Development of a luciferase-based Gram-positive bacterial reporter system for the characterization of antimicrobial agents.

Unlabelled: Mechanistic investigations are of paramount importance in elucidating the modes of action of antibiotics and facilitating the discovery of novel drugs. We reported a luciferase-based reporter system using bacterial cells to unveil mechanisms of antimicrobials targeting transcription and translation. The reporter gene encoding NanoLuciferase (NanoLuc) was integrated into the genome of the Gram-positive model organism, , to generate a reporter strain BS2019.

Development and validation of 10-year risk prediction models of cardiovascular disease in Chinese type 2 diabetes mellitus patients in primary care using interpretable machine learning-based methods.

Aim: To develop 10-year cardiovascular disease (CVD) risk prediction models in Chinese patients with type 2 diabetes mellitus (T2DM) managed in primary care using machine learning (ML) methods.

Methods: In this 10-year population-based retrospective cohort study, 141 516 Chinese T2DM patients aged 18 years or above, without history of CVD or end-stage renal disease and managed in public primary care clinics in 2008, were included and followed up until December 2017. Two-thirds of the patients were randomly selected to develop sex-specific CVD risk prediction models.

Sulfonamidyl derivatives of sigmacidin: Protein-protein interaction inhibitors targeting bacterial RNA polymerase and sigma factor interaction exhibiting antimicrobial activity against antibiotic-resistant bacteria.

RNA polymerase is an essential enzyme involved in bacterial transcription, playing a crucial role in RNA synthesis. However, it requires the association with sigma factors to initiate this process. In our previous work, we utilized a structure-based drug discovery approach to create benzoyl and benzyl benzoic acid compounds.

Copper-Catalyzed Synthesis of Functionalized Aryl Sulfonamides from Sodium Sulfinates in Green Solvents.

Functionalized aryl sulfonamides are important building blocks in the pharmaceutical industry. A one-step synthesis catalyzed by a copper salt was developed using stable solid commodity chemicals in sulfolane or, alternatively, in green solvents such as γ-valerolactone, PrOAc, or BuOAc with acetic acid. The method tolerated diverse functional groups commonly presented in current medicines and drug intermediates.

Prediction models and nomograms for 10-year risk of end-stage renal disease in Chinese type 2 diabetes mellitus patients in primary care.

Aims: To develop and validate 10-year risk prediction models, nomograms and charts for end-stage renal disease (ESRD) in Chinese patients with type 2 diabetes mellitus (T2DM) in primary care, in order to guide individualized treatment.

Materials And Methods: This was a 10-year population-based observational cohort study. A total of 141 516 Chinese T2DM patients without history of cardiovascular disease or ESRD who were managed in public primary care clinics in 2008 were included and followed up until December 2017.

Molecular basis defining the selectivity of substituted isoquinolinones for the melatonin MT receptor.

Melatonin MT and MT receptors represent attractive drug targets for the treatment of various disorders. However, the high conservation of the melatonin binding pocket has hindered the development of subtype-selective compounds. By leveraging on the recently resolved crystal structures of MT and MT receptors, this study aims to elucidate the structural basis of MT-selectivity of a panel of isoquinolinone derivatives.

Ten-year risk prediction models of complications and mortality of Chinese patients with diabetes mellitus in primary care in Hong Kong: a study protocol.

Introduction: Diabetes mellitus (DM) is a major disease burden worldwide because it is associated with disabling and lethal complications. DM complication risk assessment and stratification is key to cost-effective management and tertiary prevention for patients with diabetes in primary care. Existing risk prediction functions were found to be inaccurate in Chinese patients with diabetes in primary care.

Change in Pneumococcus Serotypes but not Mortality or Morbidity in Pre- and Post-13-Valent Polysaccharide Conjugate Vaccine Era: Epidemiology in a Pediatric Intensive Care Unit over 10 Years.

