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"Lee, Ling"
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Inhibition of Japanese encephalitis virus infection by the host zinc-finger antiviral protein
CCCH-type zinc-finger antiviral protein (ZAP) is a host factor that restricts the infection of many viruses mainly through RNA degradation, translation inhibition and innate immune responses. So far, only one flavivirus, yellow fever virus, has been reported to be ZAP-resistant. Here, we investigated the antiviral potential of human ZAP (isoform ZAP-L and ZAP-S) against three flaviviruses, Japanese encephalitis virus (JEV), dengue virus (DENV) and Zika virus (ZIKV). Infection of JEV but not DENV or ZIKV was blocked by ZAP overexpression, and depletion of endogenous ZAP enhanced JEV replication. ZAP hampered JEV translation and targeted viral RNA for 3'-5' RNA exosome-mediated degradation. The zinc-finger motifs of ZAP were essential for RNA targeting and anti-JEV activity. JEV 3'-UTR, especially in the region with dumbbell structures and high content of CG dinucleotide, was mapped to bind ZAP and confer sensitivity to ZAP. In summary, we identified JEV as the first ZAP-sensitive flavivirus. ZAP may act as an intrinsic antiviral factor through specific RNA binding to fight against JEV infection.
Journal Article
Cohort profile: The Multiethnic Lifestyle, Obesity and Diabetes Registry in Malaysia (MeLODY) retrospective cohort in a middle-income country in Southeast Asia
There is a lack of longitudinal data on type 2 diabetes (T2D) in low- and middle-income countries. We leveraged the electronic health records (EHR) system of a publicly funded academic institution to establish a retrospective cohort with longitudinal data to facilitate benchmarking, surveillance, and resource planning of a multi-ethnic T2D population in Malaysia. This cohort included 15,702 adults aged ≥ 18 years with T2D who received outpatient care (January 2002-December 2020) from Universiti Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia. The mean age of participants was 54.3 ± 12.6 years, with a T2D duration of 12.7 ± 4.8 years, HbA 1c of 8.9 ± 2.6%, body mass index of 28.2 ± 6.2 kg/m 2 , and 47.4% were men. The top three comorbidities were dyslipidaemia (87.1%), overweight/obesity (69.4%), and hypertension (62.6%). The proportion of participants achieving HbA 1c < 7%, blood pressure < 130/80 mmHg, and low-density lipoprotein cholesterol < 2.6 mmol/L was 27.8%, 24.8%, and 24.5%, respectively. The most common treatments were metformin (62.4%), sulfonylurea (32.8%), and insulin (32.7%). Given the lack of implementation of urinary albumin:creatinine ratio for early detection, chronic kidney disease (defined as estimated glomerular filtration rate < 60 mL/min/1.73m 2 ) was underestimated at 7.5%. These findings highlight opportunities for improved data collection in a middle-income country in Southeast Asia. Apart from trend analysis, this cohort will be prospectively followed for ongoing benchmarking, surveillance, and ascertainment of clinical events, including death.
Journal Article
Focus on the Primary Prevention of Intrauterine Adhesions: Current Concept and Vision
Intrauterine adhesion (IUA), and its severe form Asherman syndrome (Asherman’s syndrome), is a mysterious disease, often accompanied with severe clinical problems contributing to a significant impairment of reproductive function, such as menstrual disturbance (amenorrhea), infertility or recurrent pregnancy loss. Among these, its correlated infertility may be one of the most challenging problems. Although there are many etiologies for the development of IUA, uterine instrumentation is the main cause of IUA. Additionally, more complicated intrauterine surgeries can be performed by advanced technology, further increasing the risk of IUA. Strategies attempting to minimize the risk and reducing its severity are urgently needed. The current review will expand the level of our knowledge required to face the troublesome disease of IUA. It is separated into six sections, addressing the introduction of the normal cyclic endometrial repairing process and its abruption causing the formation of IUA; the etiology and prevalence of IUA; the diagnosis of IUA; the classification of IUA; the pathophysiology of IUA; and the primary prevention of IUA, including (1) delicate surgical techniques, such as the use of surgical instruments, energy systems, and pre-hysteroscopic management, (2) barrier methods, such as gels, intrauterine devices, intrauterine balloons, as well as membrane structures containing hyaluronate–carboxymethylcellulose or polyethylene oxide–sodium carboxymethylcellulose as anti-adhesive barrier.
Journal Article
Evaluating neuroprivacy concerns in human brain organoid research
Neuroprivacy, or the privacy of neural data, has attracted considerable interest. Here, we explore the implications of neuroprivacy in human brain organoid research, detailing different interpretations of this right. Findings suggest a limited connection between neuroprivacy and brain organoid research, underscoring the importance of further examination of this critical issue.
Neuroprivacy, or the privacy of neural data, has attracted considerable interest. Here, we explore the implications of neuroprivacy in human brain organoid research, detailing different interpretations of this right. Findings suggest a limited connection between neuroprivacy and brain organoid research, underscoring the importance of further examination of this critical issue.
