Quest for a Desolvated Structure Unveils Breathing Phenomena in a MOF Leading to Greener Catalysis in a Solventless Setup: Insights from Combined Experimental and Computational Studies.

The crystal structure of the metal-organic framework (MOF), {Mn2(1,4-bdc)2(DMF)2}n (1) (1,4-bdcH2, 1,4-benzenedicarboxylic acid; DMF, N,N-dimethylformamide), is known for a long time; however, its desolvated structure, {Mn2(1,4-bdc)2}n (1'), is not yet known. The first-principles-based computational simulation was used to unveil the structure of 1' that shows the expansion in the framework, leading to pore opening after the removal of coordinated DMF molecules. We have used 1' that contains open metal sites (OMSs) in the structure in cyanosilylation and CO2 cycloaddition reactions and recorded complete conversions in a solventless setup. The pore opening in 1' allows the facile diffusion of small aldehyde molecules into the channels, leading to complete conversion. The reactions with larger aldehydes, 2-naphthaldehyde and 9-anthracenecarboxaldehyde, also show 99.9% conversions, which are the highest reported until date in solventless conditions. The in silico simulations illustrate that larger aldehydes interact with Mn(II) OMSs on the surfaces, enabling a closer interaction and facilitating complete conversions. The catalyst shows high recyclability, exhibiting 99.9% conversions in the successive reaction cycles with negligible change in the structure. Our investigations illustrate that the catalyst 1' is economical, efficient, and robust and allows reactions in a solventless greener setup, and therefore the catalysis with 1' can be regarded as "green catalysis".

Anticancer mechanism of coumarin-based derivatives.

The structural motif of coumarins is related with various biological activities and pharmacological properties. Both natural coumarin extracted from various plants or a new coumarin derivative synthesized by modification of the basic structure of coumarin, in vitro experiments showed that coumarins are a promising class of anti-tumor agents with high selectivity. Cancer is a complex and multifaceted group of diseases characterized by the uncontrolled and abnormal growth of cells in the body. This review focuses on the anticancer mechanism of various coumarins synthesized and isolated in more than a decade. Isopentenyloxycoumarins inhibit angiogenesis by reducing CCl2 chemokine levels. Ferulin C is a potent colchicine-binding agent that destabilizes microtubules, exhibiting antiproliferative and anti-metastatic effects in breast cancer cells through PAK1 and PAK2-mediated signaling. Trimers of triphenylethylene-coumarin hybrids demonstrated significant proliferation inhibition in HeLa, A549, K562, and MCF-7 cell lines. Platinum(IV) complexes with 4-hydroxycoumarin have the potential for high genotoxicity against tumor cells, inducing apoptosis in SKOV-3 cells by up-regulating caspase 3 and caspase 9 expression. Derivatives of 3-benzyl coumarin seco-B-ring induce apoptosis, mediated through the PI3K/Akt/mTOR signaling pathway. Sesquiterpene coumarins inhibit the efflux pump of multidrug resistance-associated protein. Coumarin imidazolyl derivatives inhibit the aromatase enzyme, a major contributor to estrogen overproduction in estrogen-dependent breast cancer.

Biocompatible Drug Delivery System Based on a MOF Platform for a Sustained and Controlled Release of the Poorly Soluble Drug Norfloxacin.

Norfloxacin (NFX), an important antibacterial fluoroquinolone, is a class IV drug according to the biopharmaceutics classification system (BCS) and has low solubility and permeability issues. Such poor physicochemical properties of drug molecules lead to poor delivery and are of serious concern to the pharmaceutical industry for clinical development. We present here a conceptually new approach to deliver NFX, by loading the drug molecule on the porous platform of a biocompatible metal-organic framework (MOF), MIL-100(Fe). The loading of the drug on the MOF leading to NFX@MIL-100(Fe) was characterized by Fourier transform infrared (FTIR), UV-visible spectroscopy, thermogravimetric analyses (TGA), and nitrogen adsorption studies. Controlled experiments resulted in the high loading of the drug molecule (∼20 wt %) along with the desired sustained release. We could further control the release of norfloxacin by coating drug-loaded MIL-100(Fe) with PEG, PEG{NFX@MIL-100(Fe)}. Both drug delivery systems (DDSs), NFX@MIL-100(Fe) and PEG{NFX@MIL-100(Fe)}, were tested for their biocompatibility through toxicity studies. The DDSs are biocompatible and show insignificant cytotoxicity, as revealed by cell viability studies through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.

Hypoxic pulmonary vascular response can screen subclinical lifestyle disease in healthy population.