Aim: Pneumococcus is a common commensal and an important pathogen among children for which immunization is available. Some serotypes occasionally cause severe pneumococcal disease with high mortality and morbidity. We reviewed all pneumococcal serotypes and mortality/morbidity in a pediatric intensive care unit (PICU) following universal pneumococcal conjugate vaccine (PCV) immunization.

Late Onset Meningitis following Early Onset Septicemia: A Preventable Disease?

We report a neonate who presented with early onset or group B streptococcus (GBS) septicemia within 24 hours of birth. After discharge at day 14, she went on to develop late onset GBS meningitis at 36 days of age. The infant was treated with intravenous antibiotics on both occasions and eventually discharged home with no apparent sequelae.

Synthesis and functional characterization of substituted isoquinolinones as MT2-selective melatoninergic ligands.

A series of substituted isoquinolinones were synthesized and their binding affinities and functional activities towards human melatonin MT1 and MT2 receptors were evaluated. Structure-activity relationship analysis revealed that substituted isoquinolinones bearing a 3-methoxybenzyloxyl group at C5, C6 or C7 position respectively (C5>C6>C7 in terms of their potency) conferred effective binding and selectivity toward the MT2 receptor, with 15b as the most potent compound. Most of the tested compounds were MT2-selective agonists as revealed in receptor-mediated cAMP inhibition, intracellular Ca2+ mobilization and phosphorylation of extracellular signal-regulated protein kinases.

A molecular and chemical perspective in defining melatonin receptor subtype selectivity.

Melatonin is primarily synthesized and secreted by the pineal gland during darkness in a normal diurnal cycle. In addition to its intrinsic antioxidant property, the neurohormone has renowned regulatory roles in the control of circadian rhythm and exerts its physiological actions primarily by interacting with the G protein-coupled MT1 and MT2 transmembrane receptors. The two melatonin receptor subtypes display identical ligand binding characteristics and mediate a myriad of signaling pathways, including adenylyl cyclase inhibition, phospholipase C stimulation and the regulation of other effector molecules.

Angiotensin-[1-12] interacts with angiotensin type I receptors.

Angiotensin-(1-12) [Ang-(1-12)], a newer member of angiotensin peptides, is proposed to be converted enzymatically to angiotensin I (Ang I) and to angiotensin II (Ang II); the latter being the bioactive peptide. We studied the Ang-(1-12) and Ang II responses in COS-7 cells or CHO cells transfected with 5 μg AT1R by monitoring [Ca(2+)]i using the Fluo-4. Ang II (1 pM-1 μM) and Ang-(1-12) (5 pM-5 μM) increased [Ca(2+)]i with an EC50 of 0.

Development of substituted N-[3-(3-methoxylphenyl)propyl] amides as MT(2)-selective melatonin agonists: improving metabolic stability.

A series of novel and selective N-[3-(6-benzyloxy-3-methoxyphenyl)propyl] amides has recently been shown to possess sub-nanomolar range binding affinity to the type 2 melatonin receptor (MT(2)). Pharmacokinetics studies suggested that these compounds were subject to vigorous CYP450-mediated metabolism, resulting in a series of metabolites with significantly decreased or diminished binding affinities toward MT(2) receptor. The ether bonds were found to be the major positions susceptible to metabolism.

Characterization of substituted phenylpropylamides as highly selective agonists at the melatonin MT2 receptor.

Melatonin is a widely distributed hormone that regulates several major physiological processes, including the circadian rhythm and seasonal adaptation. The two subtypes of mammalian G protein-coupled melatonin receptors are primarily responsible for mediating the actions of melatonin. Because synthetic melatonin agonists have considerable therapeutic potentials in modulating insomnia and circadian- related sleep disorders, it is highly desirable to develop subtype-selective melatoninergic compounds.

Synthesis of substituted N-[3-(3-methoxyphenyl)propyl] amides as highly potent MT(2)-selective melatonin ligands.

A series of substituted N-[3-(3-methoxyphenyl)propyl] amides were synthesized and their binding affinities towards human melatonin MT(1) and MT(2) receptors were evaluated. It was discovered that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT(2) binding affinity and at the same time decreased MT(1) binding affinity.