3-(5-Nitrofuran-2-yl)prop-2-en-1-one Derivatives, with Potent Antituberculosis Activity, Inhibit A Novel Therapeutic Target, Arylamine N-acetyltransferase, in Mycobacteria.

In this study, the inhibitory potential of 3-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives was evaluated against a panel of bacteria, as well as mammalian cell lines to determine their therapeutic index. In addition, we investigated the mechanism of antibiotic action of the derivatives to identify their therapeutic target. We discovered compound 2 to be an extremely potent inhibitor of Mycobacterium tuberculosis H37Rv growth (MIC: 0.031 mg/L) in vitro, performing better than the currently used first-line antituberculosis drugs such as isoniazid, rifampicin, ethambutol, and pretomanid in vitro. Furthermore, compound 3 was equipotent to pretomanid against a multidrug-resistant M. tuberculosis clinical isolate. The derivatives were selective and bactericidal towards slow-growing mycobacteria. They showed low cytotoxicity towards murine RAW 264.7 and human THP-1 cell lines, with high selectivity indices. Compound 1 effectively eliminated the intracellular mycobacteria in a mycobacteria-infected macrophage model. The derivatives were assessed for their potential to inhibit mycobacterial arylamine N-acetyltransferase (NAT) and were identified as good inhibitors of recombinant mycobacterial NAT, a novel target essential for the intracellular survival of M. tuberculosis. This study provided hits for designing new potent and selective antituberculosis leads, having mycobacterial NAT inhibition as their possible endogenous mechanisms of action

Genomic analysis of the origins of extant casein variation in goats

The variation in the casein genes has a major impact on the milk composition of goats. Even though many casein polymorphisms have been identified so far, we do not know yet whether they are evolutionarily ancient (i.e., they existed before domestication) or young (i.e., they emerged after domestication). Herewith, we identified casein polymorphisms in a data set of 106 caprine whole-genome sequences corresponding to bezoars (Capra aegagrus, the ancestor of domestic goats) and 4 domestic goat (Capra hircus) populations from Europe, Africa, the Far East, and the Near East. Domestic and wild goat populations shared a substantial number of casein SNP, from 36.1% (CSN2) to 55.1% (CSN1S2). The comparison of casein variation among bezoars and the 4 domestic goat populations demonstrated that more than 50% of the casein SNP are shared by 2 or more populations, and 18 to 44% are shared by all populations. Moreover, the majority of casein alleles reported in domestic goats also segregate in the bezoar, including several alleles displaying significant associations with milk composition (e.g., the A/B alleles of the CSN1S1 and CSN3 genes, the A allele of the CSN2 gene). We conclude that much of the current diversity of the caprine casein genes comes from ancient standing variation segregating in the ancestor of modern domestic goats

Cross validation of bi-modal health-related stress assessment

This study explores the feasibility of objective and ubiquitous stress assessment. 25 post-traumatic stress disorder patients participated in a controlled storytelling (ST) study and an ecologically valid reliving (RL) study. The two studies were meant to represent an early and a late therapy session, and each consisted of a "happy" and a "stress triggering" part. Two instruments were chosen to assess the stress level of the patients at various point in time during therapy: (i) speech, used as an objective and ubiquitous stress indicator and (ii) the subjective unit of distress (SUD), a clinically validated Likert scale. In total, 13 statistical parameters were derived from each of five speech features: amplitude, zero-crossings, power, high-frequency power, and pitch. To model the emotional state of the patients, 28 parameters were selected from this set by means of a linear regression model and, subsequently, compressed into 11 principal components. The SUD and speech model were cross-validated, using 3 machine learning algorithms. Between 90% (2 SUD levels) and 39% (10 SUD levels) correct classification was achieved. The two sessions could be discriminated in 89% (for ST) and 77% (for RL) of the cases. This report fills a gap between laboratory and clinical studies, and its results emphasize the usefulness of Computer Aided Diagnostics (CAD) for mental health care

