Northern Late Winter Planetary Waves: MRO/MARCI Observations and Mars Climate Model Simulations

As does Earth, Mars presents pronounced global atmospheric circulation patterns. Solar differential heating drives mean meridional overturning (Hadley) circulations which are deep and intense, are hemispherically asymmetric, and where a cross-equatorial single cell dominates. Within middle and high latitudes, thermally indirect eddy-driven (Ferrel) circulation cells have been indicated. Differently, however, large-amplitude orography on planetary and continental scales on Mars can force very non-Earth-like hemispheric circulation patterns. Recent observations from the Mars Reconnaissance Orbiter, "Mars Color Imager" (MARCI) instrument are utilized that emphasize water ice clouds in ultra-violet (UV) wavelengths, and these measurements have been binned into "daily global maps" (DGMs) of water-ice cloud optical depth. The presence of large-scale, extratropical quasi-stationary atmospheric wave disturbances in middle and late winter of the northern hemisphere have been found to be present in such DGMs. In combination with such observations, a full-physics Mars global climate model (NASA ARC marsgcm 2.1) is applied to place the observations into context. During late northern winter, it is found that strong, forced Rossby modes (i.e., planetary waves) exist, and with direct correlation to columnintegrated cloud opacity undulating spatial patterns. At this season, zonal wavenumber s = 2 dominates (in contrast to wavenumber s = 1), consistent with MGS/TES analyses at this particular season (Banfield et al., 2003). Large-scale, planetary waves dictate the "coherence" of the northern polar vortex. Fundamentally, such forced planetary waves influence the polar vortex's impermeability (wave-induced) to tracer transport (e.g., dust and water-ice aerosol) and temporal mean water vapor spatial variations. The large-scale dynamical features of such planetary waves will be highlighted and discussed

Understanding the relationship between prevalence of microfilariae and antigenaemia using a model of lymphatic filariasis infection.

BACKGROUND: Lymphatic filariasis is a debilitating neglected tropical disease that affects impoverished communities. Rapid diagnostic tests of antigenaemia are a practical alternative to parasitological tests of microfilaraemia for mapping and surveillance. However the relationship between these two methods of measuring burden has previously been difficult to interpret. METHODS: A statistical model of the distribution of worm burden and microfilariae (mf) and resulting antigenaemic and mf prevalence was developed and fitted to surveys of two contrasting sentinel sites undergoing interventions. The fitted model was then used to explore the relationship in various pre- and post-intervention scenarios. RESULTS: The model had good quantitative agreement with the data and provided estimates of the reduction in mf output due to treatment. When extrapolating the results to a range of prevalences there was good qualitative agreement with published data. CONCLUSIONS: The observed relationship between antigenamic and mf prevalence is a natural consequence of the relationship between prevalence and intensity of adult worms and mf production. The method described here allows the estimation of key epidemiological parameters and consequently gives insight into the efficacy of an intervention programme

Essential and checkpoint functions of budding yeast ATM and ATR during meiotic prophase are facilitated by differential phosphorylation of a meiotic adaptor protein, Hop1

A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis

Residential Mobility and the Underclass: Impact of Moving in the \u27Hood

Studies of residential mobility amongst disadvantaged populations and juveniles in particular have attracted a great deal of attention with projects such as the Moving to Opportunity Study and policies aimed at reducing concentrated disadvantage by providing alternative housing assistance to low-income families. The results of these studies, however, have been inconclusive and have often not concentrated on the effects of this mobility on a broad spectrum of delinquent behaviors. Previous studies have found that residential mobility negatively affects juveniles, while other studies find that there is little effect after controlling for a wide variety of variables with scant theoretical considerations regarding modeling. This dissertation sought to address these gaps and deficiencies in the literature by examining the effects of residential mobility on a sample of highly impoverished youth by analyzing a variety of delinquent behaviors with theoretically relevant variables in order to better understand the mechanisms driving delinquent behavior. In order to test hypotheses developed from these questions, longitudinal binary and ordinal mixed-effects logit models were utilized on data drawn from the Mobile Youth Survey, which was conducted in areas of extreme poverty. The findings of the current research demonstrated that residential mobility has a weak and inconsistent effect between types of delinquent behavior. Theoretically relevant variables comprised of social bonding and strain constructs were found to mediate the significant relationship for several delinquent outcomes, indicating that these variables play a critical role in predicting delinquent behavior rather than residential mobility. Low correlations between residential mobility and delinquent outcomes indicated that for this particular population, mobility has a differential effect compared to higher socioeconomic groups analyzed in previous studies. Conclusions and implications of the current study suggested that residential mobility is not a particular concern regarding highly impoverished populations. Policies aimed at moving individuals to better neighborhoods would not have a negative effect due to the stress of moving. Addressing strain and the attenuation of social bonds would be more effective at preventing juvenile delinquency even if that means displacement of the individuals into environments that provide opportunities for the creation of stronger social bonds and lessened strain

