In-vitro cell migration enhancing constituents from Decalepis hamiltonii, a plant used in the preparation of 'Pinda oil', a medicinal oil used in Ayurveda for wound management.

Decalepis hamiltonii, Wight & Arn. (Apocyanaceae) is a one of the raw materials used in the preparation of 'Pinda oil', a medicinal oil which is used for treatment of wounds in Ayurveda. Of the hexanes, dichloromethane, and ethyl acetate extracts derived from the plant raw materials used to prepare 'Pinda oil', the hexanes extract of D. hamiltonii exhibited the highest mean percentage wound closure (75.1 ± 2.9) compared to the negative controls (1% DMSO in DMEM, 4.2 ± 1.2 and 100% DMEM, 4.1 ± 0.9) in the scratch wound assay (SWA). Fractionation of the hexanes extract of stem of D. hamiltonii led to the isolation of 2-hydroxy-4-methoxybenzaldehyde (1) and a mixture of long chain esters of lupeol (2), which showed enhanced cell migration in SWA. It was observed that the esters of lupeol bind to the cell membrane and/or enter the cells during the SWA. It was found that these constituents are also present in 'Pinda oil' which may contribute to the enhancement of wound healing activity of 'Pinda oil'.

A rare phytosterol, stigmast-5-en-3ß,7α,22α-triol and other secondary metabolites from Leea indica showing enhanced in vitro cell migration and proangiogenic activity.

Leea indica (Burm. f.) Merr. (Vitaceae) is used for the treatment of wounds in traditional medicine practiced in Sri Lanka. The current study is carried out to investigate its wound healing potential in terms of in vitro cell migration and proangiogenic activity. The scratch wound assay (SWA) guided fractionation of dichloromethane extract of L. indica led to the isolation of a rare phytosterol, stigmast-5-en-3ß,7α,22α-triol (1), betulin (2), lupeol (3), and ß-sitosterol (4) all of which showed enhanced cell migration in SWA and significant proangiogenic response in chorioallantoic membrane (CAM) assay. The identities of compounds 1-4 were established by the analysis of NMR spectroscopic data and comparison with those reported. This is the first report of the occurrence of compounds 1 and 2 in L. indica.

Supratentorial Sporadic Hemangioblastoma: A Case Report With Mutation Profiling Using Next-Generation DNA Sequencing.

The present study aimed to determine genomic changes in sporadic intracranial hemangioblastoma (HBL), and the mutation patterns were analyzed using next-generation DNA sequencing (NGS). In this NGS analysis of the HBL tumor, 67 variants of 41 genes were identified. Of these, 64 were single-nucleotide variants (SNVs), two were exonic insertions and deletions (INDEL), and one was an intronic INDEL. In total, 15 were missense exonic variants, including an insertion variant in the NRAS gene, c.1_2insA, and a deletion variant, c.745delT, in the HNF1A gene, both of these mutations produced a termination codon. Other exonic missense variants found in the tumor were CTNNB1, FGFR3, KDR, SMO, HRAS, RAI1, and a TP53 variant (c.430C>G). Moreover, the results of the present study revealed a novel variant, c.430C>G, in TP53 and two missense variants of SND1 (c.1810G>C and c.1814G>C), which were also novel. ALK (rs760315884) and FGFR2 (rs1042522) missense variants were reported previously. Notably, a total of 10 previously reported single-nucleotide polymorphisms (SNPs) were found in this tumor in genes including MLH1 (rs769364808), FGFR3 (rs769364808), two variants (rs1873778 and rs2228230) in PDGFRA, KIT (rs55986963), APC (rs41115), and RET (rs1800861). The results of this study revealed a synonymous mutation (SNP) in c.1104 G>T; p. (Ser368Ser) in the MLH1 gene. In this amino acid (AA) codon, two other variants are also known to cause missense substitutions, c.1103C>G; p. (Ser368Trp); COSM6986674) and c.1103C>T; p.(Ser368Leu; COSM3915870), were found in hematopoietic and urinary tract tissue, respectively. However, three SNPs found in genes such as ALK, KDR, and ABL1 in the HBL tumor in this study were not reported in UCSC, COSMIC, and ClinVar databases. Additionally, 19 intronic variants were identified in this tumor. One intronic SNV was present in each of the following genes: EGFR, ERBB4, KDR, SMO, CDKN2B, PTEN, PTPN11, RB1, AKT1, and ERBB2. In PIK3CA and FBXL18 genes, two intronic variants were present, and in the SND1 gene, three intronic variants were detected in the HBL tumor presented in this study. Notably, only one of these was reported in the catalog of somatic mutations in cancer. Only one 3'-untranslated region (UTR) insertion variant in the NRAS gene (c.*2010T>AT) was detected in the tumor of the present study, and this was a splice site acceptor. A TP53 intronic mutation (c.782+1G>T) was the only pathogenic splice_donor_variant found in this HBL tumor. The frequency of variants and Phred scores were markedly high, and the p-values were significant for all of the aforementioned mutations. In summary, a total of 15 missense, 10 synonymous, and 19 intronic variants were identified in the HBL tumor. Results of the present study detected one novel insertion in NRAS and one novel deletion in HNF1A genes, a novel missense variant in the TP53 gene, and two novel missense variants of SND1. Hotspot mutations in other cancer driver genes, such as PTEN, ATM, SMAD4, SMARCB1, STK11, NPM1, CDKN2A, and EGFR, which are frequently affected in gliomas, were not found in the tumor of the present study. Future studies should aim to validate oncogenic mutations that may act as novel targets for the treatment of these tumors.

Reassignment of NMR spectroscopic data of oleana-9(11),12-diene-3ß-ol isolated from Jeffreycia zeylanica and its wound healing potential in terms of cell migration and proangiogenic activity1.

Jeffreycia zeylanica (Asteraceae), a plant endemic to Sri Lanka, is used for the treatment of wounds. The scratch wound assay (SWA) guided fractionation of hexanes extract of J. zeylanica led to the isolation of oleana-9(11),12-diene-3ß-ol (1) which showed enhanced cell migration in SWA and significant proangiogenic response in chorioallantoic membrane (CAM) assay. Since the reported 1H NMR assignments of 1 were incomplete, and some 13C NMR assignments were inconsistent with our observations, reassignment of NMR spectroscopic data of 1 was carried out. Herein we report unambiguous assignment of NMR data of 1 based on 1D and 2D NMR spectra. This is the first report of 1 in J. zeylanica.

In-vitro cell migration enhancing and pro-angiogenic active secondary metabolites from Jeffreycia zeylanica (L.) H. Rob., S.C. Keeley & Skvarla (Asteraceae).

Jeffreycia zeylanica (L.) H. Rob., S. C. Keeley & Skvarla is used for the treatment of wounds in indigenous medicine practiced in Sri Lanka. The scratch wound assay (SWA) guided fractionation of hexanes extract of J. zeylanica led to the isolation of ethuliacoumarin (1), stigmasterol (2), ß-amyrin (3) and lupeol (4) and a non-resolved triterpene alcohol mixture HF5D1, all of which showed enhanced cell migration. The mixture HF5D1 contained glut-5-en-3ß-ol (5) and friedelin-3ß-ol (6). The identities of compounds 1-6 were established by the analysis of spectroscopic data and comparison of them with those reported. The compounds 1-4 and the non-resolved triterpene alcohol mixture, HF5D1 also exhibited significant proangiogenic response in chorioallantoic membrane (CAM) assay in addition to the enhanced cell migration. This is the first report of the occurrence of the compounds 1, 2, 4 and 5 in this plant.

Comprehensive Treatment Module for Medically Unexplained Physical Symptoms - A Guide for General Practitioners.

PURPOSE: This study was aimed to develop a comprehensive treatment module that the general physician can use to manage patients with Medically Unexplained Physical Symptoms (MUPS) at a primary care level.  Methods: This comprehensive module was developed after a literature review followed by its validation by a two-step Delphi technique with experts from internal medicine, psychiatry, and clinical psychology. RESULTS: The developed module for the patients with MUPS includes case diagnosis, initial evaluation, strategy for referral, and a comprehensive treatment module. The comprehensive treatment module includes symptom discussion, rapport establishment, physical health counselling, stress management, cognitive strategies for symptom control, comorbidities treatment, and medical management.  Conclusion: The developed module has unique features, such as intensive sessions with these patients, a patient-specific treatment strategy, and a holistic approach incorporating pharmacological and non-pharmacological interventions. General Practitioners across the world can use this comprehensive treatment module for the management of patients with MUPS.

Prevalence of cancer as a comorbid in COVID-19 patients and their characteristics: a meta-analysis study.

