Microcavity supported lipid bilayers; evaluation of drug- lipid membrane Interactions by electrochemical impedance and fluorescence correlation spectroscopy

Many drugs have intracellular or membrane-associated targets thus understanding their interaction with the cell membrane is of value in drug development. Cell-free tools used to predict membrane interactions should replicate the molecular organization of the membrane. Microcavity array supported lipid bilayer (MSLB) platform are versatile biophysical models of the cell membrane that combine liposome-like membrane fluidity with stability and addressability. We used an MSLB herein to interrogate drugmembrane interactions across seven drugs from different classes, including non-steroidal antiinflammatories; Ibuprofen (Ibu) and Diclofenac (Dic), antibiotics; Rifampicin (Rif), Levofloxacin (Levo) and Pefloxacin (Pef), and bisphosphonates; Alendronate (Ale) and Clodronate (Clo). Fluorescence lifetime correlation spectroscopy (FLCS) and electrochemical impedance spectroscopy (EIS) were used to evaluate the impact of drug on DOPC and binary bilayers over physiologically relevant drug concentrations. Whereas FLCS data revealed Ibu, Levo, Pef, Ale and Clo had no impact on lipid lateral mobility, EIS which is more sensitive to membrane structural change, indicated modest but significant decreases to membrane resistivity consistent with adsorption but weak penetration of drugs at the membrane. Ale and Clo, evaluated at pH 5.25, did not impact the impedance of the membrane except at concentrations exceeding 4mM. Conversely, Dic and Rif dramatically altered bilayer fluidity, suggesting their translocation through the bilayer and, EIS data, showed resistivity of the membrane decreased substantially with increasing drug concentration. Capacitance changes to the bilayer in most cases were insignificant. Using a Langmuir-Freundlich model to fit the EIS data, we propose Rsat as an empirical value that reflects permeation. Overall, the data indicate that Ibu, Levo, and Pef, adsorb at the interface of the lipid membrane but Dic and Rif interact strongly, permeating the membrane core modifying the water/ion permeability of the bilayer structure. These observations are discussed in the context of previously reported data on drug permeability and Log P

Development of low-dose protocols for thin-section CT assessment of cystic fibrosis in pediatric patients.

Purpose: To develop low-dose thin-section computed tomographic (CT) protocols for assessment of cystic fibrosis (CF) in pediatric patients and determine the clinical usefulness thereof compared with chest radiography. Materials and Methods: After institutional review board approval and informed consent from patients or guardians were obtained, 14 patients with CF and 11 patients without CF (16 male, nine female; mean age, 12.6 years ± 5.4 [standard deviation]; range, 3.5–25 years) who underwent imaging for clinical reasons underwent low-dose thin-section CT. Sections 1 mm thick (protocol A) were used in 10 patients, and sections 0.5 mm thick (protocol B) were used in 15 patients at six levels at 120 kVp and 30–50 mA. Image quality and diagnostic acceptability were scored qualitatively and quantitatively by two radiologists who also quantified disease severity at thin-section CT and chest radiography. Effective doses were calculated by using a CT dosimetry calculator. Results: Low-dose thin-section CT was performed with mean effective doses of 0.19 mSv ± 0.03 for protocol A and 0.14 mSv ± 0.04 for protocol B (P < .005). Diagnostic acceptability and depiction of bronchovascular structures at lung window settings were graded as almost excellent for both protocols, but protocol B was inferior to protocol A for mediastinal assessment (P < .02). Patients with CF had moderate lung disease with a mean Bhalla score of 9.2 ± 5.3 (range, 0–19), compared with that of patients without CF (1.1 ± 1.4; P < .001). There was excellent correlation between thin-section CT and chest radiography (r = 0.88–0.92; P < .001). Conclusion: Low-dose thin-section CT can be performed at lower effective doses than can standard CT, approaching those of chest radiography. Low-dose thin-section CT could be appropriate for evaluating bronchiectasis in pediatric patients, yielding appropriate information about lung parenchyma and bronchovascular structures

Cultural Heritage Destruction during the Islamic State's Genocide against the Yazidis

Discussions of the 2014 genocide committed by the Islámic Státe ágáinst the E zidî s (álso known ás 'Yázidis' or 'Yezidis') háve generálly focused on murder, slávery ánd sexuál exploitátion. In this páper we ánályze the destruction of E zidî tángible ánd intángible culturál heritáge ás á significánt fácet of the Islámic Státe's policy of ethnic cleánsing ánd genocide. Evidence of destruction is collected ánd presented in context with other criminál ácts. In internátionál discourse the destruction of culturál heritáge sites is most often pláced under the heáding of wár crime. Severál convictions by the ICTY ánd the conviction of Málián Islámist AlMáhdi by the ICC áre well-known. However, heritáge destruction máy álso be prosecuted ás the crime of persecution, á crime ágáinst humánity. Numerous indictments ánd convictions before internátionál courts áttest to the viábility of this ápproách. Finálly, ás per explicit cáseláw of the ICJ ánd ICTY, destruction of tángible heritáge álso serves ás evidence of the speciál intent to destroy á protected group under the crime of genocide. The E zidî áre án endogámous community át home in northern Iráq for whom fáith ánd ethnic belonging áre inextricábly linked. Belief in God ánd Táwu se Málek (the highest ángel), ánd reverence for Lálish ás the holiest pláce on eárth áre the defining feátures of the E zidî fáith. Historic ánd sácred pláces áre án essentiál párt of the E zidî identity ánd áre considered vitál to life by the locál populátion. The Islámic Státe máde no secret of its intention to erádicáte the E zidî community ánd commenced á policy of ethnic cleánsing ánd genocide on 3 August 2014. All victims were ábused ánd tortured. Mále E zidî s ábove the áge of 12 were killed. Femále E zidî s were ensláved ánd tráded in á complex ánd public network of sexuál slávery. Those who fled to Mount Sinjár were besieged in order to ensure deáth from stárvátion, thirst ánd the blázing sun. Báses of economic support, such ás olive groves ánd irrigátion wells, were systemáticálly destroyed ánd mány áreás of the E zidî homelánd were sown with lándmines ánd improvised explosive devices (IEDs) to prevent the populátion from returning. We provide originál reseárch, evidence ánd context on the destruction of E zidî tángible culturál heritáge in the Báhzáni/Báshiqá ánd Sinjár áreás of northern Iráq. We present sátellite imágery ánálysis conducted by the EAMENA project, dráwing on dátá provided by E zidî representátives. According to the Depártment of Yázidi Affáirs in the Ministry of Awqáf ánd Religious Affáirs in the Kurdistán Regionál Government 68 E zidî sites were destroyed by the Islámic Státe. We consider 16 sites in the Báhzáni/Báshiqá áreá ánd 8 in the Sinjár áreá to which áccess wás possible ánd which could be documented. We conclude thát the destruction of the culturál heritáge of the E zidî people constituted á wár crime, á crime ágáinst humánity (persecution) ánd compelling evidence of genocidál intent. We recommend the considerátion of culturál heritáge destruction in ány prosecution of átrocity crimes, especiálly the crime of genocide