Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency

Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin-deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8 + T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8 + lymphoblasts had reduced interferon-γ secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene-modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL

On The Potential of Minimal Flavour Violation

Assuming the Minimal Flavour Violation hypothesis, we derive the general scalar potential for fields whose background values are the Yukawa couplings. We analyze the minimum of the potential and discuss the fine-tuning required to dynamically generate the mass hierarchies and the mixings between different quark generations. Two main cases are considered, corresponding to Yukawa interactions being effective operators of dimension five or six (or, equivalently, resulting from bi-fundamental and fundamental scalar fields, respectively). At the renormalizable and classical level, no mixing is naturally induced from dimension five Yukawa operators. On the contrary, from dimension six Yukawa operators one mixing angle and a strong mass hierarchy among the generations result.Comment: 33 pages, 6 figures; Note added in proof on the stability of the minima of the scalar potential; results unchanged; references adde

The Impact of Flavour Changing Neutral Gauge Bosons on B->X_s gamma

The branching ratio of the rare decay B->X_s gamma provides potentially strong constraints on models beyond the Standard Model. Considering a general scenario with new heavy neutral gauge bosons, present in particular in Z' and gauge flavour models, we point out two new contributions to the B->X_s gamma decay. The first one originates from one-loop diagrams mediated by gauge bosons and heavy exotic quarks with electric charge -1/3. The second contribution stems from the QCD mixing of neutral current-current operators generated by heavy neutral gauge bosons and the dipole operators responsible for the B->X_s gamma decay. The latter mixing is calculated here for the first time. We discuss general sum rules which have to be satisfied in any model of this type. We emphasise that the neutral gauge bosons in question could also significantly affect other fermion radiative decays as well as non-leptonic two-body B decays, epsilon'/epsilon, anomalous (g-2)_mu and electric dipole moments.Comment: 31 pages, 5 figures; version published on JHEP; added magic QCD numbers for flavour-violating Z gauge boson contribution to B -> X_s gamm

Zone center phonons of the orthorhombic RMnO3 (R = Pr, Eu, Tb, Dy, Ho) perovskites

A short range force constant model (SRFCM) has been applied for the first time to investigate the phonons in RMnO3 (R = Pr, Eu, Tb, Dy, Ho) perovskites in their orthorhombic phase. The calculations with 17 stretching and bending force constants provide good agreement for the observed Raman frequencies. The infrared frequencies have been assigned for the first time. PACS Codes: 36.20.Ng, 33.20.Fb, 34.20.CfComment: 8 pages, 1 figur

Travel risk, malaria importation and malaria transmission in Zanzibar

The prevalence of Plasmodium falciparum malaria in Zanzibar has reached historic lows. Improving control requires quantifying malaria importation rates, identifying high-risk travelers, and assessing onwards transmission

Feeding into old age: long-term effects of dietary fatty acid supplementation on tissue composition and life span in mice

Smaller mammals, such as mice, possess tissues containing more polyunsaturated fatty acids (PUFAs) than larger mammals, while at the same time live shorter lives. These relationships have been combined in the ‘membrane pacemaker hypothesis of aging’. It suggests that membrane PUFA content might determine an animal’s life span. PUFAs in general and certain long-chain PUFAs in particular, are highly prone to lipid peroxidation which brings about a high rate of reactive oxygen species (ROS) production. We hypothesized that dietary supplementation of either n-3 or n-6 PUFAs might affect (1) membrane phospholipid composition of heart and liver tissues and (2) life span of the animals due to the altered membrane composition, and subsequent effects on lipid peroxidation. Therefore, we kept female laboratory mice from the C57BL/6 strain on three diets (n-3 PUFA rich, n-6 PUFA rich, control) and assessed body weights, life span, heart, and liver phospholipid composition after the animals had died. We found that while membrane phospholipid composition clearly differed between feeding groups, life span was not directly affected. However, we were able to observe a positive correlation between monounsaturated fatty acids in cardiac muscle and life span

Gauged flavour symmetry for the light generations

We study the phenomenology of a model where an SU(2)^3 flavour symmetry acting on the first two generation quarks is gauged and Yukawa couplings for the light generations are generated by a see-saw mechanism involving heavy fermions needed to cancel flavour-gauge anomalies. We find that, in constrast to the SU(3)^3 case studied in the literature, most of the constraints related to the third generation, like electroweak precision bounds or B physics observables, can be evaded, while characteristic collider signatures are predicted.Comment: 16 pages, 3 figure

