The proptech startup wanted to democratise investment in prime real estate projects through crowdfunding, but government regulations have limited its reach to high net worth individuals

The London-headquartered fintech startup Soldo has repurposed its spend management tools for local authorities in Italy to support its COVID-19 emergency response measures

The relationship wellness app is seeing a significant uptick in interest as couples are locked down together during the COVID-19 pandemic

Hilaf Hasson and Jeffrey Yelton
Trans. Amer. Math. Soc. 373 (2020), 3009-3030.
Abstract, references and article information

M. V. Pratsiovytyi and S. P. Ratushniak
Theor. Probability and Math. Statist. 99 (2020), 211-228.
Abstract, references and article information

Jeremy Brazas
Proc. Amer. Math. Soc. 148 (2019), 2655-2670.
Abstract, references and article information

On this last Sunday of 2019, I wish every Hong Kong citizen a warm, peaceful and hopeful year 2020.

A New Year holds welcome promises of a fresh start and a new beginning. The New Year is also traditionally a time for planning, greeting, reminiscing as well as some soul and heart searching.

I believe that many of you would share my feeling that the year 2019 has been a year of unremitting shocks and turbulence to our community and our economy. Indeed, it has been a severely testing time for all in Hong Kong.

It all began with the introduction into the Legislative Council of the bill to amend the Fugitive Offenders Ordinance in April. Responding to strong public sentiment, the Government suspended all work on the bill in mid-June and declared its death in early July. On September 4, the Chief Executive announced the bill's withdrawal. This was done on October 23 when the Legislative Council resumed normal business.

Despite this, the public protests which began as largely peaceful and orderly marches in June soon got out of control. Unprecedented violence and reckless destruction became the norm. Radical protesters attacked police officers as well as police stations and facilities with petrol bombs, iron bars, bricks and chemicals. Some even used high-tension slingshots, bows and arrows. During the past six months or so, over 2,600 people were injured in the social unrest, including over 500 police officers.

Meanwhile, public infrastructure and transport including a cumulative total of 85 heavy rail stations and 62 light rail stations, as well as countless shops, restaurants and shopping malls had been repeatedly vandalised. More so, nearly 21,000 square metres of paving blocks from footpaths were ripped up and used as weapons to attack Police. Over 52,000 metres of roadside railing were removed and 740 sets of traffic lights destroyed.

Last month, masked protesters battered the Hung Hom Cross-Harbour Tunnel, shutting it down for two full weeks. This vital city artery normally carries 110,000 vehicles a day, accounting for some 43% of the daily cross-harbour vehicular flow. It took a total of 800 government staff and contractor's workers some 100 hours to carry out emergency repair round-the-clock before the tunnel could be reopened. At the same time, nearby Polytechnic University was overrun by radical protesters. The same happened to the Chinese University.

Apart from recklessly damaging our universities, violent protesters turned the two campuses into arsenals on a frightening scale. When the last of the protesters finally left the universities, Police seized altogether nearly 8,000 petrol bombs plus numerous explosives, hundreds of bottles of corrosive liquid and weapons of all sorts.

This level of premeditated and organised destruction and violence could hardly be tolerated in any country or economy that upholds the rule of law. Hong Kong, I am proud to say, is among those economies that believe passionately in the primacy of rule of law. It safeguards our economy, our community, our families and our way of life.

In fact, the rule of law is among Hong Kong's much cherished core values, alongside our fiercely independent judiciary, clean government, level playing field for business and enviable freedoms. These freedoms, as enshrined in the Basic Law and the Hong Kong Bill of Rights Ordinance, include freedom of speech, of the press and free flow of information; freedom of association and assembly; free trade and free port; free flow of capital; freely convertible currency; freedom of religious belief and free education. We have also been the freest economy in the world continuously for 25 years. The unique "one country, two systems" formula has been functioning well and we enjoy the best of both worlds.

