Novel Pyrazole-Based Transition Metal Complexes: Spectral, Photophysical, Thermal and Biological Studies.

A novel bioactive Schiff base (HL) named 3-methyl-1-phenyl-5-((5-nitrosalicylidene)amino)pyrazole was prepared by condensing 5-amino-3-methyl-1-phenylpyrazole with 5-nitrosalicyldehyde in methanol on a heating mantle in refluxing condition for 1 h. Some transition metal complexes of the ligand in (1 : 1) and (1 : 2) have also been prepared by condensing the metal acetate salt with the synthesized Schiff base. The Schiff base and metal complexes were characterized by different physiochemical techniques, i. e., 1 H-NMR, InfraRed, mass spectroscopy, elemental analysis, Ultraviolet-Visible, Cyclic voltammetry, electronic spectra and Electron spin resonance. The presence of water molecules in the complexes have been calculated with the help of thermogravimetric analysis. Kinetic parameters such that entropy change, enthalpy change and activation energy have been calculated with the help of Coats-Redfern equations. Fluorescence spectra showed enhancement in the fluorescence signal of the metal complexes. Square planar geometry for the copper complexes and octahedral geometry for the other metal complexes have been proposed with help of various methods. Biological activities of all the compounds have been carried out and the results disclosed that the metal complexes have high biological activity than the Schiff base having MIC value in the range 25-3.12 µg/mL and mycelial growth inhibition 60.82-96.98 %.

Loss of Foxc1 and Foxc2 function in chondroprogenitor cells disrupts endochondral ossification.

Endochondral ossification initiates the growth of the majority of the mammalian skeleton and is tightly controlled through gene regulatory networks. The forkhead box transcription factors Foxc1 and Foxc2 regulate aspects of osteoblast function in the formation of the skeleton, but their roles in chondrocytes to control endochondral ossification are less clear. Here, we demonstrate that Foxc1 expression is directly regulated by the activity of SRY (sex-determining region Y)-box 9, one of the earliest transcription factors to specify the chondrocyte lineage. Moreover, we demonstrate that elevated expression of Foxc1 promotes chondrocyte differentiation in mouse embryonic stem cells and loss of Foxc1 function inhibits chondrogenesis in vitro. Using chondrocyte-targeted deletion of Foxc1 and Foxc2 in mice, we reveal a role for these factors in chondrocyte differentiation in vivo. Loss of both Foxc1 and Foxc2 caused a general skeletal dysplasia predominantly affecting the vertebral column. The long bones of the limbs were smaller, mineralization was reduced, and organization of the growth plate was disrupted; in particular, the stacked columnar organization of the proliferative chondrocyte layer was reduced in size and cell proliferation was decreased. Differential gene expression analysis indicated disrupted expression patterns of chondrogenesis and ossification genes throughout the entire process of endochondral ossification in chondrocyte-specific Foxc1/Foxc2 KO embryos. Our results suggest that Foxc1 and Foxc2 are required for normal chondrocyte differentiation and function, as loss of both genes results in disorganization of the growth plate, reduced chondrocyte proliferation, and delays in chondrocyte hypertrophy that prevents ossification of the skeleton.

Anti-melanoma and antioxidant properties of the methanol extract from the leaves of Phragmenthera capitata (Spreng.) Balle and Globimetula braunii (Engl.) Van Tiegh.

OBJECTIVES: Phragmenthera capitata (Spreng.) Balle and Globimetula braunii (Engler.) Van Tiegh are African mistletoe traditionally used in cancers treatment. Thus, the aim of the study was to assess the anti-melanoma potential of the methanol extract of Phragmenthera capitata (Spreng.) Balle (PCMe-OH) and Globimetula braunii (Engler.) (GBMe-OH) Van Tiegh. METHODS: Antioxidant potential was evaluated using DPPH, FRAP and hydroxyl assays. Total flavonoid and phenolic contents was also determined. MTT assay was used to estimate the effects on cell viability using SK-MLE28 and B16-F10 cell lines. Colony formation and wound healing were also assessed. Fluorometry methods were used for qualitative analysis of apoptosis and estimate ROS production. Western blot analysis was used for protein expression. RESULTS: Phragmenthera capitata (PCMe-OH) showed the highest antioxidant activity and possess the highest phenolic contents (1,490.80 ± 55 mgGAE/g extract) in comparison with G. braunii (GBMe-OH) and (1,071.40 ± 45 mgGAE/g extract). Flavonoid content was similar in both extracts (11.63 ± 5.51 mg CATE/g of extract and 12.46 ± 2.58 mg CATE/g of extract respectively). PC-MeOH showed the highest cytotoxicity effect (IC50 of 55.35 ± 1.17 µg/mL) and exhibited anti-migrative potential on B16-F10 cells. Furthermore, PC-MeOH at 55.35 and 110.7 µg/mL; promoted apoptosis-induced cell death in B16-F10 cells by increasing intracellular ROS levels and reducing Bcl-2 expression level at 110.7 µg/mL. Significant upregulation of P-PTEN expression was recorded with PC-MeOH at 110.7 µg/mL; inhibiting therefore PI3K/AKT/m-Tor signaling pathway. Moreover, at 55.37 µg/mL significant reduction of c-myc and cyclin D1 was observed; dysregulating the MAPK kinase signaling pathway and cell cycle progression. CONCLUSIONS: Phragmenthera capitata may be developed into selective chemotherapy to fight against melanoma.

Efficient removal of total arsenic (As3+/5+) from contaminated water by novel strategies mediated iron and plant extract activated waste flowers of marigold.

In this investigation, marigold flower-waste was activated with iron salts (MG-Fe), subsequently marigold plant extract (MG-Fe-Ex) for the adsorptive elimination of As3+ and As5+ from contaminated water. The governing factor such as medium pH, temperature, pollutant concentration, reaction time, adsorbent dose were considered for the study. The complete elimination of As3+/5+ was recorded with MG-Fe-Ex at pH 8.0, 90 min, 30 °C, dose 4 g/L, 20 mg/L of As3+/5+ and shaking rate 120 rpm, while under the identical experimental condition, MG-Fe exhibited 98.4% and 73.3% removal for As5+ and As3+, respectively. The MG-Fe-Ex contains iron oxides (Fe2O3 and Fe3O4) as a result of iron ions reaction with plant bioactive molecules as evident from x-ray diffraction analysis (XRD), energy dispersive x-ray spectroscopic (EDS) and Fourier transform infrared (FTIR) spectroscopic study. The adsorption data of As3+/5+ on MG-Fe and MG-Fe-Ex was best fitted by pseudo-first order kinetic and freundlich isotherm except As5+ adsorption on MG-Fe-Ex that can be described by langmuir isotherm model. The prevailing mechanism in adsorption of As3+/5+ on both adsorbent might be hydrogen bonding, electrostatic attraction and complexation. From the above, it is confirmed that MG-Fe-Ex adsorbent has high potential and can be used for the adsorptive elimination of As3+/5+ from contaminated water in sustainable and environmentally friendly way.

Effect of Intranasal Oxytocin on Resting-state Effective Connectivity in Schizophrenia.

OBJECTIVES: Evidence from several lines of research suggests the critical role of neuropeptide oxytocin in social cognition and social behavior. Though a few studies have examined the effect of oxytocin on clinical symptoms of schizophrenia, the underlying neurobiological changes are underexamined. Hence, in this study, we examined the effect of oxytocin on the brain's effective connectivity in schizophrenia. METHODS: 31 male patients with schizophrenia (SCZ) and 21 healthy male volunteers (HV) underwent resting functional magnetic resonance imaging scans with intra-nasal oxytocin (24 IU) and placebo administered in counterbalanced order. We conducted a whole-brain effective connectivity analysis using a multivariate vector autoregressive granger causality model. We performed a conjunction analysis to control for spurious changes and canonical correlation analysis between changes in connectivity and clinical and demographic variables. RESULTS: Three connections, sourced from the left caudate survived the FDR correction threshold with the conjunction analysis; connections to the left supplementary motor area, left precentral gyrus, and left frontal inferior triangular gyrus. At baseline, SCZ patients had significantly weaker connectivity from caudate to these three regions. Oxytocin, but not placebo, significantly increased the strength of connectivity in these connections. Better cognitive insight and lower negative symptoms were associated with a greater increase in connectivity with oxytocin. CONCLUSIONS: These findings provide a preliminary mechanistic understanding of the effect of oxytocin on brain connectivity in schizophrenia. The study findings provide the rationale to examine the potential utility of oxytocin for social cognitive deficits in schizophrenia.

Deep learning model using retinal vascular images for classifying schizophrenia.

