British Perceptions of Tsar Nicholas II and Empress Alexandra Fedorovna 1894-1918

Attitudes towards Tsar Nicholas II and Empress Alexandra Fedorovna can be characterised by extremes, from hostility to sentimentality. A great deal of what has been written about the imperial couple (in modern times) has been based on official records and with reference to the memoirs of people who knew the tsar and empress. This thesis recognises the importance of these sources in understanding British perceptions of Nicholas and Alexandra but it also examines reactions in a wider variety of material; including mass circulation newspapers, literary journals and private correspondence. These sources reveal a number of the strands which helped form British understanding of the tsar and empress. In particular, perceptions were influenced by internal British politics, by class and by attitudes to the role of the British Empire in world affairs, by British propaganda and by a view of Russia and her society which was at times perceptive and at others antiquated. This thesis seeks to evaluate diverse British views of Nicholas and Alexandra and to consider the reasons behind the sympathetic, the critical, the naïve and the knowledgeable perceptions of the last tsar and empress of Russia

Manipulating vector transmission reveals local processes in bacterial communities of batss

Infectious diseases result from multiple interactions among microbes and hosts, but community ecology approaches are rarely applied. Manipulation of vector populations provides a unique opportunity to test the importance of vectors in infection cycles while also observing changes in pathogen community diversity and species interactions. Yet for many vector-borne infections in wildlife, a biological vector has not been experimentally verified and few manipulative studies have been performed. Using a captive colony of fruit bats in Ghana, we observed changes in the community of Bartonella bacteria over time after the decline and subsequent reintroduction of bat flies. With reduced transmission, community changes were attributed to ecological drift and potential selection through interspecies competition mediated by host immunity. This work demonstrated that forces maintaining diversity in communities of free-living macroorganisms act in similar ways in communities of symbiotic microorganisms, both within and among hosts. Additionally, this study is the first to experimentally test the role of bat flies as vectors of Bartonella species

Identification of Genes That Promote or Antagonize Somatic Homolog Pairing Using a High-Throughput FISH–Based Screen

The pairing of homologous chromosomes is a fundamental feature of the meiotic cell. In addition, a number of species exhibit homolog pairing in nonmeiotic, somatic cells as well, with evidence for its impact on both gene regulation and double-strand break (DSB) repair. An extreme example of somatic pairing can be observed in Drosophila melanogaster, where homologous chromosomes remain aligned throughout most of development. However, our understanding of the mechanism of somatic homolog pairing remains unclear, as only a few genes have been implicated in this process. In this study, we introduce a novel high-throughput fluorescent in situ hybridization (FISH) technology that enabled us to conduct a genome-wide RNAi screen for factors involved in the robust somatic pairing observed in Drosophila. We identified both candidate “pairing promoting genes” and candidate “anti-pairing genes,” providing evidence that pairing is a dynamic process that can be both enhanced and antagonized. Many of the genes found to be important for promoting pairing are highly enriched for functions associated with mitotic cell division, suggesting a genetic framework for a long-standing link between chromosome dynamics during mitosis and nuclear organization during interphase. In contrast, several of the candidate anti-pairing genes have known interphase functions associated with S-phase progression, DNA replication, and chromatin compaction, including several components of the condensin II complex. In combination with a variety of secondary assays, these results provide insights into the mechanism and dynamics of somatic pairing

Survival Analysis of Patients with Heart Failure: Implications of Time-Varying Regression Effects in Modeling Mortality

