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Over the past few decades, wastewater generation in India has increased rapidly owing to the population boom and industrial development, while the treatment capability in India stands only at around 33%. Hence, with the aim of developing sustainable decentralised technologies at a community level, the present study was conducted to showcase the treatment of two common domestic wastewater, namely, sewage and reverse osmosis (RO) concentrate via vertical up-flow constructed wetland microbial fuel cell (CW-MFC). The proposed setup will not only aid in reducing the volumetric load on centralised systems but also can produce utilisable bioelectricity. Two CW-MFCs [CW-MFC-1 (with plants), CW-MFC-2 (without plants)] were operated to observe the wastewater treatability by analysing various physico-chemical and electrochemical parameters. The maximum chemical oxygen demand (COD) removal efficiency of CW-MFC-1 (74.29 ± 2.45%) was approximately 14–18% higher than CW-MFC-2 (65.05 ± 2.00%) because of the presence of Canna indica, which contributed towards enhanced wastewater treatment for CW-MFC-1. Hence, the incorporation of C. indicafavourably assisted in ameliorating the performance of CW-MFC-1. Also, the enrichment of the nutrients by supplementing RO concentrate majorly contributed to enhancing the electrochemical performance of both the systems. Moreover, the power densities in both the systems were almost comparable, 0.38 ± 0.05 W/m3for CW-MFC-1 and 0.33 ± 0.04 W/m3for CW-MFC-2.Thus, the present investigation exemplifies the successful treatment of RO concentrate mixed with sewage through upflow CW-MFC, which can be further used at the household level as a decentralised wastewater treatment system.

Advances in the synthesis and characterization of colloidal magnetic nanoparticles (NPs) have yielded great gains in the understanding of their complex magnetic behavior, with implications for numerous applications. Recent work using Ni NPs as a model soft ferromagnetic system, for example, achieved quantitative understanding of the superparamagnetic blocking temperature–particle diameter relationship. This hinged, however, on the critical assumption of a ferromagnetic NP volume lower than the chemical volume due to a non-ferromagnetic dead shell indirectly deduced from magnetometry. Here, we determine both the chemical and magnetic average internal structures of Ni NP ensembles viaunpolarized, half-polarized, and fully polarized small-angle neutron scattering (SANS) measurements and analyses coupled with X-ray diffraction and magnetometry. The postulated nanometric magnetic dead shell is not only detected but conclusively identified as a non-ferromagnetic Ni phosphide derived from the trioctylphosphine commonly used in hot-injection colloidal NP syntheses. The phosphide shell thickness is tunable viasynthesis temperature, falling to as little as 0.5 nm at 170 °C. Temperature- and magnetic field-dependent polarized SANS measurements additionally reveal essentially bulk-like ferromagnetism in the Ni core and negligible interparticle magnetic interactions, quantitatively supporting prior modeling of superparamagnetism. These findings advance the understanding of synthesis−structure–property relationships in metallic magnetic NPs, point to a simple potential route to ligand-free stabilization, and highlight the power of the currently available suite of polarized SANS measurement and analysis capabilities for magnetic NP science and technology.

This work addresses the rural-based chulha (stove) fabrication with less smoke emission. Many traditional cooking techniques used in Indian villages are inappropriate and cause environmental and health hazards like respiratory and vision problems as well as monetary loss. The main objective of this work is to design a stove that overcomes these problems. Emphasis has been made to increase the thermal efficiency of the stove and reduce smoke emission. Here, the focus is to incorporate proper supply of air to the burning chamber for clean burning and ensure primary and secondary combustion. Air is supplied for two purposes; these are primary and secondary combustion. Primary combustion is held in the fuel holder where fuel is burnt by the direct supply of preheated air. Secondary combustion takes place at the top of the burning chamber by burning the smoke that is produced during the primary combustion. This results in reduction of smoke and also ensures clean burning of the fuel. Moreover, refractory materials have also been used to reduce the heat loss. The materials utilized for building this model are locally available and these are low cost. The experiment has been carried out in three stages in terms of each prototype model where the modification is done on the predecessor. The effort has been made to maintain a proper balance between the efficiency of the stove and the low smoke production tendency of the stove. Experiments have been performed in each of the prototype for finding the thermal efficiency.

The prsA and vraTSR regulatory systems play a unique role in methicillin resistance by modifying the peptidoglycan cell wall PBP2 and involving cell wall stress response in Staphylococcus aureus. This study was designed to observe the transcriptional response of prsA and vraTSR system under oxacillin stress in S.aureus.