Background: Cancer patients are considered susceptible to coronavirus disease (COVID-19) due to an immunosuppressive state. This study determined the prevalence of cancer in COVID-19 patients, severe events, case fatality rate, history of anticancer therapy associated with severe events, and type of cancer in cancer patients with COVID-19 in the world. Methods: This study used a meta-analysis study approach, sourcing studies from various countries related to cancer and COVID-19. Inclusion and exclusion criteria were established to select studies. A PRISMA flowchart was presented to assess the selection process. Data from inclusion studies were analyzed using Review Manager 5.4. Results: The prevalence of cancer in COVID-19 patients was 4.63% (95% CI, 3.78-5.49%) worldwide. The lowest prevalence was the Asian study group with 2.36% (95% CI, 1.86-2.87%) and the highest prevalence was the European study group with 10.93% (95% CI, 6.62-15.24%). About 43.26% (95% CI, 34.71-51.80%) of cancer patients with COVID-19 experienced severe events of COVID-19. In total, 58.13% (95% CI, 42.79-73.48%) of cancer patients with COVID-19 who in the last month had a history of anticancer therapy experienced severe events. The prevalence of lung cancer in cancer patients with COVID-19 was 20.23% (95% CI, 7.67-32.78%). Forest plots are also presented related to the results of meta-analysis research. Conclusions: High prevalence of cancer among COVID-19 patients indicates the susceptibility of cancer patients to SARS-CoV-2 infection. Cancer in COVID-19 patients and use of anticancer therapy increase severe events of COVID-19.

A review of meibography for a refractive surgeon.

Refractive surgery has evolved from being a therapeutic correction of high refractive errors to a cosmetic correction. The expectations associated with such a surgery are enormous and one has to anticipate all possible complications and side-effects that come with the procedure and prepare accordingly. The most common amongst these is post-refractive surgery dry eye of which Meibomian gland dysfunction is a commonly associated cause. We present an understanding of various diagnostic imaging modalities that can be used for evaluating meibomian glands which can also serve as a visual aid for patient understanding. We also describe various common conditions which can silently cause changes in the gland architecture and function which are to be considered and evaluated for.

Distribution Pattern of Gymnosperms' Richness in Nepal: Effect of Environmental Constrains along Elevational Gradients.

Understanding the pattern of species distribution and the underlying mechanism is essential for conservation planning. Several climatic variables determine the species diversity, and the dependency of species on climate motivates ecologists and bio-geographers to explain the richness patterns along with elevation and environmental correlates. We used interpolated elevational distribution data to examine the relative importance of climatic variables in determining the species richness pattern of 26 species of gymnosperms in the longest elevation gradients in the world. Thirteen environmental variables were divided into three predictors set representing each hypothesis model (energy-water, physical-tolerance, and climatic-seasonality); to explain the species richness pattern of gymnosperms along the elevational gradient. We performed generalized linear models and variation partitioning to evaluate the relevant role of environmental variables on species richness patterns. Our findings showed that the gymnosperms' richness formed a hump-shaped distribution pattern. The individual effect of energy-water predictor set was identified as the primary determinant of species richness. While, the joint effects of energy-water and physical-tolerance predictors have explained highest variations in gymnosperm distribution. The multiple environmental indicators are essential drivers of species distribution and have direct implications in understanding the effect of climate change on the species richness pattern.

Suppressed phase separation of mixed-halide perovskites confined in endotaxial matrices.

The functionality and performance of a semiconductor is determined by its bandgap. Alloying, as for instance in InxGa1-xN, has been a mainstream strategy for tuning the bandgap. Keeping the semiconductor alloys in the miscibility gap (being homogeneous), however, is non-trivial. This challenge is now being extended to halide perovskites - an emerging class of photovoltaic materials. While the bandgap can be conveniently tuned by mixing different halogen ions, as in CsPb(BrxI1-x)3, the so-called mixed-halide perovskites suffer from severe phase separation under illumination. Here, we discover that such phase separation can be highly suppressed by embedding nanocrystals of mixed-halide perovskites in an endotaxial matrix. The tuned bandgap remains remarkably stable under extremely intensive illumination. The agreement between the experiments and a nucleation model suggests that the size of the nanocrystals and the host-guest interfaces are critical for the photo-stability. The stabilized bandgap will be essential for the development of perovskite-based optoelectronics, such as tandem solar cells and full-color LEDs.

Increased mitochondrial DNA copy number in maternal peripheral blood is associated with low birth weight in Lombok, Indonesia.

Fetal development depends on maternal metabolic energy from mitochondria. We investigated the association of maternal mitochondrial function, represented by mitochondrial DNA copy number (mtDNA-CN) of venous blood, with child birth weight (BW) from 528 randomly selected mothers enrolled in the Supplementation with Multiple Micronutrients Intervention Trial (ISRCTN 34151616). Real-time quantitative PCR of archived blood specimens and regression analysis adjusting for other primary determinants of BW showed that loge mtDNA-CN was inversely associated with BW (ß = -204.6, p < 0.001), particularly in the third trimester (ß = -376.8, p<0.001). Maternal mtDNA-CN may be a marker for low BW and fetal growth restriction.

