conformational flexibility of the two HEPN domains is important for proper nuclease function. The results of our work reveal critical information about how dual HEPN domains come together to drive Las1-mediated RNA cleavage.

(Institute for Operations Research and the Management Sciences) Job performance has long been understood to be the primary equalizing factor affecting promotions for men and women in the workplace, but research shows, women don't gain as much from the same performance improvements as men do. New research in the INFORMS journal Information Systems Research shows training plays an important part in promotions for women in the field of information technology.

(Elsevier) Children looking for health information online could end up more prone to obesity. A new study in the Journal of Nutrition Education and Behavior, published by Elsevier, shows a lack of digital health literacy can lead children to misinterpret portions, adopt recommendations intended for adults, or take guidance from noncredible sources.

With the northeast monsoon over southern China being generally weaker than normal for most of the time in March, the month was much warmer than usual, the Hong Kong Observatory said today.

The monthly mean temperature was 21.3 degrees Celsius, 2.2 degrees above normal and the mean minimum temperature was 19.7 degrees Celsius, 2.5 degrees above average. Both were the joint second highest on record for March.

The monthly mean maximum temperature was 23.8 degrees Celsius, 2.4 degrees above normal and the fifth highest on record for the month.

The month was also drier than usual with a total rainfall of 41.3mm, about half of the normal figure.

The accumulated rainfall recorded in the first three months of the year was 135.9mm, about 16% below average.

The Agriculture, Fisheries & Conservation Department (AFCD) announced today that country park barbecue sites and campsites will remain closed until April 23.

The 163 barbecue sites and 41 campsites managed by AFCD have been closed since March 28. Given the latest development of COVID-19, the department has decided to extend the closure.

During the closure of these facilities, no barbecuing or camping activities are allowed in country parks.

AFCD staff will step up patrols of these sites and violation of relevant regulations will be subject to prosecution.

Call 1823 for enquiries or visit the Enjoy Hiking website for updates.

The department also reminded people visiting country parks to maintain personal and environmental hygiene and maintain social distancing.

The Agriculture, Fisheries & Conservation Department (AFCD) today announced that its barbecue sites and campsites in country parks will be closed until May 7.

It made the decision in light of the latest development of the COVID-19 epidemic and to reduce social contact.

All of these sites have been closed since 6pm on March 28.

During the closure of these facilities, no one should carry out barbecuing or camping activities in country parks.

AFCD staff will step up patrols of the sites and violation of relevant regulations may be subject to prosecution.

In the past two weeks, AFCD took enforcement action against 34 people who carried out barbecuing or camping activities in country parks.

The department will continue to closely monitor the situation and review the arrangement as appropriate.

For the latest updates on facilities in country parks, visit the Enjoy Hiking website.

Carlos Gustavo T. Moreira, Maria José Pacifico and Sergio Romaña Ibarra
Bull. Amer. Math. Soc. 57 (2018), 269-292.
Abstract, references and article information

Residents may have seen a distinctive white car, fitted with advanced imaging and sensory gadgetry, on its journey to create the next generation of Hong Kong maps.

As it travels up and down the city’s streets, it records the three-dimensional shapes of buildings ranging from the iconic Convention & Exhibition Centre to the Customs Headquarters Building, and even primary school campuses.

The vehicle, dubbed the Mobile Mapping System, is one of the latest technologies used by the Lands Department to survey the city.

Five pieces of equipment work in concert to collect detailed information for the 3D City Map - a core component of the digital infrastructure underpinning Hong Kong’s smart city development.

A high-resolution camera on top of the vehicle captures 360-degree images and a 3D laser scanner collects spatial measurements. An inertial navigation system and a global navigation satellite system receiver provide precise positioning.

Lands Department Assistant Land Surveyor Charlie Hung said one of the biggest advantages of this system is its ability to quickly and efficiently acquire data, which can be used to enrich 3D models and enhance existing maps.

“We can enhance the attributed information of our basic map. For example, the lamppost number, the building name or the street number.”

Drones are also used to map the city, she added. However, air surveying may not be suitable for collecting data from ground level. This is where the Mobile Mapping System vehicle comes into play.

Better data

The 3D City Map is part of the 3D Digital Map Development, which aims to contribute to an innovative, sustainable and smart Hong Kong.

Compared with traditional maps, the 3D City Map can provide more accurate and abundantly better spatial data.

The map will cover the entire city by 2023, serving as a handy tool for analysis and planning, according to Lands Department Land Surveyor Ben Fan.

He said: “Based on the 3D digital map, we can develop various kinds of applications such as land administration, environmental assessment, town planning and also transport and engineering studies.”

The latest transport infrastructures such as the Hong Kong-Zhuhai-Macao Bridge, the Central-Wan Chai Bypass and the Heung Yuen Wai Highway have also been scanned.

In the next stage of the 3D Digital Map Development, the department will create the 3D Indoor Map. As a start, data from 150 buildings in Kowloon East will be collected first before extending to other buildings in the city.

The last stage 3D models of objects such as trees and lampposts for city modelling will be produced.

Entrepreneur Ricky Chan’s information technology company has been hard at work developing a virtual reality application that enables designers and their clients to walk through different versions of their home or office without having to physically move a single piece of furniture.

From the colour of the walls to the style of fixtures and fittings, Mr Chan’s app caters to all personal tastes and design ideas.

“We have customers who are interior designers or furniture retailers. Our virtual reality application brings their sketches to life. Designers in the past needed weeks to produce sketches. Now they can make designs instantly,” he explained.

Up to 40% of the application was developed at Smart-Space 8 in Tsuen Wan, Cyberport’s first co-working space outside its main Pok Fu Lam campus.

