Gliotoxin and related metabolites as zinc chelators: implications and exploitation to overcome antimicrobial resistance

Antimicrobial resistance (AMR) is a major global problem and threat to humanity. The search for new antibiotics is directed towards targeting of novel microbial systems and enzymes, as well as augmenting the activity of pre-existing antimicrobials. Sulphur-containing metabolites (e.g., auranofin and bacterial dithiolopyrrolones [e.g., holomycin]) and Zn2+-chelating ionophores (PBT2) have emerged as important antimicrobial classes. The sulphur-containing, non-ribosomal peptide gliotoxin, biosynthesised by Aspergillus fumigatus and other fungi exhibits potent antimicrobial activity, especially in the dithiol form (dithiol gliotoxin; DTG). Specifically, it has been revealed that deletion of the enzymes gliotoxin oxidoreductase GliT, bis-thiomethyltransferase GtmA or the transporter GliA dramatically sensitise A. fumigatus to gliotoxin presence. Indeed, the double deletion strain A. fumigatus ΔgliTΔgtmA is especially sensitive to gliotoxin-mediated growth inhibition, which can be reversed by Zn2+ presence. Moreover, DTG is a Zn2+ chelator which can eject zinc from enzymes and inhibit activity. Although multiple studies have demonstrated the potent antibacterial effect of gliotoxin, no mechanistic details are available. Interestingly, reduced holomycin can inhibit metallo-β-lactamases. Since holomycin and gliotoxin can chelate Zn2+, resulting in metalloenzyme inhibition, we propose that this metal-chelating characteristic of these metabolites requires immediate investigation to identify new antibacterial drug targets or to augment the activity of existing antimicrobials. Given that (i) gliotoxin has been shown in vitro to significantly enhance vancomycin activity against Staphylococcus aureus, and (ii) that it has been independently proposed as an ideal probe to dissect the central 'Integrator' role of Zn2+ in bacteria - we contend such studies are immediately undertaken to help address AMR

Site-specific associations of muscle thickness with bone mineral density in middle-aged and older men and women

It is unknown whether age-related site-specific muscle loss is associated with areal bone mineral density (aBMD) in older adults. To examine the relationships between aBMD and whole-body muscle thickness distribution, 97 healthy adults (46 women and 51 men) aged 50–78 years volunteered. Total and appendicular lean soft tissue mass, aBMD of the lumbar spine (LS-aBMD) and femoral neck (FN-aBMD) were determined using dual-energy X-ray absorptiometry. Muscle thickness (MT) was measured by ultrasound at nine sites of the body (forearm, upper arm, trunk, upper leg, and lower leg). Relationships of each co-variate with aBMD were tested partialling out the effect of age. aBMD was not correlated with either MT of the trunk or anterior lower leg in either sex. In men, significant and relatively strong correlations were observed between anterior and posterior upper arms, posterior lower leg, and anterior upper leg MT and LS-aBMD or FN-aBMD. In women, significant correlations were observed between anterior and posterior upper legs, posterior lower leg, and anterior upper arm MT and FN-aBMD. LS-aBMD was only correlated with forearm and posterior upper leg MT in women. In conclusion, the site-specific association of MT and aBMD differs between sexes and may be associated with the participants’ daily physical activity profile

Chapter 7: Grading a Body of Evidence on Diagnostic Tests

10.1007/s11606-012-2021-9Journal of General Internal Medicine27SUPPL.1S47-S55JGIM

Deep Learning with Lung Segmentation and Bone Shadow Exclusion Techniques for Chest X-Ray Analysis of Lung Cancer

