Investigating the Spatiotemporal Distribution of a Tick-Borne Pathogen, Ehrlichia Chaffeensis

The incidence of tick-borne diseases is on the rise in the US and around the world, due in part to emerging pathogens. However, the environmental drivers affecting these pathogens remain unclear. Most research on the topic in the US has focused on Borrelia burgdorferi, which causes Lyme, but it is unknown if the same conditions that affect B. burgdorferi also affect other pathogens, which may be carried by other ticks or reservoirs. The answer will help determine generalizable principles in tick-borne pathogen ecology, if they exist, as well as better manage for tick-borne pathogen risk in areas at risk from new and often unfamiliar pathogens. One such pathogen in the eastern US is Ehrlichia chaffeensis, which is transmitted by the lone star tick (Amblyomma americanum) and is the causative agent of monocytic ehrlichiosis, a potentially fatal illness. Here, I examine spatial and temporal variation in E. chaffeensis prevalence in southeastern Virginia and how this is influenced by the environment. in Chapter 1, I used four years of data to ask how E. chaffeensis prevalence changed between years and how this was affected by seasonal weather patterns. Using mixed-effect models, I related E. chaffeensis occurrence to temperature, humidity, vapor-pressure deficit, and precipitation up to 21 months prior to sampling. Annual prevalence varied significantly from 0.9% - 3.7%, and was positively affected by temperatures during the previous winter (i.e. before the current cohort of nymphs hatched). I hypothesize this is because winter temperature affects reservoir host mortality or natality, which would in turn affect the availability of naïve reservoir hosts in the spring. Regardless of mechanism, my findings have implications for the future because winters in this region are predicted to grow warmer, which could increase E. chaffeensis prevalence. in Chapter 2, I used five years of field data to ask how landscape context affects spatial variation in the prevalence of E. chaffeensis and interannual occupancy dynamics of its vector, A. americanum. Under a Bayesian framework, I created a metric- and scale-optimized model to relate E. chaffeensis prevalence and A. americanum turnover to the availability, quality, and fragmentation of habitat. Prevalence was highest and turnover was lowest in areas of low forest cover and low edge density, dominated by deciduous trees. Thus, highest disease risk is predicted in areas of forested areas that are either isolated or abutted against impermeable boundaries, both characteristic of many parks. Many of my results highlight the complexity of tick-borne disease dynamics and the challenges inherent to the subject; some results ran counter to my predictions and E. chaffeensis prevalence remains rare, which makes it challenging to model. That said, my work also represents important progress in an often-neglected area of tick-borne disease ecology. to my knowledge, this is the first study to address temporal variation in E. chaffeensis prevalence, and is one of few studies to relate E. chaffeensis prevalence to landscape context at a scale relevant to the pathogen\u27s hosts and to disease-risk management

Wild insects and honey bees are equally important to crop yields in a global analysis

Aim: Most of the world´s food crops are dependent on pollinators. However, there is a great deal of uncertainty in the strength of this relationship, especially regarding the relative contributions of the honey bee (often a managed species) and wild insects to crop yields on a global scale. Previous data syntheses have likewise reached differing conclusions on whether pollinator species diversity, or only the number of pollinator visits to flowers, is important to crop yield. This study quantifies the current state of these relationships and links to a dynamic version of our analyses that updates automatically as studies become available.Location: Global. Time Period: Present.Taxa studied: Insect pollinators of global crops. Methods: Using a newly created database of 93 crop pollination studies across six continents that roughly triples the number of studies previously available, we analysed the relationship between insect visit rates, pollinator diversity, and crop yields in a series of mixed-effects models. Results: We found that honey bees and wild insects contribute roughly equal amounts to crop yields worldwide, having similar average flower visitation rates and producing similar increases in yield per visit. We also found that pollinator species diversity was positively associated with increased crop yields even when total visits from all species are accounted for, though it was less explanatory than the total number of visits itself. Main conclusions: Our analysis suggests a middle ground where honey bees are not responsible for the vast majority of crop pollination as has often been assumed in the agricultural literature, and like wise wild insects are not vastly more important than honey bees, as recent global analyses have reported. We also conclude that while pollinator diversity is less important than the number of pollinator visits, these typically involve many species, underscoring the importance of conserving a diversity of wild pollinators.Fil: Reilly, James. Rutgers University; Estados UnidosFil: Bartomeus, Ignasi. Consejo Superior de Investigaciones Científicas. Estación Biológica de Doñana; EspañaFil: Simpson, Dylan. Rutgers University; Estados UnidosFil: Allen Perkins, Alfonso. Consejo Superior de Investigaciones Científicas. Estación Biológica de Doñana; España. Grupo Interdisciplinar de Sistemas Complejos; España. Universidad Politécnica de Madrid; EspañaFil: Garibaldi, Lucas Alejandro. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Patagonia Norte. Instituto de Investigaciones En Recursos Naturales, Agroecologia y Desarrollo Rural. - Universidad Nacional de Rio Negro. Instituto de Investigaciones En Recursos Naturales, Agroecologia y Desarrollo Rural.; ArgentinaFil: Winfree, Rachael. Rutgers University; Estados Unido

