ARE AB INITIO QUANTUM CHEMISTRY METHODS ABLE TO PREDICT VIBRATIONAL STATES UP TO THE DISSOCIATION LIMIT FOR MULTI-ELECTRON MOLECULES CLOSE TO SPECTROSCOPIC ACCURACY?

Author Institution: Eotvos Lorand University, Budapest, Hungary; Slovak University of Technology, Trnava, Slovak Republic; Reims University, Reims, FranceThe aim of the study was to explore the limits of initio methods towards the description of excited vibrational levels up to the dissociation limit for molecules having more than two electrons. To this end a high level {\it ab initio} potential energy function was constructed for the four-electron LiH molecule in order to accurately predict a complete set of bound vibrational levels corresponding to the electronic ground state. It was composed from: a) an {\it ab initio} non-relativistic potential obtained at the MR-CISD level including size-extensivity corrections and quintuple-sextuple $\zeta$ extrapolation of the basis, b) MVD (Mass-velocity-Darwin) relativistic corrections obtained at icMR-CISD/cc-pwCV5Z level, and c) DBOC (Diagonal Born-Oppenheimer correction) obtained at the MR-CISD/cc-pwCVTZ level. Finally, the importance of non-adiabatic effects was also tested by using atomic masses in the vibrational kinetic energy operator and by calculation of non-adiabatic coupling by {\it ab initio} methods. The calculated vibrational levels were compared with those obtained from experimental data [J.A. Coxon and C.S. Dickinson, \textit{J. Chem. Phys.}, 2004, \textbf{121}, 9378]. Our best estimate of the potential curve results in vibrational energies with a RMS deviation of only $\sim$1 \wn\ for the entire set of all empirically determined vibrational levels known so far. These results represent a drastic improvement over previous theoretical predictions of vibrational levels of $^7$LiH up to dissociation, $D_0$, which was predicted to be 19594 cm$^{-1}$. In addition, rotational levels have also been calculated. The RMS deviation between our ab initio calculations and empirical results by Coxon and Dickinson for rotational spacings $\Delta E = E(v, J = 1)-E(v, J = 0)$ over all available vibrational states of $^7$LiH from $v = 0$ to $v= 20$ is 0.010 \wn\ (with nuclear masses) and 0.006 \wn\ (with atomic masses). Note that for high vibrational states with $v > 6$ this falls within the uncertainty of the measurements

Class I major histocompatibility complexes loaded by a periodate trigger

Class I major histocompatibility complexes (MHCs) present peptide ligands on the cell surface for recognition by appropriate cytotoxic T cells. The unstable nature of unliganded MHC necessitates the production of recombinant class I complexes through in vitro refolding reactions in the presence of an added excess of peptides. This strategy is not amenable to high-throughput production of vast collections of class I complexes. To address this issue, we recently designed photocaged MHC ligands that can be cleaved by a UV light trigger in the MHC bound state under conditions that do not affect the integrity of the MHC structure. The results obtained with photocaged MHC ligands demonstrate that conditional MHC ligands can form a generally applicable concept for the creation of defined peptide−MHCs. However, the use of UV exposure to mediate ligand exchange is unsuited for a number of applications, due to the lack of UV penetration through cell culture systems and due to the transfer of heat upon UV irradiation, which can induce evaporation. To overcome these limitations, here, we provide proof-of-concept for the generation of defined peptide−MHCs by chemical trigger-induced ligand exchange. The crystal structure of the MHC with the novel chemosensitive ligand showcases that the ligand occupies the expected binding site, in a conformation where the hydroxyl groups should be reactive to periodate. We proceed to validate this technology by producing peptide−MHCs that can be used for T cell detection. The methodology that we describe here should allow loading of MHCs with defined peptides in cell culture devices, thereby permitting antigen-specific T cell expansion and purification for cell therapy. In addition, this technology will be useful to develop miniaturized assay systems for performing high-throughput screens for natural and unnatural MHC ligands

Altered compensatory cytokine signaling underlies the discrepancy between Flt3–/– and Flt3l–/– mice

The receptor Flt3 and its ligand Flt3L are both critical for dendritic cell (DC) development, but DC deficiency is more severe i

Structural Studies of West Nile Virus in Complex with Neutralizing Antibodies.

West Nile virus (WNV) is a positive strand RNA virus in the family Flaviviridae, which includes members such as dengue, Japanese encephalitis, tick-borne encephalitis, yellow fever and Hepatitis C. As with other members of the genus, it is arthropod transmitted and has recently established itself as an endemic virus in the United States. Although most infections are asymptomatic, clinical manifestations of WNV include encephalitis and death. We have been interested in investigating the nature of the immune response with particular emphasis on the role of antibodies in reducing the level of infection. We have used a combination of techniques, but primarily structure, as a tool to probe the nature of antibody-mediated virus neutralization. Our results suggest that neutralization of virus particles is more complex than originally envisioned, with multiple mechanisms utilized. Using a combination of X-ray crystallography and cryo-electron microscopy, several virus-antibody complexes have been determined at pseudo-atomic resolution. These studies suggest the following: 1) flavivirus particles exhibit dynamic motions or breathing that transiently expose cryptic epitopes; 2) although there are 180 potential binding sites for each monoclonal antibody the quasi-equivalent nature of the virion usually permits only a subset of sites to be utilized; 3) the availability of these sites, the epitope itself, and the avidity of antibody directly influence the mechanism of neutralization; and 4) particles thought to be incapable of infecting cells, so-called immature viruses, may play a critical role in immune surveillance and reactivity. The structure of the flavivirus virion and complexes of monoclonal antibodies will be presented along with data to support mechanisms antibody-mediated flavivirus neutralizatio