Contemporary psychiatric diagnosis still relies on the subjective symptom report of the patient during a clinical interview by a psychiatrist. Given the significant variability in personal reporting and differences in the skill set of psychiatrists, it is desirable to have objective diagnostic markers that could help clinicians differentiate patients from healthy individuals. A few recent studies have reported retinal vascular abnormalities in patients with schizophrenia (SCZ) using retinal fundus images. The goal of this study was to use a trained convolution neural network (CNN) deep learning algorithm to detect SCZ using retinal fundus images. A total of 327 subjects [139 patients with Schizophrenia (SCZ) and 188 Healthy volunteers (HV)] were recruited, and retinal images were acquired using a fundus camera. The images were preprocessed and fed to a convolution neural network for the classification. The model performance was evaluated using the area under the receiver operating characteristic curve (AUC). The CNN achieved an accuracy of 95% for classifying SCZ and HV with an AUC of 0.98. Findings from the current study suggest the potential utility of deep learning to classify patients with SCZ and assist clinicians in clinical settings. Future studies need to examine the utility of the deep learning model with retinal vascular images as biomarkers in schizophrenia with larger sample sizes.

Association between retinal vascular measures and brain white matter lesions in schizophrenia.

OBJECTIVE: Recent studies have examined retinal vascular abnormalities in schizophrenia as retinal vascular imaging is a non-invasive proxy to cerebral microvasculature. However, relation between retinal vascular abnormalities and brain structure is not well examined in schizophrenia. Hence in this study, for the first time, we examined the relationship between retinal vascular measures and brain white matter lesions in schizophrenia. We examined brain white matter lesions as they are considered a predictive marker for future adverse cerebrovascular event. METHODS: We acquired retinal vascular images of both eyes using a non-mydriatic camera and calculated retinal vascular diameter, tortuosity, trajectory and fractal dimension using validated methods. All patients underwent Magnetic Resonance Imaging of bran and we computed white matter hypo-intensities using Freesurfer software. We performed a linear regression analysis to examine the relationship between white matter hypo-intensities and retinal vascular measures controlling for age, sex, fasting blood sugar, creatinine, whole-brain volume, and antipsychotic dose. RESULTS: The regression model was significant in Schizophrenia patients (R=0.983;R2 =0.966;-F=10.849;p = 0.008) but not in healthy volunteers (R=0.828;R2 =0.686;F=0.182; p = 0.963). Among the retinal vascular measures, arterial tortuosity (ß = 0.963;p-0.002), tortuosity (ß = -1.002;p = 0.001) and fractal dimension (ß = -0.688;p = 0.014) were significant predictors of white matter lesions. DISCUSSION: The current study's findings support the conclusion that retinal vascular fractal dimension and tortuosity are associated with changes in cerebral white matter and may be considered proxy markers for cerebral microvasculature in schizophrenia. Considering the relationship between white matter lesions and stroke, these observations could have important clinical implications to screen schizophrenia patients for risk of adverse cerebrovascular event.

iCOMIC: a graphical interface-driven bioinformatics pipeline for analyzing cancer omics data.

Despite the tremendous increase in omics data generated by modern sequencing technologies, their analysis can be tricky and often requires substantial expertise in bioinformatics. To address this concern, we have developed a user-friendly pipeline to analyze (cancer) genomic data that takes in raw sequencing data (FASTQ format) as input and outputs insightful statistics. Our iCOMIC toolkit pipeline featuring many independent workflows is embedded in the popular Snakemake workflow management system. It can analyze whole-genome and transcriptome data and is characterized by a user-friendly GUI that offers several advantages, including minimal execution steps and eliminating the need for complex command-line arguments. Notably, we have integrated algorithms developed in-house to predict pathogenicity among cancer-causing mutations and differentiate between tumor suppressor genes and oncogenes from somatic mutation data. We benchmarked our tool against Genome In A Bottle benchmark dataset (NA12878) and got the highest F1 score of 0.971 and 0.988 for indels and SNPs, respectively, using the BWA MEM-GATK HC DNA-Seq pipeline. Similarly, we achieved a correlation coefficient of r = 0.85 using the HISAT2-StringTie-ballgown and STAR-StringTie-ballgown RNA-Seq pipelines on the human monocyte dataset (SRP082682). Overall, our tool enables easy analyses of omics datasets, significantly ameliorating complex data analysis pipelines.

Development and Characterization of Physical Modified Pearl Millet Starch-Based Films.

