973 research outputs found
Performance-based regulation and its applications
2002-2003 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe
Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds
Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets
Clinical and virological factors associated with viremia in pandemic influenza A/H1N1/2009 virus infection
BACKGROUND: Positive detection of viral RNA in blood and other non-respiratory specimens occurs in severe human influenza A/H5N1 viral infection but is not known to occur commonly in seasonal human influenza infection. Recently, viral RNA was detected in the blood of patients suffering from severe pandemic influenza A/H1N1/2009 viral infection, although the significance of viremia had not been previously studied. Our study aims to explore the clinical and virological factors associated with pandemic influenza A/H1N1/2009 viremia and to determine its clinical significance. METHODOLOGY/PRINCIPAL FINDINGS: Clinical data of patients admitted to hospitals in Hong Kong between May 2009 and April 2010 and tested positive for pandemic influenza A/H1N1/2009 was collected. Viral RNA was detected by reverse-transcription polymerase chain reactions (RT-PCR) targeting the matrix (M) and HA genes of pandemic influenza A/H1N1/2009 virus from the following specimens: nasopharyngeal aspirate (NPA), endotracheal aspirate (ETA), blood, stool and rectal swab. Stool and/ or rectal swab was obtained only if the patient complained of any gastrointestinal symptoms. A total of 139 patients were included in the study, with viral RNA being detected in the blood of 14 patients by RT-PCR. The occurrence of viremia was strongly associated with a severe clinical presentation and a higher mortality rate, although the latter association was not statistically significant. D222G/N quasispecies were observed in 90% of the blood samples. CONCLUSION: Presence of pandemic influenza A/H1N1/2009 viremia is an indicator of disease severity and strongly associated with D222G/N mutation in the viral hemagglutinin protein.published_or_final_versio
Dehydroepiandrosterone (DHEA) supplementation improves in vitro fertilization outcomes of poor ovarian responders, especially in women with low serum concentration of DHEA-S: a retrospective cohort study
Background: Dehydroepiandrosterone (DHEA) is now widely used as an adjuvant for in vitro fertilization (IVF)
cycles in poor ovarian responders (PORs). Several studies showed that DHEA supplementation could improve IVF
outcomes of PORs. However, most of the PORs do not respond to DHEA clinically. Therefore, the aim of this study
is to confirm the beneficial effects of DHEA on IVF outcomes of PORs and to investigate which subgroups of PORs
can best benefit from DHEA supplementation.
Methods: This retrospective cohort study was performed between January 2015 and December 2017. A total of
151 PORs who fulfilled the Bologna criteria and underwent IVF cycles with the gonadotropin-releasing hormone
antagonist protocol were identified. The study group (n = 67) received 90 mg of DHEA daily for an average of
3 months before the IVF cycles. The control group (n = 84) underwent the IVF cycles without DHEA pretreatment.
The basic and cycle characteristics and IVF outcomes between the two groups were compared using independent
t-tests, Chi-Square tests and binary logistic regression.
Results: The study and control groups did not show significant differences in terms of basic characteristics. The study
group demonstrated a significantly greater number of retrieved oocytes, metaphase II oocytes, fertilized oocytes, day 3
embryos and top-quality embryos at day 3 and a higher clinical pregnancy rate, ongoing pregnancy rate and live birth
rate than those measures in the control group. The multivariate analysis revealed that DHEA supplementation was
positively associated with clinical pregnancy rate (OR = 4.93, 95% CI 1.68–14.43, p = 0.004). Additionally, in the study
group, the multivariate analysis showed that serum dehydroepiandrosterone-sulfate (DHEA-S) levels < 180 μg/dl were
significantly associated with a rate of retrieved oocytes > 3 (OR = 5.92, 95% CI 1.48–23.26, p = 0.012).
Conclusions: DHEA supplementation improves IVF outcomes of PORs. In PORs with DHEA pretreatment, women with
lower DHEA-S level may have greater possibility of attaining more than 3 oocytes
Neutralisation of SARS-CoV-2 by monoclonal antibody through dual targeting powder formulation
Neutralising monoclonal antibody (mAb) is an important weapon in our arsenal for combating respiratory viral infections. However, the effectiveness of neutralising mAb has been impeded by the rapid emergence of mutant variants. Early administration of broad-spectrum mAb with improved delivery efficiency can potentially enhance efficacy and patient outcomes. WKS13 is a humanised mAb which was previously demonstrated to exhibit broad-spectrum activity against SARS-CoV-2 variants. In this study, a dual targeting formulation strategy was designed to deliver WKS13 to both the nasal cavity and lower airways, the two critical sites of infection caused by SARS-CoV-2. Dry powders of WKS13 were first prepared by spray drying, with cyclodextrin used as stabiliser excipient. Two-fluid nozzle (TFN) was used to produce particles below 5 μm for lung deposition (C-TFN formulation) and ultrasonic nozzle (USN) was used to produce particles above 10 μm for nasal deposition (C-USN formulation). Gel electrophoresis and size exclusion chromatography studies showed that the structural integrity of mAb was successfully preserved with no sign of aggregation after spray drying. To achieve dual targeting property, C-TFN and C-USN were mixed at various ratios. The aerosolisation property of the mixed formulations dispersed from a nasal powder device was examined using a Next Generation Impactor (NGI) coupled with a glass expansion chamber. When the ratio of C-TFN in the mixed formulation increased, the fraction of particles deposited in the lung increased proportionally while the fraction of particles deposited in the nasal cavity decreased correspondingly. A customisable aerosol deposition profile could therefore be achieved by manipulating the mixing ratio between C-TFN and C-USN. Dual administration of C-TFN and C-USN powders to the lung and nasal cavity of hamsters, respectively, was effective in offering prophylactic protection against SARS-CoV-2 Delta variant. Viral loads in both the lung tissues and nasal wash were significantly reduced, and the efficacy was comparable to systemic administration of unformulated WKS13. Overall, dual targeting powder formulation of neutralising mAb is a promising approach for prophylaxis of respiratory viral infections. The ease and non-invasive administration of dual targeting nasal powder may facilitate the widespread distribution of neutralising mAb during the early stage of unpredictable outbreaks
Robust Detection of Hierarchical Communities from Escherichia coli Gene Expression Data
Determining the functional structure of biological networks is a central goal
of systems biology. One approach is to analyze gene expression data to infer a
network of gene interactions on the basis of their correlated responses to
environmental and genetic perturbations. The inferred network can then be
analyzed to identify functional communities. However, commonly used algorithms
can yield unreliable results due to experimental noise, algorithmic
stochasticity, and the influence of arbitrarily chosen parameter values.
