Expression of a single major histocompatibility complex locus controls the immune complex locus controls the immune response to poly-L-(tyrosine, glutamic acid)-poly-DL-alanine—poly-L-lysine

Genetic control of the immune response linked to the major histocompatibility (H-2) complex in the mouse has been described for synthetic polypeptide antigens and for low doses of native proteins. The phenomenon is well documented(1,2). Extensive screening of intra-H-2 crossover-derived recombinant strains has localized H-2-linked immune response (Ir) genes to the I-immune response region of the H-2 complex (3). For most antigens, Ir genes are autosomal, dominant, and they segregate as single loci. It is not known whether these crossover-defined loci respresent single genes with multiple alleles or clusters of tightly linked genes (4). In 1972, Stimpfling and Durham (5) postulated that two interacting loci within the H-2 complex were required for the response to the alloantigen, H-2.2 (6), and, in 1975, Dorf et. al. (7) observed a responder phenotype in a recombinant derived from two strains which were nonresponders to the synthetic linear terpolymer, L-glutamic acid, L-lysine, L-phenylaline (GLPhe). Analysis of additional recombinants and complementation tests with F(1) hybrids clearly demonstrated that genes in two intra-I-region loci controlled the immune response to GLPhe. Subsequently, requirement for genes mapping in two intra-I-region loci were reported for porcine LDH(B)(8), the alloantigen Thy-1.1 (9), and for the synthetic terpolymers L-glutamic acid, L-lysine, L-tyrosine and L-glutamic acid, L-lysine, L- leucine (6,10). Demonstration that responses to both synthetic polypeptide and native protein antigens can be controlled by genes in two distinct I-region loci prompted speculation that the phenotypic expression of two I-region genes is a general phenomenon which may provide the key for understanding the mechanism of Ir gene function and cellular collaboration in the immune response. Benacerraf and Dorf (10) have shown that Ir gene complementation is often more effective in the cis than in the trans configuration. This concept is further supported by the data reported for GLPhe (10-12) which indicate that both of the complementing genes must be expressed in each of the cell types participating in the interaction. Failure to detect complementation for the majority of antigens under H-2-linked Ir-gene control might be attributed to the limited number of available intra-I- region recombinant strains

Genetics of substance use disorders: A review

Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by the assembly of large GWAS samples, and the development of state-of-the-art methods modeling the aggregate effect of genome-wide variation. These advances have confirmed that SUDs are highly polygenic with many variants across the genome conferring risk, the vast majority of which are of small effect. Downstream analyses have enabled finer resolution of the genetic architecture of SUDs and revealed insights into their genetic relationship with other psychiatric disorders. Recent efforts have also prioritized a closer examination of GWAS findings that have suggested non-uniform genetic influences across measures of substance use (e.g. consumption) and problematic use (e.g. SUD). Additional highlights from recent SUD GWAS include the robust confirmation of loci in alcohol metabolizing genes (e.g. ADH1B and ALDH2) affecting alcohol-related traits, and loci within the CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related traits. Similar successes are expected for cannabis, opioid, and cocaine use disorders as sample sizes approach those assembled for alcohol and nicotine

GENETIC CONTROL OF THE IMMUNE RESPONSE : MAPPING OF THEIR-1 LOCUS

Eleven strains of mice bearing recombinant H-2 chromosomes derived from known crossover events between known H-2 types were immunized with a series of branched, multichain, synthetic polypeptide antigens [(T,G)-A--L, (H,G)-A--L, and (Phe,G)-A--L]. Results with nine of the eleven H-2 recombinants indicated that the gene(s) controlling immune response to these synthetic polypeptides (Ir-1) is on the centromeric or H-2K part of the recombinant H-2 chromosome. Results with two of the eleven recombinant H-2 chromosomes indicated that Ir-1 was on the telomeric or H-2D part of the recombinant H-2 chromosome. Both of these recombinants were derived from crossovers between the H-2K locus and the Ss-Slp locus near the center of the H-2 region. One of these recombinants, H-2y, was derived from a known single crossover event. These results indicate that Ir-1 lies near the center of the H-2 region between the H-2K locus and the Ss-Slp locus. The results of a four-point linkage test were consistent with these results. In 484 offspring of a cross designed to detect recombinants between H-2 and Ir-1, only two putative recombinants were detected. Both of these recombinants were confirmed by progeny testing. Extensive analysis of one of them has shown that the crossover event occurred within the H-2 region. (Testing of the second recombinant is currently under way.) Thus, in the linkage test, recombinants between H-2 and Ir-1 are in fact intra-H-2 crossovers. These results permit assignment of Ir-1 to a position between the H-2K locus and the Ss-Slp locus

Using computed tomography colonography in patients at high risk of colorectal cancer - a prospective study in a university hospital in South America