Pearl millet is an underutilized and drought-resistant crop that is mainly used for animal feed and fodder. Starch (70%) is the main constituent of the pearl millet grain; this starch may be a good substitute for major sources of starch such as corn, rice, potatoes, etc. Starch was isolated from pearl millet grains and modified with different physical treatments (heat-moisture (HMT), microwave (MT), and sonication treatment (ST)). The amylose content and swelling capacity of the starches decreased after HMT and MT, while the reverse was observed for ST. Transition temperatures (onset (To), peak of gelatinization (Tp), and conclusion (Tc)) of the starches ranged from 62.92-76.16 °C, 67.95-81.05 °C, and 73.78-84.50 °C, respectively. After modification (HMT, MT, and ST), an increase in the transition temperatures was observed. Peak-viscosity of the native starch was observed to be 995 mPa.s., which was higher than the starch modified with HMT and MT. Rheological characteristics (storage modulus (G') and loss modulus (G'')) of the native and modified starches differed from 1039 to 1730 Pa and 83 to 94 Pa; the largest value was found for starch treated with ST and HMT. SEM showed cracks and holes on granule surfaces after HMT as well as MT starch granules. Films were prepared using both native and modified starches. The modification of the starches with different treatments had a significant impact on the moisture, transmittance, and solubility of films. The findings of this study will provide a better understanding of the functional properties of pearl millet starch for its possible utilization in film formation.

Association between retinal vascular caliber and brain structure in schizophrenia.

OBJECTIVE: Several lines of research in the last decade have indicated the potential utility of retina as a window to the brain. Emerging evidence suggests abnormalities in retinal vascular caliber in schizophrenia. However, the relationship between retinal vascular measures and brain structure has not been examined in schizophrenia to date. Hence, we examined the relationship between retinal vasculature measured using fundus photography and brain structure measured using magnetic resonance imaging. METHOD: We recruited 17 healthy volunteers and 20 patients with schizophrenia. Using a non-mydriatic camera, we captured the images for left and right eyes separately and retinal vascular calibers were calculated using a semi-automated software package. Whole-brain anatomical T1 MPRAGE images were acquired using a 3-Tesla MRI scanner. Whole-brain and regional volume and cortical thickness were calculated using the Freesurfer software package. We used FreeSurfer's QDEC interface to compute vertex-by-vertex for analysis of the volume and cortical thickness. The relation between brain volume, cortical thickness, and retinal vascular caliber was examined using partial correlation and regression analysis. RESULTS: There was a significant negative correlation between average CRVE and global cortical mean thickness in schizophrenia but not in healthy. In schizophrenia patients, there was a significant negative correlation between average CRVE and cortical thickness in frontal regions - left rostral middle frontal, left superior frontal, and right caudal middle frontal gyri and posterior brain regions - left lateral occipital gyrus and left posterior cingulate cortex. DISCUSSION: The findings of the study suggest potential utility of retinal venular diameter as a proxy marker to abnormal neurodevelopment in schizophrenia.

Examination of social decision making in patients with schizophrenia using ultimatum game.

Intact decision-making skills in the social context are essential for optimal functioning in the community. Despite its significance, social decision making in schizophrenia (SCZ) has not been adequately examined. Hence, we examined social decision making in SCZ using the Ultimatum Game(UG), a neuroeconomic paradigm that involves financial transactions between a proposer and a responder to split a sum of money between them. Thirty male patients with a diagnosis of schizophrenia as per DSM-IV (age = 30 ± 7.08) and thirty age-matched healthy male volunteers (HV;age = 28.48 ± 3.74) participated in the study. All participants functioned as responders and had to either accept or reject offers made by an anonymous proposer. We also examined whether the gender or emotional expression of the proposer influenced acceptance rates. SCZ had significantly lower acceptance rates than HV for slightly unequal offers (t = 3.94, p = < 0.0001). However, there was no significant difference between SCZ and HV for other offers. Gender and emotional expression of the proposer did not significantly influence the outcome. These results suggest aberrant social decision making and increased inequity aversion in patients with SCZ. The difficulty in incorporating social components while engaging in financial interactions could have important implications for rehabilitation, functional recovery, and successful community living in SCZ.

Cultural differences and neural correlates of cognitive insight in schizophrenia.