OBJECTIVE: Subclinical life style disease can cause endothelial dysfunction associated with perfusion abnormalities and reduced vascular compliance. Subclinical elevated beta type natriuretic peptide (BNP) has been associated with altered fluid shift from extra to intracellular space during acute hypoxia. Therefore we measured vascular response and BNP levels during acute hypoxia to study endothelial functions among healthy individuals. METHODS: Individuals were exposed to acute normobaric hypoxia of FiO2 = 0.15 for one hour in supine position and their pulmonary and systemic vascular response to hypoxia was compared. Individuals were divided into two groups based on either no response (Group 1) or rise in systolic pulmonary artery pressure to hypoxia (Group 2) and their BNP levels were compared. RESULTS: BNP was raised after hypoxia exposure in group 2 only from 18.52 ± 7 to 21.56 ± 10.82 picogram/ml, p < 0.05. Group 2 also showed an increase in mean arterial pressure and no fall in total body water in response to acute hypoxia indicating decreased endothelial function compared to Group 1. CONCLUSION: Rise in pulmonary artery pressure and BNP level in response to acute normobaric hypoxia indicates reduced endothelial function and can be used to screen subclinical lifestyle disease among healthy population.

Open metal site (OMS)-inspired investigation of adsorption and catalytic functions in a porous metal-organic framework (MOF).

In this article, we report the adsorption and catalytic study of the three-dimensional (3D) metal-organic framework (MOF) {Mn2(1,4-bdc)2(DMF)2} (1) (1,4-bdcH2, 1,4-benzene dicarboxylic acid; DMF, N,N-dimethylformamide) together with the synthesis and structure of two new Mn(II)-MOFs {Mn3(Br-bdc)3(DMF)4} (2) and {Mn3(NO2-bdc)3(DMF)4} (3) (Br-bdcH2, 2-bromo-1,4-benzene dicarboxylic acid; NO2-bdcH2, 2-nitro-1,4-benzene dicarboxylic acid) under solvothermal conditions. Compounds 2 and 3 have two-dimensional (2D) extended structures and feature trimeric {Mn3(CO2)6} units that serve as secondary building units for the frameworks. The desolvated compound of 1, denoted as 1', having potential Mn(II) open metal sites (OMSs) lined in a one-dimensional (1D) Mn-chain interconnected by carboxylate groups, exhibits guest-selective adsorption of solvent vapours wherein the compound shows a stepwise profile with H2O vapour, while a gated isotherm was recorded with MeOH. After realizing the favourable interaction of 1' with polar solvent molecules, we have used Mn(II) OMSs in 1' for efficient cyanosilylation reactions of aromatic aldehydes. We have recorded 100% conversion for eight aromatic aldehydes, while several other aldehydes showed appreciable conversion. Notably, the recorded conversions in the case of many substrates are higher than those for many other reported MOF catalysts.

A novel method to identify and correct asymmetry of dumbbells in a multi-cell elliptical superconducting cavity.

Raja Ramanna Centre for Advanced Technology (RRCAT) has an ongoing program to develop 650 MHz, 5-cell elliptical superconducting RF (SCRF) cavities under the Indian Institutes and Fermilab Collaboration. The elliptical multi-cell SCRF cavity fabrication process involves forming of half-cells and their precise machining and joining by electron beam welding to form end groups and dumbbells, which are then joined to make the final cavity. To ensure that the final welded cavity achieves physical lengths and resonant frequencies within design tolerance and has good field flatness, the measurement and correction of resonant frequency are carried out for dumbbells and end groups. A novel method to identify the frequency of individual half-cells in a dumbbell cavity and a dedicated tuning fixture to correct them had been developed. The paper details the RF characterization and correction procedure employed during fabrication of the first six 650 MHz cavities at RRCAT.

Subclinical elevated B-type Natriuretic Peptide (BNP) indicates endothelial dysfunction contributing to hypoxia susceptibility in healthy individuals.

