CeO2-dolomite as fire retardant additives on the conventional intumescent coating in steel substrate for improved performance

Multiple combinations of CeO2-Dolomite as fillers and Intumescent Flame Retardant (IFR) ingredients were used to optimize the intumescent coatings designed for I-beam steel substrates. The influenced of fillers and various combinations of flame-retardants on the fire protective performance of the coatings were evaluated using vertical Bunsen burner fire test and various characterization techniques. Formula C and Formula F having 1:1 and 2:2 CeO2-Dolomite ratio, obtained the lowest substrate temperature around 150oC and 150.4oC, respectively after 90 minutes fire exposure. Also, the morphological structures of intumescent char observed by SEM-EDX, demonstrated that Formula C and Formula F stimulated the formation of homogeneous and more compacted surface structure. X-ray photoelectron spectroscopy (XPS) provide the binding energies of C and O constituents, it was observed that [-(C2H4)n-] was the most important free radical as it could promote the formation of aromatic carbon chain in the char surface. Finally, the findings of this study revealed that the selection of appropriate fillers and combinations of flame-retardant ingredients significantly influenced the morphological structure of the char layer, of which, Formula C and Formula F produced a char with higher thermal stability, resulting to a more fire resistive IFR coating during fire exposure

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations

Purpose: To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects. Patients and methods: In total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers. The primary objective of this single-arm Phase II trial was a progression-free survival rate at 6 months (PFS6). Post hoc exploratory analyses were conducted on archival tumour tissue and serial bloods. Results: The PFS6 rate was 35% and 38% with durable objective tumour responses (OTR) in 3(19%) and 3(9%) in groups 1 and 2, respectively. Rare cancers achieving an OTR included cholangiocarcinoma, perivascular epithelioid cell (PEComa), neuroendocrine, gallbladder and endometrial cancer. O + D was safe, with five serious adverse events related to the study drug(s) in 3 (6%) patients. A higher proportion of CD38 high B cells in the blood and higher CD40 expression in tumour was prognostic of survival. Conclusions: O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Structural analysis and engineering of protein-protein interfaces in natural product biosynthetic pathways

Carrier protein (CP) dependent biosynthetic pathways are attractive targets for biosynthetic pathway engineering due to their modular architecture and the therapeutic relevance of their natural products. These pathways, which include the fatty acid synthase (FAS), polyketide synthase (PKS), and non-ribosomal peptide synthetase (NRPS), have been targeted for engineering through substitution of modules, domains and subdomains. This method, termed combinatorial biosynthesis, has been met with limited success due to the lack of proper protein-protein interactions between noncognate proteins. With catalysis mediated by specific protein-protein interactions between the carrier protein and its partner enzymes, enzymology and control remain fertile ground for discovery. Here, I investigate the biomolecular recognition between the peptidyl carrier protein (PCP) and adenylation (A) domains of type II NRPS systems as my first step in engineering these synthases. The first chapter provides a recent review of the structural biology of transient NRPS PCP and partner protein complexes to identify the specific modes of PCP recognition in the type I and type II NRPS. The second and third chapter presents a thorough structural analysis of the PCP-A domain protein-protein interface from prodigiosin and pyoluteorin biosynthesis. The PCP-A domain complexes were stabilized using a mechanism-based inhibitor, which afforded crystallization and successful structure determination of two cognate and one noncognate PCP-A domain complexes. This high-resolution information was integrated with previous NMR titration data, MD simulations, and mutagenesis studies to reveal PCP dynamics and specific protein-protein interactions that govern PCP-A domain complex formation. The fourth chapter involves application of the previously solved PCP-A domain structures towards a development of a computational protein-protein interface design protocol to create a hybrid natural product pathway. The first PCP-A domain structure solved in this work was used towards computational design of a new interface between the acyl-carrier protein (ACP) from Escherichia coli fatty acid biosynthesis. The optimized computational design protocol was able to improve noncognate A domain activity by ~1600 fold through the manipulation of electrostatic interactions to create a new protein-protein interface. Through these chapters, I have proven that the coupling of biophysical data to computational methodologies can be the next platform towards re-engineering of carrier-protein dependent pathways to create novel natural products