OBJECTIVES: The purpose of our study was to report the results of the implementation of computed tomography colonography in a university hospital setting serving a Brazilian population at high risk of colorectal cancer. METHODS: After creating a computed tomography colonography service in our institution, 85 patients at high risk of colorectal cancer underwent computed tomography colonography followed by a same-day optical colonoscopy from September 2010 to May 2012. The overall accuracy of computed tomography colonography in the detection of lesions ≥6 mm was compared to that of optical colonoscopy (direct comparison). All colonic segments were evaluated using quality imaging (amount of liquid and solid residual feces and luminal distension). To assess patient acceptance and preference, a questionnaire was completed before and after the computed tomography colonography and optical colonoscopy. Fisher's exact test was used to measure the correlations between colonic distension, discomfort during the exam, exam preference and interpretation confidence. RESULTS: Thirteen carcinomas and twenty-two lesions ≥6 mm were characterized. The sensitivity, specificity and accuracy of computed tomography colonography were 100%, 98.2% and 98.6%, respectively. Computed tomography colonography was the preferred method of investigation for 85% of patients. The preparation was reported to cause only mild discomfort for 97.6% of patients. According to the questionnaires, there was no significant relationship between colonic distension and discomfort (p>;0.05). Most patients (89%) achieved excellent bowel preparation. There was a statistically significant correlation between the confidence perceived in reading the computed tomography colonography and the quality of the preparation in each colonic segment (p≤0.001). The average effective radiation dose per exam was 7.8 mSv. CONCLUSION: It was possible to institute an efficient computed tomography colonography service at a university hospital that primarily assists patients from the public health system, with high accuracy, good acceptance and effective radiation doses. Our results seem to be comparable to other centers of excellence and fall within acceptable published guidelines, showing that a successful computed tomography colonography program can be reproduced in a South American population screened in a university hospital

A Three Dimensional Analysis of Au-Silica Core-Shell Nanoparticles Using Medium Energy Ion Scattering

The medium energy ion scattering (MEIS) facility at the IIAA Huddersfield has been used for the analysis of a monolayer of Au-silica core-shell nanoparticles deposited on Si substrate. Both spherical and rod shape particles were investigated and the spectra produced by 100 keV He+ ions scattered through angles of 90º and 125º were compared with the results of RBS-MAST [1] simulations performed on artificial 3D model cells containing the nanoparticles. The thickness of the silica shell, the diameter of the Au spheres, and the diameter and length of the Au nano-rods were determined from best fits of the measured set of MEIS spectra. In addition, the effect of ion irradiation on the silica shell and gold core was monitored by MEIS measurements in conjunction with RBS-MAST simulations. Ion bombardment was performed under largely different conditions, i.e., by 30 keV Ar+, 150 keV Fe+, or 2.8 MeV N+ ions in the dose range of 2×1015 - 2×1016 cm-2. Significant changes in the particle geometry can be observed due to ion beam-induced sputtering and recoil effects, the significance of which was estimated from full-cascade SRIM simulations. Rutherford backscattering spectrometry (RBS), Field emission scanning electron microscopy (FESEM), and Atomic Force Microscopy (AFM) techniques have been applied as complementary characterization tools to monitor the amount of gold and surface morphology on the un-irradiated and irradiated sample areas. We show that MEIS can yield spatial information on the geometrical changes of particulate systems at the nanometre scale

Determining the 7Li(n,gamma) cross section via Coulomb dissociation of 8Li

The applicability of Coulomb dissociation reactions to determine the cross section for the inverse neutron capture reaction was explored using the reaction 8Li(gamma,n)7Li. A 69.5 MeV/nucleon 8Li beam was incident on a Pb target, and the outgoing neutron and 7Li nucleus were measured in coincidence. The deduced (n,gamma) excitation function is consistent with data for the direct capture reaction 7Li(n,gamma)8Li and with low-energy effective field theory calculations.Comment: Accepted for publication in Phys. Rev.

Dependence of the flux creep activation energy on current density and magnetic field for MgB2 superconductor

Systematic ac susceptibility measurements have been performed on a MgB$_2$ bulk sample. We demonstrate that the flux creep activation energy is a nonlinear function of the current density $U(j)\propto j^{-0.2}$, indicating a nonlogarithmic relaxation of the current density in this material. The dependence of the activation energy on the magnetic field is determined to be a power law $U(B)\propto B^{-1.33}$, showing a steep decline in the activation energy with the magnetic field, which accounts for the steep drop in the critical current density with magnetic field that is observed in MgB$_2$. The irreversibility field is also found to be rather low, therefore, the pinning properties of this new material will need to be enhanced for practical applications.Comment: 11 pages, 6 figures, Revtex forma

Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8⁺ T cells and reprogramming macrophages.

Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most patients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1 <sup>+</sup> T cells in the tumor microenvironment. PD1-IL2v elicited substantial infiltration by stem-like CD8 <sup>+</sup> T cells, resulting in tumor regression and enhanced survival in mice. Combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and enhancing T cell receptor (TCR) immune repertoire diversity. These data provide a rationale for clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, particularly in immunotherapy-resistant tumors infiltrated with PD-1 <sup>+</sup> stem-like T cells