Determinants of postnatal spleen tissue regeneration and organogenesis

Abstract The spleen is an organ that filters the blood and is responsible for generating blood-borne immune responses. It is also an organ with a remarkable capacity to regenerate. Techniques for splenic auto-transplantation have emerged to take advantage of this characteristic and rebuild spleen tissue in individuals undergoing splenectomy. While this procedure has been performed for decades, the underlying mechanisms controlling spleen regeneration have remained elusive. Insights into secondary lymphoid organogenesis and the roles of stromal organiser cells and lymphotoxin signalling in lymph node development have helped reveal similar requirements for spleen regeneration. These factors are now considered in the regulation of embryonic and postnatal spleen formation, and in the establishment of mature white pulp and marginal zone compartments which are essential for spleen-mediated immunity. A greater understanding of the cellular and molecular mechanisms which control spleen development will assist in the design of more precise and efficient tissue grafting methods for spleen regeneration on demand. Regeneration of organs which harbour functional white pulp tissue will also offer novel opportunities for effective immunotherapy against cancer as well as infectious diseases

CATLIFE (Complementary Arm for Target LIke FragmEnts): Spectrometer for Target like fragments at VAMOS++

The multi-nucleon transfer reaction between 136Xe beam and 198Pt target at the beam energy 7 MeV/u was studied using the large acceptance spectrometer VAMOS++ coupled with the newly installed second arm time-of-flight and delayed $\gamma$-ray spectrometer CATLIFE (Complementary Arm for Target LIke FragmEnts). The CATLIFE detector is composed of a large area multi-wire proportional chamber and the EXOGAM HPGe clover detectors with an ion flight length of 1230 mm. Direct measurement of the target-like fragments (TLF) and the delayed $\gamma$-rays from the isomeric state helps to improve TLF identification. The use of the velocity of TLFs and the delayed $\gamma$-ray demonstrate the proof of principle and effectiveness of the new setup

Isolation of a potently neutralizing and protective human monoclonal antibody targeting yellow fever virus

Yellow fever virus (YFV) causes sporadic outbreaks of infection in South America and sub-Saharan Africa. While live-attenuated yellow fever virus vaccines based on three substrains of 17D are considered some of the most effective vaccines in use, problems with production and distribution have created large populations of unvaccinated, vulnerable individuals in areas of endemicity. To date, specific antiviral therapeutics have not been licensed for human use against YFV or any other related flavivirus. Recent advances in monoclonal antibody (mAb) technology have allowed the identification of numerous candidate therapeutics targeting highly pathogenic viruses, including many flaviviruses. Here, we sought to identify a highly neutralizing antibody targeting the YFV envelope (E) protein as a therapeutic candidate. We used human B cell hybridoma technology to isolate mAbs from circulating memory B cells from human YFV vaccine recipients. These antibodies bound to recombinant YFV E protein and recognized at least five major antigenic sites on E. Two mAbs (designated YFV-136 and YFV-121) recognized a shared antigenic site and neutralized the YFV-17D vaccine strai

Antibodies targeting epitopes on the cell-surface form of NS1 protect against Zika virus infection during pregnancy

Zika virus is an arthropod-transmitted flavivirus that can cause microcephaly and other fetal abnormalities during pregnancy. Here Wessel et al. develop antibodies against the Zika virus nonstructural protein 1 that protect non-pregnant and pregnant mice against infection, and define particular antibody epitopes and mechanisms underlying this protection

Relevance or Excellence? Setting Research Priorities for Mental Health and Psychosocial Support in Humanitarian Settings

Background: Humanitarian crises are associated with an increase in mental disorders and psychological distress. Despite the emerging consensus on intervention strategies in humanitarian settings, the field of mental health and psychosocial support (MHPSS) in humanitarian settings lacks a consensus-based research agenda. Methods: From August 2009 to February 2010, we contacted policymakers, academic researchers, and humanitarian aid workers, and conducted nine semistructured focus group discussions with 114 participants in three locations (Peru, Uganda, and Nepal), in both the capitals and remote humanitarian settings. Local stakeholders representing a range of academic expertise (psychiatry, psychology, social work, child protection, and medical anthropology) and organizations (governments, universities, nongovernmental organizations, and UN agencies) were asked to identify priority questions for MHPSS research in humanitarian settings, and to discuss factors that hamper and facilitate research. Results: Thematic analyses of transcripts show that participants broadly agreed on prioritized research themes in the following order: (1) the prevalence and burden of mental health and psychosocial difficulties in humanitarian settings, (2) how MHPSS implementation can be improved, (3) evaluation of specific MHPSS interventions, (4) the determinants of mental health and psychological distress, and (5) improved research methods and processes. Rather than differences in research themes across countries, what emerged was a disconnect between different groups of stakeholders regarding research processes: the perceived lack of translation of research findings into actual policy and programs; misunderstanding of research methods by aid workers; different appreciation of the time needed to conduct research; and disputed universality of research constructs. Conclusions: To advance a collaborative research agenda, actors in this field need to bridge the perceived disconnect between the goals of “relevance” and “excellence.” Research needs to be more sensitive to questions and concerns arising from humanitarian interventions, and practitioners need to take research findings into account in designing interventions. (Harv Rev Psychiatry 2012;20:25–36.