A novel predictive model for the anti-bacterial, anti-malarial and hERG cardiac QT prolongation properties of fluoroquinolones

Abbreviations FQs Fluoroquinolones, BBB Blood brain barrier, TdP Torsades de Pointes, GI gastrointestinal tract, IC 50 Half maximal Inhibitory concentration , MIC Minimum inhibitory concentrations, ZW zwitterion, steady state uptake (R ss), F blood plasma concentrations, CBP Chronic bacterial prostatis, BSA bovine serum albumin, MRP2 Multidrug resistance-associated protein 2 or specific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2), OATP organic anion uptake transporter, OCT organic cation influx transporter, ΔG desolvation free energy of water desolvation, ΔG lipophilicity free energy of lipophilicity or hydrophobicity, ΔG desolv,CDS free energy of water desolvation of the cavitation dispersion solvent structure (CDS), ΔG lipo,CDS free energy of lipophilicity or hydrophobicity for the CDS, DM dipole moment DM, SASA solvent accessible surface area, R 2 multiple correlation coefficient, F the F test of significance, SEE standards errors for the estimates, SE(ΔG desolvation) standard errors of ΔG desolvation , SE(ΔG lipophilicity), standard errors of ΔG lipophilicity , SE(Dipole Moment) standard errors for dipole moments, SE (Molecular Volume) standard errors for molecular volumes as calculated from " t " distribution statistics, QM quantum mechanics

Screening anti-colorectal cancer drugs: free radical chemotherapy

Abbreviations OS oxidative stress, ROS reactive oxygen species, CRC Colorectal cancer, ET electron transfer, ΔGdesolv,CDS free energy of water desolvation, ΔGlipo,CDS lipophilicity free energy, CDS cavity dispersion solvent structure of the first solvation shell, HOMO highest occupied molecular orbital, LUMO lowest unoccupied molecular orbital , R 2 multiple correlation coefficient, the F test of significance, SEE standards errors for the estimate, standard errors of the variables SE(ΔGdesolCDS), SE(ΔGlipoCDS), SE(Dipole Moment), SE (Molecular Volume), LD50 drug toxicity, ID90 drug concentration that produces 90% inhibition of cell growth Abstract It has been found that a free radical mechanism is involved in the cytotoxicity of most of a panel of 12 anti-colorectal cancer drugs tested against a panel of 9 colorectal cancer variants. The colorectal cancers Ht-29, LoVo and WiDr do not appear to involve free radical oxidative stress processes, although such processes may be too small to be detected or are kinetically slower than cell membrane or other drug-target interactions. The colorectal cancer variants 320, OM-1, 205 and SW-620 CRC show the strongest dependencies on free radical processes. The toxicity LD 50 of the tested anti-colorectal cancer drugs is linearly related to the HOMO-LUMO energy gap, and can be a useful theoretical screening tool for designing anti-colorectal cancer drugs

The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery

A multiparameter model of the diffusion, antiproliferative assays IC 50 and aerobic and hypoxic clonogenic assays for a wide range of neutral and radical anion forms of tirapazamine (TPZ) analogues has found that: (a) extravascular diffusion is governed by the desolvation, lipophilicity, dipole moment and molecular volume, similar to passive and facilitated permeation through the blood brain barrier and other cellular membranes, (b) hypoxic assay properties of the TPZ analogues show dependencies on the electron affinity, as well as lipophilicity and dipole moment and desolvation, similar to other biological processes involving permeation of cellular membranes, including nuclear membranes, (c) aerobic properties are dependent on the almost exclusively on the electron affinity, consistent with electron transfer involving free radicals being dominant with little or no drug permeation of membranes, and most likely occurring in the extracellular matrix. Application of the model to the DNA binding equilibrium constants of TPZ analogues with acridine or acridine-like moieties show that ligand water desolvation and lipophilicity are the dominant processes governing the DNA intercalation of TPZ analogues. This conclusion is consistent with DFT modelling of the complexes formed by TPZ analogues with neutral and N-protonated acridine moieties which intercalate with the guanine DNA nucleobases. A quantum mechanical study has shown that TPZ can form stable complexes with cucurbit[7]uril as a precursor to proof of principle of improved TPZ delivery to tumours. Abbreviations Tirapazamine TPZ, free energy of water desolvation ΔG desolv,CDS , lipophilicity free energy ΔG lipo,CDS , cavity dispersion solvent structure of the first solvation shell CDS, multicellular layers MCL, extracellular matrix ECM, diffusion through support membrane D s , diffusion through multicellular layer D MCL , cucurbit[n]urils CB, cucurbit[7]urils, CB[7], highest occupied molecular orbital HOMO, lowest unoccupied molecular orbital LUMO, density functional molecular orbital theory DFT, adiabatic electron affinity AEA, cisplatin CisPt, ratio aerobic property:hypoxic property HCR, aerobic aer, hypoxic hyp, DNA binding equilibrium constant K DNA, multiple correlation coefficient R 2 , the F test of significance, standards errors for the estimate (SEE) and standard errors of the variables SE(ΔG desolCDS), SE(ΔG lipoCDS), SE(Dipole Moment), SE (Molecular Volume), SE(AEA)

