Dominant-negative mutations potentiated by the HSF1-regulated proteostasis network.

Protein mutational landscapes are sculpted by the impacts of the resulting amino acid substitutions on the protein's stability and folding or aggregation kinetics. These properties can, in turn, be modulated by the composition and activities of the cellular proteostasis network. Heat shock factor 1 (HSF1) is the master regulator of the cytosolic and nuclear proteostasis networks, dynamically tuning the expression of cytosolic and nuclear chaperones and quality control factors to meet demand.

Characterising the genetic architecture of changes in adiposity during adulthood using electronic health records.

Obesity is a heritable disease, characterised by excess adiposity that is measured by body mass index (BMI). While over 1,000 genetic loci are associated with BMI, less is known about the genetic contribution to adiposity trajectories over adulthood. We derive adiposity-change phenotypes from 24.

Development of in silico models to predict viscosity and mouse clearance using a comprehensive analytical data set collected on 83 scaffold-consistent monoclonal antibodies.

Biologic drug discovery pipelines are designed to deliver protein therapeutics that have exquisite functional potency and selectivity while also manifesting biophysical characteristics suitable for manufacturing, storage, and convenient administration to patients. The ability to use computational methods to predict biophysical properties from protein sequence, potentially in combination with high throughput assays, could decrease timelines and increase the success rates for therapeutic developability engineering by eliminating lengthy and expensive cycles of recombinant protein production and testing. To support development of high-quality predictive models for antibody developability, we designed a sequence-diverse panel of 83 effector functionless IgG1 antibodies displaying a range of biophysical properties, produced and formulated each protein under standard platform conditions, and collected a comprehensive package of analytical data, including in vitro assays and in vivo mouse pharmacokinetics.

Contemporary advancements in the semi-synthesis of bioactive terpenoids and steroids.

Many natural products have intriguing biological properties that arise from their fascinating chemical structures. However, the intrinsic complexity of the structural skeleton and the reactive functional groups on natural products pose tremendous challenges to chemical syntheses. Semi-synthesis uses chemical compounds isolated from natural sources as the starting materials to produce other novel compounds with distinct chemical and medicinal properties.

One-Pot Tandem Access to Phenothiazine Derivatives from Acetanilide and 2-Bromothiophenol Rhodium-Catalyzed C-H Thiolation and Copper-Catalyzed C-N Amination.

A one-pot and step economic reaction involving Rh(III)-catalyzed C-H thiolation and relay Cu(II)-catalyzed C-N amination of acetanilide and 2-bromothiophenol is reported here, with several valuable phenothiazine products obtained. This synthesis protocol proceeds from easily starting materials, demonstrating high atom economy, broad substrate scope, and good yield. Furthermore, the directing group can be easily eliminated, and chlorpromazine is provided in a large scale; thus this synthesis protocol could be utilized to construct phenothiazine scaffolds.

Recent Advances in Metal-Catalyzed Heterocyclic C-P Bond Formation.

The phosphorus-containing heterocycles are an important class of compounds in organic chemistry. Because of their potential application in many fields, especially, the synthetic pesticides, medicine and catalyst, the phosphorus-containing heterocycles have attracted continuous attention from organic synthesis scientists. The development of efficient and low-cost catalytic systems is of great interest for the construction of heterocycles C-P bond.

Bacterial Communities Are More Sensitive to Water Addition Than Fungal Communities Due to Higher Soil K and Na in a Degraded Karst Ecosystem of Southwestern China.

Precipitation is predicted to become more intense in Southern China in the context of climate change; however, the responses of microbial communities to variations in soil moisture have not been well documented for karst areas. The climate is typically in a subtropical monsoon category with two different seasons: a dry season (December-May) and a wet season (June-November). Based on a randomized complete block design (RCBD), a water addition experiment (0, +20, +40, and +60% relative to local precipitation) was established in April 2017, with five replicates, in a degraded grass-shrub community.