In this study, the mechanical behavior of a dense-graded asphalt mixture subjected to unaged, short-term, and extended aged conditions along with one freeze-thaw moisture conditioning cycle was evaluated at two temperatures and three stress magnitudes. A stress-controlled repeated indirect tensile loading fatigue test with 0.1-s loading and a 0.4-s rest period was used for determining the fatigue life of asphalt mixture. Aging, moisture conditioning, and an increase in the test temperature adversely affected the tensile strength of the asphalt mixture. The reduction in stiffness modulus of asphalt mixture that was due to moisture conditioning increased with the increase in the level of aging. The ratio of conditioned to unconditioned stiffness modulus (stiffness modulus ratio) was noticed to be more sensitive to different aging conditions compared with the ratio of conditioned to unconditioned tensile strength (tensile strength ratio). The effect of aging on fatigue life of asphalt mixture reduced with the increase in stress from 450 kPa to 550 kPa and 650 kPa. Further, the fatigue life of asphalt mixture reduced with the increase in test temperature and moisture conditioning. The short-term and extended aged mixture had higher damage value at failure compared with the unaged mixture. The mean fatigue life represented by the scale parameter of Weibull distribution reduced with the increase in aging and moisture conditioning. Further, the reliability of fatigue life of short-term aged and extended aged asphalt mixture was lower than the unaged asphalt mixture. The fatigue model based on plateau value and fatigue life was found to be more accurate compared with other regression models considered. Statistical analysis showed that the critical combinations of factors that influenced the mechanical behavior of asphalt mixture were also dependent on the test type, which included the tensile strength test, stiffness test, and fatigue test.

Cucumis sativusL. of the Cucurbitaceae family, commonly known as cucumber, is commercially cultivated worldwide. The major phytoconstituents present in the Cucurbitaceae family are different curcurbitacins, principally cucurbitacin E. The content of cucurbitacin E differs within the species or cultivars due to factors like genetic variation and geographical location. The present study reports a simple and rapid quantitative analysis of cucurbitacin E in 5 different C. sativuscultivars by a validated high-performance thin-layer chromatography (HPTLC) method. The mobile phase contained petroleum ether, ethyl acetate and formic acid in the ratio of 40:60:0.5 (V/V). Cucurbitacin E was analyzed densitometrically and the absorbance wavelength was 254 nm. The method showed RFspot = 0.79 ± 0.06, corresponding to cucurbitacin E in various samples. The calibration curve of standard cucurbitacin E showed good linear relationship in the concentration range of 2‒10 µg/spot with a correlation coefficient (r) > 0.99. The HPTLC method was validated in terms of sensitivity, linearity, accuracy, precision, and specificity as per the International Conference on Harmonization (ICH) guidelines. The present study revealed that the content of cucurbitacin E differs among the C. sativuscultivars. This method may be beneficial for addressing the quality-related aspects of C. sativusfor food and pharmaceutical preparation.

Background: Matrix metalloproteinase 1 are zinc-dependent endopeptidases responsible for the controlled breakdown of the extracellular matrix resulting in the maintenance of homeostasis. Dysregulation of MMP1 leads to the progression of various pathological conditions like cancer, rheumatoid arthritis, cardiovascular disease, skin damage and fibrotic disorder. Thus, MMP1 inhibition is the potential drug target of many synthetic MMP1 inhibitors but lack of substrate specificity hinders their clinical applicability. Hence, inhibitors from natural products have gained widespread attention. Objective: The present study attempts screening of novel MMP1 inhibitors from the ZINC database based on experimentally reported natural inhibitors of MMP1 as a scaffold. Methods: Molecular docking study was performed with 19 experimentally reported natural inhibitors spanning across nine different classes followed by virtual screening using the selected compounds. The selected compounds were subjected to molecular dynamics simulation. Results: Twenty compounds were screened with a cut-off of -9.0 kcal/mol of predicted free energy of binding, which further converged to 6 hits after docking studies. After comparing the docking result of 6 screened hits, two best compounds were selected. ZINC02436922 had the best interaction with six hydrogen bond formation to a relatively confined region in the S1’site of MMP1 and -10.01 kcal/mol of predicted free energy of binding. ZINC03075557 was the secondbest compound with -9.57 kcal/mol predicted binding free energy. Molecular dynamics simulation of ZINC02436922 and ZINC03075557 corroborates docking study. Conclusion: This study indicated phenolic compounds ZINC02436922 and ZINC03075557 as potential MMP1 inhibitors.