Late Quaternary slip rate on the Kern Canyon fault at Soda Spring, Tulare County, California

The Kern Canyon fault represents a major tectonic and physiographic boundary in the southern Sierra Nevada of east-central California. Previous investigations of the Kern Canyon fault underscore its importance as a Late Cretaceous and Neogene shear zone in the tectonic development of the southern Sierra Nevada. Study of the late Quaternary history of activity, however, has been confounded by the remote nature of the Kern Canyon fault and deep along-strike exhumation within the northern Kern River drainage, driven by focused fluvial and glacial erosion. Recent acquisition of airborne lidar (light detection and ranging) topography along the ∼140 km length of the Kern Canyon fault provides a comprehensive view of the active surface trace. High-resolution, lidar-derived digital elevation models (DEMs) for the northern Kern Canyon fault enable identification of previously unrecognized offsets of late Quaternary moraines near Soda Spring (36.345°N, 118.408°W). Predominately north-striking fault scarps developed on the Soda Spring moraines display west-side-up displacement and lack a significant sense of strike-slip separation, consistent with detailed mapping and trenching along the entire Kern Canyon fault. Scarp-normal topographic profiling derived from the lidar DEMs suggests normal displacement of at least 2.8 +0.6/–0.5 m of the Tioga terminal moraine crest. Cosmogenic 10Be exposure dating of Tioga moraine boulders yields a tight age cluster centered around 18.1 ± 0.5 ka (n = 6), indicating a minimum normal-sense fault slip rate of ∼0.1–0.2 mm/yr over this period. Taken together, these results provide the first clear documentation of late Quaternary activity on the Kern Canyon fault and highlight its role in accommodating internal deformation of the southern Sierra Nevada

The impact of physical inactivity on glucose homeostasis when diet is adjusted to maintain energy balance in healthy, young males

Background & aims: It is unclear if dietary adjustments to maintain energy balance during reduced physical activity can offset inactivity-induced reductions in insulin sensitivity and glucose disposal to produce normal daily glucose concentrations and meal responses. Therefore, the aim of the present study was to examine the impact of long-term physical inactivity (60 days of bed rest) on daily glycemia when in energy balance.Methods: Interstitial glucose concentrations were measured using Continuous Glucose Monitoring Systems (CGMS) for 5 days before and towards the end of bed rest in 20 healthy, young males (Age: 34 ± 8 years; BMI: 23.5 ± 1.8 kg/m2). Energy intake was reduced during bed rest to match energy expenditure, but the types of foods and timing of meals was maintained. Fasting venous glucose and insulin concentrations were determined, as well as the change in whole-body glucose disposal using a hyperinsulinemic-euglycemic clamp (HIEC).Results: Following long-term bed rest, fasting plasma insulin concentration increased 40% (p = 0.004) and glucose disposal during the HIEC decreased 24% (p < 0.001). Interstitial daily glucose total area under the curve (tAUC) from pre-to post-bed rest increased on average by 6% (p = 0.041), despite a 20 and 25% reduction in total caloric and carbohydrate intake, respectively. The nocturnal period (00:00–06:00) showed the greatest change to glycemia with glucose tAUC for this period increasing by 9% (p = 0.005). CGMS measures of daily glycemic variability (SD, J-Index, M-value and MAG) were not changed during bed rest.Conclusions: Reduced physical activity (bed rest) increases glycemia even when daily energy intake is reduced to maintain energy balance. However, the disturbance to daily glucose homeostasis was much more modest than the reduced capacity to dispose of glucose, and glycemic variability was not negatively affected by bed rest, likely due to positive mitigating effects from the contemporaneous reduction in dietary energy and carbohydrate intake.Clinical trials record: NCT03594799 (registered July 20, 2018) (https://clinicaltrials.gov/ct2/show/NCT03594799)

Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR

The nuclear interactome of DYRK1A reveals a functional role in DNA damage repair

The chromosome 21 encoded protein kinase DYRK1A is essential for normal human development. Mutations in DYRK1A underlie a spectrum of human developmental disorders, and increased dosage in trisomy 21 is implicated in Down syndrome related pathologies. DYRK1A regulates a diverse array of cellular processes through physical interactions with substrates and binding partners in various subcellular compartments. Despite recent large-scale protein-protein interaction profiling efforts, DYRK1A interactions specific to different subcellular compartments remain largely unknown, impeding progress toward understanding emerging roles for this kinase. Here, we used immunoaffinity purification and quantitative mass spectrometry to identify nuclear interaction partners of endogenous DYRK1A. This interactome was enriched in DNA damage repair factors, transcriptional elongation factors and E3 ubiquitin ligases. We validated an interaction with RNF169, a factor that promotes homology directed repair upon DNA damage, and found that DYRK1A expression and kinase activity are required for maintenance of 53BP1 expression and subsequent recruitment to DNA damage loci. Further, DYRK1A knock out conferred resistance to ionizing radiation in colony formation assays, suggesting that DYRK1A expression decreases cell survival efficiency in response to DNA damage and points to a tumor suppressive role for this kinase. </div

Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study

EAVE II is funded by the Medical Research Council (MR/R008345/1) with the support of BREATHE—The Health Data Research Hub for Respiratory Health (MC_PC_19004), which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. Additional support has been provided through Public Health Scotland and the Scottish Government's director-general of Health and Social Care. FDRH acknowledges part support from the National Institutes of Health Research (NIHR) School for Primary Care Research, the NIHR Collaboration for Leadership in Applied Health Research and Care Oxford, and the NIHR Oxford Biomedical Research Centre. SVK acknowledges funding from an NRS Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2), and Scottish Government Chief Scientist Office (SPHSU13).Background The BNT162b2 mRNA (Pfizer–BioNTech) and ChAdOx1 nCoV-19 (Oxford–AstraZeneca) COVID-19 vaccines have shown high efficacy against disease in phase 3 clinical trials and are now being used in national vaccination programmes in the UK and several other countries. Studying the real-world effects of these vaccines is an urgent requirement. The aim of our study was to investigate the association between the mass roll-out of the first doses of these COVID-19 vaccines and hospital admissions for COVID-19.  Methods We did a prospective cohort study using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19—EAVE II—database comprising linked vaccination, primary care, real-time reverse transcription-PCR testing, and hospital admission patient records for 5·4 million people in Scotland (about 99% of the population) registered at 940 general practices. Individuals who had previously tested positive were excluded from the analysis. A time-dependent Cox model and Poisson regression models with inverse propensity weights were fitted to estimate effectiveness against COVID-19 hospital admission (defined as 1–adjusted rate ratio) following the first dose of vaccine.  Findings Between Dec 8, 2020, and Feb 22, 2021, a total of 1 331 993 people were vaccinated over the study period. The mean age of those vaccinated was 65·0 years (SD 16·2). The first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85–94) for reduced COVID-19 hospital admission at 28–34 days post-vaccination. Vaccine effect at the same time interval for the ChAdOx1 vaccine was 88% (95% CI 75–94). Results of combined vaccine effects against hospital admission due to COVID-19 were similar when restricting the analysis to those aged 80 years and older (83%, 95% CI 72–89 at 28–34 days post-vaccination).  Interpretation Mass roll-out of the first doses of the BNT162b2 mRNA and ChAdOx1 vaccines was associated with substantial reductions in the risk of hospital admission due to COVID-19 in Scotland. There remains the possibility that some of the observed effects might have been due to residual confounding.  Funding UK Research and Innovation (Medical Research Council), Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK.proofPeer reviewe

The causal role of breakfast in energy balance and health: a randomized controlled trial in lean adults

Background: Popular beliefs that breakfast is the most important meal of the day are grounded in cross-sectional observations that link breakfast to health, the causal nature of which remains to be explored under real-life conditions. Objective: The aim was to conduct a randomized controlled trial examining causal links between breakfast habits and all components of energy balance in free-living humans. Design: The Bath Breakfast Project is a randomized controlled trial with repeated-measures at baseline and follow-up in a cohort in southwest England aged 21–60 y with dual-energy X-ray absorptiometry–derived fat mass indexes #11 kg/m2 in women (n = 21) and #7.5 kg/m2 in men (n = 12). Components of energy balance (resting metabolic rate, physical activity thermogenesis, energy intake) and 24-h glycemic responses were measured under free-living conditions with random allocation to daily breakfast ($700 kcal before 1100) or extended fasting (0 kcal until 1200) for 6 wk, with baseline and follow-up measures of health markers (eg, hematology/biopsies). Results: Contrary to popular belief, there was no metabolic adaptation to breakfast (eg, resting metabolic rate stable within 11 kcal/d), with limited subsequent suppression of appetite (energy intake remained 539 kcal/d greater than after fasting; 95% CI: 157, 920 kcal/d). Rather, physical activity thermogenesis was markedly higher with breakfast than with fasting (442 kcal/d; 95% CI: 34, 851 kcal/d). Body mass and adiposity did not differ between treatments at baseline or follow-up and neither did adipose tissue glucose uptake or systemic indexes of cardiovascular health. Continuously measured glycemia was more variable during the afternoon and evening with fasting than with breakfast by the final week of the intervention (CV: 3.9%; 95% CI: 0.1%, 7.8%). Conclusions: Daily breakfast is causally linked to higher physical activity thermogenesis in lean adults, with greater overall dietary energy intake but no change in resting metabolism. Cardiovascular health indexes were unaffected by either of the treatments, but breakfast maintained more stable afternoon and evening glycemia than did fasting