Visible-Light-Promoted Metal- and Photocatalyst-Free Reactions between Arylglyoxylic Acids and Tetraalkylthiuram Disulfides: Synthesis of α-Ketoamides.

A convenient and new synthetic approach has been developed for the oxidative cross-coupling of the C-N bond through the reaction between arylglyoxylic acids and tetraalkylthiuram disulfides. The reaction proceeds under ambient air at room temperature in the presence of visible light. This reaction offers a metal-, base-, photocatalyst-, and solvent-free synthesis of various α-ketoamides with moderate to excellent yields via the radical pathway. In addition, this protocol demonstrates the potential application of a gram-scale synthesis.

Recent Trends in the Antidiabetic Prominence of Natural and Synthetic Analogues of Aurones.

Natural products are a boundless source for the development of pharmaceutical agents against a wide range of human diseases. Accordingly, naturally occurring aurones possess various biological benefits, such as anticancer, antioxidant, antimicrobial, antidiabetic, anti-inflammatory, antiviral and neuroprotective effects. In addition, various studies have revealed that aurones are potential templates for the regulation of diabetes mellitus and its associated complications. Likewise, certain aurones and their analogues have been found to be remarkable kinase inhibitors of DARK2, PPAR-γ, PTPM1, AGE, α-amylase and α-glucosidase, which represents a promising approach for the treatment of chronic metabolic disorders such as diabetes. Therefore, in our present study, we provide a detailed account of the advances in aurones as antidiabetic agents over the past decade.

Brønsted acidic ionic liquid-catalyzed tandem reaction: an efficient and sustainable approach towards the regioselective synthesis and molecular docking studies of 4-hydroxycoumarin-substituted indoles bearing lower E-factors.

1-Butane sulfonic acid-3-methylimidazolium tosylate, [BSMIM]OTs, is a remarkable catalyst for the cascade synthesis of coumarin-functionalized indole derivatives via a tandem cyclization reaction of aniline and phenylglyoxal monohydrate. This reaction possibly proceeds through imine formation/nucleophilic addition/cyclization. In addition, this method shows lower E-factors. A clean reaction, easily accessible reactants, metal-free and environmentally friendly reaction conditions, and reusability of the catalyst are the notable advantages of this procedure. In addition, molecular docking studies show the theoretical possibility of binding these types of synthesized compounds to key proteins in tumorigenesis.

2,7-Diazapyrenes: a brief review on synthetic strategies and application opportunities.

2,7-Diazapyrenes are promising azaaromatic scaffolds with a unique structural geometry and supramolecular properties. This core moiety and its derivatives with some N-methyl cations like N-methyl-2,7,-diazapyrenium, and N,N'-dimethyl-2,7-diazapyrenium attract special attention due to their challenging photophysical properties, especially in the context of interactions with DNA and some of its mononucleotides. This review focuses on the analysis of the main synthetic approaches to 2,7-diazapyrene and its functional derivatives employing various strategies under different reaction conditions. The opportunities of applications of 2,7-diazapyrenes, including their remarkable photophysical and supramolecular properties, DNA-bindings, in sensors, molecular electronics, supramolecular systems, and related areas are also highlighted.

Leptin Receptor q223r Polymorphism Influences Clostridioides difficile Infection-Induced Neutrophil CXCR2 Expression in an Interleukin-1ß Dependent Manner.

Neutrophils are key first-responders in the innate immune response to C. difficile infection (CDI) and play a central role in disease pathogenesis. Studies have clearly shown that tissue neutrophil numbers need to be tightly regulated for optimal CDI outcomes: while excessive colonic neutrophilia is associated with severe CDI, neutrophil depletion also results in worse outcomes. However, the biological mechanisms that control CDI-induced neutrophilia remain poorly defined. C-X-C chemokine receptor 2 (CXCR2) is a chemotactic receptor that is critical in neutrophil mobilization from bone marrow to blood and tissue sites. We have previously reported that a single nucleotide polymorphism (SNP) in leptin receptor (LEPR), present in up to 50% of people, influenced CDI-induced neutrophil CXCR2 expression and tissue neutrophilia. Homozygosity for mutant LEPR (i.e. RR genotype) was associated with higher CXCR2 expression and more tissue neutrophils. Here, we investigated the biological mechanisms that regulate neutrophil CXCR2 expression after CDI, and the influence of host genetics on this process. Our data reveal that: a) CXCR2 plays a key role in CDI-induced neutrophil extravasation from blood to colonic tissue; b) plasma from C. difficile-infected mice upregulated CXCR2 on bone marrow neutrophils; c) plasma from C. difficile-infected RR mice induced a higher magnitude of CXCR2 upregulation and had more IL-1ß; and d) IL-1ß neutralization reduced CXCR2 expression on bone marrow and blood neutrophils and their subsequent accrual to colonic tissue. In sum, our data indicate that IL-1ß is a key molecular mediator that communicates between gastro-intestinal tract (i.e. site of CDI) and bone marrow (i.e. primary neutrophil reservoir) and regulates the intensity of CDI-induced tissue neutrophilia by modulating CXCR2 expression. Further, our studies highlight the importance of host genetics in affecting these innate immune responses and provide novel insights into the mechanisms by which a common SNP influences CDI-induced neutrophilia.