Purpose:Pseudomonas aeruginosais an opportunistic pathogen with biofilm-forming ability, by the virtue of which they can evade the immune response and antimicrobial chemotherapy. Several methods have been designed for the detection of biofilms but require sophisticated instrumentation and expertise. The present study, therefore, used an improvised device, ‘fluorescence foldscope’ which is an origami-based fluorescence microscope as an easy and effective tool to detect biofilm formation. Methodology:Three representatives of P. aeruginosaof clinical origin were taken for the study along with two reference strains PA01 and ATCC27853. The strains were cultured in Luria Bertani (LB) broth with and without carbapenem (imipenem and meropenem) and cephalosporin (ceftazidime, cefotaxime and ceftriaxone) pressure, respectively. The cultures were diluted to 1:100 in LB; seeded with sterile glass slides at 90° angle and incubated for 5 consecutive days. The slides were observed with fluorescence foldscope. Results:Fluorescence emission was observed in two test isolates CD1 and CD2 at 48 and 72 h, respectively, whereas no fluorescence was observed in CD3. The fluorescence observed in the isolates was not affected by 2 μg/ml carbapenem pressure, while with 2 μg/ml ceftazidime stress, a change in fluorescence was observed in CD2 in comparison to the fluorescence observed under normal growth condition. Conclusion:Fluorescence foldscopy is an effective and reliable tool for the detection of biofilm formation in clinical isolates of P. aeruginosaunder different laboratory conditions. Biofilm-forming P. aeruginosaworsens the medical condition and is difficult to eradicate. The present study came up with an effective and reliable tool for the detection of biofilm formation in clinical isolates of P. aeruginosa.

•This study describes co-existing ESBL and AME harbouring Enterobacteriaceae in a single centre.•Diverse AME types as single and in combination were observed within the study isolates.•All the resistance genes were harboured in diverse incompatibility types of plasmid.

The carrier-type of the emerging photovoltaic Sb2Se3was evaluated for both thin films and bulk crystals via a range of complementary techniques. X-ray photoelectron spectroscopy (XPS), hot probe, Hall effect, and surface photovoltage spectroscopy showed films and crystals synthesized from the Sb2Se3granulate material to be n-type with chlorine identified as an unintentional n-type dopant via secondary ion mass spectrometry analysis. The validity of chlorine as a dopant was confirmed by the synthesis of intrinsic crystals from metallic precursors and subsequent deliberate n-type doping by the addition of MgCl2. Chlorine was also shown to be a substitutional n-type shallow dopant by density functional theory calculations. TiO2/Sb2Se3n–n isotype heterojunction solar cells with 7.3% efficiency are subsequently demonstrated, with band alignment analyzed via XPS.

Water resources contaminated with antibiotic-resistant (ABR) gastrointestinal pathogens pose severe health risks to society. Unfortunately, the limitations of traditional water treatment methodologies are leading to the evolution and dissemination of ABR microbes. In this aspect, a sonophotocatalytic (SPC) process is demonstrated for the successful disinfection of ABR SalmonellaTyphimurium (STm) using Fe-doped ZnO nanoparticles (Fe–ZnO NPs) under visible-LED light. Reactive oxygen species (ROS) produced during SPC contributed to the detrimental effects on the microbes. In general, little is known regarding how bacteria modulate their phenotypic attributes during the course of disinfection. Our investigations to understand the effects of sublethal SPC on the expression of numerous phenotypic features of STm revealed changes in the virulence and ABR profiles. Sublethal SPC caused STm to adhere more on HCT116 cells, whereas their invasion properties were substantially reduced. The loss of ABR was recorded after sublethal SPC, although the resistance was partially regained after a nutrient source was provided to the bacteria. The manifestation of a morphological transition in STm from rod to cocci observed after sublethal SPC may have resulted in the significant loss of invasiveness and ABR. Further, SPC did not result in any process resistance; thus, it is a good candidate for water disinfection.

Antibiotics were discovered for medicinal applications, notably in the last century and since then, they have been prevalently employed for prophylactic purposes in various sectors in the last few decades. Due to the non-judicial usage of antibiotics in sectors like agriculture, aquaculture, and animal husbandry, and as therapeutic substances, antibiotics have started to become a nuisance for the environment and human beings. Furthermore, the accumulation of antibiotics in the biosphere has led to the development of antibiotic resistance in microorganisms making it difficult to treat a growing number of infections. Hereafter to understand the holistic picture of the impacts associated with antibiotics on the environment, the evolution of individual antibiotic pathways for therapeutic and non-therapeutic purposes needs to be studied along with their effect on the environment. Most of the recent reviews on antibiotics either concentrate on a particular source, pathway or environmental impact; however, the present state-of-the-art review attempts to summarize and update the possible sources of antibiotics, usage, their impact on humans, and environmental health on a global scale with a special emphasis on India. Also, there is a critical discussion about the various methods employed for the removal of antibiotics from an array of sources, on both water and soil matrix. The review finally emphasize that the implication of stringent regulation and selection of appropriate technology are required to alleviate antibiotics menace from the environment.

