Vaccine-induced skewing of T cell responses protects against Chikungunya virus disease

Chikungunya virus (CHIKV) infections can cause severe and debilitating joint and muscular pain that can be long lasting. Current CHIKV vaccines under development rely on the generation of neutralizing antibodies for protection; however, the role of T cells in controlling CHIKV infection and disease is still unclear. Using an overlapping peptide library, we identified the CHIKV-specific T cell receptor epitopes recognized in C57BL/6 infected mice at 7 and 14 days post-infection. A fusion protein containing peptides 451, 416, a small region of nsP4, peptide 47, and an HA tag (CHKVf5) was expressed using adenovirus and cytomegalovirus-vectored vaccines. Mice vaccinated with CHKVf5 elicited robust T cell responses to higher levels than normally observed following CHIKV infection, but the vaccine vectors did not elicit neutralizing antibodies. CHKVf5-vaccinated mice had significantly reduced infectious viral load when challenged by intramuscular CHIKV injection. Depletion of both CD

Human gene copy number spectra analysis in congenital heart malformations

The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency “spectra” to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways

Letter from Broeckel, et al., Supporting Mason Bill, April 16, 1953

This handwritten letter, dated April 16, 1953 from Daphne Broeckel and others to United States (US) Representative Usher L. Burdick, expresses the authors\u27 support for the so-called Mason Bill, which would repeal a 20% federal admission tax on movie theater tickets.https://commons.und.edu/burdick-papers/1441/thumbnail.jp

PCSK9 variation and association with blood pressure in African Americans: Preliminary findings from the HyperGEN and REGARDS studies

Proprotein convertase subtilisin/kexin type 9 (encoded by PCSK9) plays a well-known role in the regulation of low-density lipoprotein (LDL) receptors, and an inhibitor of this enzyme is a promising new therapeutic for hyperlipidemia. Recently, animal and human studies also implicate PCSK9 genetic variation in the regulation of blood pressure. The goal of this study was to examine if common and rare polymorphisms in PCSK9 are associated with blood pressure in an African-American population at high risk for cardiovascular disease. Using genomic data assayed on the Affymetrix 6.0 array (n = 1199) and the Illumina HumanExome Beadchip (n = 1966) from the Hypertension Genetic Epidemiology Network (HyperGEN), we tested the association of PCSK9 polymorphisms with blood pressure. We used linear mixed models and the sequence kernel association test (SKAT) to assess the association of 31 common and 19 rare variants with blood pressure. The models were adjusted for age, sex, center, smoking status, principal components for ancestry and diabetes as fixed effects and family as a random effect. The results showed a marginally significant effect of two genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) (rs12048828: β = 1.8, P = 0.05 and rs9730100: β = 1.0, P = 0.05) with diastolic blood pressure (DBP); however these results were not significant after correction for multiple testing. Rare variants were cumulatively associated with DBP (P = 0.04), an effect that was strengthened by restriction to nonsynonymous or stop-gain SNPs (P = 0.02). While gene-based results for DBP did not replicate (P = 0.36), we found an association with SBP (P = 0.04) in the Reasons for Geographic And Racial Differences in Stroke study (REGARDS). The findings here suggest rare variants in PCSK9 may influence blood pressure among African Americans, laying the ground work for further validation studies

The Garden Project

The Garden Project, San Luis Obispo is a program that rehabilitates inmates through restorative justice practices at the San Luis Obispo County Jail. The program offers inmates at both the men’s and women’s honor farms opportunities to connect to the land through physical gardening practices, establish relationships with other inmates as well as outside volunteers, gain vocational skills that will benefit inmates upon their release, and ultimately empower inmates to become confident and productive members of the community

Moduli Stabilisation and the Statistics of Low-Energy Physics in the String Landscape

In this thesis we present a detailed analysis of the statistical properties of the type IIB flux landscape of string theory. We focus primarily on models constructed via the Large Volume Scenario (LVS) and KKLT and study the distribution of various phenomenologically relevant quantities. First, we compare our considerations with previous results and point out the importance of Kähler moduli stabilisation, which has been neglected in this context so far. We perform different moduli stabilisation procedures and compare the resulting distributions. To this end, we derive the expressions for the gravitino mass, various quantities related to axion physics and other phenomenologically interesting quantities in terms of the fundamental flux dependent quantities $g_s$, $W_0$ and $\mathfrak{n}$, the parameter which specifies the nature of the non-perturbative effects. Exploiting our knowledge of the distribution of these fundamental parameters, we can derive a distribution for all the quantities we are interested in. For models that are stabilised via LVS we find a logarithmic distribution, whereas for KKLT and perturbatively stabilised models we find a power-law distribution. We continue by investigating the statistical significance of a newly found class of KKLT vacua and present a search algorithm for such constructions. We conclude by presenting an application of our findings. Given the mild preference for higher scale supersymmetry breaking, we present a model of the early universe, which allows for additional periods of early matter domination and ultimately leads to rather sharp predictions for the dark matter mass in this model. We find the dark matter mass to be in the very heavy range $m_{\chi}\sim 10^{10}-10^{11}\text{ GeV}$

On the Search for Low W0

The magnitude of the vacuum expectation value of the Gukov-Vafa-Witten superpotential (Formula presented.) plays a central role in the phenomenology of type IIB flux compactifications. Recent analytical constructions have shown that perturbatively flat vacua can be used to obtain very low values of (Formula presented.). We present systematic algorithms to carry out exhaustive numerical searches for such vacua. We also analyse them in the statistical context, as part of the entire ensemble of type IIB flux vacua at low (Formula presented.). Our preliminary analysis indicates that these perturbatively flat vacua are statistically sparse in the whole set of vacua at low (Formula presented.) as calculated by Denef and Douglas. Two-moduli examples are used to illustrate these more general findings in specific settings. We find that these simple (two moduli) cases are good examples for existence proofs but they do not feature a large statistical tuning freedom for phenomenological applications

Moduli stabilisation and the statistics of SUSY breaking in the landscape

The statistics of the supersymmetry breaking scale in the string landscape has been extensively studied in the past finding either a power-law behaviour induced by uniform distributions of F-terms or a logarithmic distribution motivated by dynamical supersymmetry breaking. These studies focused mainly on type IIB flux compactifications but did not systematically incorporate the K\ue4hler moduli. In this paper we point out that the inclusion of the K\ue4hler moduli is crucial to understand the distribution of the supersymmetry breaking scale in the landscape since in general one obtains unstable vacua when the F-terms of the dilaton and the complex structure moduli are larger than the F- terms of the K\ue4hler moduli. After taking K\ue4hler moduli stabilisation into account, we find that the distribution of the gravitino mass and the soft terms is power-law only in KKLT and perturbatively stabilised vacua which therefore favour high scale supersymmetry. On the other hand, LVS vacua feature a logarithmic distribution of soft terms and thus a preference for lower scales of supersymmetry breaking. Whether the landscape of type IIB flux vacua predicts a logarithmic or power-law distribution of the supersymmetry breaking scale thus depends on the relative preponderance of LVS and KKLT vacua