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Flexible lipid nanomaterials studied by NMR spectroscopy
No full textOur review addresses how material properties emerge from atomistic-level interactions in the case of lipid membrane nanostructures. We summarize advances in solid-state nuclear magnetic resonance (NMR) spectroscopy in conjunction with alternative small-angle X-ray and neutron scattering methods for investigating lipid flexibility and dynamics. Solid-state H-2 NMR is advantageous in that it provides atomistically resolved information about the order parameters and mobility of phospholipids within liquid-crystalline membranes. Bilayer deformation in response to external perturbations occurs over a range of length scales and allows one to disentangle how the bulk material properties emerge from atomistic forces. Examples include structural parameters such as the area per lipid and volumetric thickness together with the moduli for elastic deformation. Membranes under osmotic stress allow one to further distinguish collective undulations and quasielastic contributions from short-range noncollective effects. Our approach reveals how membrane elasticity involves length scales ranging from the bilayer dimensions on down to the size of the flexible lipid segments. Collective lipid interactions of the order of the bilayer thickness and less occur in the liquid-crystalline state. Emergence of lipid material properties is significant for models of lipid-protein forces acting on the mesoscopic length scale that play key roles in biomembrane functions
A novel model for silicon recycling in the lithosphere: Evidence from the Central Asian Orogenic Belt
No full textGlobal-scale cycling of silicon through the biosphere, atmosphere, and hydrosphere has received much attention although, silicon cycling in the Earth's lithosphere remains poorly understood. As the products of internal heat and material exchange, igneous rocks preserve significant information of silicon migration through the lithosphere. Here we report silicon isotopic compositions of nine peraluminous granites from the Chinese Altai, which forms part of the Central Asian Orogenic Belt. These rocks are characterized by the heaviest delta Si-30 values (-0.13 +/- 0.03 parts per thousand to +0.78 +/- 0.05 parts per thousand) compared to global granites, with a linear variation in the silicon isotopic values against silica content, with high silica-rich granites displaying more depleted isotopic compositions. In conjunction with the whole rock weakly negative epsilon Nd(t) and uniform delta Mg-26 values, as well as high delta O-18 values, we suggest that the delta Si-30 values of these granites were mainly inherited from the magma source, rather than produced by magmatic fractionation. In addition, the wide range of initial Sr-87/ Sr-86 ratios and high Ba content of the samples suggest the role of aqueous fluids. The Chinese Altai is considered to have formed through accretion of volcanic arcs associated with subduction of the Paleo-Asian oceanic lithosphere. The magma derived through partial melting of metasomatic mantle scavenges the heavy Si-30 isotopes derived through fluids released from oceanic sediments and transfers to the upper crust where partial melting of crustal sedimentary rocks occur. Mixing of these two melts generated the peraluminous granites. Our study offers a novel insight into a potentially important mechanism of silicon cycling in the lithosphere
Nudix hydrolases with Coenzyme A (CoA) and acyl-CoA pyrophosphatase activities confer growth advantage to Mycobacterium smegmatis
No full textNudix hydrolase family proteins hydrolyse toxic by-products of cellular metabolism such as mutagenic nucleoside triphosphates, sugar nucleotides and signalling molecules. We studied the substrate specificities of Nudix hydrolases encoded by rv3672c and rv3040c from Mycobacterium tuberculosis and their respective homologues, msmeg_6185 and msmeg_2327 from M. smegmatis. The rv3672c- and msmeg_6185-encoded proteins (Rv3672 and MSMEG_6185, respectively) showed CoA pyrophosphatase (CoAse) activity that converted acyl-CoA to adenosine-3',5'-diphosphate (3', 5'-ADP) and 4-acyl phosphopantetheine. The efficiencies of Rv3672 and MSMEG_6185 in hydrolysing CoA derivatives were found to be higher than those of the Rv3040 and MSMEG_2327 (encoded by rv3040c and msmeg_2327, respectively). Further, amongst the substrates tested, Rv3672 and MSMEG_6185 used CoA and oxidized CoA as the most preferred substrates. Use of the M. smegmatis model showed that the expression of msmeg_6185 occurs in the log and stationary phases but declines during the late stationary phase and becomes undetectable during hypoxia. The co-culture competition experiments performed between the wild-type and Delta msmeg_6185 strains of M. smegmatis in different carbon sources revealed that the presence of msmeg_6185 provided growth fitness advantage to M. smegmatis, irrespective of the carbon source, implicating its function in regulation for the optimal physiological levels of acyl-CoAs in the cell
