Obesity: An overview on its current perspectives and treatment options

Obesity is a multi-factorial disorder, which is often associated with many other significant diseases such as diabetes, hypertension and other cardiovascular diseases, osteoarthritis and certain cancers. The management of obesity will therefore require a comprehensive range of strategies focussing on those with existing weight problems and also on those at high risk of developing obesity. Hence, prevention of obesity during childhood should be considered a priority, as there is a risk of persistence to adulthood. This article highlights various preventive aspects and treatment procedures of obesity with special emphasis on the latest research manifolds

The X-Ray Crystal Structure of Escherichia coli Succinic Semialdehyde Dehydrogenase; Structural Insights into NADP+/Enzyme Interactions

In mammals succinic semialdehyde dehydrogenase (SSADH) plays an essential role in the metabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to succinic acid (SA). Deficiency of SSADH in humans results in elevated levels of GABA and gamma-Hydroxybutyric acid (GHB), which leads to psychomotor retardation, muscular hypotonia, non-progressive ataxia and seizures. In Escherichia coli, two genetically distinct forms of SSADHs had been described that are essential for preventing accumulation of toxic levels of succinic semialdehyde (SSA) in cells.Here we structurally characterise SSADH encoded by the E coli gabD gene by X-ray crystallographic studies and compare these data with the structure of human SSADH. In the E. coli SSADH structure, electron density for the complete NADP+ cofactor in the binding sites is clearly evident; these data in particular revealing how the nicotinamide ring of the cofactor is positioned in each active site.Our structural data suggest that a deletion of three amino acids in E. coli SSADH permits this enzyme to use NADP+, whereas in contrast the human enzyme utilises NAD+. Furthermore, the structure of E. coli SSADH gives additional insight into human mutations that result in disease

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Hollis Croft, Sheffield, South Yorkshire: Old site and new connections

In 2017, a team from the Wessex Archaeology Sheffield office investigated a site, Hollis Croft (NGR 434990 387580), prior to the construction of a multi-million pound commercial and student housing development. Hollis Croft is one of many Sheffield’s sites where well-preserved industrial archaeology survives beneath the modern buildings. Historic building recording was followed by a watching brief, a scheme of archaeological evaluation trenching and then strip, map and sample excavations, which revealed substantial 18th-/19th-century remains of steel conversion furnaces (both cementation and crucible, constructed by Burgin and Wells and W. Fearnehough Ltd respectively). We also discovered metres of entwined brick-built flues (likely related to later steelmaking methods such as the Siemens-Martin open hearth process or Bessemer process), traces of two pubs (The Cock and The Orange Branch) and a wide range of finds – all indicative of the industrial processes and the everyday lives of the workers. Apart from the discovery of a crozzle layer covering the entire interior of the furnace (not just its base as previously thought), and the detailed impressions of the ferrous bars visible in the surface of the crozzle layer, the remains were very familiar for Sheffield and industrial archaeology. The post-excavation processes were carried out as usual following industry standards. All our findings have been brought together in a final report held in the digital archive and the physical archive (including the finds) was subsequently deposited with Museums Sheffield under SHEFM:2019.13 and Sheffield Archives. This publication is based on that final report, but edited and updated, so there are some minor differences between the documents. But, inspired by a great deal of public interest during the excavations (and Mili's love for comics), a comic book has also been created and is published here alongside what would otherwise be a more traditional offering

Hollis Croft, Sheffield, South Yorkshire. Archaeological Excavation (OASIS ID: wessexar1-309354)

The remains of two well-preserved mid- to late-19th century cementation furnaces were recorded. The refractory chambers ('chests') of the furnaces had been replaced, probably due to an inadequate provision of flues in the original design. Details of the furnaces were recorded, including the stoke hole entrance doors and the arrangement of 'fire bars' upon which fires were set in the underlying ash pits of the furnaces. Metallurgical analysis supported the view that the refractory lining of the chests (the 'crozzle') was derived from 'wheelswarf' produced by edge tool grinding. For the first time, it was confirmed that this crozzle extended up the interior sides of the refractory chamber. Another apparently new observation is that of the impression of the ferrous bars in the surface of the crozzle layer. Two crucible furnaces were identified. The crucible furnaces could not be closely dated. The cementation furnaces and crucible furnaces were part of separate works and there is no evidence to relate them. To the north of the cementation furnaces was an area of slightly later development characterised by the use of black ash mortar rather than lime mortar. This area included extensive cellars supporting a network of flues. Domestic housing and public houses were also investigated. The pottery assemblage was unusually broadly dated for Sheffield and represents a significant result. The clay tobacco pipe assemblage was of interest and examples of pipes were illustrated. A medieval penny was also recovered from a 19th century context. This archive contains a final report, two interim reports and three written schemes of investigation. The original site records have been scanned and are included alongside the record photographs and CAD survey of the excavations. The original paper archive has been deposited with Museums Sheffield (accession number SHEFM:2019.13) alongside the artefact collection. A retention and selection policy for artefacts was agreed by Wessex Archaeology and Museums Sheffield

Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates

Imbalances in GABA (&#x03B3;-aminobutyric acid) homoeostasis underlie psychiatric and movement disorders. The ability of the 65&#x00A0;kDa isoform of GAD (glutamic acid decarboxylase), GAD65, to control synaptic GABA levels is influenced through its capacity to auto-inactivate. In contrast, the GAD67 isoform is constitutively active. Previous structural insights suggest that flexibility in the GAD65 catalytic loop drives enzyme inactivation. To test this idea, we constructed a panel of GAD65/67 chimaeras and compared the ability of these molecules to auto-inactivate. Together, our data reveal the important finding that the C-terminal domain of GAD plays a key role in controlling GAD65 auto-inactivation. In support of these findings, we determined the X-ray crystal structure of a GAD65/67 chimaera that reveals that the conformation of the catalytic loop is intimately linked to the C-terminal domain