Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism

Opties voor een klimaatbestendige zoetwatervoorziening in Laag Nederland, tussentijds integratierapport

Dit rapport geeft een tussentijds overzicht van ‘state of the art’ kennis uit lopend onderzoek van het consortium ‘Climate Proof Fresh Water Supply’ (CPFWS) dat in het kader van het onderzoeksprogramma Kennis voor Klimaat wordt uitgevoerd. De focus van dit onderzoek naar een klimaatbestendige zoetwatervoorziening ligt op lokale en regionale oplossingen in Laag Nederland voor land- en tuinbouw en natuur. De zoetwatervoorziening van dit gebied wordt naast droogte vooral bedreigd door verzilting van grond- en oppervlaktewater. In zes samenhangende werkpakketten wordt geanalyseerd hoe dit gebied meer zelfvoorzienend kan worden én hoe aanpassingen in het (hoofd)watersysteem kunnen bijdragen aan de watervoorziening van het gebied. Centraal in de aanpak zijn een 3-tal casestudies in de Hotspots Haaglanden, Rotterdam Regio en Zuidwestelijke delta

On the biological relevance of MHC class II and B7 expression by tumour cells in melanoma metastases

A large number of studies have indicated that specific immune reactivity plays a crucial role in the control of malignant melanoma. In this context, expression of MHC I, MHC II and B7 molecules by melanoma cells is seen as relevant for the immune response against the tumour. For a better understanding of the biological relevance of MHC II and B7 expression by tumour cells in metastatic melanoma, we studied the expression of these molecules in melanoma metastases in relation to the inflammatory response, regression of the tumour and survival from 27 patients treated with biochemotherapy (30 mg m−2 Cisplatin and 250 mg m−2 decarbazine (dimethyl-triazene-imidazole-carboxamide, DTIC) on days 1–3 i.v., and 107 IU IFN-α2b 3 days a week s.c., q. 28d). In 19 out of 27 lesions studied, we found expression of MHC II by the tumour cells, while only in one out of 11 tumour biopsies obtained from untreated metastatic melanoma patients, MHC II expression was detected. Expression of B7.1 and B7.2 by tumour cells was found in nine out of 24 and 19 out of 24 lesions, respectively. In all cases where B7.1 expression was found, expression of B7.2 by the tumour cells was also seen. In general, no or only few inflammatory cells positive for B7 were found. Expression of MHC II by tumour cells was positively correlated with the presence of tumour-infiltrating lymphocytes, regression of the lesion, and with time to progression (TTP) and overall survival (OS) of the patient. However, no significant correlation between B7.1 or B7.2 expression and regression of the tumour, TTP or OS was found. In light of other recent findings, these data altogether do support a role as biomarker for MHC II expression by tumour cells; however, its exact immunological pathomechanism(s) remain to be established

The Galaxy Evolution Explorer: A Space Ultraviolet Survey Mission

We give an overview of the Galaxy Evolution Explorer (GALEX), a NASA Explorer Mission launched on April 28, 2003. GALEX is performing the first space UV sky-survey, including imaging and grism surveys in two bands (1350-1750 Angstroms and 1750-2750 Angstroms). The surveys include an all-sky imaging survey (m[AB] ~ 20.5), a medium imaging survey of 1000 square degrees (m[AB] ~ 23), a deep imaging survey of 100 square degrees (m[AB] ~ 25), and a nearby galaxy survey. Spectroscopic grism surveys (R=100-200) are underway with various depths and sky coverage. Many targets overlap existing or planned surveys. We will use the measured UV properties of local galaxies, along with corollary observations, to calibrate the UV-global star formation rate relationship in local galaxies. We will apply this calibration to distant galaxies discovered in the deep imaging and spectroscopic surveys to map the history of star formation in the universe over the redshift range 0 < z < 1.5, and probe the physical drivers of star formation in galaxies. The GALEX mission includes a Guest Investigator program supporting the wide variety of programs made possible by the first UV sky survey.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issue. Links to the full set of papers will be available at http:/www.galex.caltech.edu/PUBLICATIONS/ after November 22, 200

Ten-year survival of ART restorations in permanent posterior teeth

This study evaluated the 10-year clinical performance of high-viscosity glass-ionomer cement placed in posterior permanent teeth by means of the Atraumatic Restorative Treatment (ART) approach. One operator placed 167 single- and 107 multiple-surface restorations in 43 high-risk caries pregnant women (mean decayed teeth = 9.8 ± 5.5). Examinations were performed at 1-, 2-, and 10-year intervals according to ART criteria. In the last evaluation, the US Public Health Service (USPHS) criteria were also used. After 10 years, 129 restorations (47.1%) were evaluated and achieved a cumulative survival rate of 49.0% (SE 7.2%). The 10-year survival of single- and multiple-surface ART restorations assessed using the ART criteria were 65.2% (SE 7.3%) and 30.6% (SE 9.9%), respectively. This difference was significant (jackknife SE of difference; p < 0.05). Using the USPHS criteria, the 10-year survival of single- and multiple-surface ART restorations were 86.5% and 57.6%, respectively. The primary causes of failure were total loss (9.3%) and marginal defects (5.4%). The survival rates observed, especially for the single-surface restorations, confirm the potential of the ART approach for restoring and saving posterior permanent teeth

Aqueous Humor Biomarkers Identify Three Prognostic Groups in Uveal Melanoma

Purpose: To investigate whether we can identify different patterns of inflammation in the aqueous humor of a uveal melanoma (UM)-containing eye, and whether these are related to prognosis. Meth

Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism