Regioselective Synthesis of the Tetrahydrocarbazole Core of Akuammiline Alkaloids via Palladium-Catalyzed Intramolecular Arylation Reaction.

Tetrahydrocarbazole is the central core for several biologically active alkaloids, and regioselective synthesis of this core is a challenging task. Herein, we report an efficient strategy for the synthesis of this core involving palladium-catalyzed intramolecular arylation reaction with excellent regioselectivity (>99%) starting from N-phenyl-bromoalkene without having any relocation of double bonds via competitive palladium-catalyzed isomerization reaction. Broad functional group tolerance and exclusive regioselectivity have been observed for meta-substituted halide substrates. Furthermore, this reaction can be scalable on the gram scale.

Coltricia raigadensis (Hymenochaetaceae, Basidiomycota), a new species from India.

A new species of Coltricia, C. raigadensis is described from tropical region of Maharashtra, India. The species is recognized on the basis of morphological characteristics and phylogenetic analyses using rDNA ITS1-5.8S-ITS2, partial 28S rDNA and partial 18S rDNA sequences. Coltricia raigadensis is characterized by centrally stipitate basidiocarps, adpressed velutinate to tomentose pileal surface, small pores (2-4 per mm), globose to subglobose, thick walled basidiospores measuring 5.6-7 × 5-6.64 µm.

Perfusion index to predict post spinal hypotension in lower segment caesarean section.

Background and Aims: It is important to predict and prevent post-spinal hypotension in lower segment cesarean section (LSCS). Peripheral vascular tone can be monitored as a perfusion index (PI) from a pulse oximeter. We aimed to study baseline PI as a predictor of post-spinal hypotension in LSCS. Material and Methods: Prospective observational study conducted in a tertiary care teaching public hospital on patients posted for elective LSCS under spinal anesthesia. Baseline PI and hypotension were compared. A receiver operating characteristic (ROC) curve was plotted and data were analyzed using SPSS version 20. Results: Among 90 females, 43 (47.8%) had a PI ≤3.5 and 47 (52.2%) had a PI >3.5. In the PI >3.5 group, 46 (97.9%) females had hypotension and required a high volume of IV fluids, and 29 (61.7%) required vasopressors, and the association with PI was statistically significant with Pearson's Chi-square values of 32.26 and 32.36, respectively (P = 0.001). In the ROC, the area under the curve (AUC) was 0.917, proving baseline PI >2.9 as an excellent classifier (P < 0.0001,95% confidence interval [CI] 0.840-0.965) and can predict hypotension with a sensitivity of 83.08% and specificity of 96.00%. Conclusion: Baseline PI >3.5 was associated with significant post-spinal hypotension and vasopressor administration in LSCS. We established baseline PI >2.9 can predict post-spinal hypotension with high sensitivity and specificity. PI is simple, quick, and non-invasive and can be used as a predictor for post-spinal hypotension in parturients undergoing LSCS so that prophylactic measures can be considered in at-risk patients for better maternal and fetal outcomes.

Self-Assembled Lanthanum Oxide Nanoflakes by Electrodeposition Technique for Resistive Switching Memory and Artificial Synaptic Devices.

In recent years, many metal oxides have been rigorously studied to be employed as solid electrolytes for resistive switching (RS) devices. Among these solid electrolytes, lanthanum oxide (La2 O3 ) is comparatively less explored for RS applications. Given this, the present work focuses on the electrodeposition of La2 O3 switching layers and the investigation of their RS properties for memory and neuromorphic computing applications. Initially, the electrodeposited La2 O3 switching layers are thoroughly characterized by various analytical techniques. The electrochemical impedance spectroscopy (EIS) and Mott-Schottky techniques are probed to understand the in situ electrodeposition, RS mechanism, and n-type semiconducting nature of the fabricated La2 O3 switching layers. All the fabricated devices exhibit bipolar RS characteristics with excellent endurance and stable retention. Moreover, the device mimics the various bio-synaptic properties such as potentiation-depression, excitatory post-synaptic currents, and paired-pulse facilitation. It is demonstrated that the fabricated devices are non-ideal memristors based on double-valued charge-flux characteristics. The switching variation of the device is studied using the Weibull distribution technique and modeled and predicted by the time series analysis technique. Based on electrical and EIS results, a possible filamentary-based RS mechanism is suggested. The present results assert that La2 O3 is a promising solid electrolyte for memory and brain-inspired applications.

Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282.

Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.

Microwave prompted solvent-free synthesis of new series of heterocyclic tagged 7-arylidene indanone hybrids and their computational, antifungal, antioxidant, and cytotoxicity study.

In this study, we report the expeditious synthesis of ten new antifungal and antioxidant agents containing heterocyclic linked 7-arylidene indanone moiety. The solvent-free microwave technique, ample substrate scope, superfast synthesis, and very simple operation are noteworthy features of this protocol. Antifungal activities of the newly synthesized compounds were evaluated against four fungal strains namely Rhizophus oryzae, Mucor mucido, Aspergillus niger, and Candida albicans. Most of the compounds were shown strong inhibition of the investigated fungal agents. In vitro, antioxidant potential against DPPH and OH radicals affirmed that the synthesized compounds are good to excellent radicals scavenging agents. The cytotoxicity data of the synthesized compounds towards HL-60 cells uncovered that the synthesized compounds display very low to negligible cytotoxicity. The structural and quantum chemical parameters of the synthesized compounds were explored by employing density functional theory (DFT) at B3LYP functional using 6-311G(d,p) basis set. The compound 3a is discussed in detail for the theoretical and experimental correlation. Time-dependent density functional theory (TD-DFT) at CAM-B3LYP functional with 6-311G(d,p) basis set was used for the electronic absorption study in the gas phase and indichloromethane and benzene solvents. The UV-Visible absorption peaks and fundamental vibrational wavenumbers were computed and a good agreement between observed and theoretical results has been achieved. From the DFT and antifungal activity correlation, it has been found that the 7-heteroarylidene indanones with more stabilized LUMO energy levels display good antifungal potential.

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

Transcriptomic signature reveals mechanism of flower bud distortion in witches'-broom disease of soybean (Glycine max).

BACKGROUND: Soybean (Glycine max L. Merril) crop is major source of edible oil and protein for human and animals besides its various industrial uses including biofuels. Phytoplasma induced floral bud distortion syndrome (FBD), also known as witches' broom syndrome (WBS) has been one of the major biotic stresses adversely affecting its productivity. Transcriptomic approach can be used for knowledge discovery of this disease manifestation by morpho-physiological key pathways. RESULTS: We report transcriptomic study using Illumina HiSeq NGS data of FBD in soybean, revealing 17,454 differentially expressed genes, 5561 transcription factors, 139 pathways and 176,029 genic region putative markers single sequence repeats, single nucleotide polymorphism and Insertion Deletion. Roles of PmbA, Zn-dependent protease, SAP family and auxin responsive system are described revealing mechanism of flower bud distortion having abnormalities in pollen, stigma development. Validation of 10 randomly selected genes was done by qPCR. Our findings describe the basic mechanism of FBD disease, right from sensing of phytoplasma infection by host plant triggering molecular signalling leading to mobilization of carbohydrate and protein, phyllody, abnormal pollen development, improved colonization of insect in host plants to spread the disease. Study reveals how phytoplasma hijacks metabolic machinery of soybean manifesting FBD. CONCLUSIONS: This is the first report of transcriptomic signature of FBD or WBS disease of soybean revealing morphological and metabolic changes which attracts insect for spread of disease. All the genic region putative markers may be used as genomic resource for variety improvement and new agro-chemical development for disease control to enhance soybean productivity.

Prediction of volume of distribution in preclinical species and humans: application of simplified physiologically based algorithms.

The present study was aimed at developing simplified physiologically based semi-mechanistic algorithms to predict Vss and interspecies scaling factors to predict tissue-Kps which require minimum input parameters, diminish the computing complexity and have better predictability. Vss of 86 structurally diverse compounds in preclinical species and 27 compounds in humans were predicted using only lung- and muscle-Kp as inputs. Interspecies scaling factor (s) were developed based on fold-differences in individual tissue lipid contents, relative organ blood flow: relative organ weight ratio between two species. Tissue-Kps were predicted for 34 compounds using the newly developed interspecies scaling factors. The predicted-to-experimental Vss values for all the 113 compounds was 1.3 ± 0.9 with 83% values being within a factor of two. The tissue-Kps in rat, dog and human were predicted using experimental tissue-Kp data in rodents and interspecies scaling factors and here also, 83% of tissue-Kps were within two-fold of the experimental values. In conclusion, simplified physiologically based algorithms have been developed to predict both volume of distribution and tissue-Kps, in which required input parameters as well as computing complexity have been noticeably reduced.

