New Insights into Human Nondisjunction of Chromosome 21 in Oocytes

Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying nondisjunction, we examined the association between these two well established risk factors for chromosome 21 nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors

Preferences across the Menstrual Cycle for Masculinity and Symmetry in Photographs of Male Faces and Bodies

Background: Previous studies have shown that women increase their preference for masculinity during the fertile phase of the menstrual cycle. Evidence for a similar preference shift for symmetry is equivocal. These studies have required participants to choose between subtle variations in computer-generated stimuli, and preferences for more natural stimuli have not been investigated. Methodology/Principal Findings: Our study employed photographs of individual males to investigate women’s preferences for face and body masculinity and symmetry across the menstrual cycle. We collected attractiveness ratings from 25 normally cycling women at high- and low-fertility days of the menstrual cycle. Attractiveness ratings made by these women were correlated with independent ratings of masculinity and symmetry provided by different sets of raters. We found no evidence for any cyclic shift in female preferences. Correlations between attractiveness and masculinity, and attractiveness and symmetry did not differ significantly between high- and low-fertility test sessions. Furthermore, there was no significant difference between high- and low-fertility ratings of attractiveness. Conclusions: These results suggest that a menstrual cycle shift in visual preferences for masculinity and symmetry may be too subtle to influence responses to real faces and bodies, and subsequent mate-choice decisions

Erufosine, a novel alkylphosphocholine, in acute myeloid leukemia: single activity and combination with other antileukemic drugs

Alkylphosphocholines represent a new class of cytostatic drugs with a novel mode of action. Erufosine (ErPC3), the first compound of this class that can be administered intravenously, has recently been shown to be active against human tumor and leukemic cell lines. METHODS: In order to evaluate the antileukemic potential of ErPC3 in acute myeloid leukemia (AML) the lethal concentration 50% (LC 50) was determined using WST-1 assay. For analysis of cell death, staining for Annexin V and activated caspase 3 was performed. An interaction analysis was performed by calculation of combination index and construction of isobolograms. RESULTS: The LC 50 was 7.4 microg/ml after 24 h and 3.2 microg/ml after 72 h in HL 60 cells and 30.1 and 8.6 microg/ml, respectively, in 19 fresh samples from patients with AML. ErPC3 was found to be cytotoxic in HL60 cells with distinct activation of caspase 3. ErPC3 was not cross-resistant with cytarabine, idarubicine and etoposide as shown by the linear relation of respective LC 50s. The latter agents, however, exerted an additive cytotoxicity in combination with ErPC3 as revealed by isobologram analysis and combination index, although results are uneven for idarubicine. CONCLUSION: Based on these data ErPC3 appears as a novel antileukemic candidate drug, which needs to be explored further in the treatment of AML

Dynamic Replacement of Histone H3 Variants Reprograms Epigenetic Marks in Early Mouse Embryos

Upon fertilization, reprogramming of gene expression is required for embryo development. This step is marked by DNA demethylation and changes in histone variant composition. However, little is known about the molecular mechanisms causing these changes and their impact on histone modifications. We examined the global deposition of the DNA replication-dependent histone H3.1 and H3.2 variants and the DNA replication-independent H3.3 variant after fertilization in mice. We showed that H3.3, a euchromatic marker of gene activity, transiently disappears from the maternal genome, suggesting erasure of the oocyte-specific modifications carried by H3.3. After fertilization, H3.2 is incorporated into the transcriptionally silent heterochromatin, whereas H3.1 and H3.3 occupy unusual heterochromatic and euchromatin locations, respectively. After the two-cell stage, H3.1 and H3.3 variants resume their usual respective locations on heterochromatin and euchromatin. Preventing the incorporation of H3.1 and H3.2 by knockdown of the histone chaperone CAF-1 induces a reciprocal increase in H3.3 deposition and impairs heterochromatin formation. We propose that the deposition of different H3 variants influences the functional organization of chromatin. Taken together, these findings suggest that dynamic changes in the deposition of H3 variants are critical for chromatin reorganization during epigenetic reprogramming

Targeting Signal Transduction Pathways in Metastatic Breast Cancer: A Comprehensive Review

This review summarizes some of the key signaling pathways involved in tumor progression and some of the novel therapies that are in development for the treatment of metastatic breast cancer patients

Genome-Wide Association Data Reveal a Global Map of Genetic Interactions among Protein Complexes

This work demonstrates how gene association studies can be analyzed to map a global landscape of genetic interactions among protein complexes and pathways. Despite the immense potential of gene association studies, they have been challenging to analyze because most traits are complex, involving the combined effect of mutations at many different genes. Due to lack of statistical power, only the strongest single markers are typically identified. Here, we present an integrative approach that greatly increases power through marker clustering and projection of marker interactions within and across protein complexes. Applied to a recent gene association study in yeast, this approach identifies 2,023 genetic interactions which map to 208 functional interactions among protein complexes. We show that such interactions are analogous to interactions derived through reverse genetic screens and that they provide coverage in areas not yet tested by reverse genetic analysis. This work has the potential to transform gene association studies, by elevating the analysis from the level of individual markers to global maps of genetic interactions. As proof of principle, we use synthetic genetic screens to confirm numerous novel genetic interactions for the INO80 chromatin remodeling complex

Race/ethnicity and potential suicide misclassification: window on a minority suicide paradox?

