Comparative Analysis of Microsatellite and Mitochondrial Genetic Variation in \u3cem\u3eIxodes Scapularis\u3c/em\u3e

Ixodes scapularis, the black legged tick, is a species endemic to North America with a range including most of the eastern-half of the United States and portions of Canada and Mexico. The tick is an important vector of diseases transmitted to humans and animals. Since its first description in 1821, the taxonomy of the species has been controversial. Biological differences have been identified in the northern and southern populations, yet no consensus exists on population structure and the causes of this disparity. Earlier molecular studies utilizing nuclear and mitochondrial genetic markers have revealed the occurrence of two distinct lineages: a genetically diverse southern clade found in the southern-half of the distribution area of I. scapularis, and a more genetically homogeneous American clade found throughout the I. scapularis range. Although mitochondrial markers have assisted in clarifying the population history of the tick, nuclear, bi-parentally inherited markers such as microsatellite loci can provide additional information at a finer scale. Furthermore, previous studies were based on either limited sampling, which did not represent the whole geographic range of the tick, or were based on single molecular markers. In this study, we (a) generated a new dataset by collecting samples throughout the distribution range of I. scapularis; (b) developed microsatellite markers for the study of the genetic structure of I. scapularis; (c) amplified and sequenced two different mitochondrial datasets and analyzed them phylogenetically in order to compare our data with previously published reconstructions; and (d) analyzed population genetics parameters and compared results obtained by analyzing mitochondrial vs. microsatellite markers. Our data confirm some of the earlier findings, but provide additional information on the geographically distinct genetic diversity of the species, and the evolutionary mechanisms that shaped its present structure. These data may further help our understanding of how pathogens circulate within I. scapularis populations

Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults.

Adverse drug reactions (ADRs) contribute to hospitalization but data on its economic burden is scant. Pre-emptive pharmacogenetic (PGx) testing can potentially reduce ADRs and its associated costs. The objectives of this study were to quantify the economic burden of ADRs and to estimate the breakeven cost of pre-emptive PGx testing in Singapore. We collected itemized costs for 1000 random non-elective hospitalizations of adults admitted to a tertiary-care general hospital in Singapore. The presence of ADRs at admission and their clinical characteristics were reported previously. The economic burden of ADRs was assessed from two perspectives: (1) Total cost and (2) incremental costs. The breakeven cost of PGx testing was estimated by dividing avoidable hospitalization costs for ADRs due to selected drugs by the number of patients taking those drugs. The total cost of 81 admissions caused by ADRs was US$570,404. Costs were significantly higher for bleeding/elevated international normalized ratio (US$9906 vs. US$2251, p = 6.58 × 10-3) compared to other ADRs, and for drugs acting on the blood coagulation system (US$9884 vs. US$2229, p = 4.41 × 10-3) compared to other drug classes. There were higher incremental laboratory costs due to ADRs causing or being present at admission. The estimated breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was US$114 per patient. These results suggest that future studies designed to directly measure the clinical and cost impact of a pre-emptive genotyping program will help inform clinical practice and health policy decisions

Fallen Pillars: The Past, Present, and Future Population Dynamics of a Rare, Specialist Coral–Algal Symbiosis

With ongoing changes in climate, rare and ecologically specialized species are at increased risk of extinction. In sessile foundation fauna that reproduce asexually via fragmentation of existing colonies, the number of colonies does not reflect the number of genets and thus can obscure genotypic diversity. Colonies that are the product of fragmentation are not visually distinguishable from colonies that stem from sexual recruits. For this reason, molecular markers are necessary to assess genotypic variation and population structure in clonal organisms such as reef-building corals and their endosymbiotic dinoflagellates. For the rare Caribbean pillar coral, Dendrogyra cylindrus, and its endosymbiotic dinoflagellate, Breviolum dendrogyrum, we use de novo microsatellite markers to infer past demographic changes, describe modern population structure, and quantify the frequency of asexual reproduction. Our analyses show that D. cylindrus comprises three distinct populations across the Greater Caribbean whereas the symbiont could be differentiated into four populations, indicating barriers to gene flow differ between host and symbiont. In Florida, host and symbiont populations reproduced mainly asexually, yielding lower genotypic diversity than predicted from census size. When multiple coral ramets were present, they often associated with the same clonal strain of B. dendrogyrum, pointing to the high fidelity of this relationship. Models of past demographic events revealed no evidence for historical changes in population sizes, consistent with the paleontological record of D. cylindrus indicating it has been rare for hundreds of thousands of years. The most recent global thermal stress event likely triggered a severe disease outbreak among D. cylindrus in Florida, resulting in a severe population decline. Projections indicate a high likelihood that this species will become extinct in the Northern Greater Caribbean within a few decades. The ecosystem consequences of losing rare coral species and their symbionts with increasingly frequent extreme warming events are not known but require urgent study

Editorial Board Diversity at the Basket of Eight Journals: A Report to the College of Senior Scholars

