2-Fluoro-l-histidine

The title compound, C6H8FN3O2, an analog of histidine, shows a reduced side-chain pKa (ca 1). The title structure exhibits a shortening of the bond between the proximal ring N atom and the F-substituted ring C atom, indicating an increase in π-bond character due to an inductive effect of fluorine

Comparison of the Structural Stability and Dynamic Properties of Recombinant Anthrax Protective Antigen and its 2- Fluorohistidine Labeled Analogue

Protective antigen (PA) is the primary protein antigenic component of both the currently used anthrax vaccine and related recombinant vaccines under development. An analogue of recombinant PA (2-FHis rPA) has been recently shown to block the key steps of pore formation in the process of inducing cytotoxicity in cells, and thus can potentially be used as an antitoxin or a vaccine. This rPA analogue was produced by fermentation to incorporate the unnatural amino acid 2-fluorohistidine (2-FHis). In this study, the effects of 2-FHis labeling on rPA antigen’s conformational stability and dynamic properties were investigated by various biophysical techniques. Temperature/pH stability profiles of rPA and 2-FHis rPA were analyzed by the empirical phase diagram (EPD) approach, and physical stability differences between them were identified. Results showed that rPA and 2-FHis rPA had similar stability at pH 7–8. With decreasing solution pH, however, 2-FHis rPA was found to be more stable. Dynamic sensitive measurements of the two proteins at pH 5 found that 2-FHis rPA was more dynamic and/or differentially hydrated under acidic pH conditions. The biophysical characterization and stability data provide information useful for the potential development of 2-FHis rPA as a more stable rPA vaccine candidate

Seneca Valley Virus Exploits TEM8, a Collagen Receptor Implicated in Tumor Growth

Recent studies reveal that Seneca Valley Virus (SVV) exploits tumor endothelial marker 8 (TEM8) for cellular entry, the same surface receptor pirated by bacterial-derived anthrax toxin. This observation is particularly significant as SVV is a known oncolytic virus which selectively infects and kills tumor cells, particularly those of neuroendocrine origin. TEM8 is a transmembrane glycoprotein that is preferentially upregulated in some tumor cell and tumor-associated stromal cell populations. Both TEM8 and SVV have been evaluated for targeting of tumors of multiple origins, but the connection between the two was previously unknown. Here, we review currently understood interactions between TEM8 and SVV, anthrax protective antigen (PA), and collagen VI, a native binding partner of TEM8, with an emphasis on potential therapeutic directions moving forward

Evidence that histidine protonation of receptor-bound anthrax protective antigen is a trigger for pore formation

The protective antigen (PA) component of the anthrax toxin forms pores within the low pH environment of host endosomes, through mechanisms that are poorly understood. It has been proposed that pore formation is dependent on histidine protonation. In previous work, we biosynthetically incorporated 2-fluorohistidine (2-FHis), an isosteric analog of histidine with a significantly reduced pKa (~1), into PA, and showed that the pH-dependent conversion from the soluble prepore to a pore was unchanged. However, we also observed that 2-FHisPA was non-functional in the ability to mediate cytotoxicity of CHO-K1 cells by LFN-DTA, and was defective in translocation through planar lipid bilayers. Here, we show that the defect in cytotoxicity is due to both a defect in translocation and, when bound to the host cellular receptor, an inability to undergo low pH-induced pore formation. Combining X-ray crystallography with hydrogen-deuterium (H-D) exchange mass spectrometry, our studies lead to a model in which hydrogen bonds to the histidine ring are strengthened by receptor binding. The combination of both fluorination and receptor binding is sufficient to block low pH-induced pore formation

Structural Insight into Archaic and Alternative Chaperone-Usher Pathways Reveals a Novel Mechanism of Pilus Biogenesis

AVZ is supported by the Finnish Academy (grants 140959 and 273075; http://sciencenordic.com/partner/academy-finland) and Sigrid Juselius Foundation (grant 2014; www.sigridjuselius.fi/foundation). SMis supported by the Wellcome Trust (Senior Investigator Award 100280, Programme grant 079819; http://www.wellcome.ac.uk) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The epidemiological burden of obesity in childhood: a worldwide epidemic requiring urgent action

