Lattice dynamics across the ferroelastic phase transition in Ba2ZnTeO6: a Raman and first-principles study.

Structural phase transitions drive several unconventional phenomena including some illustrious ferroic attributes which are relevant for technological advancements. On this note, we have investigated the ferroelastic structural transition of perovskite-type trigonal Ba2ZnTeO6 across Tc ∼ 150 K. With the help of Raman spectroscopy and density-functional theory (DFT)-based calculations, we report new intriguing observations associated with the phase transition in Ba2ZnTeO6. We observed the presence of a central peak (quasi-elastic Rayleigh profile), huge softening in the soft mode, hysteretic phonon behavior, and signatures of coexistent phases. The existence of a central peak in Ba2ZnTeO6 is manifested by a sharp rise in the intensity of the Rayleigh profile concomitant with the huge damping (or softening) of the soft mode (at ∼31 cm-1) near Tc, shedding light on the lattice dynamics during the phase transition. This is further corroborated by our phonon calculations that show that the soft mode (Eg) in the high-symmetry structure involving TeO6 octahedral rotation (with Ba and Zn translation) condenses into Ag and Bg modes in the C2/m low-symmetry phase. While most of the phonon bands split below Tc confirming the phase transition, we observed thermal hysteretic behavior of phonon modes, which signifies the first-order nature of the transition and the presence of coexisting phases as corroborated by our temperature-dependent X-ray diffraction and specific heat measurements.

Reduction in polyamine catabolism leads to spermine-mediated airway epithelial injury and induces asthma features.

BACKGROUND: Airway epithelial injury is a crucial component of acute and severe asthma pathogenesis and a promising target for treatment of refractory asthma. However, the underlying mechanism of epithelial injury remains poorly explored. Although high levels of polyamines, mainly spermine, have been found in asthma and comorbidity, their role in airway epithelial injury and the cause of their altered levels in asthma have not been explored. METHODS: We measured key polyamine metabolic enzymes in lung samples from normal and asthmatic subjects and in mice with OVA-induced allergic airway inflammation (AAI). Polyamine metabolism was modulated using pharmacologic/genetic modulators. Epithelial stress and apoptosis were measured by TSLP levels and TUNEL assay, respectively. RESULTS: We found loss of the polyamine catabolic enzymes spermidine/spermine-N (1)-acetyltransferase-1 (SAT1) and spermine oxidase (SMOX) predominantly in bronchial epithelial cells (BECs) of human asthmatic lung samples and mice with AAI. In naïve mice, SAT1 or SMOX knockdown led to airway hyper-responsiveness, remodeling, and BEC apoptosis. Conversely, in mice with AAI, overexpression of either SAT1 or SMOX alleviated asthmatic features and reduced TSLP levels and BEC apoptosis. Similarly, while pharmacological induction of SAT1 and SMOX using the polyamine analogue bis(ethyl)norspermine (BENSPM) alleviated asthmatic features with reduced TSLP levels and BEC apoptosis, pharmacological inhibition of these enzymes using BERENIL or MDL72527, respectively, worsened them. Spermine accumulation in lungs correlated with BEC apoptosis, and spermine treatment caused apoptosis of human BEAS-2B cells in vitro. CONCLUSIONS: Spermine induces BEC injury. Induction of polyamine catabolism may represent a novel therapeutic approach for asthma via reversing BEC stress.

Choroidal metastases as the initial presentation of lung cancer: A rare scenario.

Clinical reports of symptomatic intraocular metastasis as the initial presentation of lung cancer are rare. We report the case of a 49-year-old female patient who presented with loss of vision due to choroidal metastases as the initial manifestation of her disseminated lung cancer. This particular patient was referred to us from ophthalmology department as a case of choroidal metastases from unknown primary. Detailed evaluation at our department helped detect the primary to be a nonsmall cell carcinoma of the right lung, which had multiple distant metastases.

Emergence of co-production of plasmid-mediated AmpC beta-lactamase and ESBL in cefoxitin-resistant uropathogenic Escherichia coli.

