Patents and Industrialisation. An Historical Overview of the British Case, 1624-1907

A Report to the Strategic Advisory Board on Intellectual Property Policy (SABIP), U

Interferon-γ and Proliferation Responses to Salmonella enterica Serotype Typhi Proteins in Patients with S. Typhi Bacteremia in Dhaka, Bangladesh

Salmonella enterica serotype Typhi infection is a significant global public health problem and the cause of typhoid fever. Salmonella are intracellular pathogens, and cellular immune responses are required to control and clear Salmonella infections. Despite this, there are limited data on cellular immune responses during wild type S. Typhi infection in humans. Here we report the assessment of cellular immune responses in humans with S. Typhi bacteremia through a screening approach that permitted us to evaluate interferon-γ and proliferation responses to a number of S. Typhi antigens. We detected significant interferon-γ CD4 and CD8 responses, as well as proliferative responses, to a number of recombinantly purified S. Typhi proteins as well as membrane preparation in infected patients. Antigen-specific interferon-γ responses were present at the time of clinical presentation in patients and absent in healthy controls. These observations could assist in the development of interferon-γ-based diagnostic assays for typhoid fever

Raman spectroscopy reveals age- and sex-related differences in cortical bone from people with osteoarthritis

Bone strength in human cortical bone is determined by the composition and structure of both the mineral and collagen matrices and influenced by factors such as age, gender, health, lifestyle and genetic factors. Age-related changes in the bone matrix are known to result in loss of mechanical strength and increased fragility. In this study we show how Raman spectroscopy, with its exquisite sensitivity to the molecular structure of bone, reveals new insights into age- and sex-related differences. Raman analysis of 18 samples of cortical hip bone obtained from people aged between 47–82 years with osteoarthritis (OA) found subtle changes in the lipid and collagen secondary structure, and the carbonate (CO32−) and phosphate (PO43−) mineral ratios in the bone matrix. Significant differences were observed between older and younger bones, and between older female and older male bones; no significant differences were observed between younger male and female bones. Older female bones presented the lowest mineral to matrix ratios (MMR) and highest CO32−/PO43− ratios, and relative to lipid/collagen –CH2 deformation modes at 1450 cm−1 they had lowest overall mineral content, higher collagen cross linking and lipid content but lower levels of α-helix collagen structures than older male and younger male and female bones. These observations provided further insight on bone composition changes observed in the bone volume fraction (BV/TV) for the older female bones from microCT measurements on the same samples, while tissue mineral density (TMD) measurements had shown no significant differences between the samples.</p

Differentiation of osteoclast precursors on Gellan Gum-based spongy-like hydrogels for bone tissue engineering

Bone tissue engineering with cell-scaffold constructs has been attracting a lot of attention, in particular as a tool for efficient guiding of new tissue formation. However, the majority of the current strategies used to evaluate novel biomaterials focus on osteoblasts and bone formation, while osteoclasts are often overlooked. Consequently, there is limited knowledge about the interaction between osteoclasts and biomaterials. In this study, the ability of gellan gum and hydroxyapatite reinforced gellan gum spongy-like hydrogels to support osteoclastogenesis was investigated in vitro. First, gellan gum and hydroxyapatite reinforced gellan gum spongy-like hydrogels were characterized in terms of microstructure, water uptake and mechanical properties. Then, bone marrow cells isolated from mice long bones and cultured in the spongy-like hydrogels were treated with 1,25-dihydroxyvitamin D3 to promote osteoclastogenesis. It was shown that the addition of HAp to Gellan Gum spongy-like hydrogels enables the formation of lager pores and thicker walls, promoting an increase in stiffness. hydroxyapatite reinforced gellan gum spongy-like hydrogels supported the formation of aggregates of tartrate-resistant acid phosphatase-stained cells and the expression of the genes encoding DC-Stamp and Cathepsin K, suggesting the differentiation of bone marrow cells into pre-osteoclasts. The hydroxyapatite reinforced gellan gum spongy-like hydrogels developed in this work show promise for future use in bone tissue scaffolding applications.This work was developed under the scope of the European Project skelGEN (Project No: 318553). F.R. Maia acknowledges ERC-2012-ADG 20120216-321266 (ComplexiTE) for her Postdoc scholarship and Boehringer Ingelheim Fonds for her travel grant. L. P. da Silva acknowledges Portuguese Foundation for Science and Technology (FCT) for her grant (SFRH/BD/78025/2011), J. M. Oliveira thanks FCT for his distinction attributed under the FCT Investigator program (IF/00423/2012 and IF/01285/2015). VM Correlo acknowledges Investigator FCT program (IF/01214/2014).info:eu-repo/semantics/publishedVersio

In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist

3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d][1,2,4]triazine (MRK-016) is a pyrazolotriazine with an affinity of between 0.8 and 1.5 nM for the benzodiazepine binding site of native rat brain and recombinant human alpha1-, alpha2-, alpha3-, and alpha5-containing GABA(A) receptors. It has inverse agonist efficacy selective for the alpha5 subtype, and this alpha5 inverse agonism is greater than that of the prototypic alpha5-selective compound 3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-hdyl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine (alpha5IA). Consistent with its greater alpha5 inverse agonism, MRK-016 increased long-term potentiation in mouse hippocampal slices to a greater extent than alpha5IA. MRK-016 gave good receptor occupancy after oral dosing in rats, with the dose required to produce 50% occupancy being 0.39 mg/kg and a corresponding rat plasma EC(50) value of 15 ng/ml that was similar to the rhesus monkey plasma EC(50) value of 21 ng/ml obtained using [(11)C]flumazenil positron emission tomography. In normal rats, MRK-016 enhanced cognitive performance in the delayed matching-to-position version of the Morris water maze but was not anxiogenic, and in mice it was not proconvulsant and did not produce kindling. MRK-016 had a short half-life in rat, dog, and rhesus monkey (0.3-0.5 h) but had a much lower rate of turnover in human compared with rat, dog, or rhesus monkey hepatocytes. Accordingly, in human, MRK-016 had a longer half-life than in preclinical species ( approximately 3.5 h). Although it was well tolerated in young males, with a maximal tolerated single dose of 5 mg corresponding to an estimated occupancy in the region of 75%, MRK-016 was poorly tolerated in elderly subjects, even at a dose of 0.5 mg, which, along with its variable human pharmacokinetics, precluded its further development