The recent progress of computing, machine learning, and especially deep learning, for image recognition brings a meaningful effect for automatic detection of various diseases from chest X-ray images (CXRs). Here efficiency of lung segmentation and bone shadow exclusion techniques is demonstrated for analysis of 2D CXRs by deep learning approach to help radiologists identify suspicious lesions and nodules in lung cancer patients. Training and validation was performed on the original JSRT dataset (dataset #01), BSE-JSRT dataset, i.e. the same JSRT dataset, but without clavicle and rib shadows (dataset #02), original JSRT dataset after segmentation (dataset #03), and BSE-JSRT dataset after segmentation (dataset #04). The results demonstrate the high efficiency and usefulness of the considered pre-processing techniques in the simplified configuration even. The pre-processed dataset without bones (dataset #02) demonstrates the much better accuracy and loss results in comparison to the other pre-processed datasets after lung segmentation (datasets #02 and #03).Comment: 10 pages, 7 figures; The First International Conference on Computer Science, Engineering and Education Applications (ICCSEEA2018) (www.uacnconf.org/iccseea2018) (accepted

Intracellular chloride concentration influences the GABAA receptor subunit composition

GABAA receptors (GABAARs) exist as different subtype variants showing unique functional properties and defined spatio-temporal expression pattern. The molecular mechanisms underlying the developmental expression of different GABAAR are largely unknown. The intracellular concentration of chloride ([Cl−]i), the main ion permeating through GABAARs, also undergoes considerable changes during maturation, being higher at early neuronal stages with respect to adult neurons. Here we investigate the possibility that [Cl−]i could modulate the sequential expression of specific GABAARs subtypes in primary cerebellar neurons. We show that [Cl−]i regulates the expression of α3-1 and δ-containing GABAA receptors, responsible for phasic and tonic inhibition, respectively. Our findings highlight the role of [Cl−]i in tuning the strength of GABAergic responses by acting as an intracellular messenger

Military veteran mortality following a survived suicide attempt

<p>Abstract</p> <p>Background</p> <p>Suicide is a global public health problem. Recently in the U.S., much attention has been given to preventing suicide and other premature mortality in veterans returning from Iraq and Afghanistan. A strong predictor of suicide is a past suicide attempt, and suicide attempters have multiple physical and mental comorbidities that put them at risk for additional causes of death. We examined mortality among U.S. military veterans after hospitalization for attempted suicide.</p> <p>Methods</p> <p>A retrospective cohort study was conducted with all military veterans receiving inpatient treatment during 1993-1998 at United States Veterans Affairs (VA) medical facilities following a suicide attempt. Deaths occurring during 1993-2002, the most recent available year at the time, were identified through VA Beneficiary and Records Locator System data and National Death Index data. Mortality data for the general U.S. adult population were also obtained from the National Center for Health Statistics. Comparisons within the veteran cohort, between genders, and against the U.S. population were conducted with descriptive statistics and standardized mortality ratios. The actuarial method was used estimate the proportion of veterans in the cohort we expect would have survived through 2002 had they experienced the same rate of death that occurred over the study period in the U.S. population having the age and sex characteristics.</p> <p>Results</p> <p>During 1993-1998, 10,163 veterans were treated and discharged at a VA medical center after a suicide attempt (mean age = 44 years; 91% male). There was a high prevalence of diagnosed alcohol disorder or abuse (31.8%), drug dependence or abuse (21.8%), psychoses (21.2%), depression (18.5%), and hypertension (14.2%). A total of 1,836 (18.1%) veterans died during follow up (2,941.4/100,000 person years). The cumulative survival probability after 10 years was 78.0% (95% CI = 72.9, 83.1). Hence the 10-year cumulative mortality risk was 22.0%, which was 3.0 times greater than expected. The leading causes overall were heart disease (20.2%), suicide (13.1%), and unintentional injury (12.7%). Whereas suicide was the ninth leading cause of death in the U.S. population overall (1.8%) during the study period, suicide was the leading and second leading cause among women (25.0%) and men (12.7%) in the cohort, respectively.</p> <p>Conclusions</p> <p>Veterans who have attempted suicide face elevated risks of all-cause mortality with suicide being prominent. This represents an important population for prevention activities.</p

The limited prosocial effects of meditation: A systematic review and meta-analysis

Many individuals believe that meditation has the capacity to not only alleviate mental-illness but to improve prosociality. This article systematically reviewed and meta-analysed the effects of meditation interventions on prosociality in randomized controlled trials of healthy adults. Five types of social behaviours were identified: compassion, empathy, aggression, connectedness and prejudice. Although we found a moderate increase in prosociality following meditation, further analysis indicated that this effect was qualified by two factors: type of prosociality and methodological quality. Meditation interventions had an effect on compassion and empathy, but not on aggression, connectedness or prejudice. We further found that compassion levels only increased under two conditions: when the teacher in the meditation intervention was a co-author in the published study; and when the study employed a passive (waiting list) control group but not an active one. Contrary to popular beliefs that meditation will lead to prosocial changes, the results of this meta-analysis showed that the effects of meditation on prosociality were qualified by the type of prosociality and methodological quality of the study. We conclude by highlighting a number of biases and theoretical problems that need addressing to improve quality of research in this area

Influence of ARHGEF3 and RHOA Knockdown on ACTA2 and Other Genes in Osteoblasts and Osteoclasts

Osteoporosis is a common bone disease that has a strong genetic component. Genome-wide linkage studies have identified the chromosomal region 3p14-p22 as a quantitative trait locus for bone mineral density (BMD). We have previously identified associations between variation in two related genes located in 3p14-p22, ARHGEF3 and RHOA, and BMD in women. In this study we performed knockdown of these genes using small interfering RNA (siRNA) in human osteoblast-like and osteoclast-like cells in culture, with subsequent microarray analysis to identify genes differentially regulated from a list of 264 candidate genes. Validation of selected findings was then carried out in additional human cell lines/cultures using quantitative real-time PCR (qRT-PCR). The qRT-PCR results showed significant down-regulation of the ACTA2 gene, encoding the cytoskeletal protein alpha 2 actin, in response to RHOA knockdown in both osteoblast-like (P<0.001) and osteoclast-like cells (P = 0.002). RHOA knockdown also caused up-regulation of the PTH1R gene, encoding the parathyroid hormone 1 receptor, in Saos-2 osteoblast-like cells (P<0.001). Other findings included down-regulation of the TNFRSF11B gene, encoding osteoprotegerin, in response to ARHGEF3 knockdown in the Saos-2 and hFOB 1.19 osteoblast-like cells (P = 0.003– 0.02), and down-regulation of ARHGDIA, encoding the Rho GDP dissociation inhibitor alpha, in response to RHOA knockdown in osteoclast-like cells (P<0.001). These studies identify ARHGEF3 and RHOA as potential regulators of a number of genes in bone cells, including TNFRSF11B, ARHGDIA, PTH1R and ACTA2, with influences on the latter evident in both osteoblast-like and osteoclast-like cells. This adds further evidence to previous studies suggesting a role for the ARHGEF3 and RHOA genes in bone metabolism

Numerical study of nonlinear heat transfer from a wavy surface to a high permeability medium with pseudo-spectral and smoothed particle methods

Motivated by petro-chemical geological systems, we consider the natural convection boundary layer flow from a vertical isothermal wavy surface adjacent to a saturated non-Darcian high permeability porous medium. High permeability is considered to represent geologically sparsely packed porous media. Both Darcian drag and Forchheimer inertial drag terms are included in the velocity boundary layer equation. A high permeability medium is considered. We employ a sinusoidal relation for the wavy surface. Using a set of transformations, the momentum and heat conservation equations are converted from an (x, y) coordinate system to an (x,η) dimensionless system. The two-point boundary value problem is then solved numerically with a pseudo-spectral method based on combining the Bellman–Kalaba quasi linearization method with the Chebyschev spectral collocation technique (SQLM). The SQLM computations are demonstrated to achieve excellent correlation with smoothed particle hydrodynamic (SPH) Lagrangian solutions. We study the effect of Darcy number (Da), Forchheimer number (Fs), amplitude wavelength (A) and Prandtl number (Pr) on the velocity and temperature distributions in the regime. Local Nusselt number is also computed for selected cases. The study finds important applications in petroleum engineering and also energy systems exploiting porous media and undulating (wavy) surface geometry. The SQLM algorithm is shown to be exceptionally robust and achieves fast convergence and excellent accuracy in nonlinear heat transfer simulations