HIV infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We previously showed that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3 were increased in HIVAN kidneys. Here, we demonstrate the key role of SIRT1 deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of Nef in podocytes stably expressing the HIV1 proviral genes, which was associated with the inactivation of NF-κB p65 and reduction in the HIV1 LTR promoter activity. In vivo, the administration of small molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we show that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1 infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.

In this study, the influence of aging and moisture on the two different mechanical behaviors of warm mix asphalt was studied. The cracking and permanent deformation resistance were assessed in terms of tensile strength and flow number computed using a three stage model respectively. The influence of temperature on the tensile strength and both stress and temperature levels on the permanent deformation response of aged and moisture conditioned warm mix asphalt were investigated. Results show that moisture and increase in temperature had a negative impact on the tensile strength of warm mix asphalt while aging had a positive impact. However, the variation in tensile strength of mixtures was strongly related to variation in percent air voids. Aging and interestingly moisture conditioning found to increase the resistance to permanent deformation of warm mix asphalt. Permanent deformation behavior of moisture conditioned samples was further studied to assess the impact of saturation. Results showed that the presence of moisture in samples increase the permanent deformation resistance. From the statistical analysis it was found that both the individual and interaction of aging and moisture had a significant effect on the tensile strength and flow numbers.

Introduction:It was also known that the IncP-1 plasmids are ubiquitous in environmental bacteria and those reside in soil, sewage, marine sediments and in manure. The blaNDMis associated with resistance determinants along with various mobile elements such as plasmid, insertion sequences and transposons, which facilitates its horizontal dissemination. These plasmids, if tracked, can be a starting point for the control of infection due to multidrug-resistant pathogens. The aim of the study was to investigate that IncP-type plasmids carrying blaNDMis adapted in different hosts. Materials and Methods:Thirteen of the isolates were harbouring IncP-type plasmid and they all were Escherichia coliisolated from hospitalised patients of Silchar Medical College and Hospital, India. The isolates were checked for susceptibility test, and the stability was assessed by a serial passage. These isolates were further subjected to transcriptional analysis of NDM gene as well as plasmid copy number alteration. Results:The study isolates were highly stable, and the resistance gene (blaNDM) was retained within isolates till 55thsubsequent serial passages. Plasmid copy number alteration was random in isolates when exposed to carbapenem antibiotics, whereas increasing trend in transcriptional expression was observed with the increase in imipenem concentration. Conclusion:This study was able to underscore the presence of IncP plasmid that was harbouring blaNDMand was maintained within diverse host. The finding also highlights the adaptation of the broad-host-range plasmid that responds in terms of transcriptional expression under antibiotic exposure.

AbstractObjective:Tea (Camellia sinensisLinn.; family: Theaceae) is popular as a stimulant beverage across the globe and is also utilized as a functional antioxidant in alternative medicine. This study has evaluated the impact of seasonal variation on phyto-constituents of tea.Method:The antiproliferative potential of methanolic extracts of tea leaves collected in the rainy season (MECR) was compared with the extract of tea leaves collected in the autumn season (MECA) of the same mother plant. Evaluation of in vivoantitumor activity was carried out in adult female Swiss albino mice groups inoculated with Ehrlich ascites carcinoma (EAC) cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to compare efficacy of MECR with that of MECA in the EAC cell line. Both qualitative and quantitative tests for phytochemical constituents present in MECA and MECR were performed. Antitumor efficacy of both the extracts was determined by evaluating different tumor markers showing dose-dependent cytotoxicity.Results:Statistically significant reduction in EAC-induced tumor was observed in MECR treated mice compared to MECA treated ones. Cell decimation was significantly higher with MECR treatment, where restoration of different parameters including tissue structures returned to normal. Moreover, gas chromatography–mass spectrometry (GC-MS) study revealed the presence of cyclobarbital and benzazulene derivative in MECR, which is thought to be a novel source of these chemicals.Conclusions:To our knowledge, there is no report that has attempted to reveal nutritional changes in terms of efficacy and variation in anticancer constituents in tea leaves, plucked in two seasons. This study revealed a novel source of barbital and benzazulene derivative. The unique presence of cyclobarbital and benzazulene, as revealed from GC-MS data, in methanolic extract of tea leaves collected during the rainy season (MECR) may have contributed to its enhanced in vitro(adopting MTT assay) and in vivo(on EAC-infected Swiss albino mice) cytotoxicity vis-à-vis antiproliferative properties compared to methanolic extract of tea leaves collected during the autumn season (MECA). The nature of plucking leaves in the two selected seasons is different.