Background: In recent decades, the prevalence of obesity in children has increased dramatically. This worldwide epidemic has important consequences, including psychiatric, psychological and psychosocial disorders in childhood, and increased risk of developing noncommunicable diseases later in life. Treatment of obesity is difficult, and children with excess weight are likely to become adults with obesity. These trends have led World Health Organization (WHO) member states to endorse a target of no increase in obesity in childhood by 2025. Main body: Estimates of overweight in children aged under 5 years are available jointly from UNICEF, WHO and the World Bank. Country-level estimates of obesity in children aged from 2 to 4 years have been published by the Institute for Health Metrics and Evaluation (IHME). For children aged from 5 to 19, obesity estimates are available from the NCD Risk Factor Collaboration. The global prevalence of overweight in children aged under 5 years has increased modestly, but with heterogeneous trends in low- and middle-income regions, while the prevalence of obesity in children aged from 2 to 4 has increased moderately. For children aged 5 to 19, obesity was relatively rare in 1975, but was much more common in 2016. Conclusions: It is recognised that the key drivers of this epidemic form an obesogenic environment, which includes changing food systems and reduced physical activity. Although cost-effective interventions such as WHO “best buys” have been identified, political will and implementation have so far been limited. There is therefore a need to implement effective programmes and policies in multiple sectors to address overnutrition, undernutrition, mobility and physical activity. To be successful, the obesity epidemic must be a political priority, with these issues addressed both locally and globally. This must involve coordinated work by governments, civil society, private corporations and other key stakeholders

Cyclicity in the nearshore marine to coastal, Lower Permian, Pebbley Beach Formation, southern Sydney Basin, Australia: a record of relative sea-level fluctuations at the close of the late Palaeozoic Gondwanan ice age

The Lower Permian (Artinskian to Sakmarian) Pebbley Beach Formation of the southernmost Sydney Basin in New South Wales, Australia, records sediment accumulation in shallow marine to coastal environments at the close of the Late Palaeozoic Gondwanan ice age. This paper presents a sequence stratigraphic re-evaluation of the upper half of the unit based on the integration of sedimentology and ichnology. Ten facies are recognized, separated into two facies associations. Facies Association A (7 facies) comprises variably bioturbated siltstones and sandstones with marine body fossils, interpreted to record sediment accumulation in open marine environments ranging from lower offshore to middle shoreface water depths. Evidence of deltaic influence is seen in several Association A facies. Facies Association B (3 facies) comprises mainly heterolithic, interlaminated and thinly interbedded sandstone and siltstone with some thicker intervals of dark grey, organic-rich mudstone, some units clearly filling incised channel forms. These facies are interpreted as the deposits of estuarine channels and basins. Throughout the upper half of the formation, erosion surfaces with several metres relief abruptly separate open marine facies of Association A (below) from estuarine facies of Association B (above). Vertical facies changes imply significant basinward shift of environment across these surfaces, and lowering of relative sea level on the order of 50 metres. These surfaces can be traced over several kilometres along depositional strike, and are defined as sequence boundaries. On this basis, at least nine sequences have been recognized in the upper half of the formation, each of which is \u3c10 m thick, condensed, incomplete and top-truncated. Sequences contain little if any record of the lowstand systems tract, a more substantial transgressive systems tract and a highstand systems tract that is erosionally truncated (or in some cases, missing). This distinctive stacking pattern (which suggests a dominance of retrogradation and progradation over aggradation) and 3 the implied relative sea-level drop across sequence boundaries of tens of metres are remarkably similar to some other studies of continental margin successions formed under the Neogene icehouse climatic regime. Accordingly, it is suggested that the stratigraphic architecture of the Pebbley Beach Formation was a result of an Icehouse climate regime characterised by repeated, high-amplitude cycles of relative sea-level change