AIMS: Baseline elevated B-type Natriuretic Peptide (BNP) has been found in high altitude pulmonary edema susceptible population. Exaggerated pulmonary vascular response to hypoxia may be related to endothelial dysfunction in hypoxia susceptible. We hypothesize that baseline BNP levels can predict hypoxia susceptibility in healthy individuals. MAIN METHODS: The pulmonary vascular response to hypoxia was compared in 35 male healthy individuals divided into two groups based on BNP levels (Group 1 ≤ 15 and Group 2 > 15 pg/ml). Acute normobaric hypoxia was administered to both the groups, to confirm hypoxia susceptibility in Group 2. KEY FINDINGS: Unlike Group 1, Group 2 had elevated post hypoxia BNP levels (26 vs 33.5 pg/ml, p = 0.002) while pulmonary artery pressure was comparable. A negative correlation with tissue oxygen consumption (delta pO2) and compartmental fluid shift was seen in Group 1 only. Endothelial dysfunction in Group 2 resulted in reduced vascular compliance leading to elevation of mean blood pressure on acute hypoxia exposure. BNP showed a positive correlation with endothelial dysfunction in Group 2 and has been linked to pre-diabetic disorder (HbA1c 6 ± 0.44%) and may additionally represent a lower cross-sectional area of vascular bed related to vascular remodeling mediated by chronic hypoxia. SIGNIFICANCE: Hypoxia susceptibility in healthy individuals may be related to endothelial dysfunction that limits vascular compliance during hypoxic stress. BNP level showed positive correlation with HbA1c (r = 0.49, p = 0.04) and negative correlation with delta pO2 (r = -0.52, p = 0.04) can predict reduced microvascular compliance due to endothelial dysfunction contributing to hypoxia susceptibility in healthy individuals. BNP levels≤15 pg/ml at sea level is indicative of hypoxia resistance.

Metal-Organic Frameworks as Platform for Lewis-Acid-Catalyzed Organic Transformations.

Metal-organic frameworks (MOFs) are highly promising Lewis acid catalysts; they either inherently possess Lewis acid sites (LASs) on it or the LASs can be generated through various post-synthetic methods, the later can be performed in MOFs in a trivial fashion. MOFs are suitable platform for catalysis because of its highly crystalline and porous nature. Moreover, with recent advancements, thermal and chemical stability is not a problem with many MOFs. In this Minireview, an enormous versatility of MOFs, in terms of their microporosity/mesoporosity, size/shape selectivity, chirality, pore size, etc., has been highlighted. These are advantageous for designing and performing various targeted organic transformations. Although, many organic transformations catalyzed by MOFs with LASs have been reported in the recent past. In this Minireview, we have restricted ourselves to four important organic reactions: (i) cyanosilylation, (ii) Diels-Alder reaction, (iii) C-H activation, and (iv) CO2 -addition. The discussion focuses mostly on the recent reports (42 examples).

Kinect-Assisted Performance-Sensitive Upper Limb Exercise Platform for Post-stroke Survivors.

One's ability to use upper limbs is critical for performing activities of daily living necessary for enjoying quality community life. However, after stroke, such abilities becomes adversely affected and it often deprives one of their capability to perform tasks that need coordinated movement in the upper limbs. To address issues with upper limb dysfunction, patients typically undergo rehabilitative exercises. Given the high patient to doctor ratio particularly in developing countries like India, conventional rehabilitation with patients undergoing exercises under one-on-one therapist's supervision often becomes a challenge. Thus, investigators are exploring technology such as computer-based platforms coupled with cameras that can alleviate the need for the continuous presence of a therapist and can offer a powerful complementary tool in the hands of the clinicians. Such marker-based imaging systems used for rehabilitation can offer real-time processing and high accuracy of data. However, these systems often require dedicated lab space and high set-up time. Often this is very expensive and suffers from portability issues. Investigators have been exploring marker-less imaging techniques e.g., Kinect integrated computer-based graphical user interfaces in stroke-rehabilitation such as tracking one's limb movement during rehabilitation. In our present study, we have developed a Kinect-assisted computer-based system that offered Human Computer Interaction (HCI) tasks of varying challenge levels. Execution of the tasks required one to use reaching and coordination skills of the upper limbs. Also, the system was Performance-sensitive i.e., adaptive to the individualized residual movement ability of one's upper limb quantified in terms of task performance score. We tested for the usability of our system by exposing 15 healthy participants to our system. Subsequently, seven post-stroke patients interacted with our system over a few sessions spread over 2 weeks. Also, we studied patient's mean tonic activity corresponding to the HCI tasks as a possible indicator of one's post-stroke functional recovery suggesting its potential of our system to serve as a rehabilitation platform. Our results indicate the potential of such systems toward the improvement of task performance capability of post-stroke patients with possibilities of upper limb movement rehabilitation.

Liquid chromatography-tandem mass spectrometry based method development and validation of S016-1271 (LR8P), a novel cationic antimicrobial peptide for its application to pharmacokinetic studies.