Effects of Hong Kong International Airport: An Evaluation of the Perceived Impacts in Tung Chung

A third runway expansion is being considered at Hong Kong International Airport (HKIA). While some public consultation has taken place, no studies have focused on Tung Chung, the community closest to HKIA. The goal of this study was to explore whether socioeconomic factors of Tung Chung residents affected their perceptions of impacts associated with HKIA and its proposed expansion. We administered a survey to 200 residents of Tung Chung to measure their perceptions of health, environmental, and social impacts from the airport and their opinions about the possible expansion and its effects. Many survey respondents support the third runway despite expectations of negative impacts on air and noise pollution and their personal health

Essential Role of Loop Dynamics in Type II NRPS Biomolecular Recognition.

Non-ribosomal peptides play a critical role in the clinic as therapeutic agents. To access more chemically diverse therapeutics, non-ribosomal peptide synthetases (NRPSs) have been targeted for engineering through combinatorial biosynthesis; however, this has been met with limited success in part due to the lack of proper protein-protein interactions between non-cognate proteins. Herein, we report our use of chemical biology to enable X-ray crystallography, molecular dynamics (MD) simulations, and biochemical studies to elucidate binding specificities between peptidyl carrier proteins (PCPs) and adenylation (A) domains. Specifically, we determined X-ray crystal structures of a type II PCP crosslinked to its cognate A domain, PigG and PigI, and of PigG crosslinked to a non-cognate PigI homologue, PltF. The crosslinked PCP-A domain structures possess large protein-protein interfaces that predominantly feature hydrophobic interactions, with specific electrostatic interactions that orient the substrate for active site delivery. MD simulations of the PCP-A domain complexes and unbound PCP structures provide a dynamical evaluation of the transient interactions formed at PCP-A domain interfaces, which confirm the previously hypothesized role of a PCP loop as a crucial recognition element. Finally, we demonstrate that the interfacial interactions at the PCP loop 1 region can be modified to control PCP binding specificity through gain-of-function mutations. This work suggests that loop conformational preferences and dynamism account for improved shape complementary in the PCP-A domain interactions. Ultimately, these studies show how crystallographic, biochemical, and computational methods can be used to rationally re-engineer NRPSs for non-cognate interactions

Dynamic visualization of type II peptidyl carrier protein recognition in pyoluteorin biosynthesis.

Using a covalent chemical probe and X-ray crystallography coupled to nuclear magnetic resonance data, we elucidated the dynamic molecular basis of protein recognition between the carrier protein and adenylation domain in pyoluteorin biosynthesis. These findings reveal a unique binding mode, which contrasts previously solved carrier protein and partner protein interfaces

Dynamic visualization of type II peptidyl carrier protein recognition in pyoluteorin biosynthesis.

Using a covalent chemical probe and X-ray crystallography coupled to nuclear magnetic resonance data, we elucidated the dynamic molecular basis of protein recognition between the carrier protein and adenylation domain in pyoluteorin biosynthesis. These findings reveal a unique binding mode, which contrasts previously solved carrier protein and partner protein interfaces

CeO

Multiple combinations of CeO2-Dolomite as fillers and Intumescent Flame Retardant (IFR) ingredients were used to optimize the intumescent coatings designed for I-beam steel substrates. The influenced of fillers and various combinations of flame-retardants on the fire protective performance of the coatings were evaluated using vertical Bunsen burner fire test and various characterization techniques. Formula C and Formula F having 1:1 and 2:2 CeO2-Dolomite ratio, obtained the lowest substrate temperature around 150oC and 150.4oC, respectively after 90 minutes fire exposure. Also, the morphological structures of intumescent char observed by SEM-EDX, demonstrated that Formula C and Formula F stimulated the formation of homogeneous and more compacted surface structure. X-ray photoelectron spectroscopy (XPS) provide the binding energies of C and O constituents, it was observed that [-(C2H4)n-] was the most important free radical as it could promote the formation of aromatic carbon chain in the char surface. Finally, the findings of this study revealed that the selection of appropriate fillers and combinations of flame-retardant ingredients significantly influenced the morphological structure of the char layer, of which, Formula C and Formula F produced a char with higher thermal stability, resulting to a more fire resistive IFR coating during fire exposure