Pancreaticoduodenectomy in Florida: do 20-year trends document the salutary benefits of centralization of care?

BACKGROUND: Concentration of care has been promoted as fostering superior outcomes. This study was undertaken to determine if the concentration of care is occurring in Florida for a pancreaticoduodenectomy, and if so, is it having a salutary effect. METHODS: The data for a pancreaticoduodenectomy were obtained from the Florida Agency for Health Care Administration for three 3-year periods:1992-1994, 2001-2003, 2010-2012; data were sorted by surgeon volume of pancreaticoduodenectomy during these periods and correlated with post-operative length of stay (LOS), in-hospital mortality and hospital charges (adjusted to 2012 dollars). RESULTS: Relative to 1992-1994, in 2010-2012 46% fewer surgeons performed 115% more pancreaticoduodenectomies with significant reductions in LOS and in-hospital mortality, and higher charges (P < 0.001 for each). From 1992-1994 to 2010-2012 there was an 18-fold increase in the number of pancreaticoduodenectomies by surgeons completing ≥ 12 per year (n = 45 to n = 806, respectively). During 2010-2012, the more frequently surgeons performed a pancreaticoduodenectomy, the shorter LOS, the lower in-hospital mortality, the greater the likelihood of discharge home and the lower the hospital charges (P < 0.03 for each). CONCLUSIONS: Over the last 20 years, the concentration of care has occurred in Florida with substantially fewer surgeons undertaking many more pancreaticoduodenectomies with dramatic improvements in LOS and in-hospital mortality, albeit with increased hospital charges.

Contemporary and prospective use of azathioprine (AZA) in viral, rheumatic, and dermatological disorders: a review of pharmacogenomic and nanotechnology applications.

Azathioprine (AZA) has been extensively used for immunomodulatory effects in autoimmune disorders and transplantation. This article is proposed to review the contemporary and prospective use of AZA in viral, rheumatic, and dermatological disorders. The primary objective is to draw attention to possible developments in regards to AZA application in recent years, with an emphasis on the use of pharmacogenomics and nanotechnology to improve its efficacy in practice. This study reveals that AZA, having the active metabolites 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), may be useful in the treatment of systemic lupus erythematosus (SLE), pemphigus vulgaris, and psoriasis. Pharmacogenomic testing of thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) genotypes minimizes the occurrence of myelosuppression. Furthermore, new formulations of AZA using biocompatible polymers and nanoparticles for drug delivery were reported to improve its efficacy and lower systemic toxicity. This paper aims to establish the multifunctional nature of AZA in modern medicine, thus emphasizing its potential for other applications. Through the combination of pharmacogenomic analysis along with nanotechnology application, AZA makes the promise of enhancing patients' treatment efficacy and extending the stock of medical information available. These advancements offer new possibilities for application of precision medicine and improvements in the use of AZA therapy.

Electrochemical Detection of a Breast Cancer Biomarker with an Amine-Functionalized Nanocomposite Pt-Fe3O4-MWCNTs-NH2 as a Signal-Amplifying Label.

We report an ultrasensitive sandwich-type electrochemical immunosensor to detect the breast cancer biomarker CA 15-3. Amine-functionalized composite of reduced graphene oxide and Fe3O4 nanoparticles (MRGO-NH2) was used as an electrochemical sensing platform material to modify the electrodes. The nanocomposite comprising Pt and Fe3O4 nanoparticles (NPs) anchored on multiwalled carbon nanotubes (Pt-Fe3O4-MWCNTs-NH2) was utilized as a pseudoenzymatic signal-amplifying label. Compared to reduced graphene oxide, the composite MRGO-NH2 platform material demonstrated a higher electrochemical signal. In the Pt-Fe3O4-MWCNTs-NH2 label, multiwalled carbon nanotubes provided the substratum to anchor abundant catalytic Pt and Fe3O4 NPs. The nanocomposites were thoroughly characterized using transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy. An electroanalytical study and prevalidation of the immunosensor was carried out. The immunosensor exhibited exceptional capabilities in detecting CA 15-3, offering a wider linear range of 0.0005-100 U mL-1 and a lower detection limit of 0.00008 U mL-1. Moreover, the designed immunosensor showed good specificity, reproducibility, and acceptable stability. The sensor was successfully applied to analyze samples from breast cancer patients, yielding reliable results.