The present study investigates the molecular basis of aph-mediated aminoglycoside resistance and their transmission dynamics in a tertiary care hospital of Northeast India. Two hundred forty one isolates (230 Escherichia coliand 11 Klebsiella pneumoniae)were collected and screened for aminoglycoside resistance genes. Various aphtypes were amplified using polymerase chain reaction (PCR) assay. Plasmid incompatibilty, horizontal transferability and ERIC-PCR based typing were carried out for all the positive isolates. Among them, 67 isolates showed the presence of aphgene. Aph (3”)-IIIaand aph (3’)-Viawere predominant and horizontally transferable. All the plasmids were of incompatibility I1 group. Twenty-eight different haplotypes of E. coliwere found harbouring aphgene types. This study was able to identify diverse aphtypes in a single centre and their corresponding phenotypic trait.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a multifaceted transduction system that regulates cellular responses to incoming signaling ligands. STAT3 is a central member of the JAK/STAT signaling cascade and has long been recognized for its increased transcriptional activity in cancers and autoimmune disorders but has only recently been in the spotlight for its role in the progression of kidney disease. Although genetic knockout and manipulation studies have demonstrated the salutary benefits of inhibiting STAT3 activity in several kidney disease models, pharmacological inhibition has yet to make it to the clinical forefront. In recent years, significant effort has been aimed at suppressing STAT3 activation for treatment of cancers, which has led to the development of a wide variety of STAT3 inhibitors, but only a handful have been tested in kidney disease models. Here, we review the detrimental role of dysregulated STAT3 activation in a variety of kidney diseases and the current progress in the treatment of kidney diseases with pharmacological inhibition of STAT3 activity.

ABSTRACTAdipose tissue expansion involves angiogenesis to remodel its capillary network. The enzymemethionine aminopeptidase 2(MetAP2) promotes angiogenesis.MetAP2 inhibitors suppress angiogenesis and have potential anti-obesity effect. However, impairment in adipose tissue expansion is also linked with impaired glycemic control.This study investigated the effect of BL6, a MetAP2 inhibitor, on adipogenesis and glucose disposal.To test effect on angiogenesis, Human Umbilical Vein Endothelial Cells(HUVECs) were treated with BL6 for 24h to determine tube formation. Further, to test effect on adipogenesis and glucose disposal,3T3-L1 pre-adipocytes were treated with BL6(0 µM, 20µM, 50 µM or 100µM) during differentiation. Differentiated cells were stained with Oil Red O for determining lipid accumulation, and glucose uptake assay. Protein levels and RNA expression for key genes involved in the adipogenic cascade were determined.BL6 treatment of HUVECs dose dependently blocked angiogenesis. During differentiation of pre-adipocytes, 50μM and 100µM BL6 significantly reduced lipid accumulation. Treatment with 100µM BL6 significantly decreased expression of adipogenic genes. Interestingly, BL6 treatment dose dependently increased glucose uptake by 3T3-L1 cells.MetAP2 inhibitor blocks angiogenesis, attenuates adipogenesis, yet increases cellular glucose uptake. Collectively this proof of concept study supports a possible role for MetAP2 inhibitor BL6, as a putative anti-obesity therapeutic agent.

Preparation of highly luminescent glasses involves expensive and complicated processes and usually requires high temperature. In this work, we show that luminescent silicon (Si) nanoparticle (NP)- embedded silicate gel glasses can be developed under near-ambient conditions by a remarkably simple, one-pot strategy, without using any sophisticated instrumentation or technique. Simultaneous hydrolysis and reduction of (3-aminopropyl)triethoxysilane leads to the formation of colloidal Si nanocrystals that can be transformed to a glassy phase upon slow evaporation followed by freezing. Structural investigations reveal the formation of a sodium silicate gel glass framework having discernible shear bands, along with embedded Si NPs. High photoluminescence quantum yield (ca. 35–40%), low glass-transition temperature (Tg≈ 66–73 °C), strain-tolerant mechanical stability, and inexpensive preparation make the glass attractive for applications as display materials and photonic converters.

