Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.

BACKGROUND: Adams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS. METHODS AND RESULTS: Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway. CONCLUSIONS: These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders

State of the science on controversial topics: orthodontic therapy and gingival recession (a report of the Angle Society of Europe 2013 meeting).

BACKGROUND: Controversy exists in the literature between the role of orthodontic treatment and gingival recession. Whilst movement of teeth outside the alveolar bone has been reported as a risk factor for gingival recession, others have found no such association. FINDINGS: The Angle Society of Europe devoted a study day to explore the evidence surrounding these controversies. The aim of the day was for a panel of experts to evaluate the current evidence base in relation to either the beneficial or detrimental effects of orthodontic treatment on the gingival tissue. CONCLUSIONS: There remains a relatively weak evidence base for the role of orthodontic treatment and gingival recession and thus a need to undertake a risk assessment and appropriate consent prior to the commencement of treatment. In further prospective, well designed trials are needed

Nuclear structure of Au-181 studied via beta(+)/EC decay of Hg-181 at ISOLDE

The $\beta ^+$/EC decay of mass separated samples of $^{181}$Hg was studied employing the TATRA spectrometer at the ISOLDE facility at CERN. The decay scheme was constructed for the first time. A Broad Energy Germanium detector was used to achieve this by combination of high-gain $\gamma$-ray singles spectroscopy and $\gamma$–$\gamma$ coincidences. The systematics of excited states associated with the 1$h_{11/2}$ proton-hole configuration in odd-Au isotopes was extended

Human T cell recognition of the blood stage antigen Plasmodium hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) in acute malaria

<p>Abstract</p> <p>Background</p> <p>The <it>Plasmodium </it>purine salvage enzyme, hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) can protect mice against <it>Plasmodium yoelii </it>pRBC challenge in a T cell-dependent manner and has, therefore, been proposed as a novel vaccine candidate. It is not known whether natural exposure to <it>Plasmodium falciparum </it>stimulates HGXPRT T cell reactivity in humans.</p> <p>Methods</p> <p>PBMC and plasma collected from malaria-exposed Indonesians during infection and 7–28 days after anti-malarial therapy, were assessed for HGXPRT recognition using CFSE proliferation, IFNγ ELISPOT assay and ELISA.</p> <p>Results</p> <p>HGXPRT-specific T cell proliferation was found in 44% of patients during acute infection; in 80% of responders both CD4⁺and CD8⁺T cell subsets proliferated. Antigen-specific T cell proliferation was largely lost within 28 days of parasite clearance. HGXPRT-specific IFN-γ production was more frequent 28 days after treatment than during acute infection. HGXPRT-specific plasma IgG was undetectable even in individuals exposed to malaria for at least two years.</p> <p>Conclusion</p> <p>The prevalence of acute proliferative and convalescent IFNγ responses to HGXPRT demonstrates cellular immunogenicity in humans. Further studies to determine minimal HGXPRT epitopes, the specificity of responses for Plasmodia and associations with protection are required. Frequent and robust T cell proliferation, high sequence conservation among <it>Plasmodium </it>species and absent IgG responses distinguish HGXPRT from other malaria antigens.</p

Computational Methods for Protein Identification from Mass Spectrometry Data

Protein identification using mass spectrometry is an indispensable computational tool in the life sciences. A dramatic increase in the use of proteomic strategies to understand the biology of living systems generates an ongoing need for more effective, efficient, and accurate computational methods for protein identification. A wide range of computational methods, each with various implementations, are available to complement different proteomic approaches. A solid knowledge of the range of algorithms available and, more critically, the accuracy and effectiveness of these techniques is essential to ensure as many of the proteins as possible, within any particular experiment, are correctly identified. Here, we undertake a systematic review of the currently available methods and algorithms for interpreting, managing, and analyzing biological data associated with protein identification. We summarize the advances in computational solutions as they have responded to corresponding advances in mass spectrometry hardware. The evolution of scoring algorithms and metrics for automated protein identification are also discussed with a focus on the relative performance of different techniques. We also consider the relative advantages and limitations of different techniques in particular biological contexts. Finally, we present our perspective on future developments in the area of computational protein identification by considering the most recent literature on new and promising approaches to the problem as well as identifying areas yet to be explored and the potential application of methods from other areas of computational biology

New systematic features in the neutron-deficient Au isotopes

A recently developed portable, on-line capability for γ-ray and conversion-electron spectroscopy, HIGH-TATRA is demonstrated with its application to the study of 183Hg $\to$ 183Au at ISOLDE. Key details of the low-energy level scheme of the neutron-deficient nuclide 183Au populated in this decay are presented. A broad energy germanium detector is employed to achieve this (the first-ever use of such a device in decay-scheme spectroscopy), by way of a combination of high-gain γ-ray singles spectroscopy and γ–γ coincidence spectroscopy. Further, by combining the γ-ray detectors with a liquid-nitrogen-cooled Si(Li) detector operated under high vacuum, conversion-electron singles and e–γ coincidences are obtained. These data lead to the determination of transition multipolarities and the location of a highly converted (E0 + M1 + E2) transition in the 183Au decay scheme, suggesting a possible new shape coexisting structure in this nucleus. Identification of new intruder and normal states fixes their relative energies in 183Au for the first time. New systematic features in the odd-Au isotopes are presented