A drug based model to predict enhanced transdermal and blood brain barrier drug deliverability using ultrasonic methods

Abstract A previously described equation using the free energy of water desolvation (ΔG desolv,CDS), the lipophilicity free energy (ΔG lipo,CDS), dipole moment and molecular volume that describes the ability of drugs to cross the blood brain barrier and other cell membranes has been shown to apply to transdermal permeation when combined with ultrasound treatment. The dipole moment is particularly important when seeking to predict how drugs will interact with the transient pores in the cell membrane or blood brain barrier under ultrasound treatment. A quantum mechanical DFT analysis of the molecular interaction of mannitol and BCNU interacting with a surrogate membrane based on DPhPC has shown that the unexpected greater US induced permeability of mannitol compared to BCNU is due to differences in how the dipoles of mannitol and BCNU interact with the electric dipole potential of the lipid bilayers of the blood brain barrier, specifically by interacting with the phosphatidylcholine headgroup not the ester group. This result indicates that the design of therapeutic drugs to cross dermal and BBB membranes should consider whether such drugs can interact with the phosphatidylcholine headgroup of the membranes thereby possibly lowering the dipole potential of the lipid bilayer and hence enhancing drug permeation. The observed increase in electrical conductivity of the stratium corneum of the skin and blood brain barrier upon ultrasound treatment is an important factor which determines the transient permeabilization enhancement of drugs. It is likely that the dipole moment of permeating drugs may be a critically important factor that interacts with the membrane dipole potential of the stratium corneum of the skin and blood brain barrier upon ultrasound treatment. Transient pores are known to be involved when electrical fields are exerted on biological membranes, with conductance spikes occurring during the opening and closing of these transient pores. The opening and closing of lipidic pores also involve electrically invisible (silent) pre-pores

Modafinil mechanism of action: Inhibition of the dopamine monoamine transporter DAT by modafinil like and piperidine-based analogues and the role of free radicals in the eugeroic effect

A structure activity model which incorporates the desolvation, lipophilicity, dipole moment and molecular volume of a series of modafinil like analogues has been compared to a series of saturated heterocyclic analogues in their ability to inhibit the dopamine transporter (DAT). It has been found that hydrophilicity or lipophilicity has a larger inhibitory effect for the heterocyclic analogues than the modafinil like analogues, but the heterocyclic inhibitors show no dependence on dipole moment unlike the modafinil like analogues. The modafinil like analogues have a higher desolvation requirement than the heterocyclic analogues prior to binding with DAT as expected for the more polar structures. Evidence is presented that strongly implicates the involvement of free radical species in the eugeroic ability of modafinil like and 9-fluorene analogues via a dissociative electron attachment mechanism. This eugeroic ability is largely separate from a DAT inhibition mechanism

Is there gender bias in research grant success in social sciences?: Hong Kong as a case study

