Membrane Type 1 Matrix Metalloproteinase Regulates Monocyte Migration and Collagen Destruction in Tuberculosis

Tuberculosis (TB) remains a global pandemic and drug resistance is rising. Multicellular granuloma formation is the pathological hallmark of Mycobacterium tuberculosis infection. The membrane type 1 matrix metalloproteinase (MT1-MMP or MMP-14) is a collagenase that is key in leukocyte migration and collagen destruction. In patients with TB, induced sputum MT1-MMP mRNA levels were increased 5.1-fold compared with matched controls and correlated positively with extent of lung infiltration on chest radiographs (r = 0.483; p < 0.05). M. tuberculosis infection of primary human monocytes increased MT1-MMP surface expression 31.7-fold and gene expression 24.5-fold. M. tuberculosis-infected monocytes degraded collagen matrix in an MT1-MMP-dependent manner, and MT1-MMP neutralization decreased collagen degradation by 73%. In human TB granulomas, MT1-MMP immunoreactivity was observed in macrophages throughout the granuloma. Monocyte-monocyte networks caused a 17.5-fold increase in MT1-MMP surface expression dependent on p38 MAPK and G protein-coupled receptor-dependent signaling. Monocytes migrating toward agarose beads impregnated with conditioned media from M. tuberculosis-infected monocytes expressed MT1-MMP. Neutralization of MT1-MMP activity decreased this M. tuberculosis network-dependent monocyte migration by 44%. Taken together, we demonstrate that MT1-MMP is central to two key elements of TB pathogenesis, causing collagen degradation and regulating monocyte migration

Electronic structure, structural and optical properties of thermally evaporated CdTe thin films

Copyright © 2007 Elsevier. NOTICE: this is the author’s version of a work that was accepted for publication in Physica B: Condensed Matter. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Physica B: Condensed Matter (2007), DOI: 10.1016/j.physb.2006.04.008Thin films of CdTe were deposited on glass substrates by thermal evaporation. From the XRD measurements itis found that the films are of zinc-blende-type structure. Transmittance, absorption, extinction, and refractive coefficients are measured. Electronic structure, band parameters and optical spectra of CdTe were calculated from ab initio studies within the LDA and LDA+U approximations. It is shown that LDA underestimates the band gap, energy levels of the Cd-4d states, s-d coupling and band dispersion. However, it calculates the spin-orbit coupling correctly. LDA+U did not increase much the band gap value, but it corrected the s-d coupling by shifting the Cd-4d levels towards the experimentally determined location and by splitting the LDA-derived single s peak into two peaks, which originates from admixture of s and d states. It is shown that the sd coupling plays an important role in absorption and reflectivity constants. The calculated optical spectra fairly agree with experimental data. Independent of wave-vector scissors operator is found to be a good first approximation to shift rigidly the band gap of CdTe underestimated by LDA.Research Council of NorwayAcademy of Sciences of UzbekistanUniversity Grants Commission (UGC), Indi

Structure and Magnetic Studies on UNiAlD2.2

Heavy fermion itinerant antiferromagnetic UNiAl is one of the very few U-containing compounds which absorbs H2/D2 without disproportionation. The present neutron diffraction studies on UNiAlDy (y = 2.2) are directed towards resolving controversies with regard to the occupancy of Ni atoms and the associated interstitial sites for (H/D) atoms, as well as the nature of magnetic ordering in the higher hydride phase with y ≥ 2. The fit to the neutron diffraction data is found to improve considerably if the Ni atoms originally lying in the U-atoms\u27 plane in UNiAl get shifted to the Ni-Al atoms\u27 plane in the deuteride. This is in agreement with an earlier neutron diffraction report on a deuteride sample of similar composition [T. Yamamoto et al., J. Alloys Compd. 269, 162 (1998)] and our x-ray structural studies on UNiAlH2.3 [P. Raj et al., Phys. Rev. B 63, 94414 (2001)], but differs from those of Bordallo et al., [H. N. Bordallo et al., Physica B 276-278, 706 (2000)] and of Kolomiets et al. [A. V. Kolomiets et al., J. Appl. Phys. 87, 6815 (2000)]. Our values of the structural parameters including the D-site occupancies are broadly in agreement with the results of Yamamoto et al. The magnetization studies on UNiAlD2.2 show a single antiferromagnetic transition with Néel temperature, TN=95 K. © 2001 American Institute of Physics

Maize area mapping using multi-temporal Sentinel 1A SAR data in the Belagavi district of Karnataka, India

The study explores the integration of remote sensing technologies with ground truth data for precise estimation of maize cultivation areas in the Indian Belagavi district, Karnataka, during the rabi season of 2022-23. Leveraging Sentinel-1A satellite data and advanced processing techniques, the study provides insights into crop dynamics, phenology, and spatial distribution. Ground truth data collection involved 369 points covering diverse land use and land cover types. The multi-temporal Synthetic Aperture Radar (SAR) imagery underwent automated processing, extracting features crucial for maize classification. Classification accuracy assessment revealed robust performance, with 92.4% accuracy for maize and 91.1% for non-maize locations, supported by a Kappa index of 0.83. Taluk (sub- district) wise maize area estimation highlighted spatial variations, with Saudatti emerging as the leading taluk, contributing 25.74% of the total maize cultivation area. The study underscores the importance of localized agricultural planning strategies tailored to each region's agricultural landscape. Through comprehensive analysis and accurate area estimation, policymakers and stakeholders gain valuable insights for informed decision-making, ranging from optimizing input distribution to formulating targeted policies for rural development