Despite the recent social unrest which has affected our economy and labour market, Hong Kong's institutional strengths remain robust and intact. Our fundamentals stay sound and strong. We still enjoy a high rating in various areas by international think tanks and agencies. Allow me to say that whilst Hong Kong may not have the full semblance of Western democracy, we do enjoy for a very long time the full substance of real freedom which underpins Hong Kong's success.

Over the past six months, most of the requests for public meetings, processions and protests were given the greenlight by Police. During these public events, be it small or large, Police had dutifully facilitated and ensured the safety of protesters and other road users. When the requests were not approved, it was generally a decision made in the hopes of preventing violence, ensuring peace and public order, as our society has every right to expect of its police and its government.

On November 24, we witnessed a peaceful and orderly District Council Election with a record high turnout and voting rates. My colleagues and I are looking forward to working with all new District Council members. We also look forward to expanding our dialogue with the community. While we will continue to engage different sectors of society through our usual channels, the Government will broaden and rejuvenate our communication with the public. Less than two weeks ago and after the one by the Chief Executive in September, my Principal Official colleagues have started a dialogue with the public through Facebook live. You will certainly see more of us listening and responding to people's views and concerns on these and other communication channels in the coming year.

We are also establishing an Independent Review Committee comprising experts and community leaders. The committee will look into the causes and full circumstances of the social unrest and probe into Hong Kong's deep-seated social conflicts, from affordable housing, land supply, wealth gap, upward social mobility and opportunities for our young people to social justice. The committee will recommend ways to address the real and long-entrenched community concerns that underlie the discord.

Meanwhile, our economy is inevitably affected by the twin blows of social unrest and the trade dispute between the United States and the Mainland. Businesses and people of Hong Kong are yearning for the restoration of peace and order soonest possible, and the recovery of our economy.

In response, the Government has launched four rounds of relief measures since August. These added up to more than $25 billion. A number of the measures which will benefit grassroots families and small and medium enterprises will be implemented at the beginning of the New Year.

These relief measures would not solve our economic problems. Yet, they could help businesses and people of Hong Kong stay afloat while we strive to heal our divided community and battered economy.

There are deep-seated issues that we must acknowledge and resolve if we are to end the prolonged social unrest that has shaken the familiar Hong Kong which we all love and cherish. We must be patient and perseverant in helping our city to heal, one step at a time.

The past six months have been tough for us, but we will soldier on. Hong Kong is a remarkably resilient and resourceful international city with a strong can-do spirit. We have a New Year waiting for us. We have new and expanded channels of communication opened up for us. We expect the first report of the Independent Police Complaints Council to come out soon. And we have research and concrete recommendations of the Independent Review Committee ahead of us. Working together, I am confident that we can rebuild, reclaim and rejuvenate the remarkably resilient spirit of Hong Kong.

On this note, I wish all of you a New Year blessed with peace, harmony and goodwill.

Chief Secretary Matthew Cheung gave these remarks on RTHK's "Letter to Hong Kong" programme aired on December 29.

The Leisure & Cultural Services Department will present Nobody but a princess..., a multimedia production featuring Nordic singers, dancers from the Hong Kong Ballet and overseas acrobats from November 8 to 10.

A story of a modern princess who discovers her identity and true love through her fantastic journey of wonders, the performance will be staged in a custom-made giant dome, complete with a state-of-the-art kinetic light display and pyrotechnics.

It will be held at 6pm, 7pm and 8.30pm from November 8 to 10 at the Cultural Centre Piazza.

The show will be conducted in English and include a strobe light effect. Admission is free.

Click here for details.

Let’s discuss student opinion forms, course evaluations, student evaluation of teaching forms, whatever term you use. Article after article year after year highlight how toxic they are. More recently the emphasis has been on how they differ according to instructor … Continue reading →

As we all know, Hong Kong as well as most parts of the world are facing a pandemic that has an enormous negative impact on our social and economic life. At this juncture, we don't have any accurate way to predict what will happen in the coming months. Two months ago, we were worried about whether COVID-19 would become a pandemic. Yet, the scale of the pandemic as we see now is not what we could have imagined two months ago. What we can do now is tackle the social and economic crisis upfront and build the resilience of our society, in particular, our employment market, so that when the time comes where social and economic activities can resume no matter how gradually or rapidly, our society can bounce back as soon as possible.