Cognitive insight refers to a person's ability to examine their psychotic experiences and the inferences they draw from these experiences. Several studies suggest that cultural factors influence cognitive insight and the processes involved therein; a few studies have suggested differences between Western and Asian societies. However, there are no studies on cognitive insight and its neural correlates in non-Western populations. Hence, we examined factor structure of Beck's cognitive insight scale (BCIS) in a large sample of patients with schizophrenia (SCZ) and healthy volunteers (HV) from India and assessed the relationship between cortical thickness and cognitive insight. We recruited 240 participants (SCZ-140; HV-100). Of these, 58 participants (SCZ-33; HV-25) underwent magnetic resonance imaging. We found a three-factor structure for BCIS which is different from the original two factor structure; self-reflection (SR) of original two-factor structure was sub-divided into- SR1, introspection and SR2, openness to feedback. There was a significant difference between HV and SCZ in the new factors, SR1 and SR2 but not in the original SR factor. Difference was also seen on MRI analysis; while there was a significant positive correlation between original SR factor and thickness of right posterior cingulate cortex, SR2 was positively correlated with thickness of left ventrolateral prefrontal cortex. The difference in factor structure in Indian participants and their distinct neural correlates point to cultural differences in cognitive insight. While in western societies the constructs of introspection and openness to feedback might integrate, they might be separate entities in Asian population.

Calreticulin Expression in Human Non-Small Cell Lung Cancers Correlates with Increased Accumulation of Antitumor Immune Cells and Favorable Prognosis.

A high density of tumor-infiltrating mature dendritic cells (DC) and CD8(+) T cells correlates with a positive prognosis in a majority of human cancers. The recruitment of activated lymphocytes to the tumor microenvironment, primed to recognize tumor-associated antigens, can occur in response to immunogenic cell death (ICD) of tumor cells. ICD is characterized by the preapoptotic translocation of calreticulin (CRT) from the endoplasmic reticulum (ER) to the cell surface as a result of an ER stress response accompanied by the phosphorylation of eukaryotic initiation factor 2α (eIF2α). We conducted a retrospective study on two independent cohorts of patients with non-small cell lung cancer (NSCLC) to investigate the prognostic potential of CRT. We report that the level of CRT expression on tumor cells, which correlated with eIF2α phosphorylation, positively influenced the clinical outcome of NSCLC. High CRT expression on tumor cells was associated with a higher density of infiltrating mature DC and effector memory T-cell subsets, suggesting that CRT triggers the activation of adaptive immune responses in the tumor microenvironment. Accordingly, patients with elevated CRT expression and dense intratumoral infiltration by DC or CD8(+) T lymphocytes had the best prognosis. We conclude that CRT expression constitutes a new powerful prognostic biomarker that reflects enhanced local antitumor immune responses in the lung. Cancer Res; 76(7); 1746-56. ©2016 AACR.

A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+ T cell receptor repertoire clonality.

T and B cell receptor (TCR and BCR, respectively) Vß or immunoglobulin heavy chain complementarity-determining region 3 sequencing allows monitoring of repertoire changes through recognition, clonal expansion, affinity maturation, and T or B cell activation in response to antigen. TCR and BCR repertoire analysis can advance understanding of antitumor immune responses in the tumor microenvironment. TCR and BCR repertoires of sorted CD4+, CD8+ or CD19+ cells in tumor, non-tumoral distant tissue (NT), and peripheral compartments (blood/draining lymph node [P]) from 47 non-small cell lung cancer (NSCLC) patients (agemedian = 68 y) were sequenced. The clonotype spectra were assessed among different tissues and correlated with clinical and immunological parameters. In all tissues, CD4+ and CD8+ TCR repertoires had greater clonality relative to CD19+ BCR. CD4+ T cells exhibited greater clonality in NT compared to tumor (p = 0.002) and P (p < 0.001), concentrated among older patients (age > 68). Younger patients exhibited greater CD4+ T cell diversity in P compared to older patients (p = 0.05), and greater CD4+ T cell clonality in tumor relative to P (p < 0.001), with fewer shared clonotypes between tumor and P than older patients (p = 0.04). More interestingly, greater CD4+ and CD8+ T cell clonality in tumor and P, respectively (both p = 0.05), correlated with high density of tumor-associated tertiary lymphoid structure (TLS) B cells, a biomarker of higher overall survival in NSCLC. Results indicate distinct adaptive immune responses in NSCLC, where peripheral T cell diversity is modulated by age, and tumor T cell clonal expansion is favored by the presence of TLSs in the tumor microenvironment.