Are alternative strategies required to accelerate the global elimination of lymphatic filariasis? Insights from mathematical models

Background: With the 2020 target year for elimination of lymphatic filariasis (LF) approaching, there is an urgent need to assess how long mass drug administration (MDA) programs with annual ivermectin + albendazole (IA) or diethylcarbamazine + albendazole (DA) would still have to be continued, and how elimination can be accelerated. We addressed this using mathematical modeling. Methods: We used 3 structurally different mathematical models for LF transmission (EPIFIL, LYMFASIM, TRANSFIL) to simulate trends in microfilariae (mf) prevalence for a range of endemic settings, both for the current annual MDA strategy and alternative strategies, assessing the required duration to bring mf prevalence below the critical threshold of 1%. Results: Three annual MDA rounds with IA or DA and good coverage (≥65%) are sufficient to reach the threshold in settings that are currently at mf prevalence <4%, but the required duration increases with increasing mf prevalence. Switching to biannual MDA or employing triple-drug therapy (ivermectin, diethylcarbamazine, and albendazole [IDA]) could reduce program duration by about one-third. Optimization of coverage reduces the time to elimination and is particularly important for settings with a history of poorly implemented MDA (low coverage, high systematic noncompliance). Conclusions: Modeling suggests that, in several settings, current annual MDA strategies will be insufficient to achieve the 2020 LF elimination targets, and programs could consider policy adjustment to accelerate, guided by recent monitoring and evaluation data. Biannual treatment and IDA hold promise in reducing program duration, provided that coverage is good, but their efficacy remains to be confirmed by more extensive field studies

Inhibitor development in non-severe haemophilia across Europe

Evidence about inhibitor formation in non-severe haemophilia and the potential role for clotting factor concentrate type is scant. It was the aim of this study to report inhibitor development in non-severe haemophilia patients enrolled in the European Haemophilia Safety Surveillance (EUHASS) study. Inhibitors are reported quarterly and total treated patients annually. Incidence rates and 95 % confidence intervals (95 % CI) were calculated according to diagnosis and concentrate used. Between 1–10–2008 and 31–12–2012, 68 centres reported on 7,969 patients with non-severe haemophilia A and 1,863 patients with non-severe haemophilia B. For haemophilia A, 37 inhibitors occurred in 8,622 treatment years, resulting in an inhibitor rate of 0.43/100 treatment years (95 % CI 0.30–0.59). Inhibitors occurred at a median age of 35 years, after a median of 38 exposure days (EDs; P25-P75: 20–80); with 72 % occurring within the first 50 EDs. In haemophilia B, one inhibitor was detected in 2,149 treatment years, resulting in an inhibitor rate of 0.05/100 years (95% CI 0.001–0.26). This inhibitor developed at the age of six years, after six EDs. The rate of inhibitors appeared similar across recombinant and plasma derived factor VIII (FVIII) concentrates. Rates for individual concentrates could not be calculated at this stage due to low number of events. In conclusion, inhibitors in non-severe haemophilia occur three times more frequently than in previously treated patients with severe haemophilia at a rate of 0.43/100 patient years (haemophilia A) and 0.05/100 years (haemophilia B). Although the majority of inhibitors developed in the first 50 EDs, inhibitor development continued with increasing exposure to FVIII

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy

Met Receptor Inhibitor SU11274 Localizes in the Endoplasmic Reticulum

We discovered that SU11274, a class I c-Met inhibitor, fluoresces when excited by 488 nm laser light and showed rapid specific accumulation in distinct subcellular compartments. Given that SU11274 reduces cancer cell viability, we exploited these newly identified spectral properties to determine SU11274 intracellular distribution and accumulation in human pancreatic cancer cells. The aim of the studies reported here was to identify organelle(s) to which SU11274 is trafficked. We conclude that SU11274 rapidly and predominantly accumulates in the endoplasmic reticulum