Examining natural selection in wild populations is challenging, but crucial to understanding many ecological and evolutionary processes. Additionally, in hybridizing populations, natural selection ...may be an important determinant of the eventual outcome of hybridization. We characterized several components of relative fitness in hybridizing populations of Yellowstone cutthroat trout and rainbow trout in an effort to better understand the prolonged persistence of both parental species despite predictions of extirpation. Thousands of genomic loci enabled precise quantification of hybrid status in adult and subsequent juvenile generations; a subset of those data also identified parent–offspring relationships. We used linear models and simulations to assess the effects of ancestry on reproductive output and mate choice decisions. We found a relatively low number of late‐stage (F3+) hybrids and an excess of F2 juveniles relative to the adult generation in one location, which suggests the presence of hybrid breakdown decreasing the fitness of F2+ hybrids later in life. Assessments of reproductive output showed that Yellowstone cutthroat trout are more likely to successfully reproduce and produce slightly more offspring than their rainbow trout and hybrid counterparts. Mate choice appeared to be largely random, though we did find statistical support for slight female preference for males of similar ancestry. Together, these results show that native Yellowstone cutthroat trout are able to outperform rainbow trout in terms of reproduction and suggest that management action to exclude rainbow trout from spawning locations may bolster the now‐rare Yellowstone cutthroat trout.
Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and ...25-hydroxyvitamin D 25(OH)D using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.
We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% 95% CI -0.10 to -0.02, p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 95% CI -7.1 to -1.3, p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).
On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
P1 Suffolk University Law Library became a selective federal depository library in 1981. Over the years, the library selected approximately 11 percent of the material available from the Government ...Printing Office (GPO) under the Federal Depository Library Program (FDLP). The majority of the depository collection was housed in Pallot Library, the law library's "satellite" facility, separate from the main library but on the same floor of the law school building. Pallot Library offered complete public access to the depository material and staffing that was in accordance with the FDLP rules. The main law library and the university's Sawyer Library held a few depository documents that could also be used by the public. P 2 In 1997, the law library staff began to consider the possibility of leaving the depository system. We began the process of leaving before we moved from our old space into our new building. During that time, our government documents librarian left, the director of the university library retired and was replaced, and the regional depository library suffered a catastrophic flood. This article details the factors behind our decision, the process of leaving, and our adventures along the way. We attempt to evaluate the results to date and offer lessons learned through our experience. Rationales behind the Decision to Leave Public Access P3 The Federal Depository Library Program requires that "depository libraries should engage in no activity that inhibits free public access." 1 More officially, "Depository libraries shall make Government publications available ...
Summary Adenocarcinomas of the colon and rectum are graded using a 2-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading ...system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas. We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female; mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with low-grade tumors (20% versus 6%; P < .001). Using Cox regression models, adjusting for sex and age at diagnosis and stratifying by the American Joint Committee on Cancer stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of all-cause and colorectal cancer–specific mortality: hazard ratio 2.09 (95% confidence interval CI, 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P < .001. A new grading system separating adenocarcinoma into low grade (all histologic low grade and MSI high grade) and high grade (MSS histologic high grade) gave a lower Akaike information criterion value when compared with the current grading system and thus represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor.
NCCN Task Force Report: Oral chemotherapy Weingart, Saul N; Brown, Elizabeth; Bach, Peter B ...
Journal of the National Comprehensive Cancer Network,
06/2008, Letnik:
6 Suppl 3
Journal Article
Recenzirano
Odprti dostop
Oral chemotherapy is emerging as a new option for well-selected patients who can manage potentially complex oral regimens and self-monitor for potential complications. If a choice between oral and ...parenteral therapy is available, patients may opt for oral chemotherapy because it is more convenient to administer, allows them to avoid multiple office visits, and gives them a sense of control over their own cancer care. Whether these potential advantages are maintained in regimens that combine oral and parenteral drugs is less clear. The use of oral chemotherapeutic agents profoundly affects all aspects of oncology, including creating significant safety and adherence issues, shifting some traditional roles and responsibilities of oncologists, nurses, and pharmacists to patients and caregivers. The financing of chemotherapy is also affected. To address these issues, the NCCN convened a multidisciplinary task force consisting of oncologists, nurses, pharmacists, and payor representatives to discuss the impact of the increasing use of oral chemotherapy.
Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is ...challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10
). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.