Plasmid-mediated AmpC (pAmpC) and ESBL co-production was detected in Escherichia coli a major etiologic agent of urinary tract infection. Isolates resistant to cefoxitin by CLSI methodology were tested for pAmpC beta-lactamase using phenylboronic acid and ESBLs by combined disk diffusion method. pAmpC/ESBL genes were characterized by PCR and sequencing. Transconjugation experiments were done to study the transfer of pAmpC and ESBL production from clinical isolates as donor to E. coli J53 AziR as recipient. Incompatibility groups of transmissible plasmids were classified by PCR-based replicon typing (PBRT). Among 148 urine culture positive isolates, E. coli was reported in 39.86 % (59/148), with 93.22 % (55/59) of cefoxitin resistance. pAmpC production was detected in 25, with varied distribution of blaCMY-2 and blaDHA-1type genes alone (n = 13 and 7 respectively) or in combination (n = 5). ESBL co-production was observed in 88 % (22/25) of pAmpC producing isolates with predominance of blaTEM (n = 20). Twenty-three transconjugants showed transmission of pAmpC-and ESBL-resistant genes with co-carriage of blaCMY-2 and blaTEM (n = 15) in plasmids of IncF type (n = 9) being predominant, followed by IncI1 (n = 4) and IncH1 (n = 2) in combination. All clinical isolates were clonally diverse. Resistance against different beta-lactams in uropathogenic E. coli has been an emerging concern in resource- poor countries such as India. Knowledge on the occurrence of AmpC beta-lactamases and ESBL amongst this pathogen and its transmission dynamics may aid in hospital infection control.

Microencapsulation of a putative probiotic Enterobacter species, C6-6, to protect rainbow trout, Oncorhynchus mykiss (Walbaum), against bacterial coldwater disease.

Flavobacterium psychrophilum is the causative agent of bacterial coldwater disease (BCWD), which has a major impact on salmonid aquaculture globally. An Enterobacter species, C6-6, isolated from the gut of rainbow trout, Oncorhynchus mykiss (Walbaum), has been identified as a potential probiotic species providing protection against BCWD. This study examined the effects of alginate microencapsulation on the protective efficacy of C6-6 against BCWD in vivo when administered to rainbow trout fry orally or by intraperitoneal (IP) injection. Viable C6-6 bacteria were microencapsulated successfully, and this process (microencapsulation) did not significantly deteriorate its protective properties as compared to the administration of non-microencapsulated C6-6 bacteria. Both oral and IP delivery of C6-6 achieved significantly better protection than control treatments that did not contain C6-6 bacteria. The highest relative percent survival (RPS) resulted from IP delivery (71.4%) and was significantly greater than the highest oral RPS (38.6%). Successful intestinal colonization was not critical to protective effects of C6-6. The study showed that C6-6 administration, with or without encapsulation, was a viable choice for protecting fry from BCWD especially when administered intraperitoneally.

Exploring crucial structural attributes of quinolinyl methoxyphenyl sulphonyl-based hydroxamate derivatives as ADAM17 inhibitors through classification-dependent molecular modelling approaches.

A Disintegrin and Metalloproteinase 17 (ADAM17), a Zn2+-dependent metalloenzyme of the adamalysin family of the metzincin superfamily, is associated with various pathophysiological conditions including rheumatoid arthritis and cancer. However, no specific inhibitors have been marketed yet for ADAM17-related disorders. In this study, 94 quinolinyl methoxyphenyl sulphonyl-based hydroxamates as ADAM17 inhibitors were subjected to classification-based molecular modelling and binding pattern analysis to identify the significant structural attributes contributing to ADAM17 inhibition. The statistically validated classification-based models identified the importance of the P1' substituents such as the quinolinyl methoxyphenyl sulphonyl group of these compounds for occupying the S1' - S3' pocket of the enzyme. The quinolinyl function of these compounds was found to explore stable binding of the P1' substituents at the S1' - S3' pocket whereas the importance of the sulphonyl and the orientation of the P1' moiety also revealed stable binding. Based on the outcomes of the current study, four novel compounds of different classes were designed as promising ADAM17 inhibitors. These findings regarding the crucial structural aspects and binding patterns of ADAM17 inhibitors will aid the design and discovery of novel and effective ADAM17 inhibitors for therapeutic advancements of related diseases.