S016-1271 (LR8P) is a broad spectrum novel cationic antimicrobial peptide. The objective of the present study was to develop a selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) based bioanalytical method of S016-1271 peptide in mice and human plasma in order to uncover its pharmacokinetic aspects. The chromatographic separation of S016-1271 (FR8P as internal standard) was achieved on a Waters™ X select CSH-C18 column (75 × 3.0 mm, 2.5 µ) using mixture of acetonitrile and triple distilled water (TDW) both containing 0.05% formic acid as mobile phase. A seven minute linear gradient method was designed to separate analytes from ion suppression at a flow rate of 0.3 mL/min. The extraction of analytes from mice and human plasma was performed through solid phase extraction technique using mixed mode weak cation exchange cartridge (Thermo SOLA WCX 10 mg 1CC) with an extraction recovery of analytes about 75%. Mass spectrometric detection of S016-1271 and FR8P was performed with optimized multiple reaction monitoring (MRM) transitions (Q1/Q3) at 658.8 [M+3H] 3+/653.2 [M+3H-NH3] 3+ and 443.4 [M+5H]5+ /434.7 [y12-NH3]4+,respectively in positive electrospray ionization (ESI) mode. The linearity in mice and human plasma was established over a concentration range of 7.81-250 ng/mL with regression coefficient (r2 > 0.99). The currently developed method was validated as per US-FDA guidelines and found to be within the acceptable limits. The method was successfully applied to intravenous (IV) pharmacokinetic study in mice wherein the levels were detected upto 24 h. The peptide demonstrated poor distribution characteristics which were demonstrated through volume of distribution at steady state (202.71 ± 47.02 mL/kg less than total body water of mice; 580 mL/kg). The clearance of the peptide predominantly occurred through central compartment (central clearance is 25 fold greater than peripheral clearance). Also, the in vitro pharmacokinetic studies demonstrated the stability of S016-1271 in plasma and high plasma protein binding in mice and humans.

Evidence for altered metabolic pathways during environmental stress: (1)H-NMR spectroscopy based metabolomics and clinical studies on subjects of sea-voyage and Antarctic-stay.

The Antarctic context is an analogue of space travel, with close similarity in ambience of extreme climate, isolation, constrained living spaces, disrupted sleep cycles, and environmental stress. The present study examined the impact of the harsh habitat of Antarctica on human physiology and its metabolic pathways, by analyzing human serum samples, using (1)H-NMR spectroscopy for identification of metabolites; and quantifying other physiological and clinical parameters for correlation between expression data and metabolite data. Sera from seven adult males (of median age 36years) who participated in this study, from the 28th Indian Expeditionary group to the Antarctica station Maitri, were collected in chronological sequence. These included: i) baseline control; ii) during ship journey; iii) at Antarctica, in the months of March, May, August and November; to enable study of temporal evolution of monitored physiological states. 29 metabolites in serum were identified from the 400MHz (1)H-NMR spectra. Out of these, 19 metabolites showed significant variations in levels, during the ship journey and the stay at Maitri, compared to the base-line levels. Further biochemical analysis also supported these results, indicating that the ship journey, and the long-term Antarctic exposure, affected kidney and liver functioning. Our metabolite data highlights for the first time the effect of environmental stress on the patho-physiology of the human system. Multivariate analysis tools were employed for this metabonomics study, using (1)H-NMR spectroscopy.

Antimicrobial Activities of Leaf Extracts of Guava (Psidium guajava L.) on Two Gram-Negative and Gram-Positive Bacteria.

Aim. To determine the antimicrobial potential of guava (Psidium guajava) leaf extracts against two gram-negative bacteria (Escherichia coli and Salmonella enteritidis) and two gram-positive bacteria (Staphylococcus aureus and Bacillus cereus) which are some of foodborne and spoilage bacteria. The guava leaves were extracted in four different solvents of increasing polarities (hexane, methanol, ethanol, and water). The efficacy of these extracts was tested against those bacteria through a well-diffusion method employing 50 µ L leaf-extract solution per well. According to the findings of the antibacterial assay, the methanol and ethanol extracts of the guava leaves showed inhibitory activity against gram-positive bacteria, whereas the gram-negative bacteria were resistant to all the solvent extracts. The methanol extract had an antibacterial activity with mean zones of inhibition of 8.27 and 12.3 mm, and the ethanol extract had a mean zone of inhibition of 6.11 and 11.0 mm against B. cereus and S. aureus, respectively. On the basis of the present finding, guava leaf-extract might be a good candidate in the search for a natural antimicrobial agent. This study provides scientific understanding to further determine the antimicrobial values and investigate other pharmacological properties.

Wintering in Antarctica: impact on immune response of Indian expeditioners.