Unemployment has edged up bit by bit since the latter part of 2019. Statistics and daily news about business closures are telling us that unemployment is going up rapidly. While we should see what can be done to help those unemployed, the more important and urgent task is to see how we can "stop the bleeding", which essentially means job retention. The Employment Support Scheme, with a budget of over $80 billion, is designed exactly for that purpose. Through providing time-limited financial support, the whole idea of this scheme is to preserve jobs by enabling employers to keep their employees in employment for the coming months, and also when business resumes, employers can immediately grab the opportunities.

The central idea of the Employment Support Scheme is to provide wage subsidy that is equivalent to 50% of the wages of the employees up to a wage cap of $18,000 per month. The subsidy is given to the employers so that they can keep their staff for the coming six months. The employers will be required to have no redundancy or layoffs during the months that they receive wage subsidies from the Government.

In Hong Kong, we do not have a pay-as-you-go income tax system. Neither do we have a social insurance system nor a central provident fund to cover everyone in our workforce. That means we do not have any existing system covering every employer and employee in Hong Kong that we can devise a wage subsidy scheme that covers everyone. Any system meant to cover everyone in our workforce must be mandatory in nature and that will take time for us to have the relevant legislation in place and subsequently the system built.

However, schemes under the Mandatory Provident Fund (MPF) and the other Occupational Retirement Schemes provide a framework that we can develop a wage subsidy scheme to cover the great majority of the workforce. This is definitely not sufficient. In particular, we have identified three sectors that do not have good coverage in the provident fund systems. They are the catering industry, the construction industry and the passenger transport sector. Under the Anti-epidemic Fund, we have three sector-specific schemes to assist the employers and the employees in these sectors.

Many freelance workers or those in the so-called slash economy do not make contributions to the MPF. Though we have over 200,000 self-employed persons having an account in the MPF system, they do not pay MPF regularly. While we will provide a one-off wage subsidy to those self-employed persons who have made MPF contributions within the past 15 months, we also have three separate but mutually exclusive schemes operating under the Home Affairs Bureau, the Education Bureau and the Social Welfare Department, providing the same one-off wage subsidy to those freelance workers who provide arts and sports training. The one-off wage subsidy is $7,500.

Though all the schemes I mentioned above still cannot cover everyone in the workforce, this is the best we can do in making use of existing systems so that we can launch this round of the Anti-epidemic Fund in the shortest possible time to help our employers and employees to survive the challenges that are with us now. Any new systems to be built from scratch will not be able to provide the necessary timely support that employers and employees desperately need.

As mentioned earlier, unemployment is increasing at a disturbing rate. The basic unemployment protection system in Hong Kong relies on two legs. One is the Severance Payment or Long Service Payment payable by the employers, which is equivalent to two-thirds of the monthly salary times the number of years of service with the employer. The other is the Comprehensive Social Security Assistance (CSSA) Scheme. The CSSA provides a level of income support to families for their basic level of living in the context of Hong Kong. The CSSA provides a safety net to any family not having sufficient means, including those who are unemployed.

Apart from the income test, the CSSA also has an asset test. For the purpose of providing extra help to those unemployed during this difficult time, the Government will double the existing asset limit for the able-bodied for a limited period of six months, allowing more families with people unemployed to become eligible to receive CSSA. We estimated that about 40,000 families will benefit from this enhancement.

Unfortunately, over the years there is a social stigma towards the CSSA system. People in desperation may be deterred from applying for CSSA simply because of the stigma. This is the time for us to destigmatise the CSSA system. It is the safety net for citizens of Hong Kong. It is the responsibility of an affluent society like Hong Kong to provide the basic level of living to those who cannot afford to do so on their own. This is the time, this difficult time, that this safety net should perform its basic function.

We are doing our best to support Hong Kong in this epidemic fight. Let's weather the storm and brave the challenges together.

