The complex relationship between weather and dengue virus transmission in Thailand.

Using a novel analytical approach, weather dynamics and seasonal dengue virus transmission cycles were profiled for each Thailand province, 1983-2001, using monthly assessments of cases, temperature, humidity, and rainfall. We observed systematic differences in the structure of seasonal transmission cycles of different magnitude, the role of weather in regulating seasonal cycles, necessary versus optimal transmission "weather-space," basis of large epidemics, and predictive indicators that estimate risk. Larger epidemics begin earlier, develop faster, and are predicted at Onset change-point when case counts are low. Temperature defines a viable range for transmission; humidity amplifies the potential within that range. This duality is central to transmission. Eighty percent of 1.2 million severe dengue cases occurred when mean temperature was 27-29.5°C and mean humidity was > 75%. Interventions are most effective when applied early. Most cases occur near Peak, yet small reductions at Onset can substantially reduce epidemic magnitude. Monitoring the Quiet-Phase is fundamental in effectively targeting interventions pre-emptively

Ultraviolet Completion of Flavour Models

Effective Flavour Models do not address questions related to the nature of the fundamental renormalisable theory at high energies. We study the ultraviolet completion of Flavour Models, which in general has the advantage of improving the predictivity of the effective models. In order to illustrate the important features we provide minimal completions for two known A4 models. We discuss the phenomenological implications of the explicit completions, such as lepton flavour violating contributions that arise through the exchange of messenger fields.Comment: 18 pages, 8 figure

Constructing Dirac linear fermions in terms of non-linear Heisenberg spinors

We show that the massive (or massless) neutrinos can be described as special states of Heisenberg nonlinear spinors. As a by-product of this decomposition a particularly attractive consequence appears: the possibility of relating the existence of only three species of mass-less neutrinos to such internal non-linear structure. At the same time it allows the possibility that neutrino oscillation can occurs even for massless neutrinos

Evidence for Anthropogenic Surface Loading as Trigger Mechanism of the 2008 Wenchuan Earthquake

Two and a half years prior to China's M7.9 Wenchuan earthquake of May 2008, at least 300 million metric tons of water accumulated with additional seasonal water level changes in the Minjiang River Valley at the eastern margin of the Longmen Shan. This article shows that static surface loading in the Zipingpu water reservoir induced Coulomb failure stresses on the nearby Beichuan thrust fault system at <17km depth. Triggering stresses exceeded levels of daily lunar and solar tides and perturbed a fault area measuring 416+/-96km^2. These stress perturbations, in turn, likely advanced the clock of the mainshock and directed the initial rupture propagation upward towards the reservoir on the "Coulomb-like" Beichuan fault with rate-and-state dependent frictional behavior. Static triggering perturbations produced up to 60 years (0.6%) of equivalent tectonic loading, and show strong correlations to the coseismic slip. Moreover, correlations between clock advancement and coseismic slip, observed during the mainshock beneath the reservoir, are strongest for a longer seismic cycle (10kyr) of M>7 earthquakes. Finally, the daily event rate of the micro-seismicity (M>0.5) correlates well with the static stress perturbations, indicating destabilization.Comment: 22 pages, 4 figures, 3 table

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

Reactor mixing angle from hybrid neutrino masses

In terms of its eigenvector decomposition, the neutrino mass matrix (in the basis where the charged lepton mass matrix is diagonal) can be understood as originating from a tribimaximal dominant structure with small deviations, as demanded by data. If neutrino masses originate from at least two different mechanisms, referred to as "hybrid neutrino masses", the experimentally observed structure naturally emerges provided one mechanism accounts for the dominant tribimaximal structure while the other is responsible for the deviations. We demonstrate the feasibility of this picture in a fairly model-independent way by using lepton-number-violating effective operators, whose structure we assume becomes dictated by an underlying $A_4$ flavor symmetry. We show that if a second mechanism is at work, the requirement of generating a reactor angle within its experimental range always fixes the solar and atmospheric angles in agreement with data, in contrast to the case where the deviations are induced by next-to-leading order effective operators. We prove this idea is viable by constructing an $A_4$-based ultraviolet completion, where the dominant tribimaximal structure arises from the type-I seesaw while the subleading contribution is determined by either type-II or type-III seesaw driven by a non-trivial $A_4$ singlet (minimal hybrid model). After finding general criteria, we identify all the $\mathbb{Z}_N$ symmetries capable of producing such $A_4$-based minimal hybrid models.Comment: 18 pages, 5 figures. v3: section including sum rules added, accepted by JHE

Inspiratory muscle warm-up does not improve cycling time-trial performance

Purpose: This study examined the effects of an active cycling warm-up, with and without the addition of an inspiratory muscle warm-up (IMW), on 10-km cycling time-trial performance

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

Emergent Properties of Tumor Microenvironment in a Real-life Model of Multicell Tumor Spheroids

Multicellular tumor spheroids are an important {\it in vitro} model of the pre-vascular phase of solid tumors, for sizes well below the diagnostic limit: therefore a biophysical model of spheroids has the ability to shed light on the internal workings and organization of tumors at a critical phase of their development. To this end, we have developed a computer program that integrates the behavior of individual cells and their interactions with other cells and the surrounding environment. It is based on a quantitative description of metabolism, growth, proliferation and death of single tumor cells, and on equations that model biochemical and mechanical cell-cell and cell-environment interactions. The program reproduces existing experimental data on spheroids, and yields unique views of their microenvironment. Simulations show complex internal flows and motions of nutrients, metabolites and cells, that are otherwise unobservable with current experimental techniques, and give novel clues on tumor development and strong hints for future therapies.Comment: 20 pages, 10 figures. Accepted for publication in PLOS One. The published version contains links to a supplementary text and three video file