Moving up the On-Site Sanitation ladder in urban India through better systems and standards.

Wastewater management predominantly takes the form of On-Site Sanitation (OSS) in low- and lower-middle-income countries (LMICs). In India, households construct and operate OSS systems in the absence of regulatory oversight and seldom in compliance with the national technical standards - posing a risk to water sources and public health. The present paper reviews novel evidence on the quality of these systems from a multi-state survey of 3000 households in India to identify policy and practice interventions for creating sustainable urban sanitation futures. The paper argues for local and national governments to unlock the potential of OSS as a safe and long-term wastewater management solution through (1) re-envisioning the system design to simultaneously meet household and environmental needs, (2) fostering prefabrication of systems as a means to distribute the compliance responsibility optimally, and (3) updating technical standards for facilitating such a paradigm shift.

Obeticholic acid ameliorates severity of Clostridioides difficile infection in high fat diet-induced obese mice.

Severe Clostridiodes difficile infection (CDI) is life-threatening and responds poorly to treatment. Obesity is associated with development of severe CDI. Therefore, to define the mechanisms that exacerbate disease severity, we examined CDI pathogenesis in high-fat diet (HFD)-fed obese mice. Compared to control mice, HFD-fed mice failed to clear C. difficile bacteria which resulted in protracted diarrhea, weight loss and colonic damage. After infection, HFD-induced obese mice had an intestinal bile acid (BA) pool that was dominated by primary BAs which are known promoters of C. difficile spore germination, and lacked secondary BAs that inhibit C. difficile growth. Concurrently, synthesis of primary BAs from liver was significantly increased in C. difficile-infected HFD-fed mice. A key pathway that regulates hepatic BA synthesis is via feedback inhibition from intestinal Farnesoid X receptors (FXRs). Our data reveal that the proportion of FXR agonist BAs to FXR antagonist BAs in the intestinal lumen was significantly reduced in HFD-fed mice after CDI. Treatment of HFD-fed mice with an FXR agonist Obeticholic acid, resulted in decreased primary BA synthesis, fewer C. difficile bacteria and better CDI outcomes. Thus, OCA treatment holds promise as a therapy for severe CDI.

Facile synthesis of substituted quinolines by iron(iii)-catalyzed cascade reaction between anilines, aldehydes and nitroalkanes.

A library of substituted quinolines has been synthesized by the reaction of aldehydes, anilines and nitroalkanes using a catalytic amount of Fe(iii) chloride. The reaction is a simple, efficient, one-pot, three-component domino strategy in ambient air which afforded the products in high yields. A probable pathway of the reaction is a sequential aza-Henry reaction/cyclization/denitration. The use of commercially available chemicals as starting materials, an inexpensive metal catalyst, aerobic reaction conditions, tolerance of a wide range of functional groups, and operational simplicity are the notable advantages of this present protocol.

Impact of Different Sociodemographic Factors on Mental Health Status of Female Cancer Patients Receiving Chemotherapy for Recurrent Disease.

CONTEXT: Deterioration in mental health and poor quality of life (QOL) among women suffering from breast and ovarian cancer is not a direct result of the illness but mediated by many other psychosocial variables. AIMS: The study intended to examine if there was any effect of educational level, residential status, family type, duration of treatment, and income level of family on anxiety, depression, and QOL among the breast and ovarian cancer patients, undergoing second- or subsequent-line chemotherapy. SUBJECTS AND METHODS: Forty married female cancer patients with breast and ovarian cancer, aging between 40 and 60 years, education level ranges from no formal education to postgraduate degree, income level ranges from Rs. 1000 per month to Rs. 20000 per month, and undergoing second- or subsequent-line chemotherapy for the past 1-10 years were studied. Levels of anxiety and depression were determined by Hospital Anxiety and Depression Scale. The QOL was measured by using WHO QOLBREF scale. STATISTICAL ANALYSIS USED: Mean and standard deviation and Levene's F values were calculated. If Levene's F value was significant, then Mann-Whitney U-test was done or else independent samples t-test was used. RESULTS: Among all the variables, education, residential status, and income affect significantly on anxiety, depression, and QOL. CONCLUSIONS: Early detection of psychosocial variables is essential for better screening of the cancer patients undergoing chemotherapy, and therefore, further psychological intervention can be planned accordingly.

Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection.