The immune system is one of the major thrust areas in understanding the effects of adverse climatic conditions on human health. Exposure to the Antarctic environment, such as isolation, cold, UV radiations, magnetic field, blizzards, circadian biorhythms, and fear of the unknown, modify various components of the immune system. Members of Antarctic expeditions suffer significant emotional strain as a result of physical isolation and social deprivation. The present study was performed on winter team members of the 28th Indian Scientific Expedition. In this study, different immunological parameters, which mainly include cytokines (TNF-α, IFN-γ, TGF-ß, and IL-4), chemokine MIP-1α, immunoglobulins (IgA, IgM and IgG), cortisol and netrin-1, were assayed in sera by ELISA. Results showed that TNF-α and MIP-1α levels were significantly increased in March, May and August while IFN-γ levels were increased in March and May while TGF-ß levels showed a significant decrease in March and May. Serum IgA levels were significantly increased during the entire period of the stressful expedition. Therefore, the present study suggests that serum IgA could be a potential biomarker for extreme environmental conditions.

Effect of temperature on behavioural isolation: a study with Drosophila ananassae populations.

Experiments were conducted to study sexual isolation among two natural populations of Drosophila ananassae maintained at 18 degrees C and 24 degrees C for 12 generations in the laboratory to see the effect of this environmental variable on behavioural isolation. Multiple choice technique was used and matings were observed directly in Elens Wattiaux mating chamber. Results showed sexual isolation among strains that were maintained at different temperatures, indicating that temperature may have affected the mating behaviour of the flies which resulted in the induction of ethological isolation among the strains.

Ship-borne journey induces Th1 cytokines level in antarctic summer expeditioners.

It has become apparent that extreme environmental conditions of Antarctic continent alters many immune responses. The present study was conducted on 28th Indian Antarctic expeditioners. The investigations were carried out to explore the effect of multiple stresses like isolation, cold and UV exposure on human immunity. Thirty blood samples were collected between 6 and 7 AM, after an overnight fast at different stages of the expedition - viz. the pre-exposure sample was collected at Delhi on 25(th) October 2008. The expedition started its ship journey from Capetown, on 6(th) January, 2009 and on-board blood was collected on 31(st) January 2009. After 1 month stay at Maitri, blood was collected on 3(rd) March 2009. Different parameters studied included levels of cytokines, chemokines and cortisol. The ship-borne journey induced a dramatic increase in TNF-α, IFN-γ, and B cell activating factor (BAFF) levels and moderate decreases in TGF-ß and cortisol levels. However, after being off board for 1 month at Maitri station, levels of above cytokines, cortisol and BAFF were decreased but MIP-1α was significantly increased. These data for the first time suggest that ship-borne journey to the Antarctic continent results in tremendous stress to the body, which eventually resulted in increased TH1-biased immunity.

Isolated ulcerative skin lesion caused by Salmonella Weltevreden.

Salmonella enterica serovar Weltevreden is not a commonly isolated serotype in India. We report isolation of Salmonella Weltevreden, from an unusual site--an ulcer on the gluteal region of a patient who had undergone coronary artery bypass surgery. To our knowledge, Salmonellae have never been reported to cause isolated ulcerative lesions on the skin. This is the first report of an isolated ulcerative lesion on the skin caused by Salmonella Weltevreden. Our findings indicate that there may be modes of pathogenesis of Salmonella infections that we are yet unaware of. Further work and extensive reporting of all Salmonella infections are necessary to elucidate these mechanisms.

In vitro antitumor mechanisms of various Scutellaria extracts and constituent flavonoids.

Scutellaria is a traditional herbal remedy with potential anti-cancer activity. The purpose of this study was to evaluate anticancer mechanisms of thirteen Scutellaria species and analyze their leaf, stem and root extracts for levels of common biologically active flavonoids: apigenin, baicalein, baicalin, chrysin, scutellarein, and wogonin. Malignant glioma, breast carcinoma and prostate cancer cells were used to determine tumor-specific effects of Scutellaria on cell proliferation, apoptosis and cell cycle progression, via the MTT assay and flow cytometry-based apoptosis and cell cycle analysis. The extracts and individual flavonoids inhibited the proliferation of malignant glioma and breast carcinoma cells without affecting primary or non-malignant cells. The flavonoids exhibited different mechanisms of anti-tumor activity as well as positive interactions. The antitumor mechanisms involved induction of apoptosis and cell cycle arrest at G1/G2. Of the extracts tested, leaf extracts of S. angulosa, S. integrifolia, S. ocmulgee and S. scandens were found to have strong anticancer activity. This study provides basis for further mechanistic and translational studies into adjuvant therapy of malignant tumors using Scutellaria leaf tissues.