Inelastic Neutron scattering in CeSi_{2-x}Ga_x ferromagnetic Kondo lattice compounds

Inelastic neutron scattering investigation on ferromagnetic Kondo lattice compounds belonging to CeSi_{2-x}Ga_{x}, x = 0.7, 1.0 and 1.3, system is reported. The thermal evolution of the quasielastic response shows that the Kondo interactions dominate over the RKKY interactions with increase in Ga concentration from 0.7 to 1.3. This is related to the increase in k-f hybridization with increasing Ga concentration. The high energy response indicates the ground state to be split by crystal field in all three compounds. Using the experimental results we have calculated the crystal field parameters in all three compounds studied here.Comment: 12 Pages Revtex, 2 eps figures

Surfactant-assisted room-temperature synthesis of CdSe nanoclusters

Abstract CdSe nanoclusters of about 22 nm average size have been synthesized by a surfactant-assisted chemical method at room temperature. The asgrown nanoclusters were near stoichiometric and 70% of them were of hexagonal wurtzite crystalline phase. With undefined shapes, the crystalline nanoclusters remained arbitrarily oriented in a compact powder form. The morphology and structural behavior of the nanoclusters were studied by scanning electron microscopy and transmission electron microscopy. Thermal stability of the nanoclusters was studied by thermogravimetric analysis. Presence of very small clusters (<5 nm) in the sample revealed a blue shifted excitonic absorption peak along with the excitonic peak of bigger clusters

A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties. The Connectivity Map was a novel concept and innovative tool first introduced by Lamb et al to connect small molecules, genes, and diseases using genomic signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the Connectivity Map had some limitations, particularly there was no effective safeguard against false connections if the observed connections were considered on an individual-by-individual basis. Further when several connections to the same small-molecule compound were viewed as a set, the implicit null hypothesis tested was not the most relevant one for the discovery of real connections. Here we propose a simple and robust method for constructing the reference gene-expression profiles and a new connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with the two example gene-signatures (HDAC inhibitors and Estrogens) used by Lamb et al and also a new gene signature of immunosuppressive drugs. Our testing with this new method shows that it achieves a higher level of specificity and sensitivity than the original method. For example, our method successfully identified raloxifene and tamoxifen as having significant anti-estrogen effects, while Lamb et al's Connectivity Map failed to identify these. With these properties our new method has potential use in drug development for the recognition of pharmacological and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a ZIP fil

Genome sequence of an Enterobacter helveticus strain, 1159/04 (= LMG 23733), isolated from fruit powder

We report the draft genome sequence of Enterobacter helveticus strain LMG 23733, isolated from fruit powder. The draft genome assembly for E. helveticus strain LMG 23733 has a size of 4,635,476 bp and a G+C content of 55.9%

Computational de novo design of a four-helix bundle protein - DND-4HB

The de novo design of proteins is a rigorous test of our understanding of the key determinants of protein structure. The helix bundle is an interesting de novo design model system due to the diverse topologies that can be generated from a few simple α-helices. Previously, non-computational studies demonstrated that connecting amphipathic helices together with short loops can sometimes generate helix bundle proteins, regardless of the bundle's exact sequence. However using such methods, the precise positions of helices and side-chains cannot be predetermined. Since protein function depends on exact positioning of residues, we examined if sequence design tools in the program Rosetta could be used to design a four-helix bundle with a predetermined structure. Helix position was specified using a folding procedure that constrained the design model to a defined topology, and iterative rounds of rotamer-based sequence design and backbone refinement were used to identify a low energy sequence for characterization. The designed protein, DND_4HB, unfolds cooperatively (Tm >90°C) and a NMR solution structure shows that it adopts the target helical bundle topology. Helices 2, 3 and 4 agree very closely with the design model (backbone RMSD = 1.11 Å) and >90% of the core side-chain χ1 and χ2 angles are correctly predicted. Helix 1 lies in the target groove against the other helices, but is displaced 3 Å along the bundle axis. This result highlights the potential of computational design to create bundles with atomic-level precision, but also points at remaining challenges for achieving specific positioning between amphipathic helices

Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an <i>in vitro</i> model of CNS tuberculosis

Central nervous system tuberculosis (CNS TB) has a high mortality and morbidity associated with severe inflammation. The blood-brain barrier (BBB) protects the brain from inflammation but the mechanisms causing BBB damage in CNS TB are uncharacterized. We demonstrate that Mycobacterium tuberculosis (Mtb) causes breakdown of type IV collagen and decreases tight junction protein (TJP) expression in a co-culture model of the BBB. This increases permeability, surface expression of endothelial adhesion molecules and leukocyte transmigration. TJP breakdown was driven by Mtb-dependent secretion of matrix metalloproteinase (MMP)-9. TJP expression is regulated by Sonic hedgehog (Shh) through transcription factor Gli-1. In our model, the hedgehog pathway was downregulated by Mtb-stimulation, but Shh levels in astrocytes were unchanged. However, Scube2, a glycoprotein regulating astrocyte Shh release was decreased, inhibiting Shh delivery to brain endothelial cells. Activation of the hedgehog pathway by addition of a Smoothened agonist or by addition of exogenous Shh, or neutralizing MMP-9 activity, decreased permeability and increased TJP expression in the Mtb-stimulated BBB co-cultures. In summary, the BBB is disrupted by downregulation of the Shh pathway and breakdown of TJPs, secondary to increased MMP-9 activity which suggests that these pathways are potential novel targets for host directed therapy in CNS TB