A global disorder of imprinting in the human female germ line

Imprinted genes are expressed differently depending on whether they are carried by a chromosome of maternal or paternal origin. Correct imprinting is established by germline-specific modifications; failure of this process underlies several inherited human syndromes. All these imprinting control defects are cis-acting, disrupting establishment or maintenance of allele-specific epigenetic modifications across one contiguous segment of the genome. In contrast, we report here an inherited global imprinting defect. This recessive maternal-effect mutation disrupts the specification of imprints at multiple, non-contiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole, in which abnormal extra-embryonic tissue proliferates while development of the embryo is absent or nearly so. This disorder offers a genetic route to the identification of trans-acting oocyte factors that mediate maternal imprint establishment

Characterisation of polyphosphate coated aluminium-doped titania nanoparticles during milling

This paper investigates the characterisation of alumina-doped titania nanoparticles, milled under high-shear over time, in the presence of sodium hexametaphosphate (SHMP) dispersant. Transmission electron microscopy (TEM) indicated that prolonged milling times led to the formation of 10 nm particle fines which were electrostatically attracted to larger particles, where no change in the crystal structure was observed. The primary particle size measured by dynamic light scattering (DLS) and TEM were in agreement and showed no change in primary particle size (∼250 nm) with respect to milling time, however, there was a clear reduction in the magnitude of the slow mode decay associated to aggregates. The TiO₂ was found to have an isoelectric point (iep) in the range of pH 3 to 4.5, where an increase in milling time led to a lower pHiep, indicative of an increase in SHMP coverage, which was further supported by an intensification in phosphorus content measured by X-ray fluorescence (XRF). Phosphorus content and zeta potential analysis before and after centrifugal washing showed that SHMP was partially removed or hydrolysed for the longer milled pigment samples, whereas no change was observed for shorter milled samples. Relaxation NMR was also performed, where enhanced relaxation rates at longer milling times were associated partially to increases in surface area and exposure of Al sites, as well as physicochemical changes to SHMP density and structure. It is thought that extended milling times may lead to hydrolysis or other structural changes of the dispersant from the high energy milling conditions, allowing easier removal of SHMP for longer milled pigments

Effects of deletion of the Streptococcus pneumoniae lipoprotein diacylglyceryl transferase gene lgt on ABC transporter function and on growth in vivo

Lipoproteins are an important class of surface associated proteins that have diverse roles and frequently are involved in the virulence of bacterial pathogens. As prolipoproteins are attached to the cell membrane by a single enzyme, prolipoprotein diacylglyceryl transferase (Lgt), deletion of the corresponding gene potentially allows the characterisation of the overall importance of lipoproteins for specific bacterial functions. We have used a Δlgt mutant strain of Streptococcus pneumoniae to investigate the effects of loss of lipoprotein attachment on cation acquisition, growth in media containing specific carbon sources, and virulence in different infection models. Immunoblots of triton X-114 extracts, flow cytometry and immuno-fluorescence microscopy confirmed the Δlgt mutant had markedly reduced lipoprotein expression on the cell surface. The Δlgt mutant had reduced growth in cation depleted medium, increased sensitivity to oxidative stress, reduced zinc uptake, and reduced intracellular levels of several cations. Doubling time of the Δlgt mutant was also increased slightly when grown in medium with glucose, raffinose and maltotriose as sole carbon sources. These multiple defects in cation and sugar ABC transporter function for the Δlgt mutant were associated with only slightly delayed growth in complete medium. However the Δlgt mutant had significantly reduced growth in blood or bronchoalveolar lavage fluid and a marked impairment in virulence in mouse models of nasopharyngeal colonisation, sepsis and pneumonia. These data suggest that for S. pneumoniae loss of surface localisation of lipoproteins has widespread effects on ABC transporter functions that collectively prevent the Δlgt mutant from establishing invasive infection

From venture idea to venture formation:The role of sensemaking, sensegiving and sense receiving

This article explores the sensemaking processes entrepreneurs use when transitioning between venture ideas and venture formation. Adopting a sensemaking/sensegiving approach and utilising an interpretivist methodology, we use sensemaking to analyse the entrepreneurial journey of four diverse entrepreneurs. In so doing, we make three contributions: first, we locate the early stages of the entrepreneurial context as a primary site where sensemaking occurs as entrepreneurs deal with the differences between expectations and reality. Second, we show how sensemaking occurs when entrepreneurs build a causal map of the problem they wish to address and how social exchanges are crucial as entrepreneurs then refine that idea with other sensegivers. Finally, we extend scholarly understanding through explaining the ways in which sensemaking, sensegiving and sense receiving contribute to the entrepreneurs' decision to act and create a new venture

A mathematical and computational review of Hartree-Fock SCF methods in Quantum Chemistry