Forecasting dengue and influenza incidences using a sparse representation of Google trends, electronic health records, and time series data
No full textAuthor summary Dengue and influenza-like illness (ILI) are leading causes of viral infection in the world and hence it is important to develop accurate methods for forecasting their incidence. We use Autoregressive Likelihood Ratio method, which is a computationally efficient implementation of the variable selection method, in order to obtain a sparse (non-lasso) representation of time series, Google Trends and electronic health records (for ILI) data. This method is used to forecast dengue incidence in five countries/states and ILI incidence in USA. We show that this method outperforms existing time series methods in forecasting these diseases. The method is general and can also be used to forecast other diseases. Dengue and influenza-like illness (ILI) are two of the leading causes of viral infection in the world and it is estimated that more than half the world's population is at risk for developing these infections. It is therefore important to develop accurate methods for forecasting dengue and ILI incidences. Since data from multiple sources (such as dengue and ILI case counts, electronic health records and frequency of multiple internet search terms from Google Trends) can improve forecasts, standard time series analysis methods are inadequate to estimate all the parameter values from the limited amount of data available if we use multiple sources. In this paper, we use a computationally efficient implementation of the known variable selection method that we call the Autoregressive Likelihood Ratio (ARLR) method. This method combines sparse representation of time series data, electronic health records data (for ILI) and Google Trends data to forecast dengue and ILI incidences. This sparse representation method uses an algorithm that maximizes an appropriate likelihood ratio at every step. Using numerical experiments, we demonstrate that our method recovers the underlying sparse model much more accurately than the lasso method. We apply our method to dengue case count data from five countries/states: Brazil, Mexico, Singapore, Taiwan, and Thailand and to ILI case count data from the United States. Numerical experiments show that our method outperforms existing time series forecasting methods in forecasting the dengue and ILI case counts. In particular, our method gives a 18 percent forecast error reduction over a leading method that also uses data from multiple sources. It also performs better than other methods in predicting the peak value of the case count and the peak time
Resonant heavy Higgs searches at the HL-LHC
No full textIn this work, we show the importance of searches for heavy resonant scalars (H) and pseudoscalars (A). Taking cue from the present searches, we make projections for searches in an extended scalar sector at the high luminosity run of the Large Hadron Collider. We study the three most relevant search channels, i.e., H -> hh, H/A t (t) over bar and b (b) over barH/A. Upon studying multifarious final states for the resonant double Higgs production, we find that the b (b) over bar gamma gamma (sigma(pp -> H -> hh) is an element of 81.27, 14.45] fb for m(H) is an element of 300, 600] GeV at 95% C.L.) and b (b) over barb (b) over bar (5.4, 2.5] fb for m(H) is an element of 800, 1000] GeV at 95% C.L.) channels are the most constraining. For the b (b) over barH channel, we can exclude sigma(pp -> b (b) over barH) is an element of 22.2, 3.7] fb for m(H) is an element of 300, 500] GeV. Finally, we consider the phenomenological Minimal Supersymmetric Standard Model as an example and impose various present constraints and our future direct search-limits and obtain strong constraints on the m(A) - tan beta parameter space, where m(A) and tan beta are respectively the mass of the pseudoscalar and the ratio of the vacuum expectation values of the two Higgs doublets. Assuming that the heavy Higgs boson decays only to Standard Model (SM) states, we find that the H -> hh -> b (b) over bar gamma gamma (H -> t (t) over bar) channel excludes tan beta as low as 4 (m(A)is an element of 400, 800] GeV) at 95% CL. This weakens up to similar to 5.5 when the b (b) over barH channel dominates. Upon allowing for non-SM decay modes, the limits weaken
Nanoforest of 3C-SiC/graphene by laser chemical vapor deposition with high electrochemical performance