Despite growing attention to gender disparities in higher education, women in academia still receive less research funding and recognition. Previous research on this gender gap has focused on biomedical, science, technology, engineering, and mathematics in the West—relatively silent on social sciences and Asia. This study examined how well staff gender, submission rate, success rate, and amount per award could predict annual changes in the number and amount of grant funding for academic years 2015/2016–2020/2021 in the Faculty of Social Science at the University of Hong Kong, a leading institution in social sciences in Asia. Decomposition analysis revealed that, compared to men, women had higher submission rates, which significantly contributed to an increase in the number of awards for the University in recent years in two major funding mechanisms (namely, General Research Fund and Early Career Scheme), especially from 2019/2020 to 2020/2021. Women also outperformed men in the success rate in the Early Career Scheme (i.e., within the first three years of faculty appointment). Both submission rate and success rate contributed to changes in award number and the total amount for the University over time. Overall, women had a higher submission rate, successful rate, and amount per award than their male counterparts. We have identified good practices and distinctive contextual factors in Hong Kong that likely contribute to the lack of gender bias for research grant application results in Social Sciences

New Role for Cdc14 Phosphatase: Localization to Basal Bodies in the Oomycete Phytophthora and Its Evolutionary Coinheritance with Eukaryotic Flagella

Cdc14 protein phosphatases are well known for regulating the eukaryotic cell cycle, particularly during mitosis. Here we reveal a distinctly new role for Cdc14 based on studies of the microbial eukaryote Phytophthora infestans, the Irish potato famine agent. While Cdc14 is transcribed constitutively in yeast and animal cells, the P. infestans ortholog is expressed exclusively in spore stages of the life cycle and not in vegetative hyphae where the bulk of mitosis takes place. PiCdc14 expression is first detected in nuclei at sporulation, and during zoospore formation the protein accumulates at the basal body, which is the site from which flagella develop. The association of PiCdc14 with basal bodies was supported by co-localization studies with the DIP13 basal body protein and flagellar β-tubulin, and by demonstrating the enrichment of PiCdc14 in purified flagella-basal body complexes. Overexpressing PiCdc14 did not cause defects in growth or mitosis in hyphae, but interfered with cytoplasmic partitioning during zoosporogenesis. This cytokinetic defect might relate to its ability to bind microtubules, which was shown using an in vitro cosedimentation assay. The use of gene silencing to reveal the precise function of PiCdc14 in flagella is not possible since we showed previously that silencing prevents the formation of the precursor stage, sporangia. Nevertheless, the association of Cdc14 with flagella and basal bodies is consistent with their phylogenetic distribution in eukaryotes, as species that lack the ability to produce flagella generally also lack Cdc14. An ancestral role of Cdc14 in the flagellar stage of eukaryotes is thereby proposed

Prevalence and Risk Factors of Human Papillomavirus (HPV) Infection in Southern Chinese Women – A Population-Based Study

Background: Persistent high-risk type Human papillomavirus (HPV) infection is recognized as a necessary cause of cervical cancer. This study aimed to compare the HPV prevalence and risk factors between women residing in Hong Kong (HK) and Guangzhou (GZ) region of China. Methodology/Principal Findings: A total of 1,570 and 1,369 women were recruited from HK and GZ, respectively. The cytology samples were collected and tested for HPV infection. The overall and type-specific HPV prevalence and the potential risk factors for acquisition of HPV infection were studied. Women with normal cytology in the GZ cohort had significantly higher HPV prevalence (10%) than those in the HK cohort (6.2%, p<0.001). The patterns of the age-specific HPV prevalence were also different between the two cohorts. In the HK cohort, women at the age of 20-29 years old had the highest prevalence and a second peak was observed in the age of ≥60 years old. In the GZ cohort, the highest HPV prevalence was also observed in 20-29 years old but declined as the age increased and a second peak was not seen. HPV16 and HPV52 were the most common high-risk types found in the HK and GZ cohorts, respectively. Age was the most consistently observed independent risk factor for HPV infection in the HK, while the number of sexual partners had association in the GZ cohort. Conclusions/Significance: Our study provides the current status and the epidemiological characteristics of HPV prevalence in Southern Chinese women. The results strongly suggested that population education and the effective cervical cancer screening would be vital in the prevention of cervical cancer. © 2011 Liu et al.published_or_final_versio