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Biological therapy is opening up a new age for the treatment of cancer. The bacteria -cancer interaction was firstly observed by Busch and Fehleisen (1). To reducing the potential of pathogenicity of using active bacterial, using bacterial products like proteins, enzymes, immune-toxins, that straightaway target malignancy cells and regress the volume of the tumor through expansion inhibition, induction of apoptosis (2). This study was aimed at testing the antiangiogenic bacterial neuraminidase against mammalian adenocarcinoma AN3 transplanted into syngeneic immunocompetent mice through intratumoral injection to determine the antitumor activity in vivo. Histopathological sections for the treated tumor mass demonstrated proliferation of granulation tissue with substantial necrosis region. This study indicated the role of bacterial neuraminidase in reducing the volume of the solid tumor when compared with an untreated group which is a confirmed feature that makes it as anti-tumor agent.

Newcastle disease virus (NDV) is promising antitumor agent that triggers immediate cytolysis of the tumor, apoptosis and activation of the immune system. This study was aimed at testing the antiangiogenic NDV Performance on a model of breast cancer. NDV has been studied against mammalian adenocarcinoma AN3 transplanted into syngeneic immunocompetent mice through intratumoral injection to determine the antitumor activity of NDV in vivo. Histopathological sections for the treated tumor mass demonstrated proliferation of granulation tissue with substantial necrosis region. This study indicated the role of Iraqi strain NDV in reducing the volume of solid tumor when compared with untreated group which is confirmed feature that make NDV Iraqi strain as anti-tumor agents.

Bacterial nitric oxide reductases (NORs) catalyse the reduction of NO to N2O and H2O. NORs are found either in denitrification chains, or in pathogens where their primary role is detoxification of NO produced by the immune defense of the host. Although NORs belong to the heme-copper oxidase superfamily, comprising proton-pumping O2-reducing enzymes, the best studied NORs, cNORs (cytochrome c-dependent), are non-electrogenic. Here, we focus on another type of NOR, qNOR (quinol-dependent). Recombinant qNOR from Neisseria meningitidis, a human pathogen, purified from Escherichia coli, showed high catalytic activity and spectroscopic properties largely similar to cNORs. However, in contrast to cNOR, liposome-reconstituted qNOR showed respiratory control ratios above two, indicating that NO reduction by qNOR was electrogenic. Further, we determined a 4.5 Å crystal structure of the N. meningitidis qNOR, allowing exploration of a potential proton transfer pathway from the cytoplasm by mutagenesis. Most mutations had little effect on the activity, however the E-498 variants were largely inactive, while the corresponding substitution in cNOR was previously shown not to induce significant effects. We thus suggest that, contrary to cNOR, the N. meningitidis qNOR uses cytoplasmic protons for NO reduction. Our results allow possible routes for protons to be discussed.

Research over the decades has gradually and sequentially shown that both intratumor heterogeneity and multifocality make prostate cancer difficult to target. Different challenges associated with generation of risk-stratification tools that correlate genomic landscape with clinical outcomes severely influence clinical efficacy of therapeutic strategies. Androgen receptor mediated signaling has gained great appreciation and rewiring of AR induced signaling cascade in absence of androgen, structural variants of AR have provided near complete resolution of genomic landscape and underlying mechanisms of prostate cancer. In this review we have attempted to provide an overview of most recent advancements in our knowledge related to different signaling cascades including TGF, SHH, Notch, JAK-STAT in prostate cancer progression and development. © 2016 by the C.M.B. Association. 2014AA093503 Natural Science Foundation of Shandong Province: ZR2015HQ027, ZR2014HQ031 2013ZX09103003, 2014ZX-091022043-0001 National Natural Science Foundation of China: 81573457, 81273550 This work was supported by 863 High Technology Project (No. 2014AA093503) and National Innovative Drugs Development program of China (No. 2014ZX-091022043-0001 and 2013ZX09103003). We are also grateful to the support by the Natural Science Foundation of China (No. 81273550 and 81573457) as well as the Natural Science Foundation of Shandong Province of China (No. ZR2014HQ031, and ZR2015HQ027).