Furthermore, the results obtained typically provide only a simplistic view of
the network partitioned into disjoint communities and provide no information of
the relationship between communities. Here, we present methods to robustly
detect coregulated and functionally enriched gene communities and demonstrate
their application and validity for Escherichia coli gene expression data.
Applying a recently developed community detection algorithm to the network of
interactions identified with the context likelihood of relatedness (CLR)
method, we show that a hierarchy of network communities can be identified.
These communities significantly enrich for gene ontology (GO) terms, consistent
with them representing biologically meaningful groups. Further, analysis of the
most significantly enriched communities identified several candidate new
regulatory interactions. The robustness of our methods is demonstrated by
showing that a core set of functional communities is reliably found when
artificial noise, modeling experimental noise, is added to the data. We find
that noise mainly acts conservatively, increasing the relatedness required for
a network link to be reliably assigned and decreasing the size of the core
communities, rather than causing association of genes into new communities.Comment: Due to appear in PLoS Computational Biology. Supplementary Figure S1
was not uploaded but is available by contacting the author. 27 pages, 5
figures, 15 supplementary file
Combination of the novel histone deacetylase inhibitor YCW1 and radiation induces autophagic cell death through the downregulation of BNIP3 in triple-negative breast cancer cells in vitro and in an orthotopic mouse model
Arsenic Trioxide Enhances the Radiation Sensitivity of Androgen-Dependent and -Independent Human Prostate Cancer Cells
Prostate cancer is the most common malignancy in men. In the present study, LNCaP (androgen-sensitive human prostate cancer cells) and PC-3 cells (androgen-independent human prostate cancer cells) were used to investigate the anti-cancer effects of ionizing radiation (IR) combined with arsenic trioxide (ATO) and to determine the underlying mechanisms in vitro and in vivo. We found that IR combined with ATO increases the therapeutic efficacy compared to individual treatments in LNCaP and PC-3 human prostate cancer cells. In addition, combined treatment showed enhanced reactive oxygen species (ROS) generation compared to treatment with ATO or IR alone in PC-3 cells. Combined treatment induced autophagy and apoptosis in LNCaP cells, and mainly induced autophagy in PC-3 cells. The cell death that was induced by the combined treatment was primarily the result of inhibition of the Akt/mTOR signaling pathways. Furthermore, we found that the combined treatment of cells pre-treated with 3-MA resulted in a significant change in AO-positive cells and cytotoxicity. In an in vivo study, the combination treatment had anti-tumor growth effects. These novel findings suggest that combined treatment is a potential therapeutic strategy not only for androgen-dependent prostate cancer but also for androgen-independent prostate cancer
Dehydration of emulsified lubricating oil by three fields: swirl centrifugal field, pulse electric field and vacuum temperature field
6-Shogaol Induces Apoptosis in Human Hepatocellular Carcinoma Cells and Exhibits Anti-Tumor Activity In Vivo through Endoplasmic Reticulum Stress
6-Shogaol is an active compound isolated from Ginger (Zingiber officinale Rosc). In this work, we demonstrated that 6-shogaol induces apoptosis in human hepatocellular carcinoma cells in relation to caspase activation and endoplasmic reticulum (ER) stress signaling. Proteomic analysis revealed that ER stress was accompanied by 6-shogaol-induced apoptosis in hepatocellular carcinoma cells. 6-shogaol affected the ER stress signaling by regulating unfolded protein response (UPR) sensor PERK and its downstream target eIF2α. However, the effect on the other two UPR sensors IRE1 and ATF6 was not obvious. In prolonged ER stress, 6-shogaol inhibited the phosphorylation of eIF2α and triggered apoptosis in SMMC-7721 cells. Salubrinal, an activator of the PERK/eIF2α pathway, strikingly enhanced the phosphorylation of eIF2α in SMMC-7721 cells with no toxicity. However, combined treatment with 6-shogaol and salubrinal resulted in significantly increase of apoptosis and dephosphorylation of eIF2α. Overexpression of eIF2α prevented 6-shogaol-mediated apoptosis in SMMC-7721 cells, whereas inhibition of eIF2α by small interfering RNA markedly enhanced 6-shogaol-mediated cell death. Furthermore, 6-shogaol-mediated inhibition of tumor growth of mouse SMMC-7721 xenograft was associated with induction of apoptosis, activation of caspase-3, and inactivation of eIF2α. Altogether our results indicate that the PERK/eIF2α pathway plays an important role in 6-shogaol-mediated ER stress and apoptosis in SMMC-7721 cells in vitro and in vivo
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