Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding

Background: A significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity. Objective: To identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found. Methods: Genetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry. Results: We report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining. Conclusions: Genetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count

Salinity and Simulated Herbivory Influence Spartina alterniflora Traits and Defense Strategy

Sea level rise is expected to push saline waters into previously fresher regions of estuaries, and higher salinities may expose oligohaline marshes to invertebrate herbivores typically constrained by salinity. The smooth cordgrass, Spartina alterniflora (syn. Sporobolus alterniflorus), can defend itself against herbivores in polyhaline marshes, however it is not known if S. alterniflora’s defense varies along the mesohaline to oligohaline marsh gradient in estuaries. I found that S. alterniflora from a mesohaline marsh is better defended than plants from an oligohaline marsh, supporting the optimal defense theory. Higher salinity treatments lowered carbon content, C:N, and new stem biomass production, traits associated with a tolerance strategy, suggesting that salinity may mediate the defense response of S. alterniflora. Further, simulated herbivory increased the nitrogen content and decreased C:N of S. alterniflora. This indicates that grazing may increase S. alterniflora susceptibility to future herbivory via improved forage quality. Simulated herbivory also decreased both belowground and new stem biomass production, highlighting a potential pathway in which herbivory can indirectly facilitate marsh loss, as S. alterniflora biomass is critical for vertical accretion and marsh stability under future sea level rise scenarios

Optimal central-place foraging by beavers: Tree-size selection in relation to defensive chemicals of quaking aspen

At a newly occupied pond, beavers preferentially felled aspen smaller than 7.5 cm in diameter and selected against larger size classes. After one year of cutting, 10% of the aspen had been cut and 14% of the living aspen exhibited the juvenile growth form. A phenolic compound which may act as a deterrent to beavers was found in low concentrations in aspen bark, and there was no significant regression of relative concentration of this compound on tree diameter. At a pond which had been intermittently occupied by beavers for over 20 years, beavers selected against aspen smaller than 4.5 cm in diameter, and selected in favor of aspen larger than 19.5 cm in diameter. After more than 28 years of cutting at this site, 51% of the aspen had been cut and 49% of the living aspen were juvenileform. The phenolic compound was found in significantly higher concentrations in aspen bark than at the newly occupied site, and there was a significant negative regression of relative concentration on tree diameter. The results of this study show that responses to browsing by trees place constraints on the predictive value of standard energy-based optimal foraging models, and limitations on the use of such models. Future models should attempt to account for inducible responses of plants to damage and increases in concentrations of secondary metabolites through time.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47775/1/442_2004_Article_BF00379963.pd

An examination of non-heterosexual romantic relationships

This paper examines the differences and similarities between heterosexual and sexual minority individuals in various settings. It also examines theories of sexual deviance and how they relate to social and political ideologies of sexual minority individuals. I briefly summarize the current political debate surrounding sexual minorities, and finally suggest some societal level changes that could possibly help alleviate some of the issues this topic has created for U.S. citizens. In my review of this literature, I conclude that expanding the institution of marriage to be inclusive of sexual minorities would only benefit our country. This current debate provides an excellent opportunity to reevaluate societal norms of gender and romantic relationships.Honors CollegeThesis (B.?.

Challenges in implementing government-managed guidance on VTE risk assessment

Background: Implementing venous thromboembolism (VTE) risk assessment guidance on admission to hospital has proved difficult worldwide. In 2010, VTE risk assessment in English hospitals was linked to financial sanctions. This study investigated possible barriers and facilitators for VTE risk assessment in medical patients and evaluated the impact of local and national initiatives. Setting: Acute Medical Unit in one English National Health Service university teaching hospital. Methods: This was a mixed methods study; National Research Ethics Service approval was granted. Data were collected over four 1-week periods; November 2009 (1), January 2010 (2), April 2010 (3) and April 2011 (4). Case notes for all medical patients admitted during these periods were reviewed. Thirty-six staff were observed admitting 71 of these patients; 24 observed staff participated in a structured interview. Results: 876 case notes were reviewed. In total, 82.1% of patients had one or more VTE risk factors and 25.3% one or more bleeding risks. VTE risk assessment rose from a baseline of 6.9–19.6%, following local initiatives, and to 98.7% following financially sanctioned government targets. A similar increase in appropriate prescribing of prophylaxis was seen, but inappropriate prescribing also rose. No staff observed in period 1 conducted VTE risk assessment, risk-assessment forms were largely ignored or discarded during period 2; and electronic recording systems available during period 3 were not accessed. Few patients were asked any VTE-related questions in periods 1, 2 or 3. Interviewees’ actual knowledge of VTE risk was not related to perceived knowledge level. Eight of the 24 staff interviewed were aware of national policies or guidance: none had seen them. Principal barriers identified to risk assessment were: involvement of multiple staff in individual admissions; interruptions; lack of policy awareness; time pressure and complexity of tools. Conclusions: National financial sanctions appear effective in implementing guidance, where other local measures have failed

An examination of non-heterosexual romantic relationships

This paper examines the differences and similarities between heterosexual and sexual minority individuals in various settings. It also examines theories of sexual deviance and how they relate to social and political ideologies of sexual minority individuals. I briefly summarize the current political debate surrounding sexual minorities, and finally suggest some societal level changes that could possibly help alleviate some of the issues this topic has created for U.S. citizens. In my review of this literature, I conclude that expanding the institution of marriage to be inclusive of sexual minorities would only benefit our country. This current debate provides an excellent opportunity to reevaluate societal norms of gender and romantic relationships.Thesis (B.?.)Honors Colleg

How Important are Sanitation Practices in the D. Suzukii World?

KEYWORDS: Invasive pests, SWD, Sanitation, Drosophila suzukii, spotted wing Drosophil