Successful Thoracic Duct Embolization Following Fontan-Related Chylothorax in a Six-Year-Old Girl: A Case Report.

Chylothorax is a severe complication following the Fontan procedure, causing significant morbidity and mortality due to nutritional depletion and fluid loss. We present a case involving a six-year-old girl with tricuspid atresia, atrial septal defect (ASD), ventricular septal defect (VSD), and severe pulmonary stenosis (PS), presenting with fever, non-productive cough, and increased work of breathing. Cyanosis was noted, improving with oxygen. Imaging revealed bilateral pleural effusion, with pleural fluid analysis confirming chylothorax. Despite normal laboratory reports, retrograde transvenous lymphangiography indicated thoracic duct leakage. The patient underwent successful thoracic duct embolization, resulting in the resolution of the effusion and stabilization of her condition. She was discharged in a stable state, with follow-up care.

Diastereoselective synthesis of bridged polycyclic alkaloids via tandem acylation/intramolecular Diels-Alder reaction.

A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-ß-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron ß-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-ß-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.

A mild and efficient one-pot synthesis of ß-amino carbonyl compounds via Mannich reaction under ambient temperature condition.

We have developed an efficient protocol for the synthesis of ß-amino carbonyl compounds using phenylboronic acid as effective and eco-friendly catalyst via one-pot three-component Mannich reaction. Excellent yields, mild reaction condition, and simple experimental work-up procedure are some of the advantages of this method, which makes it a useful protocol for the synthesis of ß-amino carbonyl compounds.

Rheological investigation and its correlation with permeability coefficient of drug loaded carbopol gel: influence of absorption enhancers.

CONTEXT: The present study was planned to investigate the effect of absorption enhancers on the microstructure of Losartan potassium gel and hence its influence on the diffusion of Losartan potassium across nasal mucosa. METHOD: Losartan potassium loaded carbopol gel (1% w/v) with and without absorption enhancers was prepared. Polyethylene glycol (PEG) 4000 and ethanol were used as absorption enhancers. Microstructural elucidation of prepared gels was done using shear rheology. Ex vivo drug release studies were performed on the prepared gels. RESULTS: It was observed that the absorption enhancers PEG 4000 and ethanol altered the gel microstructure. The prepared gels were viscoelastic in nature suggesting their suitability for topical application. Permeability coefficient of Losartan potassium loaded into gels was found to be inversely proportional to the storage modulus. Thus increase in storage modulus lead to slow drug diffusion. CONCLUSION: The current study emphasizes on the fact that selection of polymeric carrier for nasal drug delivery and/or absorption enhancer strongly influence the microstructure of the gel and hence the pharmaceutical performance of the formulation.

Nonsurgical management of large periapical lesion in mature and immature teeth using different calcium hydroxide formulations: case series.

This case series evaluates the effectiveness of different calcium hydroxide formulations with various vehicles in management of large periapical lesion in mature and immature teeth. This will help clinicians to make informed judgments about which formulations of calcium hydroxide should be used for specific endodontic procedures.

Solid pseudo papillary tumor of the pancreas: An unusual tumor in children.

An 11-year-old girl with a pancreatic solid pseudo papillary tumor (SPT) is reported. Contrast enhanced computerized tomography (CECT) & Magnetic resonant imaging (MRI) abdomen revealed a well-defined inhomogenous mass arising from the retro-peritoneum in the left upper quadrant of the abdomen possibly from the tail of the pancreas. USG guided biopsy of tumor showed benign pseudo papillary tumor of pancreas. Complete excision of the tumor was carried out. Histopathology revealed pancreatic pseudo papillary tumor. Patient did well postoperatively & is on regular follow-up.

Biliary fascioliasis: Management in a child using endoscopic retrograde cholangio pancreatography.

A 9-year-old boy presented with right upper abdominal pain and fever. The radiologic investigations revealed multiple cholangitic abscesses with cholangitis and worms in common bile duct. Endoscopic retrograde cholangio pancreatographic (ERCP) sphincterotomy, basketing, ballooning and extraction of Fasciola hepatica worms from the common bile duct were done.