Pinpointing prime structural attributes of potential MMP-2 inhibitors comprising alkyl/arylsulfonyl pyrrolidine scaffold: a ligand-based molecular modelling approach validated by molecular dynamics simulation analysis.

MMP-2 overexpression is strongly related to several diseases including cancer. However, none of the MMP-2 inhibitors have been marketed as drug candidates due to various adverse effects. Here, a set of sulphonyl pyrrolidines was subjected to validation of molecular modelling followed by binding mode analysis to explore the crucial structural features required for the discovery of promising MMP-2 inhibitors. This study revealed the importance of hydroxamate as a potential zinc-binding group compared to the esters. Importantly, hydrophobic and sterical substituents were found favourable at the terminal aryl moiety attached to the sulphonyl group. The binding interaction study revealed that the S1' pocket of MMP-2 similar to 'a basketball passing through a hoop' allows the aryl moiety for proper fitting and interaction at the active site to execute potential MMP-2 inhibition. Again, the sulphonyl pyrrolidine moiety can be a good fragment necessary for MMP-2 inhibition. Moreover, some novel MMP-2 inhibitors were also reported. They showed the significance of the 3rd position substitution of the pyrrolidine ring to produce interaction inside S2' pocket. The current study can assist in the design and development of potential MMP-2 inhibitors as effective drug candidates for the management of several diseases including cancers in the future.

Exploring different classification-dependent QSAR modelling strategies for HDAC3 inhibitors in search of meaningful structural contributors.

Histone deacetylase 3 (HDAC3), a Zn2+-dependent class I HDACs, contributes to numerous disorders such as neurodegenerative disorders, diabetes, cardiovascular disease, kidney disease and several types of cancers. Therefore, the development of novel and selective HDAC3 inhibitors might be promising to combat such diseases. Here, different classification-based molecular modelling studies such as Bayesian classification, recursive partitioning (RP), SARpy and linear discriminant analysis (LDA) were conducted on a set of HDAC3 inhibitors to pinpoint essential structural requirements contributing to HDAC3 inhibition followed by molecular docking study and molecular dynamics (MD) simulation analyses. The current study revealed the importance of hydroxamate function for Zn2+ chelation as well as hydrogen bonding interaction with Tyr298 residue. The importance of hydroxamate function for higher HDAC3 inhibition was noticed in the case of Bayesian classification, recursive partitioning and SARpy models. Also, the importance of substituted thiazole ring was revealed, whereas the presence of linear alkyl groups with carboxylic acid function, any type of ester function, benzodiazepine moiety and methoxy group in the molecular structure can be detrimental to HDAC3 inhibition. Therefore, this study can aid in the design and discovery of effective novel HDAC3 inhibitors in the future.

Achieving Energy Efficiency and Impact of SAR in a WBAN Through Optimal Placement of the Relay Node.

Wireless Body Area Network (WBAN) is an emerging and promising specialized area in Wireless networks that deals with crucial health-related datasets. Unlike other wireless networks, as this type of network deals with medical facts, losing it is fatal. WBAN is a highly constrained network. Reducing energy consumption and enhancing lifetime are the two most important challenges of WBANs. One way to achieve these is by deploying relay nodes optimally in WBANs. Generally, a relay node is placed at the midpoint of the line joining the source and the destination (D) nodes. We show that such simplistic deployment of the relay nodes is not the optimal deployment, which can hamper the overall lifetime of WBANs. In this paper, we have investigated the best location to deploy a relay node on a human body. We assume that an adaptive decode and forward relay node (R) can move linearly between the source (S) and the destination (D) nodes. Moreover, the assumption is that a relay node can be deployed linearly and that the body part of a human is a flat surface and hard. We have investigated the most energy-efficient data payload size based on the optimally placed relay location. The impact of such a deployment on different system parameters, such as distance (d), payload (L), modulation scheme, specific absorption rate, and an end to end outage (O) are examined as well. It is observed that in every aspect optimal deployment of the relay node performs an important role to enhance the lifetime of wireless body area networks. Sometimes linear relay deployment is very difficult to implement, especially on the different body parts of the human body. To address these issues, we have examined the optimal region for the relay node based on a 3D non-linear system model. The paper provides guidance for both linear and non-linear relay deployment along with the optimal data payload size under various circumstances and also considered the impact of specific absorption rates on the human body.

Assessing structural insights into in-house arylsulfonyl L-(+) glutamine MMP-2 inhibitors as promising anticancer agents through structure-based computational modelling approaches.

MMP-2 is potentially contributing to several cancer progressions including leukaemias. Therefore, considering MMP-2 as a promising target, novel anticancer compounds may be designed. Here, 32 in-house arylsulfonyl L-(+) glutamines were subjected to various structure-based computational modelling approaches to recognize crucial structural attributes along with the spatial orientation for higher MMP-2 inhibition. Again, the docking-based 2D-QSAR study revealed that the Coulomb energy conferred by Tyr142 and total interaction energy conferred by Ala84 was crucial for MMP-2 inhibition. Importantly, the docking-dependent CoMFA and CoMSIA study revealed the importance of favourable steric, electrostatic, and hydrophobic substituents at the terminal phenyl ring. The MD simulation study revealed a lower fluctuation in the RMSD, RMSF, and Rg values indicating stable binding interactions of MMP-2 and these molecules. Moreover, the residual hydrogen bond and their interaction analysis disclosed crucial amino acid residues responsible for forming potential hydrogen bonding for higher MMP-2 inhibition. The results can effectively aid in the design and discovery of promising small-molecule drug-like MMP-2 inhibitors with greater anticancer potential in the future.

Exploration of structural alerts and fingerprints for novel anticancer therapeutics: a robust classification-QSAR dependent structural analysis of drug-like MMP-9 inhibitors.

Among various matrix metalloproteinases (MMPs), overexpression of MMP9 has been established as a key player in a variety of cancers. Therefore, MMP9 has emerged as a promising biomolecule that may be targeted to design potent inhibitors as novel anticancer therapeutics. In this study, a large database containing 1,123 drug-like MMP-9 inhibitors was considered for robust classification-dependent fragment-based QSAR study through SARpy, Bayesian classification, and recursive partitioning analyses and were validated by both internal and external validation techniques. In a nutshell, all these classification-dependent techniques revealed some common structural alerts and sub-structural fingerprints responsible for modulating MMP-9 inhibition. These observations are in agreement with the interactions obtained from the ligand-bound co-crystal structures of MMP-9 justifying the robustness of the current study. Finally, based on these crucial structural fragments, some new lead compounds were designed and further validated by the binding mode of interaction analysis. Therefore, these findings may be beneficial in designing novel and potential MMP-9 inhibitors in the future as a weapon to combat several cancers.

Protein interactions, molecular docking, antimicrobial and antifungal studies of terpyridine ligands.

Resistance to antibiotics/antibacterials/antifungals in pathogenic microbes has been developing over the past few decades and has recently become a commonplace public-health peril. Thus, alternative nontoxic potent antibiotic agents are covertly needed to control antibiotic-resistant outbreaks. In an effort to combat the challenges posed by the co-occurrence of multidrug resistance, two terpyridine ligands 4'-(4-N,N'-dimethylaminophenyl)-2,2':6',2″-terpyridine (L1) and 4'-(4-tolyl)-2,2':6',2″-terpyridine (L2) have been designed, prepared and confirmed their structure by spectral studies. Thereafter, antimicrobial assay was performed against gram positive and negative bacterial strains along with fungal strains. Both compounds L1 and L2 exhibited remarkable inhibitory activities against bacteria, Escherichia coli and Staphylococcus aureus at MIC values 6.25 and 3.125 µg/ml, respectively. In addition, in silico molecular docking studies were ascertained with bacterial DNA gyrase and fungal demethylase. Furthermore, both L1 and L2 could bind Bovine Serum Albumin (BSA) protein and binding interaction has been studied with the help of UV-Visible and fluorescence spectroscopy. While fluorescence of BSA unperturbed in the presence of L2, an addition of L1 to the solution of BSA resulted significant quenching. The binding constant calculations at different temperature confirmed that the fluorescence quenching between BSA and L1 is predominantly static in nature. The toxicity of L1 and L2 was checked using Drosophila melanogaster. The toxicity analysis suggest both the dyes are non-cytotoxic in nature.Communicated by Ramaswamy H. Sarma.