Gender and gaze gesture recognition for human-computer interaction

© 2016 Elsevier Inc. The identification of visual cues in facial images has been widely explored in the broad area of computer vision. However theoretical analyses are often not transformed into widespread assistive Human-Computer Interaction (HCI) systems, due to factors such as inconsistent robustness, low efficiency, large computational expense or strong dependence on complex hardware. We present a novel gender recognition algorithm, a modular eye centre localisation approach and a gaze gesture recognition method, aiming to escalate the intelligence, adaptability and interactivity of HCI systems by combining demographic data (gender) and behavioural data (gaze) to enable development of a range of real-world assistive-technology applications. The gender recognition algorithm utilises Fisher Vectors as facial features which are encoded from low-level local features in facial images. We experimented with four types of low-level features: greyscale values, Local Binary Patterns (LBP), LBP histograms and Scale Invariant Feature Transform (SIFT). The corresponding Fisher Vectors were classified using a linear Support Vector Machine. The algorithm has been tested on the FERET database, the LFW database and the FRGCv2 database, yielding 97.7%, 92.5% and 96.7% accuracy respectively. The eye centre localisation algorithm has a modular approach, following a coarse-to-fine, global-to-regional scheme and utilising isophote and gradient features. A Selective Oriented Gradient filter has been specifically designed to detect and remove strong gradients from eyebrows, eye corners and self-shadows (which sabotage most eye centre localisation methods). The trajectories of the eye centres are then defined as gaze gestures for active HCI. The eye centre localisation algorithm has been compared with 10 other state-of-the-art algorithms with similar functionality and has outperformed them in terms of accuracy while maintaining excellent real-time performance. The above methods have been employed for development of a data recovery system that can be employed for implementation of advanced assistive technology tools. The high accuracy, reliability and real-time performance achieved for attention monitoring, gaze gesture control and recovery of demographic data, can enable the advanced human-robot interaction that is needed for developing systems that can provide assistance with everyday actions, thereby improving the quality of life for the elderly and/or disabled

Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line

© 2018 The Author(s). Background: Disulfiram (DS), an antialcoholism medicine, demonstrated strong anticancer activity in the laboratory but did not show promising results in clinical trials. The anticancer activity of DS is copper dependent. The reaction of DS and copper generates reactive oxygen species (ROS). After oral administration in the clinic, DS is enriched and quickly metabolised in the liver. The associated change of chemical structure may make the metabolites of DS lose its copper-chelating ability and disable their anticancer activity. The anticancer chemical structure of DS is still largely unknown. Elucidation of the relationship between the key chemical structure of DS and its anticancer activity will enable us to modify DS and speed its translation into cancer therapeutics. Methods: The cytotoxicity, extracellular ROS activity, apoptotic effect of DS, DDC and their analogues on cancer cells and cancer stem cells were examined in vitro by MTT assay, western blot, extracellular ROS assay and sphere-reforming assay. Results: Intact thiol groups are essential for the in vitro cytotoxicity of DS. S-methylated diethyldithiocarbamate (S-Me-DDC), one of the major metabolites of DS in liver, completely lost its in vitro anticancer activity. In vitro cytotoxicity of DS was also abolished when its thiuram structure was destroyed. In contrast, modification of the ethyl groups in DS had no significant influence on its anticancer activity. Conclusions: The thiol groups and thiuram structure are indispensable for the anticancer activity of DS. The liver enrichment and metabolism may be the major obstruction for application of DS in cancer treatment. A delivery system to protect the thiol groups and development of novel soluble copper-DDC compound may pave the path for translation of DS into cancer therapeutics.This work was supported by grant from British Lung Foundation (RG14–8) and Innovate UK (104022).Published versio

Titration of betaine therapy to optimize therapy in an infant with 5,10-methylenetetrahydrofolate reductase deficiency

PubMed ID: 19434424Betaine therapy was given for 2 years to a 2- year-old boy with 5,10-methylenetetrahydrofolate reductase deficiency. Used as a methyl donor to lower homocysteine levels through methylation of methionine, betaine has been reported to be effective in treating homocystinuria. Satisfactory biochemical and clinical responses were obtained with the following regimen: betaine started in the newborn period at increasing doses to reach 1 g given six times a day. It is suggested that frequent administration of a moderate dose may provide clinical and biochemical benefit. © Springer-Verlag 2009

An Ontological Approach to Inform HMI Designs for Minimizing Driver Distractions with ADAS

ADAS (Advanced Driver Assistance Systems) are in-vehicle systems designed to enhance driving safety and efficiency as well as comfort for drivers in the driving process. Recent studies have noticed that when Human Machine Interface (HMI) is not designed properly, an ADAS can cause distraction which would affect its usage and even lead to safety issues. Current understanding of these issues is limited to the context-dependent nature of such systems. This paper reports the development of a holistic conceptualisation of how drivers interact with ADAS and how such interaction could lead to potential distraction. This is done taking an ontological approach to contextualise the potential distraction, driving tasks and user interactions centred on the use of ADAS. Example scenarios are also given to demonstrate how the developed ontology can be used to deduce rules for identifying distraction from ADAS and informing future designs

MKS3/TMEM67 mutations are a major cause of COACH syndrome, a joubert syndrome related disorder with liver involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/ aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs