Fragment-based QSAR study to explore the structural requirements of DPP-4 inhibitors: a stepping stone towards better type 2 diabetes mellitus management.

Dipeptidyl peptidase-4 (DPP-4) inhibitors belong to a prominent group of pharmaceutical agents that are used in the governance of type 2 diabetes mellitus (T2DM). They exert their antidiabetic effects by inhibiting the incretin hormones like glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide which, play a pivotal role in the regulation of blood glucose homoeostasis in our body. DPP-4 inhibitors have emerged as an important class of oral antidiabetic drugs for the treatment of T2DM. Surprisingly, only a few 2D-QSAR studies have been reported on DPP-4 inhibitors. Here, fragment-based QSAR (Laplacian-modified Bayesian modelling and Recursive partitioning (RP) approaches have been utilized on a dataset of 108 DPP-4 inhibitors to achieve a deeper understanding of the association among their molecular structures. The Bayesian analysis demonstrated satisfactory ROC values for the training as well as the test sets. Meanwhile, the RP analysis resulted in decision tree 3 with 2 leaves (Tree 3: 2 leaves). This present study is an effort to get an insight into the pivotal fragments modulating DPP-4 inhibition.

Chemical analysis of low carbon content coals and their applications as dye adsorbent.

Coal is primarily a fuel material but lately it has been utilized as an adsorbent for removing toxic metal ions. However, its usage for removing organic pollutants is not well studied. We report here a systematic study on the use of coal samples of varying carbon contents as adsorbents for removing Basic Blue 41 as a model cationic dye. The coal samples were collected from coal mines and were thoroughly characterized. The concentrations of carbon, hydrogen, oxygen, nitrogen and sulphur contents were measured by CHNS analyzer. The concentrations of aluminum, silicon, sulphur, titanium and iron were determined by EDXRF, which corresponded to silicon dioxide (quartz) and aluminium silicate (kaolinite) as the major mineral inclusions, corroborated by XRD results and micrographs showing elemental maps determined from SEM-EDAX. The coal samples with low carbon content revealed higher adsorption capacity (qe âˆ¼ 8.0-9.3 mg/g) of Basic Blue dye at optimized adsorbent dose (2 mg/mL), pH 9 and contact time (120 min). The adsorption kinetic studies satisfied pseudo second order model and the intra-particle diffusion of the dye was evident. The dye adsorption followed Langmuir adsorption isotherm, and the qmax values ranged between 17 and 30 mg/g for low carbon content coal. The FT-IR, Brunauer-Emmett-Teller (BET) surface area and zeta potential results of the coal samples could explain the adsorption phenomenon of cationic dye. The kinetic and thermodynamic studies revealed that the adsorption of Basic Blue 41 dye was based on chemisorptions mechanism.

Gene-specific MicroRNA antagonism protects against HIV Tat and TGF-ß-mediated suppression of CFTR mRNA and function.

BACKGROUND: MicroRNAs play an important role in health and disease. TGF-ß signaling, upregulated by HIV Tat, and in chronic airway diseases and smokers upregulates miR-145-5p to suppress cystic fibrosis transmembrane conductance regulator (CFTR). CFTR suppression in chronic airway diseases like Cystic Fibrosis, COPD and smokers has been associated with suppressed MCC and recurrent lung infections and inflammation. This can explain the emergence of recurrent lung infections and inflammation in people living with HIV. METHODS: Tat-induced aberrant microRNAome was identified by miRNA expression analysis. microRNA mimics and antagomirs were used to validate the identified miRNAs involved in Tat mediated CFTR mRNA suppression. CRISPR-based editing of the miRNA target sites in CFTR 3'UTR was used to determine rescue of CFTR mRNA and function in airway epithelial cell lines and in primary human bronchial epithelial cells exposed to TGF-ß and Tat. FINDINGS: HIV Tat upregulates miR-145-5p and miR-509-3p. The two miRNAs demonstrate co-operative effects in suppressing CFTR. CRISPR-based editing of the miRNA target site preserves CFTR mRNA and function in airway epithelial cells INTERPRETATION: Given the important roles of TGF-ß signaling and the multitude of genes regulated by miRNAs, we demonstrate that CRISPR-based gene-specific microRNA antagonism approach can preserve CFTR mRNA and function in the context of HIV Tat and TGF-ß signaling without suppressing expression of other genes regulated by miR-145-5p.

Density-functional-theory approach to the Hamiltonian adaptive resolution simulation method.

In the Hamiltonian adaptive resolution simulation method (H-AdResS) it is possible to simulate coexisting atomistic (AT) and ideal gas representations of a physical system that belong to different subdomains within the simulation box. The Hamiltonian includes a field that bridges both models by smoothly switching on (off) the intermolecular potential as particles enter (leave) the AT region. In practice, external one-body forces are calculated and applied to enforce a reference density throughout the simulation box, and the resulting external potential adds up to the Hamiltonian. This procedure suggests an apparent dependence of the final Hamiltonian on the system's thermodynamic state that challenges the method's statistical mechanics consistency. In this paper, we explicitly include an external potential that depends on the switching function. Hence, we build a grand canonical potential for this inhomogeneous system to find the equivalence between H-AdResS and density functional theory (DFT). We thus verify that the external potential inducing a constant density profile is equal to the system's excess chemical potential. Given DFT's one-to-one correspondence between external potential and equilibrium density, we find that a Hamiltonian description of the system is compatible with the numerical implementation based on enforcing the reference density across the simulation box. In the second part of the manuscript, we focus on assessing our approach's convergence and computing efficiency concerning various model parameters, including sample size and solute concentrations. To this aim, we compute the excess chemical potential of water, aqueous urea solutions and Lennard-Jones (LJ) mixtures. The results' convergence and accuracy are convincing in all cases, thus emphasising the method's robustness and capabilities.

Novel Approaches of CRISPR-Cas Technology in Airway Diseases.

Clustered regularly interspaced palindromic repeats (CRISPR) technique plays a vital role in preclinical modelling of many respiratory diseases. Diseases such as chronic obstructive pulmonary disease (COPD), asthma, acute tracheal bronchitis, pneumonia, tuberculosis, lung cancer, and influenza infection continue to significantly impact human health. CRISPR associated (Cas) proteins, isolated from the immune system of prokaryotes, are one component of a very useful technique to manipulate gene sequences or editing and gene expression with significant implications for respiratory research in the field of molecular biology. CRISPR technology is a promising tool that is easily adaptable for specific editing of DNA sequences of interest with a goal towards modifying or eliminating gene function. Among its many potential applications, CRISPR can be applied to correcting genetic defects as well as for therapeutic approaches for treatment. This review elucidates recent advances in CRISPR-Cas technology in airway diseases.

TGF-ß1 increases viral burden and promotes HIV-1 latency in primary differentiated human bronchial epithelial cells.

Combination antiretroviral therapy (cART) has increased the life expectancy of HIV patients. However, the incidence of non-AIDS associated lung comorbidities, such as COPD and asthma, and that of opportunistic lung infections have become more common among this population. HIV proteins secreted by the anatomical HIV reservoirs can have both autocrine and paracrine effects contributing to the HIV-associated comorbidities. HIV has been recovered from cell-free bronchoalveolar lavage fluid, alveolar macrophages, and intrapulmonary lymphocytes. We have recently shown that ex-vivo cultured primary bronchial epithelial cells and the bronchial brushings from human subjects express canonical HIV receptors CD4, CCR5 and CXCR4 and can be infected with HIV. Together these studies suggest that the lung tissue can serve as an important reservoir for HIV. In this report, we show that TGF-ß1 promotes HIV latency by upregulating a transcriptional repressor BLIMP-1. Furthermore, we identify miR-9-5p as an important intermediate in TGF-ß-mediated BLIMP-1 upregulation and consequent HIV latency. The transcriptionally suppressed HIV can be reactivated by common latency reactivating agents. Together our data suggest that in patients with chronic airway diseases, TGF-ß can elevate the HIV viral reservoir load that could further exacerbate the HIV associated lung comorbidities.

CT imaging features of skeletal muscle metastasis.

AIM: To define the computed tomography (CT) features common in skeletal muscle metastases and their prevalence and to identify the most commonly associated primary malignancy and the most common muscle groups in which skeletal muscle metastases are found. METHODS AND MATERIALS: Institutional review board (IRB) waiver for informed consent was obtained. A retrospective review was conducted of CT examinations from a single, large, academic centre picture archiving and communication system (PACS) database, performed from August 2009 to July 2013. All 10,426 examinations and 8,524 unique patients reviewed had a confirmed diagnosis of malignancy. The CT reports were screened manually to identify disease involving the skeletal muscles. Images of the 60 initial studies identified were then reviewed. Cases that showed direct invasion of the tumour into the skeletal muscles, and follow-up studies of the same patient were excluded. The 27 included cases were classified under five distinct patterns. RESULTS: In the present study, the prevalence for skeletal muscle metastasis was 0.33% across all malignancies. The most common primary involved was breast cancer (25%). The most common pattern was focal intramuscular mass with homogeneous contrast enhancement. The most common sites of skeletal muscle metastasis were in the abdomen (43%) and thorax (33%) musculature. CONCLUSION: Breast cancer was the most commonly associated primary malignancy and a focal, homogeneously enhancing intramuscular mass was the most common presentation. Although skeletal muscle metastasis remains a rare entity, its incidence rate should increase with the increased usage of whole-body PET CT for cancer staging.

Cigarette smoke promotes HIV infection of primary bronchial epithelium and additively suppresses CFTR function.

Recurrent lung infections are a common cause of morbidity and mortality in people living with HIV and this is exacerbated in smokers even when administered combination antiretroviral therapy (cART). The incidence of pneumonia is increased with smoking and treatment interruption and is directly dependent on viral load in patients when adjusted for CD4 counts. CFTR dysfunction plays an important role in aberrant airway innate immunity as it is pivotal in regulating mucociliary clearance (MCC) rates and other antibacterial mechanisms of the airway. In our earlier work, we have demonstrated that bronchial epithelium expresses canonical HIV receptors CD4, CCR5 and CXCR4 and can be infected with HIV. HIV Tat suppresses CFTR mRNA and function via TGF-ß signaling. In the present study, we demonstrate that cigarette smoke (CS) potentiates HIV infection of bronchial epithelial cells by upregulating CD4 and CCR5 expression. HIV and CS individually and additively suppress CFTR biogenesis and function, possibly explaining the increased incidence of lung infections in HIV patients and its exacerbation in HIV smokers.

Photoluminescence Quenching Based Visual and Spectroscopic Method for Mercury Sensing by Surface-Modified Cadmium Sulphide Quantum Dots.

Here we present a simple yet efficient analytical method for sensing ultratrace levels of Hg2+ ions by highly water soluble CdS quantum dots functionalized with thiourea as a probe. The bluish photoluminescence emission of the probe responded to a systematic linear photoluminescence quenching in the presence of increasing concentration of Hg2+ ions. The photoluminescence quenching by Hg2+ ions was attributed to agglomeration of the quantum dots, which has been confirmed by zeta potential measurements. The sensitivity (31.38 L/mg) and LoD (0.11 µg/L) of Hg2+ ion detection by our method are two folds improved with respect to the existing data of CdS as sensor. The improved detection is attributable to synthesis of less than 3 nm diameter CdS quantum dots which rendered very high water solubility and hence facilitated better interaction with Hg2+ ions. The detection of Hg2+ ion was free from most interfering cations and anions, except for minor interference from Cu2+ and Pb2+ corresponding their concentrations expected in ground water. Further, the scope for visual detection of Hg2+ was explored, which revealed naked eye recognizable photoluminescence quenching of the probe treated 0.3 mg/L of Hg2+ ion when excited by a light source of 365 nm. The suitability of our probe to analyze Hg2+ in real samples has been demonstrated by Hg2+ spike analysis in groundwater and river water samples.

Rapid Photoluminescence Quenching Based Detection of Cu2+ in Aqueous Medium by CdS Quantum Dots Surface Passivated by Thiourea.

Presented here is a simple yet rapid and efficient analytical method for visual as well as spectroscopic method for sensing of trace concentrations of Cu2+ ions in aqueous medium by systematic photoluminescence quenching of a highly water soluble probe made of CdS quantum dots surface modified by thiourea. The salient features of this work describe rapid detection (2 min equilibration time) of Cu2+ ions at wider linear concentration range (0.025 - 10 mg/L) corresponding to a sensitivity of 2.81(mg/L)-1 and limit of quantification of 47.3 µg/L, respectively, suitable for Cu2+ sensing in drinking water and ground water. Further, the detection of Cu2+ ion was free from most interfering cations and anions, except for minor interference from Cr3+, Hg2+ and Pb2+. The robustness of our probe for Cu2+ sensing is demonstrated from efficient Cu2+ spike recovery analysis in groundwater and river water samples.

Genetic and other risk factors for suicidal ideation and the relationship with depression.

BACKGROUND: There is a genetic contribution to the risk of suicide, but sparse prior research on the genetics of suicidal ideation. METHODS: Active and passive suicidal ideation were assessed in a Sri Lankan population-based twin registry (n = 3906 twins) and a matched non-twin sample (n = 2016). Logistic regression models were used to examine associations with socio-demographic factors, environmental exposures and psychiatric symptoms. The heritability of suicidal ideation was assessed using structural equation modelling. RESULTS: The lifetime prevalence of any suicidal ideation was 13.0% (11.7-14.3%) for men; 21.8% (20.3-23.2%) for women, with no significant difference between twins and non-twins. Factors that predicted suicidal ideation included female gender, termination of marital relationship, low education level, urban residence, losing a parent whilst young, low standard of living and stressful life events in the preceding 12 months. Suicidal ideation was strongly associated with depression, but also with abnormal fatigue and alcohol and tobacco use. The best fitting structural equation model indicated a substantial contribution from genetic factors (57%; CI 47-66) and from non-shared environmental factors (43%; CI 34-53) in both men and women. In women this genetic component was largely mediated through depression, but in men there was a significant heritable component to suicidal ideation that was independent of depression. CONCLUSIONS: These are the first results to show a genetic contribution to suicidal ideation that is independent of depression outside of a high-income country. These phenomena may be generalizable, because previous research highlights similarities between the aetiology of mental disorders in Sri Lanka and higher-income countries.

Contributions of specific causes of death to lost life expectancy in severe mental illness.

The life expectancy gap between people with severe mental illness (SMI) and the general population persists and may even be widening. This study aimed to estimate contributions of specific causes of death to the gap. Age of death and primary cause of death were used to estimate life expectancy at birth for people with SMI from a large mental healthcare case register during 2007-2012. Using data for England and Wales in 2010, death rates in the SMI cohort for each primary cause of death category were replaced with gender- and age-specific norms for that cause. Life expectancy in SMI was then re-calculated and, thus, the contribution of that specific cause of death estimated. Natural causes accounted for 79.2% of lost life-years in women with SMI and 78.6% in men. Deaths from circulatory disorders accounted for more life-years lost in women than men (22.0% versus 17.4%, respectively), as did deaths from cancer (8.1% versus 0%), but the contribution from respiratory disorders was lower in women than men (13.7% versus 16.5%). For women, cancer contributed more in those with non-affective than affective disorders, while suicide, respiratory and digestive disorders contributed more in those with affective disorders. In men, respiratory disorders contributed more in non-affective disorders. Other contributions were similar between gender and affective/non-affective groups. Loss of life expectancy in people with SMI is accounted for by a broad range of causes of death, varying by gender and diagnosis. Interventions focused on multiple rather than individual causes of death should be prioritised accordingly.

Arsenic in groundwater of the Kolkata Municipal Corporation (KMC), India: Critical review and modes of mitigation.

This study represents the first comprehensive report of groundwater arsenic contamination status in the Kolkata Municipal Corporation (KMC). During the past 23 years, 4210 groundwater samples were analysed from all 141 wards in the KMC: 14.2% and 5.2% samples had arsenic >10 µg/l and >50 µg/l, respectively, representing 77 and 37 wards. The study shows that the number of arsenic contaminated samples (and wards) in the southern part of the KMC exceeds that of other parts of the city. The daily intake of arsenic from drinking water was estimated as 0.95 µg per kg bw and the cancer risk was estimated as 1425/106. Analyses of biological samples (hair, nail and urine) showed elevated concentrations of arsenic indicating the presence of subclinical arsenic poisoning, predicting an enhanced lifetime cancer risk for the population in southern part of the KMC. In the KMC, groundwater is not a sustainable source of freshwater due to arsenic, high iron, hardness and total dissolved solids. Its continued use is impelled by the lack of an adequate infrastructure to treat and supply surface water and in some wards the unaccounted for water (UFW) is even >45% incurred during distribution. The rare imposition of a water tax makes the water supply systems unsustainable and fosters indifference to water conservation. To mitigate the arsenic problem, continuous groundwater monitoring for pollutants, a treated surface water supply with strict policy implications, rainwater harvesting in the urban areas and introduction of water taxes seem to be long-term visible solutions.

A novel approach for reducing toxic emissions during high temperature processing of electronic waste.

A novel approach is presented to capture some of the potentially toxic elements (PTEs), other particulates and emissions during the heat treatment of e-waste using alumina adsorbents. Waste PCBs from mobile phones were mechanically crushed to sizes less than 1mm; their thermal degradation was investigated using thermo-gravimetric analysis. Observed weight loss was attributed to the degradation of polymers and the vaporization of organic constituents and volatile metals. The sample assembly containing PCB powder and adsorbent was heat treated at 600°C for times ranging between 10 and 30min with air, nitrogen and argon as carrier gases. Weight gains up to ∼17% were recorded in the adsorbent thereby indicating the capture of significant amounts of particulates. The highest level of adsorption was observed in N2 atmosphere for small particle sizes of alumina. SEM/EDS results on the adsorbent indicated the presence of Cu, Pb, Si, Mg and C. These studies were supplemented with ICP-OES analysis to determine the extent of various species captured as a function of operating parameters. This innovative, low-cost approach has the potential for utilization in the informal sector and/or developing countries, and could play a significant role in reducing toxic emissions from e-waste processing towards environmentally safe limits.

HIV Infects Bronchial Epithelium and Suppresses Components of the Mucociliary Clearance Apparatus.

Recurrent lung infections and pneumonia are emerging as significant comorbidities in the HIV-infected population in the era of combination antiretroviral therapy (cART). HIV infection has been reported to suppress nasal mucociliary clearance (MCC). Since the primary components driving nasal MCC and bronchial MCC are identical, it is possible that bronchial MCC is affected as well. Effective MCC requires optimal ciliary beating which depends on the maintenance of the airway surface liquid (ASL), a function of cystic fibrosis transmembrane conductance regulator (CFTR) activity and the integrity of the signaling mechanism that regulates ciliary beating and fluid secretion. Impairment of either component of the MCC apparatus can compromise its efficacy and promote microbial colonization. We demonstrate that primary bronchial epithelium expresses HIV receptor CD4 and co-receptors CCR5 and CXCR4 and can be infected by both R5 and X4 tropic strains of HIV. We show that HIV Tat suppresses CFTR biogenesis and function in primary bronchial epithelial cells by a pathway involving TGF-ß signaling. HIV infection also interferes with bronchial epithelial cell differentiation and suppresses ciliogenesis. These findings suggest that HIV infection suppresses tracheobronchial mucociliary clearance and this may predispose HIV-infected patients to recurrent lung infections, pneumonia and chronic bronchitis.

Highly Sensitive and Selective Method for Detecting Ultratrace Levels of Aqueous Uranyl Ions by Strongly Photoluminescent-Responsive Amine-Modified Cadmium Sulfide Quantum Dots.

Detection of ultratrace levels of aqueous uranyl ions without using sophisticated analytical instrumentation and a tedious sample preparation method is a challenge for environmental monitoring and mitigation. Here we present a novel yet simple analytical method for highly sensitive and specific detection of uranyl ions via photoluminescence quenching of CdS quantum dots. We have demonstrated a new approach for synthesizing highly water-soluble and strong photoluminescence-emitting CdS quantum dots (i.e., CdS-MAA and CdS-MAA-TU) of sizes less than 3 nm. The structural, morphological, and optical properties of both the batches of CdS quantum dots were thoroughly characterized by XRD, high-resolution transmission electron microscopy (HRTEM), zeta potential, UV-visible absorption, and photoluminescence spectroscopy. Compared to the batch of CdS quantum dots prepared by capping with only mercaptoacetic acid (CdS-MAA), the batch prepared by capping with mercaptoacetic acid and thiourea in tandem (CdS-MAA-TU) exhibited higher quantum yield= 16.64 ± 1.02%, and more importantly, CdS-MAA-TU exhibited significantly a higher order of photoluminescence quenching responses when treated with ultratrace concentrations of uranyl ions. Under the optimized conditions, the sensitivity of detecting uranyl ion by CdS-MAA-TU was several folds better (0.316 L/ µg) than that of CdS-MAA (0.0053 (L/µg/), as determined from their respective Stern-Volmer plots. Qualitatively, CdS-MAA-TU probe can be used for visual detection of uranyl ions of concentration greater than 5 µg/L. However, the instrumental method of analysis based on photoluminescence spectroscopy confirmed the feasibility for quantitative analysis of ultratrace concentrations of uranyl ions as implied from a very low limit of detection (LoD = 0.07 µg/L) and limit of quantification (LoQ = and 0.231 µg/L). Systematic studies revealed very high selectivity for uranyl ion detection, though minor interference from Cu(2+), Pb(2+), Hg(2+), CO3(2-), and SO4(2-) was found. The recovery analysis performed by spiking uranyl ions (0.5 µg/L to 10.0 µg/L) in groundwater and river water samples, confirmed the robustness of the as-developed CdS-MAA-TU QDs for detecting ultratrace levels of uranyl ions in real water sample matrix. The very simple and effective strategy reported here should facilitate developing reliable sensors for detecting uranyl ion contamination in drinking water.

Small molecule inhibition of cAMP response element binding protein in human acute myeloid leukemia cells.

The transcription factor CREB (cAMP Response-Element Binding Protein) is overexpressed in the majority of acute myeloid leukemia (AML) patients, and this is associated with a worse prognosis. Previous work revealed that CREB overexpression augmented AML cell growth, while CREB knockdown disrupted key AML cell functions in vitro. In contrast, CREB knockdown had no effect on long-term hematopoietic stem cell activity in mouse transduction/transplantation assays. Together, these studies position CREB as a promising drug target for AML. To test this concept, a small molecule inhibitor of CREB, XX-650-23, was developed. This molecule blocks a critical interaction between CREB and its required co-activator CBP (CREB Binding Protein), leading to disruption of CREB-driven gene expression. Inhibition of CBP-CREB interaction induced apoptosis and cell-cycle arrest in AML cells, and prolonged survival in vivo in mice injected with human AML cells. XX-650-23 had little toxicity on normal human hematopoietic cells and tissues in mice. To understand the mechanism of XX-650-23, we performed RNA-seq, ChIP-seq and Cytometry Time of Flight with human AML cells. Our results demonstrate that small molecule inhibition of CBP-CREB interaction mostly affects apoptotic, cell-cycle and survival pathways, which may represent a novel approach for AML therapy.