“Cyberport provides funding that helps to lower our expenses and we can hold seminars here with a rental fee that is much lower than the market price,” Mr Chan added.
 

The 20,000 sq ft space launched last year was specifically designed with young entrepreneurs in mind and provides workshops and seminars for startups. For companies that wish to join the Smart-Space 8 community, one of its founders must be aged between 18 and 35 and the company itself should not have been in operation for longer than seven years.

Smart-Space 8 users are entitled to comprehensive entrepreneurial support and value-added services to accelerate their businesses such as the Cyberport Creative Micro Fund and Cyberport Incubation Programme.

Mr Chan, who lives in the New Territories, said the added bonus of setting up shop in Smart-Space 8 is the commute, as Cyberport in Pok Fu Lam is farther away for him and his clients.

Cyberport may be expanding beyond Pok Fu Lam, but some entrepreneurs like agriculture technology company CEO and founder Gordon Tam have opted to stay at the home campus because of the incentives available.

“The business network here is unique. There are so many startups and we encourage and learn from each other.”

Mr Tam’s company sells vegetables from an indoor farm to local supermarkets and is now exploring the overseas market. He credits the vibrant community and ecosystem at Cyberport for building up his business.

“Traditional agriculture comes with a host of problems and the efficiency of Hong Kong’s agriculture industry is relatively low. This is why we are looking into indoor agriculture. We want to grow plants in industrial buildings.”

When Mr Tam joined the Cyberport Incubation Programme, his firm was offered two years of rent reduction. But more importantly, he said, the space is a one-of-a-kind ecosystem where his team can brainstorm ideas and continue to innovate.

Other startup owners share the same sentiment. Information technology company CEO and founder Stark Chan noted that with Cyberport as a public body, it offers a lot of support and rents are more stable.

“We have been here since we first started up. My colleagues are familiar with this environment and the atmosphere is good for innovation,” Mr Chan said.

Stretching from Sai Kung on the east coast to Tuen Mun in the west, the whopping 100 km-long MacLehose Trail is the longest and first long-distance hiking trail in Hong Kong.

The trail is divided into 10 sections and traverses eight country parks which embrace magnificent natural scenery, interesting historical relics and a wide range of wild fauna and flora, winding past the coastline, rugged mountains, valleys and reservoirs to provide a diverse outdoor experience for hikers.

It was even named as one of the world's 20 dream trails by National Geographic.

A lot of hard work went into building the trail, with Agriculture, Fisheries & Conservation Department workers out in the elements without much shelter, often carrying heavy equipment uphill and downhill over varied terrain.

Building bonds

Wan Keung and Lai Hing joined the department around 40 years ago. They both took part in the MacLehose Trail project which was started in 1979 to promote hiking activities in Hong Kong.

The project was named after the then-Governor Sir Murray MacLehose - who was himself a keen walker - for his significant efforts to conserve Hong Kong’s countryside.

“I have contributed a lot to the trail. I am happy as it is packed with people now,” said Mr Wan.

While Mr Lai added: “We are going to retire, but the trail will be here for a long time.”

Despite working on the same project, the pair - now in their 60s - only met for the first time recently because they were assigned to different work stations back then. However, they became firm friends instantly.

From setting up the many signposts along the way, to hand-building the heavy stone steps, the two men eagerly shared all the skills and techniques they learnt on the project.

Listening to their conversations now it is hard to imagine that when they first started work, both had little practical knowledge about constructing a trail. They acquired welding, plastering and woodwork skills through hands-on experience and with the support of their seniors. But that was not the biggest challenge they encountered.

“Building the trail was really difficult, as there were so many sections. We were either drowned in sweat or drenched by rain while working,” Mr Lai explained.

One poignant memory for Mr Wan was of working during wildfires that raged through the countryside.

“There was only one thing for it: we stayed until the fire was extinguished. That was really hard.”

Lasting legacy

After nine months’ hard work the MacLehose Trail was finally opened on October 26, 1979.

These days Mr Wan and Mr Lai enjoy the trail for leisure instead of work.

Both said receiving compliments from family and friends or witnessing the sheer enjoyment of hikers on the trail made their hard work worthwhile.

They now hope to pass on their skills to the younger workers, so that a new generation of Hong Kong people can take care of the trail and ensure it lasts for decades to come.

(Cleveland Clinic) A new Cleveland Clinic study demonstrates the importance of genetics evaluation and genetic testing for children, adolescents and young adults with solid tumor cancers. The study was published today in Nature Communications.

(Impact Journals LLC) Volume 11, Issue 18 of @Oncotarget Clinical implications of chromatin accessibility assessed by ATAC-seq profiling in human cancers especially in a large patient cohort is largely unknown.

(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.

(Wiley) Heart failure and cancer are conditions with a number of shared characteristics. A new study published in the Journal of Internal Medicine found that in patients with heart failure, several known tumor markers can also be indicators of heart failure severity and progression.

(Memorial Sloan Kettering Cancer Center) Scientists at the Sloan Kettering Institute have solved the puzzle of how small chromosomes ensure that they aren't skipped over during meiosis, the process that makes sperm and egg.

(Walter and Eliza Hall Institute) The anti-cancer medicine venetoclax could improve the current therapy for estrogen receptor-positive (ER+) breast cancer - the most common form of breast cancer in Australia - according to preclinical studies led by Walter and Eliza Hall Institute researchers. The promising preclinical results for this 'triple therapy' have underpinned a phase 1 clinical trial in Melbourne, Australia, that is combining venetoclax with hormone therapy and CDK4/6 inhibitors in patients with ER+ breast cancer.

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