No full textNanoforests of 3C-SiC/graphene films are prepared by laser chemical vapor deposition (LCVD). The effectiveness of nanoforest-like 3C-SiC/graphene film as electrode materials for supercapacitors has been investigated by cyclic voltammetry and galvanostatic charge-discharge tests in 0.5 M H2SO4 solution. The specific capacitance is 8.533 mF/cm(2) at a current density of 20 mu A/cm(2), which is 15 times higher than of previous reports of composited 3C-SiC/graphene films. The electrode exhibits good rate capability and cycling stability with 90.5% capacitance retention after 10000 cycles. The nanoforest-like 3C-SiC/graphene thick film shows a 3D porous structure with exposed graphene conductive network contributing to the greatly enhanced electrochemical performance in an environmentally aqueous electrolyte. These nanoforest-like 3C-SiC/graphene films can be promising for electrochemical energy storage applications
Targeted sequencing of the DMD locus: A comprehensive diagnostic tool for all mutations
No full textBackground & objectives: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder and is caused mainly by deletion, duplication and point mutations in the DMD gene. Diagnosis of DMD has been a challenge as the mutations in the DMD gene are heterogeneous and require more than one diagnostic strategy for the validation of the mutation. This study was planned to evaluate the targeted next-generation sequencing (NGS) as a single platform to detect all types of mutations in the DMD gene, thereby reducing the time and costs compared to conventional sequential testing and also provide precise genetic information for emerging gene therapies.Methods: The study included 20 unrelated families and 22 patients from an Indian population who were screened for DMD based on phenotypes such as scoliosis, toe walking and loss of ambulation. Peripheral blood DNA was isolated and subjected to multiplex ligation-dependent probe amplification (MLPA) and targeted NGS of the DMD gene to identify the nature of the mutation.Results: In the study patients, 77 per cent of large deletion mutations and 23 per cent single-nucleotide variations (SNVs) were identified. Novel mutations were also identified along with reported deletions, point mutations and partial deletions within the exon of the DMD gene.Interpretation & conclusions: Our findings showed the importance of NGS in the routine diagnostic practice in the identification of DMD mutations over sequential testing. It may be used as a single-point diagnostic strategy irrespective of the mutation type, thereby reducing the turnaround time and cost for multiple diagnostic tests such as MLPA and Sanger sequencing. Though MLPA is a sensitive technique and is the first line of a diagnostic test, the targeted NGS of the DMD gene may have an advantage of having a single diagnostic test. A study on a larger number of patients is needed to highlight NGS as a single, comprehensive platform for the diagnosis of DMD
In-silico identification of small molecules targeting H-Ras and in-vitro cytotoxicity with caspase-mediated apoptosis in carcinoma cells
No full textH-Ras oncogene plays a critical role in the transformation of normal cells to a malignant phenotype through constitutive activation of the GTP bound protein leading to uncontrolled cell proliferation in several human cancers. Thus, H-Ras oncoprotein serves as an excellent target for anticancer drug discovery. To identify novel H-Ras inhibitors, we performed structure-based virtual screening of the Maybridge HitFinder (TM) library using Schrodinger suite. Thirty ligands from the chemical library were identified as they showed preferential in silico binding initially to H-Ras proteins with Gly12Val, Gly13Asp, and Gly12Val-Gly13Asp mutations. Absorption, distribution, metabolism, excretion, and toxicity profile confirmed drug-like properties of the compounds. Three representative molecules were tested for antiproliferative effect on T24 urinary bladder carcinoma cell line, MCF-7 breast cancer cell line and HDF-7 normal dermal fibroblast cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Two compounds (Cmpds) showed antiproliferative activity exclusively in the cancer cell lines with minimal effect on the control HDF-7 cells. The effect of compound treatment on cell cycle progression, assessed by propidium iodide (PI) staining, depicted increased arrest of T24 cell line in the sub G1 phase. Further, Annexin-V PI dual staining and pan caspase inhibitor Z-VAD-fmk indicated caspase-dependent apoptotic activity of Cmpds 1 and 3. Our findings demonstrate caspase-dependent apoptotic activity of Cmpds 1 and 3 selectively against Gly12Val mutated T24 cancer cell line implicating a potential for treatment of bladder cancer. We envisage that these molecules may be promising candidates with potential therapeutic value in H-Ras mutation-associated cancers
Targeted Proteomics Comes to the Benchside and the Bedside: Is it Ready for Us?