Minimal flavour violation extensions of the seesaw

We analyze the most natural formulations of the minimal lepton flavour violation hypothesis compatible with a type-I seesaw structure with three heavy singlet neutrinos N, and satisfying the requirement of being predictive, in the sense that all LFV effects can be expressed in terms of low energy observables. We find a new interesting realization based on the flavour group $SU(3)_e\times SU(3)_{\ell+N}$ (being $e$ and $\ell$ respectively the SU(2) singlet and doublet leptons). An intriguing feature of this realization is that, in the normal hierarchy scenario for neutrino masses, it allows for sizeable enhancements of $\mu \to e$ transitions with respect to LFV processes involving the $\tau$ lepton. We also discuss how the symmetries of the type-I seesaw allow for a strong suppression of the N mass scale with respect to the scale of lepton number breaking, without implying a similar suppression for possible mechanisms of N productionComment: 14 pages, 6 figure

Microscopic Realization of the Kerr/CFT Correspondence

Supersymmetric M/string compactifications to five dimensions contain BPS black string solutions with magnetic graviphoton charge P and near-horizon geometries which are quotients of AdS_3 x S^2. The holographic duals are typically known 2D CFTs with central charges c_L=c_R=6P^3 for large P. These same 5D compactifications also contain non-BPS but extreme Kerr-Newman black hole solutions with SU(2)_L spin J_L and electric graviphoton charge Q obeying Q^3 \leq J_L^2. It is shown that in the maximally charged limit Q^3 -> J_L^2, the near-horizon geometry coincides precisely with the right-moving temperature T_R=0 limit of the black string with magnetic charge P=J_L^{1/3}. The known dual of the latter is identified as the c_L=c_R=6J_L CFT predicted by the Kerr/CFT correspondence. Moreover, at linear order away from maximality, one finds a T_R \neq 0 quotient of the AdS_3 factor of the black string solution and the associated thermal CFT entropy reproduces the linearly sub-maximal Kerr-Newman entropy. Beyond linear order, for general Q^3<J_L^2, one has a finite-temperature quotient of a warped deformation of the magnetic string geometry. The corresponding dual deformation of the magnetic string CFT potentially supplies, for the general case, the c_L=c_R=6J_L CFT predicted by Kerr/CFT.Comment: 18 pages, no figure

Prevalence of sleep complaints in Colombia at different altitudes

AbstractStudy objectivesTo determine the prevalence of sleep complaints in adults in Colombia at different altitudes.DesignCross-sectional, population-based and observational study.SettingUrban areas in three cities (Bogotá, Bucaramanga, Santa Marta) located between 15 and 2640 masl. Subjects Over 18 years old.InterventionsEpworth sleepiness scale (ESS), Pittsburgh sleep quality index (PSQI), Berlin questionnaire, STOP-Bang questionnaire and diagnostic criteria for restless leg syndrome (IRLSSG).Measurements and resultsThe overall prevalence of sleep complaints was 59.6% (CI 95%: 57.3; 61.8%). According to the Pittsburgh scale, 45.3% (CI 95%: 43.0; 47.5) required medical assistance. The Berlin questionnaire indicated that 19.0% (CI 95%: 17.3; 20.8%) had a high risk of sleep apnea (OSA) compared to 26.9% (CI 95%: 24.9; 29.0%) according to STOP-Bang. Among the subjects, 13.7% (CI 95%: 12.3; 15.3%) had excessive daytime sleepiness and 37.7% (CI 95%: 35.5; 39.8%) had a restless leg syndrome. When comparing cities, significant differences in the overall frequency of subjects requiring care were found between Santa Marta (higher frequency) and the other two cities. Differences in sleep problem frequency (Pittsburgh) were observed between Bogota (higher frequency) and Bucaramanga and also between Santa Marta (higher frequency) and the other two cities. The high risk of OSA (STOP-Bang) was different between Bogota (higher frequency) and Bucaramanga and also between Santa Marta (high frequency) and Bucaramanga.ConclusionsWe observed a high prevalence of sleep complaints with significant differences among the cities, indicating a need to pay a greater attention to these problems