The toxicity of nanomaterials can sometimes be attributed to photogenerated reactive oxygen species (ROS), but these ROS can also be scavenged by nanomaterials, yielding opportunities for crossover between the properties. The morphology of nanomaterials also influences such features due to defect-induced properties. Here we report morphology-induced crossover between pro-oxidant activity (ROS generation) and antioxidant activity (ROS scavenging) of MgO. To study this process in detail, we prepared three different nanostructures of MgO (nanoparticles, nanoplates, and nanorods) and characterized them by HRTEM. These three nanostructures effectively generate superoxide anions (O2•–) and hydroxyl radicals (•OH) at higher concentrations (>500 μg/mL) but scavenge O2•–at lower concentrations (40 μg/mL) with successful crossover at 200 μg/mL. Nanorods of MgO generate the highest levels of O2•–, whereas nanoparticles scavenge O2•–to the highest extent (60%). Photoluminescence studies reveal that such crossover is based on the suppression of F2+and the evolution of F+, F2+, and F23+defect centers. The evolution of these defect centers reflects the antibacterial activity of MgO nanostructures which is initiated at 200 μg/mL against Gram-positive S. aureusATCC 29737 and among different bacterial strains including Gram-positive B. subtilisATCC 6633 and M. luteusATCC 10240 and Gram-negative E. coliATCC K88 and K. pneumoniaeATCC 10031. Nanoparticles exhibited the highest antibacterial (92%) and antibiofilm activity (17%) against B. subtilisATCC 6633 in the dark. Interestingly, the nitrogen-centered free radical DPPH is scavenged (100%) by nanoplates due to its large surface area (342.2 m2/g) and the presence of the F2+defect state. The concentration-dependent interaction with an antioxidant defense system (ascorbic acid (AA)) highlights nanoparticles as potent scavengers of O2•–in the dark. Thus, our findings establish guidelines for the selection of MgO nanostructures for diverse therapeutic applications.

Podocyte injury and loss contribute to the progression of glomerular diseases, including diabetic kidney disease. We previously found that the glomerular expression of Sirtuin-1 (SIRT1) is reduced in human diabetic glomeruli and that the podocyte-specific loss of SIRT1 aggravated albuminuria and worsened kidney disease progression in diabetic mice. SIRT1 encodes an NAD-dependent deacetylase that modifies the activity of key transcriptional regulators affected in diabetic kidneys, including NF-κB, STAT3, p53, FOXO4, and PGC1-α. However, whether the increased glomerular SIRT1 activity is sufficient to ameliorate the pathogenesis of diabetic kidney disease has not been explored. We addressed this by inducible podocyte-specific SIRT1 overexpression in diabetic OVE26 mice. The induction of SIRT1 overexpression in podocytes for six weeks in OVE26 mice with established albuminuria attenuated the progression of diabetic glomerulopathy. To further validate the therapeutic potential of increased SIRT1 activity against diabetic kidney disease, we developed a new, potent and selective SIRT1 agonist, BF175. In cultured podocytes BF175 increased SIRT1-mediated activation of PGC1-α and protected against high glucose-mediated mitochondrial injury. In vivo, administration of BF175 for six weeks in OVE26 mice resulted in a marked reduction in albuminuria and in glomerular injury in a manner similar to podocyte-specific SIRT1 overexpression. Both podocyte-specific SIRT1 overexpression and BT175 treatment attenuated diabetes-induced podocyte loss and reduced oxidative stress in glomeruli of OVE26 mice. Thus, increased SIRT1 activity protects against diabetes-induced podocyte injury and effectively mitigates the progression of diabetic kidney disease.

Aging and moisture damage are considered as major environmental factors which affect the performance of bituminous mixtures. This study investigated the effect of aging and moisture invasion on the performance of bituminous mixtures in terms of tensile strength and rutting resistance. Two different types of aggregates sources and one unmodified bituminous binder with and without warm additive were used. Bituminous mixtures were subjected to two levels of aging conditions (short-term and long-term aged) and two levels of moisture conditions (1 and 3 freeze-thaw cycles). A total of 24 different combinations were investigated for tensile strength and permanent deformation characteristics. Mineralogical investigations characterized the crushed stone as calcareous and bank run as siliceous aggregates. Results from this study demonstrate that levels of aging had a significant impact on the tensile strength of bituminous mixtures with warm mix additive as compared to conventional bituminous mixtures. Fracture work density, a surrogate cracking parameter was able to adequately capture the influence of aggregate mineralogy on the moisture susceptibility of long term aged mixtures. In addition, moisture conditioning was found to influence fracture work density of mixtures more than aging. Further, the rutting resistance of mixtures was determined in terms of flow numbers obtained using Francken model. In general, the rutting resistance of conventional mixtures was relatively higher than a mixture with warm mix additive. As expected, the flow number of conventional mixtures increased with aging and further reduced with moisture conditioning. Interestingly, the flow numbers of bituminous mixtures with warm mix additive was not negatively impacted by moisture at short term aged conditions. However, flow number of both mixtures after long term aging exhibited a similar trend. Additionally, statistical analysis showed that an increase in freeze-thaw cycles from one to three did not significantly impact the tensile characteristics of the mixtures.