Journal Article
Analyzing Precision Agriculture Adoption across the Globe: A Systematic Review of Scholarship from 1999–2020
Precision agriculture (PA) is a holistic, sustainable, innovative systems approach that assists farmers in production management. Adopting PA could improve sustainable food security and community economic sustainability. Developing an understanding of PA adoption attributes is needed in order to assist extension practitioners to promote adoption and better understand the innovation adoption phenomena. A systematic review of literature was conducted to investigate attributes that foster PA adoption. Thirty-three publications were examined, and four themes were found among the reviewed publications. The results were interpreted using Rogers’ diffusion of innovations framework to address the research objectives. Relative advantage and compatibility were two dominant attributes needed to strengthen the adoption of PA, and the complexity attribute was rarely communicated to promote the adoption of PA. The systematic review indicated the rate of farmer’s PA adoption does not occur at the highest potential levels due to inadequate communication of PA attributes from change agents to farmers. Extension field staff need professional development in communicating the five PA adoption attributes to farmers in order to improve PA adoption and enhance local sustainable food security. Thus, authors recommend future complexity studies from agricultural extension specialists’ perspectives to comprehend demonstratable approaches to motivate farmers’ adoption of PA.
Journal Article
Ebselen alleviates testicular pathology in mice with Zika virus infection and prevents its sexual transmission
Despite the low case fatality, Zika virus (ZIKV) infection has been associated with microcephaly in infants and Guillain-Barré syndrome. Antiviral and vaccine developments against ZIKV are still ongoing; therefore, in the meantime, preventing the disease transmission is critical. Primarily transmitted by Aedes species mosquitoes, ZIKV also can be sexually transmitted. We used AG129 mice lacking interferon-α/β and -γ receptors to study the testicular pathogenesis and sexual transmission of ZIKV. Infection of ZIKV progressively damaged mouse testes, increased testicular oxidative stress as indicated by the levels of reactive oxygen species, nitric oxide, glutathione peroxidase 4, spermatogenesis-associated-18 homolog in sperm and pro-inflammatory cytokines including IL-1β, IL-6, and G-CSF. We then evaluated the potential role of the antioxidant ebselen (EBS) in alleviating the testicular pathology with ZIKV infection. EBS treatment significantly reduced ZIKV-induced testicular oxidative stress, leucocyte infiltration and production of pro-inflammatory response. Furthermore, it improved testicular pathology and prevented the sexual transmission of ZIKV in a male-to-female mouse sperm transfer model. EBS is currently in clinical trials for various diseases. ZIKV infection could be on the list for potential use of EBS, for alleviating the testicular pathogenesis with ZIKV infection and preventing its sexual transmission.
Journal Article
Molecular mechanisms of thiazide-like diuretics-mediated inhibition of the human Na-Cl cotransporter
Thiazide-type and thiazide-like diuretics are structurally distinct first-line antihypertensive drugs that target the sodium-chloride cotransporter (NCC) in the kidney. Thiazide-like diuretics are reported to have better cardioprotective effects than thiazide-type diuretics, but whether this is due to differences in NCC-inhibition mechanisms, if there is any, remains unclear. To understand the molecular mechanisms of NCC inhibition by thiazide-like diuretics, we determine the structures of human NCC (hNCC) bound to two of the most widely used thiazide-like diuretics, chlorthalidone and indapamide, using cryogenic electron microscopy (cryo-EM). Structural analyses reveal shared features and distinctions between NCC-inhibition by thiazide-like and thiazide-type diuretics. Furthermore, structural comparisons allow us to identify polymorphisms in hNCC that have substantial differential effects on the potencies of specific thiazide-like and thiazide-type diuretics. Our work provides important insights into the molecular pharmacology of NCC and a blueprint for developing precision medicine to manage hypertension with thiazide-like and thiazide-type diuretics.
Thiazide-like diuretics, which target the sodium-chloride cotransporter (NCC), are first-line antihypertensive medications. Here, the authors determine the structures of human NCC in complex with two widely used thiazide-like diuretics, chlorthalidone and indapamide, and identify NCC polymorphisms that differentially affect drug-specific sensitivity.
Journal Article
Cardiorenal diseases in type 2 diabetes mellitus: clinical trials and real-world practice
Patients with type 2 diabetes mellitus (T2DM) can have multiple comorbidities and premature mortality due to atherosclerotic cardiovascular disease, hospitalization with heart failure and/or chronic kidney disease. Traditional drugs that lower glucose, such as metformin, or that treat high blood pressure and blood levels of lipids, such as renin–angiotensin-system inhibitors and statins, have organ-protective effects in patients with T2DM. Amongst patients with T2DM treated with these traditional drugs, randomized clinical trials have confirmed the additional cardiorenal benefits of sodium–glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA) and nonsteroidal mineralocorticoid receptor antagonists. The cardiorenal benefits of SGLT2i extended to patients with heart failure and/or chronic kidney disease without T2DM, whereas incretin-based therapy (such as GLP1RA) reduced cardiovascular events in patients with obesity and T2DM. However, considerable care gaps exist owing to insufficient detection, therapeutic inertia and poor adherence to these life-saving medications. In this Review, we discuss the complex interconnections of cardiorenal–metabolic diseases and strategies to implement evidence-based practice. Furthermore, we consider the need to conduct clinical trials combined with registers in specific patient segments to evaluate existing and emerging therapies to address unmet needs in T2DM.Cardiorenal diseases are common in patients with type 2 diabetes mellitus (T2DM), with substantial morbidity and premature mortality. This Review discusses how atherosclerotic cardiovascular disease and cardiorenal diseases can be prevented in T2DM, considering evidence from clinical trials and its implementation in clinical practice.
Journal Article