Excess Electron and Hole in 1-Benzylpyridinium-Based Ionic Liquids.

The study of ionic liquids that may be compatible with the type of radiation chemistry events occurring in nuclear separation processes is a topic of high current interest. In this article, we focus on two ionic liquids based on the benzylpyridinium cation. This cation has been proposed to be able to capture either an excess electron or hole without undergoing fast dissociation. Shkrob, Wishart, and collaborators ( J. Phys. Chem. B 2013 , 117 ( 46 ), 14385 - -14399 ) have indicated that the stabilization is likely in the form of dimers in solution with the excess electron localized on adjacent pyridinium rings and the excess hole localized on phenyl rings. Our first-principles dynamical studies support these ideas but present a more nuanced view of the time-dependent behavior that is likely to occur at short time for systems at room temperature.

Comparison of the Structural Response to Pressure of Ionic Liquids with Ether and Alkyl Functionalities.

The response of ionic liquids to external perturbations including elevated pressure is a topic of current interest for applications such as tribology. Ionic liquids come in many classes, including those that are amphiphilic and some that are mostly polar having either cationic or anionic tails that are functionalized. The current study compares the effect of elevated pressure on two ionic liquids with different types of cationic tail. 1-Decyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (C10mim+/NTf2-) is amphiphilic whereas isoelectronic ether-functionalized 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (C7O3mim+/NTf2-) has cationic tails that are more polar and conformationally different. We find that the response to elevated pressure for these two systems is quite unsimilar. Intramolecular conformational changes as well as changes in the structure of liquid nanodomains appear to be significantly more prominent in the case of C10mim+/NTf2-. Whereas both the density of C10mim+/NTf2- and C7O3mim+/NTf2- change at elevated pressure, the change is more dramatic for C10mim+/NTf2-. The very different response for each of these two types of ionic liquids can be clearly gleaned from distribution functions in real space and the partial subcomponents of the X-ray structure function, S(q), in reciprocal space. Liquid structure in the case of C7O3mim+/NTf2-, and the intramolecular conformational structure of C7O3mim+ in particular, appear to be more resilient to pressure changes than those in the isoelectronic amphiphilic analogue.

Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.

There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. Here, we establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders antifungal-resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating the protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for treating fungal infectious disease that evades resistance.

Structure of cyano-anion ionic liquids: X-ray scattering and simulations.

Ionic liquids with cyano anions have long been used because of their unique combination of low-melting temperatures, reduced viscosities, and increased conductivities. Recently we have shown that cyano anions in ionic liquids are particularly interesting for their potential use as electron donors to excited state photo-acceptors [B. Wu et al., J. Phys. Chem. B 119, 14790-14799 (2015)]. Here we report on bulk structural and quantum mechanical results for a series of ionic liquids based on the 1-ethyl-3-methylimidazolium cation, paired with the following five cyano anions: SeCN(-), SCN(-), N(CN)2 (-), C(CN)3 (-), and B(CN)4 (-). By combining molecular dynamics simulations, high-energy X-ray scattering measurements, and periodic boundary condition DFT calculations, we are able to obtain a comprehensive description of the liquid landscape as well as the nature of the HOMO-LUMO states for these ionic liquids in the condensed phase. Features in the structure functions for these ionic liquids are somewhat different than the commonly observed adjacency, charge-charge, and polarity peaks, especially for the bulkiest B(CN)4 (-) anion. While the other four cyano-anion ionic liquids present an anionic HOMO, the one for Im2,1 (+)/B(CN)4 (-) is cationic.

Unlocking the Origin of Superior Performance of a Si-Ge Core-Shell Nanowire Quantum Dot Field Effect Transistor.

The sustained advancement in semiconducting core-shell nanowire technology has unlocked a tantalizing route for making next generation field effect transistor (FET). Understanding how to control carrier mobility of these nanowire channels by applying a gate field is the key to developing a high performance FET. Herein, we have identified the switching mechanism responsible for the superior performance of a Si-Ge core-shell nanowire quantum dot FET over its homogeneous Si counterpart. A quantum transport approach is used to investigate the gate-field modulated switching behavior in electronic current for ultranarrow Si and Si-Ge core-shell nanowire quantum dot FETs. Our calculations reveal that for the ON state, the gate-field induced transverse localization of the wave function restricts the carrier transport to the outer (shell) layer with the pz orbitals providing the pathway for tunneling of electrons in the channels. The higher ON state current in the Si-Ge core-shell nanowire FET is attributed to the pz orbitals that are distributed over the entire channel; in the case of Si nanowire, the participating pz orbital is restricted to a few Si atoms in the channel resulting in a smaller tunneling current. Within the gate bias range considered here, the transconductance is found to be substantially higher in the case of a Si-Ge core-shell nanowire FET than in a Si nanowire FET, which suggests a much higher mobility in the Si-Ge nanowire device.