Intrinsic Optical Properties of Boston Keratoprosthesis.

Purpose: To benchmark the optical performance of Boston Keratoprosthesis (B-KPro).

Methods: Back focal lengths (BFL) of B-KPros for various eye axial lengths were measured using an optical bench, International Organization for Standardization-certified for intraocular lens characterization, and compared against manufacturer's specification. The modulation transfer function (MTF) and the resolution efficiencies were measured.

Regio- and stereoselectivity in the CYP450-catalyzed hydroxylation of complex terpenoids: a QM/MM study.

The site-selective C-H oxidation of terpenoids by P450 attracts great attention because of their wide range of biological activities. However, the binding and catalytic mechanism of P450 for the hydroxylation of complex terpenoid substrates remains elusive, which has limited the rational engineering of P450 as a biocatalyst for terpenoid biosynthesis. Here, we studied the origin of the selectivity and reactivity of P450BM3 in the hydroxylation of terpenoids by combining molecular dynamics simulations and QM/MM calculations, using artemisinin as a model compound.

The ozone-water complex: CCSD(T)/CBS structures and anharmonic vibrational spectroscopy of O(HO), (n = 1 - 2).

Ozone-water complexes O(HO) (n = 1-2) have been studied using coupled cluster theory with triple excitations CCSD(T) with correlation consistent basis sets aug-cc-pVnZ (n = D, T, Q) and complete basis set (CBS) extrapolation techniques. We identified seven dimer (n = 1) and nine trimer species (n = 2) with open C and cyclic D ozone. Calculations at the CCSD(T)/CBS level of theory for C O(HO) on the counterpoise (CP)-corrected potential energy surface yield a dissociation energy of D = 2.

Clinical Characteristics of Coronavirus Disease 2019 in China.

Background: Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients.

Methods: We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death.

Ablative Chemoembolization for Hepatocellular Carcinoma: A Prospective Phase I Case-Control Comparison with Conventional Chemoembolization.

Purpose To evaluate the feasibility, safety, and treatment effectiveness of ablative chemoembolization (ACE) in the treatment of hepatocellular carcinoma (HCC) and compare with a similar patient cohort who underwent conventional transarterial chemoembolization (cTACE). Materials and Methods This was a prospective phase I nonrandomized study conducted between March 2013 and October 2016 in accordance to the Declaration of Helsinki and Declaration Good Clinical Practice with written informed consent. There were 36 men and eight women (median age, 64 years [interquartile range, 58-74] and 74.

Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer.

Background: Circulating cell-free Epstein-Barr virus (EBV) DNA is a biomarker for nasopharyngeal carcinoma. We conducted a prospective study to investigate whether EBV DNA in plasma samples would be useful to screen for early nasopharyngeal carcinoma in asymptomatic persons.

Methods: We analyzed EBV DNA in plasma specimens to screen participants who did not have symptoms of nasopharyngeal carcinoma.

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals.

Data Set for the Reporting of Carcinomas of the Cervix: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

A comprehensive pathologic report is essential for optimal patient management, cancer staging and prognostication. In many countries, proforma reports are used but the content of these is variable. The International Collaboration on Cancer Reporting is an alliance formed by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer and the European Society of Pathology, for the purpose of developing standardized, evidence-based reporting data sets for each cancer site.

High-sensitivity intravascular photoacoustic imaging of lipid-laden plaque with a collinear catheter design.

A highly sensitive catheter probe is critical to catheter-based intravascular photoacoustic imaging. Here, we present a photoacoustic catheter probe design on the basis of collinear alignment of the incident optical wave and the photoacoustically generated sound wave within a miniature catheter housing for the first time. Such collinear catheter design with an outer diameter of 1.

[Study on the Effects of Ginsenoside Rb1 on DPPC Bilayers by Using Thermo-Raman Spectrum and DSC].