Background: Several models have been designed to predict survival of patients with heart failure. These, while available and widely used for both stratifying and deciding upon different treatment options on the individual level, have several limitations. Specifically, some clinical variables that may influence prognosis may have an influence that change over time. Statistical models that include such characteristic may help in evaluating prognosis. The aim of the present study was to analyze and quantify the impact of modeling heart failure survival allowing for covariates with time-varying effects known to be independent predictors of overall mortality in this clinical setting. Methodology: Survival data from an inception cohort of five hundred patients diagnosed with heart failure functional class III and IV between 2002 and 2004 and followed-up to 2006 were analyzed by using the proportional hazards Cox model and variations of the Cox's model and also of the Aalen's additive model. Principal Findings: One-hundred and eighty eight (188) patients died during follow-up. For patients under study, age, serum sodium, hemoglobin, serum creatinine, and left ventricular ejection fraction were significantly associated with mortality. Evidence of time-varying effect was suggested for the last three. Both high hemoglobin and high LV ejection fraction were associated with a reduced risk of dying with a stronger initial effect. High creatinine, associated with an increased risk of dying, also presented an initial stronger effect. The impact of age and sodium were constant over time. Conclusions: The current study points to the importance of evaluating covariates with time-varying effects in heart failure models. The analysis performed suggests that variations of Cox and Aalen models constitute a valuable tool for identifying these variables. The implementation of covariates with time-varying effects into heart failure prognostication models may reduce bias and increase the specificity of such models.CNPq Brazilian Foundation for Scientific and Technological DevelopmentCNPq - Brazilian Foundation for Scientific and Technological Development [150653/2008-5

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Foliar δ15N values characterize soil N cycling and reflect nitrate or ammonium preference of plants along a temperate grassland gradient

The natural abundance of stable 15N isotopes in soils and plants is potentially a simple tool to assess ecosystem N dynamics. Several open questions remain, however, in particular regarding the mechanisms driving the variability of foliar δ15N values of non-N2 fixing plants within and across ecosystems. The goal of the work presented here was therefore to: (1) characterize the relationship between soil net mineralization and variability of foliar Δδ15N (δ15Nleaf − δ15Nsoil) values from 20 different plant species within and across 18 grassland sites; (2) to determine in situ if a plant’s preference for NO3− or NH4+ uptake explains variability in foliar Δδ15N among different plant species within an ecosystem; and (3) test if variability in foliar Δδ15N among species or functional group is consistent across 18 grassland sites. Δδ15N values of the 20 different plant species were positively related to soil net mineralization rates across the 18 sites. We found that within a site, foliar Δδ15N values increased with the species’ NO3− to NH4+ uptake ratios. Interestingly, the slope of this relationship differed in direction from previously published studies. Finally, the variability in foliar Δδ15N values among species was not consistent across 18 grassland sites but was significantly influenced by N mineralization rates and the abundance of a particular species in a site. Our findings improve the mechanistic understanding of the commonly observed variability in foliar Δδ15N among different plant species. In particular we were able to show that within a site, foliar δ15N values nicely reflect a plant’s N source but that the direction of the relationship between NO3− to NH4+ uptake and foliar Δδ15N values is not universal. Using a large set of data, our study highlights that foliar Δδ15N values are valuable tools to assess plant N uptake patterns and to characterize the soil N cycle across different ecosystems

Modulators of Cytoskeletal Reorganization in CA1 Hippocampal Neurons Show Increased Expression in Patients at Mid-Stage Alzheimer's Disease

During the progression of Alzheimer's disease (AD), hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB) III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB), mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression

Integrin-Specific Mechanoresponses to Compression and Extension Probed by Cylindrical Flat-Ended AFM Tips in Lung Cells

Cells from lung and other tissues are subjected to forces of opposing directions that are largely transmitted through integrin-mediated adhesions. How cells respond to force bidirectionality remains ill defined. To address this question, we nanofabricated flat-ended cylindrical Atomic Force Microscopy (AFM) tips with ∼1 µm2 cross-section area. Tips were uncoated or coated with either integrin-specific (RGD) or non-specific (RGE/BSA) molecules, brought into contact with lung epithelial cells or fibroblasts for 30 s to form focal adhesion precursors, and used to probe cell resistance to deformation in compression and extension. We found that cell resistance to compression was globally higher than to extension regardless of the tip coating. In contrast, both tip-cell adhesion strength and resistance to compression and extension were the highest when probed at integrin-specific adhesions. These integrin-specific mechanoresponses required an intact actin cytoskeleton, and were dependent on tyrosine phosphatases and Ca2+ signaling. Cell asymmetric mechanoresponse to compression and extension remained after 5 minutes of tip-cell adhesion, revealing that asymmetric resistance to force directionality is an intrinsic property of lung cells, as in most soft tissues. Our findings provide new insights on how lung cells probe the mechanochemical properties of the microenvironment, an important process for migration, repair and tissue homeostasis

Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths

Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth Heligmosomoides polygyrus drives rapid polyclonal expansion of Foxp3(+)Helios(+)CD4(+) thymic (t)Tregs in the lamina propria and mesenteric lymph nodes while Foxp3(+)Helios(-)CD4(+) peripheral (p)Treg expand more slowly. Notably, in partially resistant BALB/c mice parasite survival positively correlates with Foxp3(+)Helios(+)CD4(+) tTreg numbers. Boosting of Foxp3(+)Helios(+)CD4(+) tTreg populations by administration of recombinant interleukin-2 (rIL-2):anti-IL-2 (IL-2C) complex increased worm persistence by diminishing type-2 responsiveness in vivo, including suppression of alternatively activated macrophage and granulomatous responses at the sites of infection. IL-2C also increased innate lymphoid cell (ILC) numbers, indicating that Treg functions dominate over ILC effects in this setting. Surprisingly, complete removal of Tregs in transgenic Foxp3-DTR mice also resulted in increased worm burdens, with "immunological chaos" evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-γ. In contrast, worm clearance could be induced by anti-CD25 antibody-mediated partial depletion of early Treg, alongside increased T helper type 2 responses and without incurring pathology. These findings highlight the overarching importance of the early Treg response to infection and the non-linear association between inflammation and the prevailing Treg frequency

Characterising droughts in Central America with uncertain hydro-meteorological data

Central America is frequently affected by droughts that cause significant socio-economic and environmental problems. Drought characterisation, monitoring and forecasting are potentially useful to support water resource management. Drought indices are designed for these purposes, but their ability to characterise droughts depends on the characteristics of the regional climate and the quality of the available data. Local comprehensive and high-quality observational networks of meteorological and hydrological data are not available, which limits the choice of drought indices and makes it important to assess available datasets. This study evaluated which combinations of drought index and meteorological dataset were most suitable for characterising droughts in the region. We evaluated the standardised precipitation index (SPI), a modified version of the deciles index (DI), the standardised precipitation evapotranspiration index (SPEI) and the effective drought index (EDI). These were calculated using precipitation data from the Climate Hazards Group Infra-Red Precipitation with Station (CHIRPS), the CRN073 dataset, the Climate Research Unit (CRU), ECMWF Reanalysis (ERA-Interim) and a regional station dataset, and temperature from the CRU and ERA-Interim datasets. The gridded meteorological precipitation datasets were compared to assess how well they captured key features of the regional climate. The performance of all the drought indices calculated with all the meteorological datasets was then evaluated against a drought index calculated using river discharge data. Results showed that the selection of database was more important than the selection of drought index and that the best combinations were the EDI and DI calculated with CHIRPS and CRN073. Results also highlighted the importance of including indices like SPEI for drought assessment in Central America.Universidad de Costa Rica/[805-B0-810]/UCR/Costa RicaUniversidad de Costa Rica/[805-A9-532]/UCR/Costa RicaUniversidad de Costa Rica/[805-B3-600]/UCR/Costa RicaUniversidad de Costa Rica/[805-B0-065]/UCR/Costa RicaUniversidad de Costa Rica/[805-B3-413]/UCR/Costa RicaUniversidad de Costa Rica/[805-B4-227]/UCR/Costa RicaUniversidad de Costa Rica/[805-B4-228]/UCR/Costa RicaUniversidad de Costa Rica/[805-B5-295]/UCR/Costa RicaUppsala University/[54100006]//SueciaMarie Curie Intra-European Fellowship/[No.329762]//EuropaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigaciones Geofísicas (CIGEFI)UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Físic