This is the Letter to Hong Kong by Secretary for Labour & Welfare Dr Law Chi-kwong on anti-epidemic measures and the Employment Support Scheme carried on Radio Television Hong Kong Radio 3 on April 19.

Beatrice K. Gandara
Nov 1, 2011; 24:199-205
From Research to Practice

Donna Tomky
Jan 1, 2005; 18:39-44
Articles

(Fundação de Amparo à Pesquisa do Estado de São Paulo) Thanks to its magnetic properties, the material -- zinc-doped manganese chromite -- can be used in a range of products, from gas sensors to data storage devices.

(University of Jyväskylä - Jyväskylän yliopisto) Researchers at the universities of Jyvaskyla and Xiamen discovered a novel way to make functional macroscopic crystalline materials out of nanometer-size 34-atom silver-gold intermetallic clusters. The cluster material has a highly anisotropic electrical conductivity, being a semiconductor in one direction and an electrical insulator in other directions. The research was published in Nature Communications on May 6, 2020.

(To watch the full press briefing with sign language interpretation, click here.)

The Centre for Health Protection today said recovered COVID-19 patients or those who did not have any symptoms may be discharged from hospital 10 days after the onset of symptoms or a positive test result.

Its Communicable Disease Branch Head Dr Chuang Shuk-kwan told a press briefing that the revised discharge criteria was based on the latest scientific evidence.

“Our Scientific Committee on Emerging & Zoonotic Diseases met yesterday and examined the latest scientific evidence on whether the virus will be viable from a patient.

“And the available evidence showed that this virus is usually not detected after 10 days since the onset of symptoms of patients. Some patients may have persistent positive PCR (polymerase chain reaction) for a long period of time.”

Dr Chuang noted that patients still had to meet the criteria of having two clinical specimens test negative, or testing positive for the SARS-CoV-2 antibody to be discharged.

“We have revised the discharge criteria to include the patient who (must have) been staying in the hospital for at least 10 days after the onset of symptoms. So this is the additional criteria, in addition to the previous criteria of two consecutive negative specimens.

“We added another criteria (which is) in case a patient has stayed in the hospital for a long time, more than 10 days since the onset of symptoms, but he or she has persistent positive PCR despite the Ct (cycle threshold) value being very high, they can check their serology, the antibody. So if the antibody turns positive, usually it is after 10 days, then he or she can be discharged.

“So this is based on the latest scientific evidence.”

Haploinsufficiency of Meis homeobox 2 (MEIS2), encoding a transcriptional regulator, is associated with human cleft palate, and Meis2 inactivation leads to abnormal palate development in mice, implicating MEIS2 functions in palate development. However, its functional mechanisms remain unknown. Here we observed widespread MEIS2 expression in the developing palate in mice. Wnt1Cre-mediated Meis2 inactivation in cranial neural crest cells led to a secondary palate cleft. Importantly, about half of the Wnt1Cre;Meis2f/f mice exhibited a submucous cleft, providing a model for studying palatal bone formation and patterning. Consistent with complete absence of palatal bones, the results from integrative analyses of MEIS2 by ChIP sequencing, RNA-Seq, and an assay for transposase-accessible chromatin sequencing identified key osteogenic genes regulated directly by MEIS2, indicating that it plays a fundamental role in palatal osteogenesis. De novo motif analysis uncovered that the MEIS2-bound regions are highly enriched in binding motifs for several key osteogenic transcription factors, particularly short stature homeobox 2 (SHOX2). Comparative ChIP sequencing analyses revealed genome-wide co-occupancy of MEIS2 and SHOX2 in addition to their colocalization in the developing palate and physical interaction, suggesting that SHOX2 and MEIS2 functionally interact. However, although SHOX2 was required for proper palatal bone formation and was a direct downstream target of MEIS2, Shox2 overexpression failed to rescue the palatal bone defects in a Meis2-mutant background. These results, together with the fact that Meis2 expression is associated with high osteogenic potential and required for chromatin accessibility of osteogenic genes, support a vital function of MEIS2 in setting up a ground state for palatal osteogenesis.