The research on the interactions between Ginsenosides and biomembranes plays a crucial role in thorough understanding the pharmacological activity and biologyical effect of Chinese medicine Panax ginseng. With the bilayer structure, DPPC often serves as an simulation model of the cell membrane to study the role of drug molecules and cell membranes. Ginsenoside Rb1, one of the most important components of Panaxginseng, playing the significant roles of pharmacological effects and biological properties.

High-speed intravascular photoacoustic imaging at 1.7 μm with a KTP-based OPO.

Lipid deposition inside the arterial wall is a hallmark of plaque vulnerability. Based on overtone absorption of C-H bonds, intravascular photoacoustic (IVPA) catheter is a promising technology for quantifying the amount of lipid and its spatial distribution inside the arterial wall. Thus far, the clinical translation of IVPA technology is limited by its slow imaging speed due to lack of a high-pulse-energy high-repetition-rate laser source for lipid-specific first overtone excitation at 1.

Cross-Linking Poly(lactic acid) Film Surface by Neutral Hyperthermal Hydrogen Molecule Bombardment.

Constructing a dense cross-linking layer on a polymer film surface is a good way to improve the water resistance of poly(lactic acid) (PLA). However, conventional plasma treatments have failed to achieve the aim as a result of the unavoidable surface damage arising from the charged species caused by the uncontrolled high energy coming from colliding ions and electrons. In this work, we report a modified plasma method called hyperthermal hydrogen-induced cross-linking (HHIC) technology to construct a dense cross-linking layer on PLA film surfaces.

FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.

Background: Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive.

Methods: We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity.

Circulating fibroblast growth factor 21 levels predict progressive kidney disease in subjects with type 2 diabetes and normoalbuminuria.

Background: Elevated fibroblast growth factor 21 (FGF21) levels have been suggested, from cross-sectional studies, as an indicator of subclinical diabetic nephropathy. We investigated whether serum FGF21 was predictive of the development of diabetic nephropathy.

Method: Baseline serum FGF21 levels were measured in 1136 Chinese type 2 diabetic subjects recruited from the Hong Kong West Diabetes Registry.

Elevated circulating pigment epithelium-derived factor predicts the progression of diabetic nephropathy in patients with type 2 diabetes.

Context: Pigment epithelium-derived factor (PEDF), a circulating glycoprotein with antiangiogenic, antioxidative, and anti-inflammatory properties, protects against diabetic nephropathy (DN) in animal models.

Objective: We investigated whether circulating PEDF predicted the progression of DN in a 4-year prospective study.

Design, Setting, And Participants: Baseline plasma PEDF levels were measured in type 2 diabetic subjects recruited from the Hong Kong West Diabetes Registry.

Evaluation of carotid angioplasty and stenting for radiation-induced carotid stenosis.

Background And Purpose: We aimed to evaluate the procedural safety, clinical, and angiographic outcome of carotid angioplasty and stenting for high-grade (≥70%) radiation-induced carotid stenosis (RIS) using atherosclerotic stenosis (AS) as a control.

Methods: In this 6-year prospective nonrandomized study, we compared the carotid angioplasty and stenting outcome of 65 consecutive patients (84 vessels) with RIS with that of a control group of 129 consecutive patients (150 vessels) with AS. Study end points were 30-day periprocedural stroke or death, ipsilateral ischemic stroke, technical success, procedural characteristics, instent restenosis (ISR; ≥50%) and symptomatic ISR.

Unresectable hepatocellular carcinoma: randomized controlled trial of transarterial ethanol ablation versus transcatheter arterial chemoembolization.

Purpose: To compare effectiveness of transarterial ethanol ablation (TEA) and transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma and determine whether TEA leads to better overall survival and tumor response than TACE.

Materials And Methods: In this institutional review board-approved preregistered randomized controlled trial (n = 200), informed consent was obtained. Primary outcome was overall survival; secondary outcomes were time to progression (TTP), progression-free survival (PFS), tumor response at computed tomography, and treatment-related toxicity.