Clostridium difficile is an important cause of nosocomial diarrhea in the western world. Toxins (A, B, and binary toxins) generated by C. difficile bacteria damage intestinal epithelial cells. Hallmarks of host response to C. difficile infection (CDI) include upregulation of inflammatory mediators and tissue infiltration by immune cells. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that is known to enhance the host immune response to infectious pathogens. Additionally, MIF can adversely impact host survival to numerous infections. The role of MIF in the pathogenesis of CDI remains poorly understood. Here, we show that patients with CDI had significantly higher circulating MIF compared to patients who had diarrhea but tested negative for C. difficile (non-CDI controls). Similarly, in a mouse model, C. difficile challenge significantly increased levels of plasma and tissue MIF. Antibody-mediated depletion of MIF decreased C. difficile-induced inflammatory responses, clinical disease, and mortality. Together, these results uncover a potential role for MIF in exacerbating CDI and suggest that use of anti-MIF antibodies may represent a therapeutic strategy to curb host inflammatory responses and improve disease outcomes in CDI.

Effect of Supportive Psychotherapy on Mental Health Status and Quality of Life of Female Cancer Patients Receiving Chemotherapy for Recurrent Disease.

CONTEXT: Cancer patients receiving chemotherapy for their recurrent disease often report the presence of anxiety and depression. AIMS: In the study, we intended to find out the mental health status and overall quality of life (QOL) of such patients and to identify the effect of supportive psychotherapy. SUBJECTS AND METHODS: Forty cancer patients undergoing second or subsequent line chemotherapy(CCT) were selected for psychotherapy session. Pre- and post-psychotherapy evaluation of anxiety and depression was determined by hospital anxiety depression scale. The QOL was measured before and after psychotherapy sessions by using WHO QOL-BREF scale. STATISTICAL ANALYSIS USED: Statistical analysis was done by paired t-test, using SPSS V.20. RESULTS: Among 40 patients, 17 patients had breast cancer, and the remaining had ovarian cancer. All breast cancer and 19 ovarian cancer patients were receiving 2nd line CCT. Four ovarian cancer patients were undergoing 3rd line CCT. Results indicated that mean scores (± standard deviation) of anxiety 13.95 (±4) and depression 15.5 (±4.4) both exceeded the cut-off score of 11 and mean score of QOL physical health 29.77 (±10.1), psychological health 31.3 (±10.1), social relationship 35.1 (±9.6), and environmental condition 25.9 (±9.9) was below cut-off score of 60. After psychotherapy, there was significant reduction in anxiety (P < 0.01), depression (P < 0.01) and improvement on QOL physical heath (P = 0.02), psychological health (P < 0.01), environmental condition (P < 0.01), and social relationship (P < 0.01). CONCLUSIONS: Supportive psychotherapy helps to reduce the level of anxiety, depression, and increase the QOL. Therefore, psychotherapeutic intervention should be encouraged along with chemotherapy to promote positive mental health and to obtain full benefit of their physical treatment.

Early axis growth during seed germination is gravitropic and mediated by ROS and calcium.

In plant establishment, seed germination is characterized by the emergence of a radicle for secured anchorage to the soil and nutrient and water uptake. Early growth of germinating axes appears to be gravisensitive, and the regulation of this process is largely uncharacterized, particularly in case of epigeally germinating species. Our previous work on the germination of Vigna radiata seeds demonstrated the role of apoplastic reactive oxygen species (ROS) in germination-associated axis growth. This study attempts to explore a possibly similar role of ROS in the gravitropic bending of germinating axes. Pharmacological and histological studies correlated the curvature growth of the axis (due to cell elongation in the cortical region of the upper side) with apoplastic superoxide accumulation. The superoxide was produced by diphenylene iodonium chloride (DPI)-insensitive NADH oxidase, which was different from the DPI-sensitive NADPH oxidase active in the apical elongation zone of the radicle. This NADH oxidase was differentially controlled by IAA, and its activation required influx of apoplastic Ca2+. This study shows that the early axis growth in germinating seeds is gravisensitive, which is distinct spatially as well as temporally from the elongation growth of the axis (radicle) and controlled by auxin and cytosolic Ca2+ through NADH oxidase-dependent ROS production.

Selective endosomal microautophagy is starvation-inducible in Drosophila.