The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.

β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro. β-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation. Liquid chromatography–tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain. We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination. We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes. In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain.

Heme-regulatory motifs (HRMs) are present in many proteins that are involved in diverse biological functions. The C-terminal tail region of human heme oxygenase-2 (HO2) contains two HRMs whose cysteine residues form a disulfide bond; when reduced, these cysteines are available to bind Fe3+-heme. Heme binding to the HRMs occurs independently of the HO2 catalytic active site in the core of the protein, where heme binds with high affinity and is degraded to biliverdin. Here, we describe the reversible, protein-mediated transfer of heme between the HRMs and the HO2 core. Using hydrogen-deuterium exchange (HDX)-MS to monitor the dynamics of HO2 with and without Fe3+-heme bound to the HRMs and to the core, we detected conformational changes in the catalytic core only in one state of the catalytic cycle—when Fe3+-heme is bound to the HRMs and the core is in the apo state. These conformational changes were consistent with transfer of heme between binding sites. Indeed, we observed that HRM-bound Fe3+-heme is transferred to the apo-core either upon independent expression of the core and of a construct spanning the HRM-containing tail or after a single turnover of heme at the core. Moreover, we observed transfer of heme from the core to the HRMs and equilibration of heme between the core and HRMs. We therefore propose an Fe3+-heme transfer model in which HRM-bound heme is readily transferred to the catalytic site for degradation to facilitate turnover but can also equilibrate between the sites to maintain heme homeostasis.

Cytochrome c oxidase (CcO) reduces O2 to water, coupled with a proton-pumping process. The structure of the O2-reduction site of CcO contains two reducing equivalents, Fea32+ and CuB1+, and suggests that a peroxide-bound state (Fea33+–O−–O−–CuB2+) rather than an O2-bound state (Fea32+–O2) is the initial catalytic intermediate. Unexpectedly, however, resonance Raman spectroscopy results have shown that the initial intermediate is Fea32+–O2, whereas Fea33+–O−–O−–CuB2+ is undetectable. Based on X-ray structures of static noncatalytic CcO forms and mutation analyses for bovine CcO, a proton-pumping mechanism has been proposed. It involves a proton-conducting pathway (the H-pathway) comprising a tandem hydrogen-bond network and a water channel located between the N- and P-side surfaces. However, a system for unidirectional proton-transport has not been experimentally identified. Here, an essentially identical X-ray structure for the two catalytic intermediates (P and F) of bovine CcO was determined at 1.8 Å resolution. A 1.70 Å Fe–O distance of the ferryl center could best be described as Fea34+ = O2−, not as Fea34+–OH−. The distance suggests an ∼800-cm−1 Raman stretching band. We found an interstitial water molecule that could trigger a rapid proton-coupled electron transfer from tyrosine-OH to the slowly forming Fea33+–O−–O−–CuB2+ state, preventing its detection, consistent with the unexpected Raman results. The H-pathway structures of both intermediates indicated that during proton-pumping from the hydrogen-bond network to the P-side, a transmembrane helix closes the water channel connecting the N-side with the hydrogen-bond network, facilitating unidirectional proton-pumping during the P-to-F transition.

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.

Lens proteins become increasingly cross-linked through nondisulfide linkages during aging and cataract formation. One mechanism that has been implicated in this cross-linking is glycation through formation of advanced glycation end products (AGEs). Here, we found an age-associated increase in stiffness in human lenses that was directly correlated with levels of protein–cross-linking AGEs. α-Crystallin in the lens binds to other proteins and prevents their denaturation and aggregation through its chaperone-like activity. Using a FRET-based assay, we examined the stability of the αA-crystallin–γD-crystallin complex for up to 12 days and observed that this complex is stable in PBS and upon incubation with human lens–epithelial cell lysate or lens homogenate. Addition of 2 mm ATP to the lysate or homogenate did not decrease the stability of the complex. We also generated complexes of human αA-crystallin or αB-crystallin with alcohol dehydrogenase or citrate synthase by applying thermal stress. Upon glycation under physiological conditions, the chaperone–client complexes underwent greater extents of cross-linking than did uncomplexed protein mixtures. LC-MS/MS analyses revealed that the levels of cross-linking AGEs were significantly higher in the glycated chaperone–client complexes than in glycated but uncomplexed protein mixtures. Mouse lenses subjected to thermal stress followed by glycation lost resilience more extensively than lenses subjected to thermal stress or glycation alone, and this loss was accompanied by higher protein cross-linking and higher cross-linking AGE levels. These results uncover a protein cross-linking mechanism in the lens and suggest that AGE-mediated cross-linking of α-crystallin–client complexes could contribute to lens aging and presbyopia.