Reperfusion therapy in ST-elevation myocardial infarction: guidelines, strategies, pharmacology, and stent selection.

Treatment of acute ST-elevation myocardial infarction (STEMI) has rapidly evolved with many advances made in the past decade. Percutaneous coronary intervention is the preferred strategy when available, although there remains a role for thrombolytic therapy, with prompt reperfusion as the primary goal. With regards to antithrombotic therapy, bivalirudin now has a significant role in STEMI care with improved outcomes over unfractionated heparin plus GP IIb/IIIa inhibitors. Dual antiplatelet therapy has become a mainstay of treatment with combination of aspirin and clopidogrel, as well as an expanding role of more potent novel agents, prasugrel and ticagrelor. In primary PCI in STEMI, coronary stents are now being used routinely, although short-term and long-term outcomes of drug-eluting stents (DES) versus bare metal stents (BMS) continue to be studied. Recent meta-analyses have examined the trade-off of lower rates of in-stent restenosis and need for target vessel revascularization with DES versus the potential increase in the risk of stent thrombosis and need for longer course of dual antiplatelet therapy. This review will discuss the current STEMI guidelines and strategies, recent advances in pharmacotherapy, and data on stent selection.

Effect of vermicomposting on calcium, sulphur and some heavy metal content of different biodegradable organic wastes under liming and microbial inoculation.

A study was conducted to evaluate the changes in total calcium and sulphur and some heavy metal (Zn, Cu, and Pb) concentration of different organic wastes affected by liming and microorganism inoculation. Vermicomposting was an effective technology for disposal of organic substrates like municipal solid wastes (MSW), possessing comparatively higher concentration of heavy metals. The addition of lime in initial organic substrates significantly (P ≤ 0.05) increased total calcium and total sulphur content of vermicomposts. Inoculation of microorganisms significantly (P ≤ 0.05) reduced the heavy metal content of final products as compared to control. Fungal strains were comparatively more effective in detoxification of heavy metals than B. polymyxa.

High concentration of adenosine in human visceral leishmaniasis despite increased ADA and decreased CD73.

Absence of an effective Th-1 response has been demonstrated as a major cause for the disease pathology among patients with visceral leishmaniasis (VL). Defining strategies to prevent the development of Th-2 response and/or initiate/activate effective Th-1 response may be of help to reduce the growing incidence of drug unresponsiveness. Adenosine, which is considered as an endogenous anti-inflammatory agent is generated in injured/inflamed tissues by the enzymatic catabolism of adenosine triphosphate (ATP), and it suppresses inflammatory responses of essentially all immune cells. The extracellular adenosine-producing pathway comprises two major enzymes CD39 (ATP → ADP → AMP) and CD73 (AMP → Adenosine). In contrast, the adenosine-degrading pathway contains only one major enzyme adenosine deaminase (ADA). Our study shows high concentration of adenosine in diseased condition, varying expression of enzyme involved in adenosine-producing (CD73↓) and adenosine-degrading (ADA↑) pathways. These are less studied in infections like VL but are very important in terms of endogenous regulation of immune response among patients.

Design and gamma scintigraphic evaluation of colon specific pectin-EC pellets of secnidazole prepared by powder layering technology.