<p>Abstract</p> <p>Background</p> <p>Suicide officially kills approximately 30,000 annually in the United States. Analysis of this leading public health problem is complicated by undercounting. Despite persisting socioeconomic and health disparities, non-Hispanic Blacks and Hispanics register suicide rates less than half that of non-Hispanic Whites.</p> <p>Methods</p> <p>This cross-sectional study uses multiple cause-of-death data from the US National Center for Health Statistics to assess whether race/ethnicity, psychiatric comorbidity documentation, and other decedent characteristics were associated with differential potential for suicide misclassification. Subjects were 105,946 White, Black, and Hispanic residents aged 15 years and older, dying in the US between 2003 and 2005, whose manner of death was recorded as suicide or injury of undetermined intent. The main outcome measure was the relative odds of potential suicide misclassification, a binary measure of manner of death: injury of undetermined intent (includes misclassified suicides) versus suicide.</p> <p>Results</p> <p>Blacks (adjusted odds ratio [AOR], 2.38; 95% confidence interval [CI], 2.22-2.57) and Hispanics (1.17, 1.07-1.28) manifested excess potential suicide misclassification relative to Whites. Decedents aged 35-54 (AOR, 0.88; 95% CI, 0.84-0.93), 55-74 (0.52, 0.49-0.57), and 75+ years (0.51, 0.46-0.57) showed diminished misclassification potential relative to decedents aged 15-34, while decedents with 0-8 years (1.82, 1.75-1.90) and 9-12 years of education (1.43, 1.40-1.46) showed excess potential relative to the most educated (13+ years). Excess potential suicide misclassification was also apparent for decedents without (AOR, 3.12; 95% CI, 2.78-3.51) versus those with psychiatric comorbidity documented on their death certificates, and for decedents whose mode of injury was "less active" (46.33; 43.32-49.55) versus "more active."</p> <p>Conclusions</p> <p>Data disparities might explain much of the Black-White suicide rate gap, if not the Hispanic-White gap. Ameliorative action would extend from training in death certification to routine use of psychological autopsies in equivocal-manner-of-death cases.</p

Necrotrophism Is a Quorum-Sensing-Regulated Lifestyle in Bacillus thuringiensis

How pathogenic bacteria infect and kill their host is currently widely investigated. In comparison, the fate of pathogens after the death of their host receives less attention. We studied Bacillus thuringiensis (Bt) infection of an insect host, and show that NprR, a quorum sensor, is active after death of the insect and allows Bt to survive in the cadavers as vegetative cells. Transcriptomic analysis revealed that NprR regulates at least 41 genes, including many encoding degradative enzymes or proteins involved in the synthesis of a nonribosomal peptide named kurstakin. These degradative enzymes are essential in vitro to degrade several substrates and are specifically expressed after host death suggesting that Bt has an active necrotrophic lifestyle in the cadaver. We show that kurstakin is essential for Bt survival during necrotrophic development. It is required for swarming mobility and biofilm formation, presumably through a pore forming activity. A nprR deficient mutant does not develop necrotrophically and does not sporulate efficiently in the cadaver. We report that necrotrophism is a highly regulated mechanism essential for the Bt infectious cycle, contributing to spore spreading

Automation of a problem list using natural language processing

BACKGROUND: The medical problem list is an important part of the electronic medical record in development in our institution. To serve the functions it is designed for, the problem list has to be as accurate and timely as possible. However, the current problem list is usually incomplete and inaccurate, and is often totally unused. To alleviate this issue, we are building an environment where the problem list can be easily and effectively maintained. METHODS: For this project, 80 medical problems were selected for their frequency of use in our future clinical field of evaluation (cardiovascular). We have developed an Automated Problem List system composed of two main components: a background and a foreground application. The background application uses Natural Language Processing (NLP) to harvest potential problem list entries from the list of 80 targeted problems detected in the multiple free-text electronic documents available in our electronic medical record. These proposed medical problems drive the foreground application designed for management of the problem list. Within this application, the extracted problems are proposed to the physicians for addition to the official problem list. RESULTS: The set of 80 targeted medical problems selected for this project covered about 5% of all possible diagnoses coded in ICD-9-CM in our study population (cardiovascular adult inpatients), but about 64% of all instances of these coded diagnoses. The system contains algorithms to detect first document sections, then sentences within these sections, and finally potential problems within the sentences. The initial evaluation of the section and sentence detection algorithms demonstrated a sensitivity and positive predictive value of 100% when detecting sections, and a sensitivity of 89% and a positive predictive value of 94% when detecting sentences. CONCLUSION: The global aim of our project is to automate the process of creating and maintaining a problem list for hospitalized patients and thereby help to guarantee the timeliness, accuracy and completeness of this information