Electron density and pair correlation functions in metals

Imperial Users onl

Pathways into homelessness among post 9/11 era veterans

This article may not exactly replicate the final version published in the APA journal. It is not the copy of record.Despite the scale of veteran homelessness and government–community initiatives to end homelessness among veterans, few studies have featured individual veteran accounts of experiencing homelessness. Here we track veterans’ trajectories from military service to homelessness through qualitative, semistructured interviews with 17 post-9/11-era veterans. Our objective was to examine how veterans become homeless—including the role of military and postmilitary experiences—and how they negotiate and attempt to resolve episodes of homelessness. We identify and report results in 5 key thematic areas: transitioning from military service to civilian life, relationships and employment, mental and behavioral health, lifetime poverty and adverse events, and use of veteran-specific services. We found that veterans predominantly see their homelessness as rooted in nonmilitary, situational factors such as unemployment and the breakup of relationships, despite very tangible ties between homelessness and combat sequelae that manifest themselves in clinical diagnoses such as posttraumatic stress disorder. Furthermore, although assistance provided by the U.S. Department of Veterans Affairs (VA) and community-based organizations offer a powerful means for getting veterans rehoused, veterans also recount numerous difficulties in accessing and obtaining VA services and assistance. Based on this, we offer specific recommendations for more systematic and efficient measures to help engage veterans with VA services that can prevent or attenuate their homelessness

Chilaiditi’s Syndrome

the surgical team for management of a suspected perforated duodenal ulcer. Subsequent CT imaging of thorax and abdomen revealed hepato-diaphragmatic interposition of the transverse colon, as well as extensive colitis. He was managed conservatively and discharged home well after four days. Chilaiditi’s sign is the appearance of free air under the diaphragm caused by interposition of the transverse colon between the liver and diaphragm. It is usually asymptomatic and is an incidental finding. It is estimated to occur in 0.25% to 0.28 % of the general population 1 and was first described by Demetrious Chilaiditi in 1910. 2 When the sign is observed in association with symptoms such as abdominal pain or vomiting it is termed Chilaiditi’s syndrome. It is in this scenario that the radiographic findings may be mistaken fo

Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5

International audienceAbstractBackgroundThe cytoplasmic RIG-like receptors are responsible for the early detection of viruses and other intracellular microbes by activating the innate immune response mediated by type I interferons (IFNs). RIG-I and MDA5 detect virus-specific RNA motifs with short 5′-tri/diphosphorylated, blunt-end double-stranded RNA (dsRNA) and >0.5–2 kb long dsRNA as canonical agonists, respectively. However, in vitro, they can bind to many RNA species, while in cells there is an activation threshold. As SF2 helicase/ATPase family members, ATP hydrolysis is dependent on co-operative RNA and ATP binding. Whereas simultaneous ATP and cognate RNA binding is sufficient to activate RIG-I by releasing autoinhibition of the signaling domains, the physiological role of the ATPase activity of RIG-I and MDA5 remains controversial.ResultsA cross-analysis of a rationally designed panel of RNA binding and ATPase mutants and truncated receptors, using type I IFN promoter activation as readout, allows us to refine our understanding of the structure-function relationships of RIG-I and MDA5. RNA activation of RIG-I depends on multiple critical RNA binding sites in its helicase domain as confirmed by functional evidence using novel mutations. We found that RIG-I or MDA5 mutants with low ATP hydrolysis activity exhibit constitutive activity but this was fully reverted when associated with mutations preventing RNA binding to the helicase domain. We propose that the turnover kinetics of the ATPase domain enables the discrimination of self/non-self RNA by both RIG-I and MDA5. Non-cognate, possibly self, RNA binding would lead to fast ATP turnover and RNA disassociation and thus insufficient time for the caspase activation and recruitment domains (CARDs) to promote downstream signaling, whereas tighter cognate RNA binding provides a longer time window for downstream events to be engaged.ConclusionsThe exquisite fine-tuning of RIG-I and MDA5 RNA-dependent ATPase activity coupled to CARD release allows a robust IFN response from a minor subset of non-self RNAs within a sea of cellular self RNAs. This avoids the eventuality of deleterious autoimmunity effects as have been recently described to arise from natural gain-of-function alleles of RIG-I and MDA5

Structural Analysis of dsRNA Binding to Anti-viral Pattern Recognition Receptors LGP2 and MDA5

International audienceRIG-I and MDA5 sense virus-derived short 5'ppp blunt-ended or long dsRNA, respectively, causing interferon production. Non-signaling LGP2 appears to positively and negatively regulate MDA5 and RIG-I signaling, respectively. Co-crystal structures of chicken (ch) LGP2 with dsRNA display a fully or semi-closed conformation depending on the presence or absence of nucleotide. LGP2 caps blunt, 3' or 5' overhang dsRNA ends with 1 bp longer overall footprint than RIG-I. Structures of 1:1 and 2:1 complexes of chMDA5 with short dsRNA reveal head-to-head packing rather than the polar head-to-tail orientation described for long filaments. chLGP2 and chMDA5 make filaments with a similar axial repeat, although less co-operatively for chLGP2. Overall, LGP2 resembles a chimera combining a MDA5-like helicase domain and RIG-I like CTD supporting both stem and end binding. Functionally, RNA binding is required for LGP2-mediated enhancement of MDA5 activation. We propose that LGP2 end-binding may promote nucleation of MDA5 oligomerization on dsRNA

Host Determinant Residue Lysine 627 Lies on the Surface of a Discrete, Folded Domain of Influenza Virus Polymerase PB2 Subunit

Understanding how avian influenza viruses adapt to human hosts is critical for the monitoring and prevention of future pandemics. Host specificity is determined by multiple sites in different viral proteins, and mutation of only a limited number of these sites can lead to inter-species transmission. Several of these sites have been identified in the viral polymerase, the best characterised being position 627 in the PB2 subunit. Efficient viral replication at the relatively low temperature of the human respiratory tract requires lysine 627 rather than the glutamic acid variant found systematically in avian viruses. However, the molecular mechanism by which any of these host specific sites determine host range are unknown, although adaptation to host factors is frequently evoked. We used ESPRIT, a library screening method, to identify a new PB2 domain that contains a high density of putative host specific sites, including residue 627. The X-ray structure of this domain (denoted the 627-domain) exhibits a novel fold with the side-chain of Lys627 solvent exposed. The structure of the K627E mutated domain shows no structural differences but the charge reversal disrupts a striking basic patch on the domain surface. Five other recently proposed host determining sites of PB2 are also located on the 627-domain surface. The structure of the complete C-terminal region of PB2 comprising the 627-domain and the previously identified NLS-domain, which binds the host nuclear import factor importin alpha, was also determined. The two domains are found to pack together with a largely hydrophilic interface. These data enable a three-dimensional mapping of approximately half of PB2 sites implicated in cross-species transfer onto a single structural unit. Their surface location is consistent with roles in interactions with other viral proteins or host factors. The identification and structural characterization of these well-defined PB2 domains will help design experiments to elucidate the effects of mutations on polymerase–host factor interactions