The aim of the present study was to prepare a colon targeted pellet formulation of secnidazole and to evaluate the formulation in vitro and in vivo by a gamma scintigraphy method. Pectin/ethyl cellulose in different ratios and in different coating labels with plasticizer was used to prepare secnidazole pellets by a powder layering technique. The formulations were tagged with 99mTC-DTPA, a tracer in gamma scintigraphy to evaluate its transit behavior in rabbits. Morphology and compatibility were studied using Scanning Electron Microscopy, IR spectroscopy and Differential Scanning Calorimetry were used for the characterization of prepared pellets. The in-vitro study suggested that pectin (59%) esterification and ethyl cellulose 45cps at 20% coating label led to an optimum bacterial enzyme dependent released behavior. The optimized formulation was subjected to an in-vivo transit study. Scintigraphy images clearly indicated that the formulation can delay the drug release prior to the colon. The average time of gastric emptying and colon arrival was 57 min and 6.08 h, respectively. The coated pellets prepared by powder layering technology successfully released drug in the colon indicating that site specificity has been achieved with pectin 59% esterification and ethyl cellulose 45 cps at 1:2 ratio with 20% coating label.

Cytoarchitectural and surface ultrastructural analysis of the olfactory epithelium of Oreochromis nilotica (Linnaeus).

The olfactory organ of Oreochromis nilotica was studied by means of light and scanning electron microscopes. The oval shaped olfactory apparatus consists of 19-20 lamellae radiating from a central raphe. The receptor epithelium occupies the restricted area of the middle swollen region of the lamellae and is framed with receptor cells (both ciliated and microvillous) and rod cells. The larger part of the lateral surface of the olfactory lamella is covered with non-receptor epithelium, which is made up of stratified epithelial cells and mucous cells. The functional significance of various cells lining the olfactory epithelium of this fish are discussed.

Robust classification-based molecular modelling of diverse chemical entities as potential SARS-CoV-2 3CLpro inhibitors: theoretical justification in light of experimental evidences.

COVID-19 is the most unanticipated incidence of 2020 affecting the human population worldwide. Currently, it is utmost important to produce novel small molecule anti-SARS-CoV-2 drugs urgently that can save human lives globally. Based on the earlier SARS-CoV and MERS-CoV infection along with the general characters of coronaviral replication, a number of drug molecules have been proposed. However, one of the major limitations is the lack of experimental observations with different drug molecules. In this article, 70 diverse chemicals having experimental SARS-CoV-2 3CLproinhibitory activity were accounted for robust classification-based QSAR analysis statistically validated with 4 different methodologies to recognize the crucial structural features responsible for imparting the activity. Results obtained from all these methodologies supported and validated each other. Important observations obtained from these analyses were also justified with the ligand-bound crystal structure of SARS-CoV-2 3CLpro enzyme. Our results suggest that molecules should contain a 2-oxopyrrolidine scaffold as well as a methylene (hydroxy) sulphonic acid warhead in proper orientation to achieve higher inhibitory potency against SARS-CoV-2 3CLpro. Outcomes of our study may be able to design and discover highly effective SARS-CoV-2 3CLpro inhibitors as potential anticoronaviral therapy to crusade against COVID-19.

Emotion recognition in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome characterised by akinesis, rigidity, falls, supranuclear gaze palsy and cognitive, particularly executive, dysfunction. This study examined the extent to which emotion recognition is affected by PSP. Although deficits in the recognition of emotion have been reported in several diseases which share clinicopathological characteristics with PSP, it has never been studied systematically in PSP. Twenty-four patients with probable or definite PSP and matched healthy controls were studied using tests of facial identity and facial emotion recognition. Patients were not impaired in recognising famous faces, but they showed significant deficits in the recognition of emotions, particularly negative emotions. Moreover, emotion recognition was strongly correlated with the severity of other cognitive deficits in PSP, but not disease duration. Deficits in emotion recognition form an integral part of the cognitive spectrum of the disease. The findings point to the pathological involvement of key regions necessary for the processing of emotions and to a subtype of PSP with cognitive and emotion recognition impairments. The acknowledgement of deficits in emotion recognition is important for management of both patients and their carers.

Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations.

Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum immunoglobulin E (IgE) concentration. No linkage was found between these markers and specific IgE antibody concentrations. Analysis of total IgE within a subset of 128 IgE antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially to the interleukin-4 gene (IL4). A combination of segregation and maximum likelihood analyses provided further evidence for this linkage. These analyses suggest that IL4 or a nearby gene in 5q31.1 regulates IgE production in a nonantigen-specific (noncognate) fashion.