Oxaspirol B with p97 Inhibitory Activity and Other Oxaspirols from Lecythophora sp. FL1375 and FL1031, Endolichenic Fungi Inhabiting Parmotrema tinctorum and Cladonia evansii.

A new metabolite, oxaspirol D (4), together with oxaspirols B (2) and C (3) were isolated from Lecythophora sp. FL1375, an endolichenic fungus isolated from Parmotrema tinctorum, whereas Lecythophora sp. FL1031 inhabiting the lichen Cladonia evansii afforded oxaspirols A (1), B (2), and C (3). Of these, oxaspirol B (2) showed moderate p97 ATPase inhibitory activity. A detailed characterization of all oxaspirols was undertaken because structures proposed for known oxaspirols have involved incomplete assignments of NMR spectroscopic data leading only to their planar structures. Thus, the naturally occurring isomeric mixture (2a and 2b) of oxaspirol B was separated as their diacetates (5a and 5b) and the structures and absolute configurations of 1, 2a, 2b, 3, and 4 were determined by the application of spectroscopic techniques including two-dimensional NMR and the modified Mosher's ester method. Oxaspirol B (2) and its diacetates 5a and 5b were evaluated for their ATPase inhibitory activities of p97, p97 mutants, and other ATP-utilizing enzymes, and only 2 was found to be active, indicating the requirement of some structural features in oxaspirols for their activity. Additional biochemical and cellular assays suggested that 2 was a reversible, non-ATP competitive, and specific inhibitor of p97.

BODIPY-Based Fluorescent Probes for Sensing Protein Surface-Hydrophobicity.

Mapping surface hydrophobic interactions in proteins is key to understanding molecular recognition, biological functions, and is central to many protein misfolding diseases. Herein, we report synthesis and application of new BODIPY-based hydrophobic sensors (HPsensors) that are stable and highly fluorescent for pH values ranging from 7.0 to 9.0. Surface hydrophobic measurements of proteins (BSA, apomyoglobin, and myoglobin) by these HPsensors display much stronger signal compared to 8-anilino-1-naphthalene sulfonic acid (ANS), a commonly used hydrophobic probe; HPsensors show a 10- to 60-fold increase in signal strength for the BSA protein with affinity in the nanomolar range. This suggests that these HPsensors can be used as a sensitive indicator of protein surface hydrophobicity. A first principle approach is used to identify the molecular level mechanism for the substantial increase in the fluorescence signal strength. Our results show that conformational change and increased molecular rigidity of the dye due to its hydrophobic interaction with protein lead to fluorescence enhancement.

Functional chromatographic technique for natural product isolation.

Natural product discovery arises through a unique interplay between chromatographic purification and biological assays. Currently, most techniques used for natural product purification deliver leads without a defined biological action. We now describe a technique, referred to herein as functional chromatography, that deploys biological affinity as the matrix for compound isolation.

Boron nitride nanotubes for spintronics.

With the end of Moore's law in sight, researchers are in search of an alternative approach to manipulate information. Spintronics or spin-based electronics, which uses the spin state of electrons to store, process and communicate information, offers exciting opportunities to sustain the current growth in the information industry. For example, the discovery of the giant magneto resistance (GMR) effect, which provides the foundation behind modern high density data storage devices, is an important success story of spintronics; GMR-based sensors have wide applications, ranging from automotive industry to biology. In recent years, with the tremendous progress in nanotechnology, spintronics has crossed the boundary of conventional, all metallic, solid state multi-layered structures to reach a new frontier, where nanostructures provide a pathway for the spin-carriers. Different materials such as organic and inorganic nanostructures are explored for possible applications in spintronics. In this short review, we focus on the boron nitride nanotube (BNNT), which has recently been explored for possible applications in spintronics. Unlike many organic materials, BNNTs offer higher thermal stability and higher resistance to oxidation. It has been reported that the metal-free fluorinated BNNT exhibits long range ferromagnetic spin ordering, which is stable at a temperature much higher than room temperature. Due to their large band gap, BNNTs are also explored as a tunnel magneto resistance device. In addition, the F-BNNT has recently been predicted as an ideal spin-filter. The purpose of this review is to highlight these recent progresses so that a concerted effort by both experimentalists and theorists can be carried out in the future to realize the true potential of BNNT-based spintronics.