At the 2019 International Conference on Information Systems (ICIS), the College of Senior Scholars appointed a committee to investigate diversity in the editorial boards of their Basket of Eight journals. Editorial board diversity signals that a journal welcomes and includes all authors. The committee compared the gender, regional and ethnic diversity of the editorial boards to that of AIS members in the Academic membership category. This comparison showed that the editorial boards overall had fewer female members, more members from Region 1, and fewer from Region 3 than one would reasonably expect. Furthermore, several ethnicities appeared on the boards in smaller or larger numbers than one would expect, in comparison to their proportions among AIS Academic members. The individual journals also differed a great deal among themselves with respect to these diversity criteria. Regrettably, every journal fell below what one would reasonably expect with respect to either gender, regional, or ethnic diversity. Based on these findings, we make recommendations for the College of Senior Scholars, editors in chief of the Basket of Eight journals, the AIS Council, and individuals who lead other organizations of IS scholars

Crosstalk between MSH2–MSH3 and polβ promotes trinucleotide repeat expansion during base excision repair

Studies in knockout mice provide evidence that MSH2–MSH3 and the BER machinery promote trinucleotide repeat (TNR) expansion, yet how these two different repair pathways cause the mutation is unknown. Here we report the first molecular crosstalk mechanism, in which MSH2–MSH3 is used as a component of the BER machinery to cause expansion. On its own, pol β fails to copy TNRs during DNA synthesis, and bypasses them on the template strand to cause deletion. Remarkably, MSH2–MSH3 not only stimulates pol β to copy through the repeats but also enhances formation of the flap precursor for expansion. Our results provide direct evidence that MMR and BER, operating together, form a novel hybrid pathway that changes the outcome of TNR instability from deletion to expansion during the removal of oxidized bases. We propose that cells implement crosstalk strategies and share machinery when a canonical pathway is ineffective in removing a difficult lesion

Hyperglycemia Induces Oxidative Stress and Impairs Axonal Transport Rates in Mice

studies to determine the effect of hyperglycemia on the neurons in the central nervous system (CNS). While olfactory dysfunction is indicated in diabetes, the effect of hyperglycemia on olfactory receptor neurons (ORNs) remains unknown. In this study, we utilized manganese enhanced MRI (MEMRI) to assess the impact of hyperglycemia on axonal transport rates in ORNs. We hypothesize that (i) hyperglycemia induces oxidative stress and is associated with reduced axonal transport rates in the ORNs and (ii) hyperglycemia-induced oxidative stress activates the p38 MAPK pathway in association with phosphorylation of tau protein leading to the axonal transport deficits.-weighted MEMRI imaging was used to determine axonal transport rates post-streptozotocin injection in wildtype (WT) and superoxide dismutase 2 (SOD2) overexpressing C57Bl/6 mice. SOD2 overexpression reduces mitochondrial superoxide load. Dihydroethidium staining was used to quantify the reactive oxygen species (ROS), specifically, superoxide (SO). Protein and gene expression levels were determined using western blotting and Q-PCR analysis, respectively.STZ-treated WT mice exhibited significantly reduced axonal transport rates and significantly higher levels of ROS, phosphorylated p38 MAPK and tau protein as compared to the WT vehicle treated controls and STZ-treated SOD2 mice. The gene expression levels of p38 MAPK and tau remained unchanged.Increased oxidative stress in STZ-treated WT hyperglycemic mice activates the p38 MAPK pathway in association with phosphorylation of tau and attenuates axonal transport rates in the olfactory system. In STZ-treated SOD-overexpressing hyperglycemic mice in which superoxide levels are reduced, these deficits are reversed

Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

BackgroundUnderstanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients.MethodsSeventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup.ResultsThe majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P < .05. Patients treated with a gross total resection also had better outcomes for the HUI3 hearing (P = .04). However, those who underwent a gross total resection reported having worse outcomes on the HUI3 vision (P = .02). No differences in HRQL were evident as a function of subgroup.ConclusionsBy examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long-term outcomes

Fallen Pillars: The Past, Present, and Future Population Dynamics of a Rare, Specialist Coral–Algal Symbiosis

With ongoing changes in climate, rare and ecologically specialized species are at increased risk of extinction. In sessile foundation fauna that reproduce asexually via fragmentation of existing colonies, the number of colonies does not reflect the number of genets and thus can obscure genotypic diversity. Colonies that are the product of fragmentation are not visually distinguishable from colonies that stem from sexual recruits. For this reason, molecular markers are necessary to assess genotypic variation and population structure in clonal organisms such as reef-building corals and their endosymbiotic dinoflagellates. For the rare Caribbean pillar coral, Dendrogyra cylindrus, and its endosymbiotic dinoflagellate, Breviolum dendrogyrum, we use de novo microsatellite markers to infer past demographic changes, describe modern population structure, and quantify the frequency of asexual reproduction. Our analyses show that D. cylindrus comprises three distinct populations across the Greater Caribbean whereas the symbiont could be differentiated into four populations, indicating barriers to gene flow differ between host and symbiont. In Florida, host and symbiont populations reproduced mainly asexually, yielding lower genotypic diversity than predicted from census size. When multiple coral ramets were present, they often associated with the same clonal strain of B. dendrogyrum, pointing to the high fidelity of this relationship. Models of past demographic events revealed no evidence for historical changes in population sizes, consistent with the paleontological record of D. cylindrus indicating it has been rare for hundreds of thousands of years. The most recent global thermal stress event likely triggered a severe disease outbreak among D. cylindrus in Florida, resulting in a severe population decline. Projections indicate a high likelihood that this species will become extinct in the Northern Greater Caribbean within a few decades. The ecosystem consequences of losing rare coral species and their symbionts with increasingly frequent extreme warming events are not known but require urgent study