We present here a review of the fundamental topics of Hartree-Fock theory in Quantum Chemistry. From the molecular Hamiltonian, using and discussing the Born-Oppenheimer approximation, we arrive to the Hartree and Hartree-Fock equations for the electronic problem. Special emphasis is placed in the most relevant mathematical aspects of the theoretical derivation of the final equations, as well as in the results regarding the existence and uniqueness of their solutions. All Hartree-Fock versions with different spin restrictions are systematically extracted from the general case, thus providing a unifying framework. Then, the discretization of the one-electron orbitals space is reviewed and the Roothaan-Hall formalism introduced. This leads to a exposition of the basic underlying concepts related to the construction and selection of Gaussian basis sets, focusing in algorithmic efficiency issues. Finally, we close the review with a section in which the most relevant modern developments (specially those related to the design of linear-scaling methods) are commented and linked to the issues discussed. The whole work is intentionally introductory and rather self-contained, so that it may be useful for non experts that aim to use quantum chemical methods in interdisciplinary applications. Moreover, much material that is found scattered in the literature has been put together here to facilitate comprehension and to serve as a handy reference.Comment: 64 pages, 3 figures, tMPH2e.cls style file, doublesp, mathbbol and subeqn package

Serum antibodies against genitourinary infectious agents in prostate cancer and benign prostate hyperplasia patients: a case-control study

<p>Abstract</p> <p>Background</p> <p>Infection plays a role in the pathogenesis of many human malignancies. Whether prostate cancer (PCa) - an important health issue in the aging male population in the Western world - belongs to these conditions has been a matter of research since the 1970 s. Persistent serum antibodies are a proof of present or past infection. The aim of this study was to compare serum antibodies against genitourinary infectious agents between PCa patients and controls with benign prostate hyperplasia (BPH). We hypothesized that elevated serum antibody levels or higher seroprevalence in PCa patients would suggest an association of genitourinary infection in patient history and elevated PCa risk.</p> <p>Methods</p> <p>A total of 434 males who had undergone open prostate surgery in a single institution were included in the study: 329 PCa patients and 105 controls with BPH. The subjects' serum samples were analysed by means of enzyme-linked immunosorbent assay, complement fixation test and indirect immunofluorescence for the presence of antibodies against common genitourinary infectious agents: human papillomavirus (HPV) 6, 11, 16, 18, 31 and 33, herpes simplex virus (HSV) 1 and 2, human cytomegalovirus (CMV), Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, Neisseria gonorrhoeae and Treponema pallidum. Antibody seroprevalence and mean serum antibody levels were compared between cases and controls. Tumour grade and stage were correlated with serological findings.</p> <p>Results</p> <p>PCa patients were more likely to harbour antibodies against Ureaplasma urealyticum (odds ratio (OR) 2.06; 95% confidence interval (CI) 1.08-4.28). Men with BPH were more often seropositive for HPV 18 and Chlamydia trachomatis (OR 0.23; 95% CI 0.09-0.61 and OR 0.45; 95% CI 0.21-0.99, respectively) and had higher mean serum CMV antibody levels than PCa patients (p = 0.0004). Among PCa patients, antibodies against HPV 6 were associated with a higher Gleason score (p = 0.0305).</p> <p>Conclusions</p> <p>Antibody seropositivity against the analyzed pathogens with the exception of Ureaplasma does not seem to be a risk factor for PCa pathogenesis. The presence or higher levels of serum antibodies against the genitourinary pathogens studied were not consistently associated with PCa. Serostatus was not a predictor of disease stage in the studied population.</p

Predicting mortality of residents at admission to nursing home: A longitudinal cohort study

<p>Abstract</p> <p>Background</p> <p>An increasing numbers of deaths occur in nursing homes. Knowledge of the course of development over the years in death rates and predictors of mortality is important for officials responsible for organizing care to be able to ensure that staff is knowledgeable in the areas of care needed. The aim of this study was to investigate the time from residents' admission to Icelandic nursing homes to death and the predictive power of demographic variables, health status (health stability, pain, depression and cognitive performance) and functional profile (ADL and social engagement) for 3-year mortality in yearly cohorts from 1996-2006.</p> <p>Methods</p> <p>The samples consisted of residents (N = 2206) admitted to nursing homes in Iceland in 1996-2006, who were assessed once at baseline with a Minimum Data Set (MDS) within 90 days of their admittance to the nursing home. The follow-up time for survival of each cohort was 36 months from admission. Based on Kaplan-Meier analysis (log rank test) and non-parametric correlation analyses (Spearman's rho), variables associated with survival time with a p-value < 0.05 were entered into a multivariate Cox regression model.</p> <p>Results</p> <p>The median survival time was 31 months, and no significant difference was detected in the mortality rate between cohorts. Age, gender (HR 1.52), place admitted from (HR 1.27), ADL functioning (HR 1.33-1.80), health stability (HR 1.61-16.12) and ability to engage in social activities (HR 1.51-1.65) were significant predictors of mortality. A total of 28.8% of residents died within a year, 43.4% within two years and 53.1% of the residents died within 3 years.</p> <p>Conclusion</p> <p>It is noteworthy that despite financial constraints, the mortality rate did not change over the study period. Health stability was a strong predictor of mortality, in addition to ADL performance. Considering these variables is thus valuable when deciding on the type of service an elderly person needs. The mortality rate showed that more than 50% died within 3 years, and almost a third of the residents may have needed palliative care within a year of admission. Considering the short survival time from admission, it seems relevant that staff is trained in providing palliative care as much as restorative care.</p

Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 5′ untranslated region of the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP). Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC) lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid in the discovery of novel therapeutics for FXS and other autism-spectrum disorders sharing common pathophysiology.FRAXA Research FoundationHarvard Stem Cell Institute (seed grant)Stanley Medical Research InstituteNational Institute of Mental Health (U.S.) (grant #R33MH087896