Autophagy delivers cytosolic components to lysosomes for degradation and is thus essential for cellular homeostasis and to cope with different stressors. As such, autophagy counteracts various human diseases and its reduction leads to aging-like phenotypes. Macroautophagy (MA) can selectively degrade organelles or aggregated proteins, whereas selective degradation of single proteins has only been described for chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI). These 2 autophagic pathways are specific for proteins containing KFERQ-related targeting motifs. Using a KFERQ-tagged fluorescent biosensor, we have identified an eMI-like pathway in Drosophila melanogaster. We show that this biosensor localizes to late endosomes and lysosomes upon prolonged starvation in a KFERQ- and Hsc70-4- dependent manner. Furthermore, fly eMI requires endosomal multivesicular body formation mediated by ESCRT complex components. Importantly, induction of Drosophila eMI requires longer starvation than the induction of MA and is independent of the critical MA genes atg5, atg7, and atg12. Furthermore, inhibition of Tor signaling induces eMI in flies under nutrient rich conditions, and, as eMI in Drosophila also requires atg1 and atg13, our data suggest that these genes may have a novel, additional role in regulating eMI in flies. Overall, our data provide the first evidence for a novel, starvation-inducible, catabolic process resembling endosomal microautophagy in the Drosophila fat body.

The Formin DAAM Functions as Molecular Effector of the Planar Cell Polarity Pathway during Axonal Development in Drosophila.

Recent studies established that the planar cell polarity (PCP) pathway is critical for various aspects of nervous system development and function, including axonal guidance. Although it seems clear that PCP signaling regulates actin dynamics, the mechanisms through which this occurs remain elusive. Here, we establish a functional link between the PCP system and one specific actin regulator, the formin DAAM, which has previously been shown to be required for embryonic axonal morphogenesis and filopodia formation in the growth cone. We show that dDAAM also plays a pivotal role during axonal growth and guidance in the adult Drosophila mushroom body, a brain center for learning and memory. By using a combination of genetic and biochemical assays, we demonstrate that Wnt5 and the PCP signaling proteins Frizzled, Strabismus, and Dishevelled act in concert with the small GTPase Rac1 to activate the actin assembly functions of dDAAM essential for correct targeting of mushroom body axons. Collectively, these data suggest that dDAAM is used as a major molecular effector of the PCP guidance pathway. By uncovering a signaling system from the Wnt5 guidance cue to an actin assembly factor, we propose that the Wnt5/PCP navigation system is linked by dDAAM to the regulation of the growth cone actin cytoskeleton, and thereby growth cone behavior, in a direct way.

catena-Poly[[(triphenyl-phosphane)copper(I)]-di-µ-iodido-[(triphenyl-phosphane)copper(I)]-µ-{1,2-bis-[1-(pyridin-4-yl)ethyl-idene]hydrazine}].

In the title coordination polymer, [Cu(2)I(2)(C(14)H(14)N(4))(C(18)H(15)P)(2)](n), the Cu(I) atom is coordinated by two I atoms, one P atom and one N atom in a fairly regular tetra-hedral arrangement. A crystallographic inversion centre generates a Cu(2)I(2) diamond with a Cu-Cu separation of 3.0120 (5) Å. The complete N,N'-(1-pyridin-4-yl-ethethyl-idene)-hydrazine mol-ecule is also generated by inversion symmetry, and this bridging ligand leads to [011] polymeric chains in the crystal structure.

Multicolor photoswitching microscopy for subdiffraction-resolution fluorescence imaging.

We introduce a general approach for multicolor subdiffraction-resolution fluorescence imaging based on photoswitching of standard organic fluorophores. Photoswitching of ordinary fluorophores such as ATTO520, ATTO565, ATTO655, ATTO680, or ATTO700, i.e. the reversible transition from a fluorescent to a nonfluorescent state in aqueous buffers exploits the formation of long-lived triplet radical anions through reaction with reducing agents such as beta-mercaptoethylamine and repopulation of the singlet ground state by interaction with molecular oxygen. Thus, the time the different fluorophores reside in the fluorescent state can be easily adjusted by the excitation intensity and the concentration of the reducing agent. We demonstrate the potential of multicolor photoswitching microscopy with subdiffraction-resolution on cytoskeletal networks and molecular quantification of proteins in the inner mitochondrial membrane with approximately 20 nm optical resolution.

N,N'-Bis(4-pyridylmethyl-ene)octane-1,8-diamine.

The complete molecule of the title compound, C(20)H(26)N(4), is generated by a crystallographic centre of inversion and the central eight-carbon chain adopts a fully extended conformation. In the crystal, the molecules pack in layers parallel to (010).

Benzil bis-(ketazine).

THE TITLE COMPOUND (SYSTEMATIC NAME: 1,1',2,2'-tetra-phenyl-2,2'-azinodiethanone), C(28)H(20)N(2)O(2), was obtained by the reaction of benzil monohydrazone with chromium(III) nitrate. The dibenzyl-idene hydrazine unit is nearly planar (r.m.s. deviation = 0.073 Å) and the two benzoyl units are oriented almost perpendicular to it [dihedral angle = 87.81 (2), 87.81 (2)°]. The mol-ecules are linked into chains along the c axis by C-H⋯O hydrogen bonds and the chains are cross-linked via C-H⋯π inter-actions involving the benzoyl phenyl rings.