Tidal Spartina-dominated saltmarshes and estuaries on the Southeast US coast are global hotspots of productivity. In coastal Georgia, tidal amplitudes and saltmarsh productivity are the highest along ...the Southeast US coast. Coastal Georgia is characterized by a humid subtropical seasonal climate, and inter-annual variability in precipitation, and freshwater discharge. The 2012–2013 timeframe encompassed contrasting levels of discharge for the Savannah River, a major Georgia river, with a 4.3-fold greater discharge in summer 2013 relative to summer 2012. In situ measurements of temperature, salinity, precipitation and Secchi depth, and water samples were collected weekly at high tide throughout 2012 and 2013 from the Skidaway River Estuary, a tidal saltmarsh-dominated estuary in coastal Georgia influenced by Savannah River hydrology. The effects of elevated discharge on the seasonal trends of water column components were evaluated. The shift from low discharge (2012) to high discharge (2013) led to decreased salinity in summer 2013, but no significant increases in inorganic nutrient (NH4, NOx, SiO2 and PO4) concentrations. Dissolved inorganic carbon (DIC) concentrations decreased, and DIC stable isotopic signatures (δ13C-DIC values) were depleted in summer 2013 relative to summer 2012. In 2013 dissolved organic carbon (DOC) concentrations, chromophoric and fluorescent dissolved organic matter (DOM: CDOM, FDOM) intensities, specific UV-absorbance (SUVA254) and relative humic-like fluorescence were all higher than in 2012, indicating that, as discharge increased in 2013, estuarine water became enriched in terrigenous DOM. Secchi depth and particulate organic carbon (POC) and nitrogen (PON) concentrations displayed clear seasonal patterns that were not significantly altered by discharge. However, δ13C-POC and δ15N-PON isotopic signatures indicated higher terrigenous contributions at elevated discharge. Discharge influenced cyanobacterial composition, but did not affect total abundance of phytoplankton (<52 μm) or chlorophyll-a concentrations, a proxy for phytoplankton biomass. Phytoplankton community dynamics were primarily seasonally-driven. Bacterioplankton abundance and community composition, based upon flow cytometry, were affected by discharge, possibly due to decreased salinity and/or increased inputs of terrigenous DOM. Seasonal patterns in inorganic nutrient, POC, PON and chlorophyll-a concentrations, and Secchi depth were not significantly influenced by the 2013 increase in discharge. For other components, most notably δ13C-DIC values, DOM and bacterioplankton, the influence of increased discharge in 2013 was superimposed upon their seasonal patterns. This study showed that in addition to tidal mixing and in situ saltmarsh and estuarine production and removal processes, the level of riverine freshwater discharge impacted the quantity and character of many water column components in this tidal saltmarsh ecosystem.
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•Effects of freshwater discharge on a tidal saltmarsh-estuary are evaluated.•Increased discharge caused decreased salinity in the estuary water column.•Bulk chlorophyll and phytoplankton abundance were not affected by high discharge.•High discharge affected cyanobacteria and heterotrophic bacteria composition.•High discharge increased terrigenous-like dissolved and particulate organic matter.
Although leukocyte telomere length (TL) shortens over the lifespan and is associated with diseases of aging, little is known about the relationships between TL, memory, and brain structure. ...Sixty-nine functionally normal older adults (mean age = 71.7) were assessed at 2 time points (mean interval = 2.9 years). Linear mixed models assessed relationships between TL and hippocampal volume, fractional anisotropy, and mean diffusivity (MD) of the fornix and verbal and visual episodic memory. Unstandardized coefficients are reported in the following, and p values are not corrected for multiple comparisons. A negative baseline trend was observed between TL and fornix MD (b = −0.01, p = 0.06), but no other cross-sectional associations were significant (ps > 0.16). Greater TL shortening at follow-up was associated with greater hippocampal volume loss (b = 27.09, p < 0.001), even after controlling for global volume loss (b = 10.83, p = 0.002). Greater telomere attrition was also associated with larger increases in fornix MD (b = −0.01, p = 0.012) and decreases in fornix fractional anisotropy (b = 0.004, p = 0.002). TL was not associated with changes in episodic memory (ps > 0.23). These relationships may reflect neurobiological influences that affect both TL and brain structure, as well as the effect of TL on brain aging via mechanisms such as cellular senescence and inflammation.
Rift Valley Fever (RVF) is an emerging arboviral disease of livestock and humans. Although the disease is caused by a mosquito-borne virus, humans are infected through contact with, or inhalation of, ...virus-laden particles from contaminated animal carcasses. Some individuals infected with RVF virus (RVFV) develop meningoencephalitis, resulting in morbidity and mortality. Little is known about the pathogenic mechanisms that lead to neurologic sequelae, and thus, animal models that represent human disease are needed. African green monkeys (AGM) exposed to aerosols containing RVFV develop a reproducibly lethal neurological disease that resembles human illness. To understand the disease process and identify biomarkers of lethality, two groups of 5 AGM were infected by inhalation with either a lethal or a sublethal dose of RVFV. Divergence between lethal and sublethal infections occurred as early as 2 days postinfection (dpi), at which point CD8
T cells from lethally infected AGM expressed activated caspase-3 and simultaneously failed to increase levels of major histocompatibility complex (MHC) class II molecules, in contrast to surviving animals. At 4 dpi, lethally infected animals failed to demonstrate proliferation of total CD4
and CD8
T cells, in contrast to survivors. These marked changes in peripheral blood cells occur much earlier than more-established indicators of severe RVF disease, such as granulocytosis and fever. In addition, an early proinflammatory (gamma interferon IFN-γ, interleukin 6 IL-6, IL-8, monocyte chemoattractant protein 1 MCP-1) and antiviral (IFN-α) response was seen in survivors, while very late cytokine expression was found in animals with lethal infections. By characterizing immunological markers of lethal disease, this study furthers our understanding of RVF pathogenesis and will allow the testing of therapeutics and vaccines in the AGM model.
Rift Valley Fever (RVF) is an important emerging viral disease for which we lack both an effective human vaccine and treatment. Encephalitis and neurological disease resulting from RVF lead to death or significant long-term disability for infected people. African green monkeys (AGM) develop lethal neurological disease when infected with RVF virus by inhalation. Here we report the similarities in disease course between infected AGM and humans. For the first time, we examine the peripheral immune response during the course of infection in AGM and show that there are very early differences in the immune response between animals that survive infection and those that succumb. We conclude that AGM are a novel and suitable monkey model for studying the neuropathogenesis of RVF and for testing vaccines and therapeutics against this emerging viral pathogen.
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