The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.

In bacteria, the restart of stalled DNA replication forks requires the DNA helicase PriA. PriA can recognize and remodel abandoned DNA replication forks, unwind DNA in the 3'-to-5' direction, and facilitate the loading of the helicase DnaB onto the DNA to restart replication. Single-stranded DNA–binding protein (SSB) is typically present at the abandoned forks, but it is unclear how SSB and PriA interact, although it has been shown that the two proteins interact both physically and functionally. Here, we used atomic force microscopy to visualize the interaction of PriA with DNA substrates with or without SSB. These experiments were done in the absence of ATP to delineate the substrate recognition pattern of PriA before its ATP-catalyzed DNA-unwinding reaction. These analyses revealed that in the absence of SSB, PriA binds preferentially to a fork substrate with a gap in the leading strand. Such a preference has not been observed for 5'- and 3'-tailed duplexes, suggesting that it is the fork structure that plays an essential role in PriA's selection of DNA substrates. Furthermore, we found that in the absence of SSB, PriA binds exclusively to the fork regions of the DNA substrates. In contrast, fork-bound SSB loads PriA onto the duplex DNA arms of forks, suggesting a remodeling of PriA by SSB. We also demonstrate that the remodeling of PriA requires a functional C-terminal domain of SSB. In summary, our atomic force microscopy analyses reveal key details in the interactions between PriA and stalled DNA replication forks with or without SSB.

Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.

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 maximum monthly rental subsidy for each recycler under the One-off Rental Support Scheme will be increased from $25,000 to $37,500, the Environmental Protection Department announced today.

To help the recycling industry cope with the current economic situation and operational difficulties due to the COVID-19 epidemic, the Recycling Fund has allocated $50 million in additional funds to raise the scheme’s subsidy level.

The fund has now earmarked up to $250 million in total funding to fight the virus and help the recycling industry ride out difficult times.

On April 15, the Advisory Committee on Recycling Fund agreed to strengthen support under the scheme by increasing the rental assistance from 50% to 75% for the subsidy period from April to September.

The maximum monthly rental subsidy for each recycler will be increased to $37,500, while the maximum total rental subsidy for the 12 months will be increased from $300,000 to $375,000.

The scheme was launched last year to benefit about 500 street-corner recycling shops and 400 recycling sites.

In the face of current economic difficulties, the fund announced in February an extension of the subsidy period from six months to 12 months, lasting until September.     

As of April 9, the scheme has approved 103 applications, involving subsidies of more than $20 million.

The application deadline for the scheme is September 30. Enquiries can be made to 2788 5658 or via email.

Tenants of the EcoPark, country park refreshment kiosks and the Hong Kong Wetland Park will benefit from increased rental concessions for government premises.

To help tenants cope with the economic impact of the COVID-19 epidemic, rental concessions of government premises from April to September will be increased from 50% to 75%.

The Environment Bureau said tenants of the EcoPark, country park refreshment kiosks and the Hong Kong Wetland Park will receive additional rental concessions of about $3.6 million.

Together with the 50% rental concessions provided by the Government from last October to March, these tenants will receive concessions of more than $17 million within 12 months, the bureau said.

Meanwhile, tenants of the Hong Kong Wetland Park will receive a full rental waiver during the park’s closure.

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