This dissertation examines how concerns about food system transformations affect how middle class consumers in Islamabad, Pakistan, perceive and approach food consumption in their everyday lives. The dissertation is situated in the context of risky food environments and food fears resulting from intensified, industrialised, and increasingly lengthened global food systems. Working within food geography and food environments paradigms, this dissertation explores how the transformation of food systems is associated with increasing anxiety about food security and safety for middle class urban consumers in Islamabad. Qualitative data gathered from semi-structured interviews and participant observation is used to illustrate the effects external influences, such as energy scarcity and violent events, have on everyday food environments. The dissertation examines the ways in which conceptualisations of 'good food', and trust relationships are negotiated in these dynamic food environments. The intensely geographical nature of these food environments and food systems, and the role of place-specific contexts on perceptions and adaptations related to food anxieties are emphasised. Situated in literatures on food anxiety and food consumption emerging from geography, food studies, and anthropology, this dissertation challenges dominant discourses on alternative and ethical consumption in a globalising food system. The results of this research not only contribute to literature on South Asia, but also contribute to consumption practices of a burgeoning middle class in developing countries.

The field of crystallography, which has had a major impact on the sciences in the last 100 years, is continuing to expand scientific horizons as technical and conceptual boundaries are overcome. Structure-function-dynamics will become an integrated theme for many studies as will obtaining structures without the 'benevolent tyranny' of crystals.

The intestinal mucosal barrier, part of the innate immune defence, is responsive to the external environment and changes in response to infection. There is disparate evidence for the epithelial and goblet cell products within the intrinsic barrier being part of a response to resolve infection. We comprehensively analysed the changes of mucosal glycoconjugates during acute and chronic infection by utilising the Trichuris muris (T. muris) model. Transcription factors, atonal homolog 1 (Math-1) and SAM pointed domain containing ETS transcription factor (Spdef) were activated during acute infection, which promoted stem cell fate towards a secretory cell phenotype. The thickness of the intermediate barrier, the carbohydrate-rich glycocalyx, composed of cell surface mucins increased with exposure to T. muris, with an increase in Muc4, Muc13 and Muc17. Overall, hypersecretion of glycoproteins into the extrinsic barrier (mediated by IL-13) via the gamma amino-butyric acid-α3 receptor (GABA-α3), was observed during acute infection. Furthermore, altered glycosylation was observed during acute and chronic infection; mucins were more highly charged during acute infection than during chronic infection. This study readdresses the changes within the mucosal barrier, in particular in the cell surface and secreted mucins during acute and chronic nematode infection.

To assess the causes of low tetanus toxoid (TT) vaccination coverage in pregnant women a mixture of quantitative and qualitative methods were adopted at the community, primary health care delivery and management levels in Lahore district, Pakistan. Out of a random sample of 362 women who had delivered during the previous 3 months, 87% recalled receiving 2 doses of TT. The main reasons for non-vaccination were poor knowledge about the importance of TT (32% of women) or the place and time to get vaccinated (18%). According to the managers and primary health care medical officers, the main reasons for low coverage were lack of awareness about the importance of vaccination among the public and misconceptions about TT vaccination (e.g. that it was a contraceptive).

Enzyme mechanisms are often probed by structure-informed point mutations and measurement of their effects on enzymatic properties to test mechanistic hypotheses. In many cases, the challenge is to report on complex, often inter-linked elements of catalysis. Evidence for long-range effects on enzyme mechanism resulting from mutations remains sparse, limiting the design/redesign of synthetic catalysts in a predictable way. Here we show that improving the accessibility of the active site pocket of copper nitrite reductase by mutation of a surface-exposed phenylalanine residue (Phe306), located 12 Å away from the catalytic site type-2 Cu (T2Cu), profoundly affects intra-molecular electron transfer, substrate-binding and catalytic activity. Structures and kinetic studies provide an explanation for the lower affinity for the substrate and the alteration of the rate-limiting step in the reaction. Our results demonstrate that distant residues remote from the active site can have marked effects on enzyme catalysis, by driving mechanistic change through relatively minor structural perturbations., Residues within the catalytic site of enzymes are important for activity, but whether more distant residues are also sensitive to mutation is unclear. Here, Leferink et al. show that mutation of residues in copper nitrate reductase that are 12Å away from the active site perturb enzyme function.

S-Adenosylmethionine (SAMe) is the principal methyl donor of the cell and is synthesized via an ATP-driven process by methionine adenosyltransferase (MAT) enzymes. It is tightly linked with cell proliferation in liver and colon cancer. In humans, there are three genes, mat1A, mat2A and mat2B, which encode MAT enzymes. mat2A and mat2B transcribe MATα2 and MATβ enzyme subunits, respectively, with catalytic and regulatory roles. The MATα2β complex is expressed in nearly all tissues and is thought to be essential in providing the necessary SAMe flux for methylation of DNA and various proteins including histones. In human hepatocellular carcinoma mat2A and mat2B genes are upregulated, highlighting the importance of the MATα2β complex in liver disease. The individual subunits have been structurally characterized but the nature of the complex has remained elusive despite its existence having been postulated for more than 20 years and the observation that MATβ is often co-localized with MATα2. Though SAMe can be produced by MAT(α2)4 alone, this paper shows that the V max of the MATα2β complex is three- to fourfold higher depending on the variants of MATβ that participate in complex formation. Using X-ray crystallography and solution X-ray scattering, the first structures are provided of this 258 kDa functional complex both in crystals and solution with an unexpected stoichiometry of 4α2 and 2βV2 subunits. It is demonstrated that the N-terminal regulates the activity of the complex and it is shown that complex formation takes place surprisingly via the C-terminal of MATβV2 that buries itself in a tunnel created at the interface of the MAT(α2)2. The structural data suggest a unique mechanism of regulation and provide a gateway for structure-based drug design in anticancer therapies.

A new coarse-grained model of the E. coli cytoplasm is developed by describing the proteins of the cytoplasm as flexible units consisting of one or more spheres that follow Brownian dynamics (BD), with hydrodynamic interactions (HI) accounted for by a mean

Against a world average of 25% area under forests, Pakistan has around 5% and Punjab has only 2% area under manageable and productive forests. The present deteriorating condition of the forests in Punjab has bleak prospects of improvement and expansion in near future due to ever increasing demand for agriculture produce. In view of the present situation the best possible solution seems to be offered by Farm forestry/agroforestry that models planting trees and agricultural crops together, which unfortunately, has not been utilized to its full potential. Based on physiographic, climate and ecology, Pakistan is divided into nine major ecological or vegetative zones, which are further sub-divided into 18 habitat types – an arrangement for the development of protected areas system in terms of representative ecotypes. During the survey of farm plantations about 400 soil samples were collected and their physical and chemical analysis was conducted for the comparison of the four Agro ecological zones of the Punjab Province of Pakistan with regards to agroforestry. A comparison of the characteristics of soils taken from various farm plantations necessitated a prior evaluation of nitrogen and phosphorous as well as their composition in order to ascertain whether the soils were texturally similar or not. In case of Agroforestry, the type of soil is one of the major factors for the classification of different suitable species of plants. The results of the soil analysis of various Agro ecological zones and the consequent recommendation of the associated suitable species, aids the agrofarmers to pick out the best possible option.Keywords: Soil analysis, agro-ecological zones, agroforestry, nitrogen and phosphorous.

Pakistan in general and the province of Punjab in particular have a narrow forest resource. More than 90% of the fuel wood and about 72% of timber requirements are being met from trees growing on the private farm lands, based on agro forestry / social forestry / community forestry as compared with the state forests. It is obvious that trees have to be grown in conjunction with agricultural crops on private farm lands. The main objectives of the study pertain to agro forestry trend in Punjab, Province of Pakistan along with the identification of the agroeclogical zones of the province including evaluation of adaptation level of agro forestry interventions; assessment of the aptitude of agro-foresters towards tree planting and hurdles in expansion of the agro forestry. For this, a survey of 257 farm plantations (FP) was conducted in 20 districts of the Punjab Province and more than 257 agro-farmers were interviewed through a prescribed performa. However, a correlation between linear and compact designs of the agro forestry was established. From the study of the survey results, it has also been noticed that out of 257 FP, only three FP belonged to the lessees and 254 belonged to land owners. It was also noted that number of FP considerably increased during 1995 to 2000, when the Punjab forest department transferred technology and provided various incentives and financial subsidies. The farmers can further increase it, if the government revives financial/technical incentives and marketing facilities.Key words: Agro forestry, linear and compact design, land tenure, agroeclogical zones, spacing.

Iron K-edge e.x.a.f.s. data for the iron-vanadium cofactor (FeVaco) from Azotobacter chroococcum vanadium nitrogenase reported here provide further evidence for the structural similarity between this and the iron-molybdenum nitrogenase cofactor (FeMoco) from Klebsiella pneumoniae molybdenum nitrogenase [Arber, Flood, Garner, Gormal, Hasnain & Smith (1988) Biochem. J. 252, 421-425]. The e.x.a.f.s. data are consistent with the vanadium being present in a V-Fe-S cluster, thus confirming that the N-methylformamide extract of the VFe protein component of A. chroococcum vanadium nitrogenase does indeed contain a polynuclear metal-sulphur cluster. Additionally, a long Fe-Fe distance is observed as 0.369 nm, demonstrating the presence of a long-range order in the cluster.

Sixteen ribosomal proteins (r-proteins) from the 50S ribosomal subunit of the archaebacterium Halobacterium cutirubrum have been purified and their amino acid composition and partial N-terminal amino acid sequence have been determined. These proteins as a group are much more acidic than the large subunit r-proteins from eubacteria or eukaryotes. Little sequence homology is evident between the 50S subunit archaebacterial r-proteins and the equivalent proteins from the eubacterium Escherichia coli.

The main aim is to perform mutational analysis of CTLA4 gene Exon 1 in SLE patients. A total of 61 SLE patients fulfilling “American College of Rheumatology (ACR) criteria" and 61 controls were enrolled in this study. The region of CTLA4 gene exon 1 was amplified by using Step-down PCR technique. Extracted DNA of band 354 bp was sequenced to analyze mutations in the exon-1 of CTLA-4 gene. Further, protein sequences were identified from nucleotide sequences of CTLA4 Exon 1 by using Expasy software and through Blast P software it was found that CTLA4 protein sequences of Pakistani SLE patients were similar to that of Chinese SLE population. No variations were found after patients sequences were compared with that of the control sequence. Furthermore it was found that CTLA4 protein sequences of Pakistani SLE patients were similar to that of Chinese SLE population. Thus CTLA4 gene may not be responsible for an autoimmune disease SLE., {"references":["C. Kek-Hang, P. Suat-Moi, C. Ching-Hoong, T. Si-Yen, L. Lay-Hoong,\nL,\" Study of CTLA-4 gene polymorphisms in SLE samples from\nMalaysia\". Annals of Human Biology, 2010, 37:274-280.","M.L. Budarf, P. Goyette, G. Boucher, J. Lian, R.R. Graham, J.O.\nClaudio,T. Hudson, D. Gladman, A.F. Clarke, Pope, A.E., Peschken, et\nal \"A targeted association study in SLE identifies multiple susceptibility\nalleles\". Genes and immunity, 2010, 10:1038.","H. Bashyam, \"CTLA-4: From conflict to clinic\". J Exp Med, 2007,\n204:1243.","D. Holmberg , C.M. Cilio, M. Lundholm, V. Motta, \"CTLA-4 (CD152)\nand its involvement in autoimmune disease\". Autoimmunity, 2005; 38:\n225 - 233"]}

Portal venous thrombosis (PVT) is an uncommon complication in post-liver transplant recipients. The reported incidence is 1-4%. It may occur within a month, called early or after one month of transplantation, known as late PVT. Early PVT has a poor prognosis, leading to graft failure in most cases. Treatment of such cases is quite challenging because of difficult alternative portal inflow establishment. We performed successful thrombolysis of acute major PVT with a unique technique using ultrasound-guided percutaneous trans-splenic vein access in a post-liver transplant recipient. The per-cutaneous trans- splenic vein approach-based thrombolysis described here in this report might be very helpful in similar cases. This technique minimizes the potential risk of graft loss, avoids re-exploration, has a low risk of bleeding, and is cost-effective.

Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic activity, are known to cause amyotrophic lateral sclerosis (ALS). Several destabilizing factors contribute to pathogenicity including a reduced ability to complete the normal maturation process which comprises folding, metal cofactor acquisition, intra-subunit disulphide bond formation and dimerization. Immature SOD1 forms toxic oligomers and characteristic large insoluble aggregates within motor system cells. Here we report that the cysteine-reactive molecule ebselen efficiently confers the SOD1 intra-subunit disulphide and directs correct SOD1 folding, depopulating the globally unfolded precursor associated with aggregation and toxicity. Assisted formation of the unusual SOD1 cytosolic disulphide bond could have potential therapeutic applications. In less reducing environments, ebselen forms a selenylsulphide with Cys111 and restores the monomer–dimer equilibrium of A4V SOD1 to wild-type. Ebselen is therefore a potent bifunctional pharmacological chaperone for SOD1 that combines properties of the SOD1 chaperone hCCS and the recently licenced antioxidant drug, edaravone., Mutations in superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Here the authors present the SOD1 crystal structure bound to the small cysteine-reactive molecule ebselen and show that ebselen is a chaperone for SOD1.

Single-crystal X-ray diffraction of Cs3ScSi6O15shows the presence of main reflections and satellite reflections up to the fourth order along thec*direction. The (3+1)-dimensional incommensurately modulated structure was solved in superspace group X{\bar 3}m1(00\gamma)0s0 [a= 13.861 (1),c= 6.992 (1) Å,V= 1163.4 (2) Å3] with a modulation wavevectorq= 0.14153 (2)c*. Refinement of three modulation waves for positional and anisotropic displacement parameter values for all atoms converged toRobsvalues for all, main and satellite reflections of first, second and third order of 0.0200, 0.0166, 0.0181, 0.0214 and 0.0303, respectively. Cs3ScSi6O15forms a mixed tetrahedral–octahedral framework with prominent six-membered rings of [SiO4]-tetrahedra interconnected by [ScO6]-octahedra. Apart from Sc, all atoms are strongly affected by positional modulation with maximum atomic displacements of up to 0.93 Å causing rigid polyhedral arrangements to perform tilt and twist movements relative to each other, such as a rotation of the Sc-octahedra around the \bar 3-axis by over 38°. Cs has an irregular coordination environment; however, considering distances up to 3.5 Å, the bond-valence sum changes by no more than 0.02 as a function oftand thus overall kept at a level ofca1.075.

Introduced by the British colonization and today the official language of the Indian Nation in association with Hindi, English is spoken as a second language by a minority of the educated population of 8 to 11% according to current estimations. A chance for India to converse with the world cultures, in compensation for centuries of domination, or conversely an inherited alienating burden still preventing this conversation from being on equal terms? The paper will dwell on such issues, after a factual evaluation of the role of English in the Indian pluralism, and a study of the consequences of its historical infiltration in the whole system of the State.; Introduit par la colonisation britannique et aujourd'hui langue officielle de l'Union Indienne avec le hindi, l'anglais est parlé comme langue seconde par une minorité de la population éduiquée qui ne dépasse pas 10%. Est-ce une chance pour l'Inde d'entrer en dialogue avec les cultures du monde, en compensation des siècles de dominations subis, ou au contraire une aliénation héritée représentant un poids supllémentaire qui empêche encore un dialogue en termes d'égalité? L'étude analyse les réponses possibles à de telles questions, après une évaluation factuelle du rôle de l'anglais dans le pluralisme indien, et l'examen des conséquences historiques de la pénétration de l'anglais -- langue et modes de pensée -- au coeur du système administratif et politique de l'Etat.

Introduced by the British colonization and today the official language of the Indian Nation in association with Hindi, English is spoken as a second language by a minority of the educated population of 8 to 11% according to current estimations. A chance for India to converse with the world cultures, in compensation for centuries of domination, or conversely an inherited alienating burden still preventing this conversation from being on equal terms? The paper will dwell on such issues, after a factual evaluation of the role of English in the Indian pluralism, and a study of the consequences of its historical infiltration in the whole system of the State., Introduit par la colonisation britannique et aujourd'hui langue officielle de l'Union Indienne avec le hindi, l'anglais est parlé comme langue seconde par une minorité de la population éduiquée qui ne dépasse pas 10%. Est-ce une chance pour l'Inde d'entrer en dialogue avec les cultures du monde, en compensation des siècles de dominations subis, ou au contraire une aliénation héritée représentant un poids supllémentaire qui empêche encore un dialogue en termes d'égalité? L'étude analyse les réponses possibles à de telles questions, après une évaluation factuelle du rôle de l'anglais dans le pluralisme indien, et l'examen des conséquences historiques de la pénétration de l'anglais -- langue et modes de pensée -- au coeur du système administratif et politique de l'Etat.

Introduced by the British colonization and today the official language of the Indian Nation in association with Hindi, English is spoken as a second language by a minority of the educated population of 8 to 11% according to current estimations. A chance for India to converse with the world cultures, in compensation for centuries of domination, or conversely an inherited alienating burden still preventing this conversation from being on equal terms? The paper will dwell on such issues, after a factual evaluation of the role of English in the Indian pluralism, and a study of the consequences of its historical infiltration in the whole system of the State.; Introduit par la colonisation britannique et aujourd'hui langue officielle de l'Union Indienne avec le hindi, l'anglais est parlé comme langue seconde par une minorité de la population éduiquée qui ne dépasse pas 10%. Est-ce une chance pour l'Inde d'entrer en dialogue avec les cultures du monde, en compensation des siècles de dominations subis, ou au contraire une aliénation héritée représentant un poids supllémentaire qui empêche encore un dialogue en termes d'égalité? L'étude analyse les réponses possibles à de telles questions, après une évaluation factuelle du rôle de l'anglais dans le pluralisme indien, et l'examen des conséquences historiques de la pénétration de l'anglais -- langue et modes de pensée -- au coeur du système administratif et politique de l'Etat.

The L-type neutral amino acid transporter 1 (LAT1/SLC7A5) is one of 7 light chains that can form a heteromeric amino acid transporter (HAT) with the type II single pass glycoprotein CD98hc (SLC3A2). LAT1-CD98hc transports essential amino acids and some of their catabolites, such as tryptophan, methionine and kynurenine, across the plasma membranes of normal and cancer cells. It is also a drug transporter, carrying drugs such as gabapentin and L-DOPA across the blood brain barrier. The atypical heterodimeric nature of LAT1-CD98hc and its role in disease and drug delivery, motivate the structural characterisation of the HAT. Sequence analysis revealed two putative cholesterol binding motifs conserved between dDAT and LAT1 as well as 32 putative CRAC/CARC motifs. The crystal structures of various bacterial homologues of LAT1 were used for structure prediction, in order to visualise these putative cholesterol binding motifs and assess their plausibility. Here is presented the first binding mode analysis of ligands to the inward facing occluded conformation of LAT1. Substrates had lower predicted free energies of binding to the inward facing conformation compared to the outward open. The putative gating residue F252 may play a role in binding to aromatic substrates via p-p stacking in the outward open conformation and with all substrates via p-cation bonding with their amino termini in the inward facing occluded conformation. Based on the docking analysis, inhibitors of LAT1, JPH203 and SKN203 are predicted to transportable substrates of the transporter and KMH233 a non-transportable competitive inhibitor with a unique binding mode. LAT1 was overexpressed in HEK293 cells and co-purified with CD98hc to a sufficient biochemical homogeneity for structural characterisation. The role of cholesterol hemisuccinate in stabilizing detergent solubilized LAT1-CD98hc was established. Detergent solubilized and purified LAT1-CD98hc was subject to structural analysis by single particle electron cryo-microscopy to a resolution of 12 Å. Multibody 3D auto-refinement and principal component analysis revealed flexibility and limited interaction between CD98hc ectodomain and LAT1, contrary to predictions based on homology to LAT2-CD98hc. Docking of CD98hc allowed for visualisation and generation of molecular movies of the structural dynamics of LAT1- CD98hc ectodomain, based on these the ectodomain of CD98hc seems tethered to LAT1 via the inter-subunit disulphide bond and interaction between their transmembrane domains.