No full textWhile mass spectrometry (MS)-based quantification of small molecules has been successfully used for decades, targeted MS has only recently been used by the proteomics community to investigate clinical questions such as biomarker verification and validation. Targeted MS holds the promise of a paradigm shift in the quantitative determination of proteins. Nevertheless, targeted quantitative proteomics requires improvisation in making sample processing, instruments, and data analysis more accessible. In the backdrop of the genomic era reaching its zenith, certain questions arise: is the proteomic era about to come? If we are at the beginning of a new future for protein quantification, are we prepared to incorporate targeted proteomics at the benchside for basic research and at the bedside for the good of patients? Here, an overview of the knowledge required to perform targeted proteomics as well as its applications is provided. A special emphasis is placed on upcoming areas such as peptidomics, proteoform research, and mass spectrometry imaging, where the utilization of targeted proteomics is expected to bring forth new avenues. The limitations associated with the acceptance of this technique for mainstream usage are also highlighted. Also see the video abstract here https://youtu.be/mieB47B8gZw
Lithosphere�asthenosphere interaction and carbonatite metasomatism in the genesis of Mesoproterozoic shoshonitic lamprophyres at Korakkodu, Wajrakarur kimberlite field, Eastern Dharwar Craton, southern India
No full textThe spatial and temporal association between lamprophyres and kimberlites provides unique opportunities to explore their genetic relationships. This paper explores such a relationship by detailing mineralogical and geochemical aspects of Korakkodu lamprophyre dykes located within the well-known Mesoproterozoic diamondiferous Wajrakarur Kimberlite field (WKF), towards the south-western margin of Paleo�Mesoproterozoic Cuddapah Basin, Eastern Dharwar Craton, southern India. Mineralogy reveals that these dykes belong to calc-alkaline variety of lamprophyres, but their geochemistry display mixed signals of both alkaline and calc-alkaline lamprophyres. These lamprophyres are highly potassic, and their high Al 2 O 3 and low-TiO 2 content implies a shoshonitic character. Low Mg#, Ni, and Cr concentration highlight their evolved nature. High (La/Yb) N and (Gd/Yb) N content is consistent with their derivation from low degrees of partial melting, whereas highly fractionated nature suggests the presence of garnet in their source. Absence of prominent Nb-Ta anomaly implies to the dilution of lithospheric mantle source by melts rich in HFSEs and low La/Nb ratio compared to those of the calc-alkaline island arc volcanics and suggests an asthenospheric overprint on lithospheric mantle source. Carbonatite metasomatism in the source region of these lamprophyres is apparent from conspicuously high-Zr/Hf ratio, and the HFSE budget of these lamprophyres are principally controlled by the presence of phlogopite veins in their lithospheric source. An extremely heterogeneous and layered lithospheric mantle beneath Eastern Dharwar Craton has been inferred from the divergent genetic history of Mesoproterozoic lamprophyres and kimberlites in the Wajrakarur field. © 2019 John Wiley & Sons, Ltd