Diffuse large B-cell lymphomas (DLBCLs) contain 2 major molecular subtypes; namely, the germinal center B-cell-like (GCB) and the activated B-cell-like (ABC) DLBCLs. It is well documented that ABC-DLBCL cases have a significantly poorer survival response than GCB-DLBCLs in both the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and the rituximab (R)-CHOP eras. However, the underlying cause of this subtype disparity is poorly understood. Nevertheless, these clinical observations raise the possibility for an ABC-DLBCL–specific resistance mechanism that is directed toward 1 of the CHOP components and is inadequately addressed by rituximab. Here, we report that the main cytotoxic ingredient in CHOP, doxorubicin (Dox), has subtype-specific mechanisms of cytotoxicity in DLBCLs resulting from differences in the subcellular distribution pattern. Specifically, in cell line models of ABC-DLBCL, Dox is often enriched in the cytoplasm away from the nuclear DNA. As a result, Dox-induced cytotoxicity in ABC-DLBCLs is often dependent on oxidative stress, rather than DNA damage response. These findings are corroborated by gene signature analysis, which demonstrates that basal oxidative stress status predicts treatment outcome among patients with ABC-DLBCL, but not patients with GCB-DLBCL. In terms of redox-related resistance mechanism, our results suggest that STAT3 confers Dox resistance in ABC-DLBCLs by reinforcing an antioxidant program featuring upregulation of the SOD2 gene. Furthermore, a small-molecule STAT3 inhibitor synergizes with CHOP to trigger oxidative stress and kill ABC-DLBCL cells in preclinical models. These results provide a mechanistic basis for development of novel therapies that target either STAT3 or redox homeostasis to improve treatment outcomes for ABC-DLBCLs.

Diffuse large B-cell lymphomas (DLBCLs) contain 2 major molecular subtypes; namely, the germinal center B-cell-like (GCB) and the activated B-cell-like (ABC) DLBCLs. It is well documented that ABC-DLBCL cases have a significantly poorer survival response than GCB-DLBCLs in both the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and the rituximab (R)-CHOP eras. However, the underlying cause of this subtype disparity is poorly understood. Nevertheless, these clinical observations raise the possibility for an ABC-DLBCL–specific resistance mechanism that is directed toward 1 of the CHOP components and is inadequately addressed by rituximab. Here, we report that the main cytotoxic ingredient in CHOP, doxorubicin (Dox), has subtype-specific mechanisms of cytotoxicity in DLBCLs resulting from differences in the subcellular distribution pattern. Specifically, in cell line models of ABC-DLBCL, Dox is often enriched in the cytoplasm away from the nuclear DNA. As a result, Dox-induced cytotoxicity in ABC-DLBCLs is often dependent on oxidative stress, rather than DNA damage response. These findings are corroborated by gene signature analysis, which demonstrates that basal oxidative stress status predicts treatment outcome among patients with ABC-DLBCL, but not patients with GCB-DLBCL. In terms of redox-related resistance mechanism, our results suggest that STAT3 confers Dox resistance in ABC-DLBCLs by reinforcing an antioxidant program featuring upregulation of the SOD2gene. Furthermore, a small-molecule STAT3 inhibitor synergizes with CHOP to trigger oxidative stress and kill ABC-DLBCL cells in preclinical models. These results provide a mechanistic basis for development of novel therapies that target either STAT3 or redox homeostasis to improve treatment outcomes for ABC-DLBCLs.

Introduction:Although the medicinal use of boron-containing compounds (BCCs) had long been limited to antiseptics, in the last few decades, these compounds have been used as antibiotics or chemotherapeutic agents. In the last few years, boron has been included in the moieties of many known drugs to improve their capacity in binding to their respective target receptors.Areas covered:The current review focuses on research and patent literature of the last decade related to the development of BCCs as preventive, diagnostic and therapeutic tools. It explores the possible mechanisms of action of these compounds as well as the advantageous features of their structure and chemico-pharmacological properties.Expert opinion:Although uncertainties exist about the mechanism of action of BCCs, increasing evidence about their toxicological profile strongly suggests that many can be safely administered to humans. Even stronger evidence exists regarding the capacity of BCCs to reach multiple targets that are involved in the treatment of common diseases. It seems fair to say that some BCCs will reach the market for medicinal use in the near future, not only for targeting microbial or neoplastic systems but also for acting on cell-signaling processes involved in many other disorders.

The pregnane X receptor (PXR) is a master regulator of xenobiotic clearance and is implicated in deleterious drug interactions (e.g., acetaminophen hepatotoxicity) and cancer drug resistance. However, small-molecule targeting of this receptor has been difficult; to date, directed synthesis of a relatively specific PXR inhibitor has remained elusive. Here we report the development and characterization of a first-in-class novel azole analog [1-(4-(4-(((2R,4S)-2-(2,4-difluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)ethanone (FLB-12)] that antagonizes the activated state of PXR with limited effects on other related nuclear receptors (i.e., liver X receptor, farnesoid X receptor, estrogen receptor α, peroxisome proliferator-activated receptor γ, and mouse constitutive androstane receptor). We investigated the toxicity and PXR antagonist effect of FLB-12 in vivo. Compared with ketoconazole, a prototypical PXR antagonist, FLB-12 is significantly less toxic to hepatocytes. FLB-12 significantly inhibits the PXR-activated loss of righting reflex to 2,2,2-tribromoethanol (Avertin) in vivo, abrogates PXR-mediated resistance to 7-ethyl-10-hydroxycamptothecin (SN-38) in colon cancer cells in vitro, and attenuates PXR-mediated acetaminophen hepatotoxicity in vivo. Thus, relatively selective targeting of PXR by antagonists is feasible and warrants further investigation. This class of agents is suitable for development as chemical probes of PXR function as well as potential PXR-directed therapeutics.

Mitogen-activated protein kinase (MAPK) pathways are major signal transduction systems by which eukaryotic cells convert environmental cues to intracellular events such as proliferation and differentiation.  We have identified a Trypanosoma cruzihomologue of the MAPK family that we have called TcMAPK2.  Sequence analyses demonstrates TcMAPK2 has high homology with lower eukaryotic ERK2 but has significant differences from mammalian ERK2.  Enzymatic assays of both recombinant TcMAPK2 and native protein obtained by immunoprecipitation using anti-TcMAPK2 demonstrated that both preparations of TcMAPK2 were catalytically active.  Immunofluorescence analysis of the subcellular localization of TcMAPK2 determined it is mainly cytoplasmic in epimastigotes, along the flagella in trypomastigotes and on the plasma membrane of intracellular amastigotes.  Phosphorylated TcMAPK2 was highest in trypomastigotes and lowest in amastigotes.  Recombinant TcMAPK2 was able to phosphorylate the recombinant protein of a cAMP specific phosphodiesterase.  Over-expression of TcMAPK2 in epimastigotes inhibited growth and development leading to death.  TcMAPK2 has an important role in the stress response of the parasite and may be important in regulating proliferation and differentiation.

This study comprehensively evaluated different parameters based on tensile strength testing to assess the cracking resistance of asphalt mixtures subjected to aging and moisture conditioning. For this purpose, two sources of aggregates were selected to produce hot and warm mix asphalt mixtures. Asphalt mixtures were subjected to short term and long term aging, three levels of moisture conditioning (freeze thaw cycles), and tested at two temperatures (15 °C and 25 °C). The load-displacement data was used to determine the fracture work density, fracture energy, toughness index, cracking resistance index, cracking tolerance index, and rate dependent cracking index. It was noticed that moisture conditioning increased the variability of the different parameters. The cracking tolerance index and rate dependent cracking index parameter hada much higher coefficient of variation (CoV) with a maximum value close to 50%. Indirect tensile strength, fracture energy, and fracture work density appropriately captured the effect of moisture on cracking resistance of mixtures. The cracking resistance index, cracking tolerance index, and rate dependent cracking index increased with an increase in the moisture conditioning level. The Statistical analysis showed that tensile strength, fracture work density, and fracture energy were significantly influenced by different aging and moisture conditions evaluated. Fracture energy showed better association with fatigue life of asphalt mixtures subjected to three freeze-thaw cycles compared to tensile strength. Further, the fatigue life prediction models showed that both indirect tensile strength and fracture energy significantly influence the fatigue life of asphalt mixtures subjected to aging and moisture conditioning.

Enzyme-mimicking activities of different nanomaterials (nanozymes) and the recent progress in the construction of nanozyme-based biosensors with various examples are discussed in this review.Physicochemical properties of nanomaterials (size, composition, pH, temperature, surface chemistry) play crucial role in the nanozyme activities.The emerging nanozyme-based biosensors promise great potential for point-of-care diagnostic applications following the ASSURED criteria defined by WHO.

The capability of gold nanomaterials to mimic enzyme activities offers new approaches for diagnosis and treatment in the field of biomedicine, which are discussed in this review.Controlling the physicochemical properties of the nanomaterials (size, morphology and surface chemistry) remains the first obstacle for endeavouring real-life applications.Numerous examples of ex vivo applications in the field of diagnosis are a reality today, whereas further controlling side effects is required for in vivo applications like tumour treatment or intracellular ROS level control.

MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor–β (TGF-β) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34+ cells, providing direct evidence of overactivation of TGF-β pathway in this disease. Suppression of the TGF-β signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-β–mediated gene activation in BM stromal cells, and reverses TGF-β–mediated cell-cycle arrest in BM CD34+ cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-β1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-β signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.

MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor–β (TGF-β) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34+cells, providing direct evidence of overactivation of TGF-β pathway in this disease. Suppression of the TGF-β signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-β–mediated gene activation in BM stromal cells, and reverses TGF-β–mediated cell-cycle arrest in BM CD34+cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-β1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-β signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.