Human Cholesterol Biosynthesis Defects

Cholesterol plays an essential role in normal embryogenesis and perturbations in its de novo synthesis are responsible for organ malformations in the cholesterol biosynthesis defects. Ten distinct inherited disorders have been linked to different enzyme defects in the isoprenoid/cholesterol biosynthetic pathway: mevalonic aciduria, hyperimmunoglobulinemia syndrome, squalene synthase deficiency, lanosterol synthase deficiency, hydrops-ectopic calcification-moth-eaten (Greenberg) skeletal dysplasia, X-linked dominant chondrodysplasia punctata, congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome, lathosterolosis, Smith-Lemli-Opitz syndrome and desmosterolosis. These Mendelian disorders are clinically heterogeneous with protean manifestations reflecting the important role of cholesterol, and its intermediary metabolites, in embryogenesis and development. Key clinical features commonly represented by the cholesterol biosynthesis defects include structural brain malformations, axial skeletal developmental anomalies and genital and cardiac malformations. The aetiology of the underlying pathophysiology is unclear and multifactorial but may be due to lowered cholesterol and/or the elevated, teratogenic levels of the intermediate sterol precursors. Herein, we will review clinical, biochemical and molecular aspects of the known human cholesterol biosynthesis defects

Australian dust storm associated with extensive Aspergillus sydowii fungal "Bloom" in coastal waters

A massive central Australian dust storm in September 2009 was associated with abundant fungal spores (150,000/m(3)) and hyphae in coastal waters between Brisbane (27 degrees S) and Sydney (34 degrees S). These spores were successfully germinated from formalinpreserved samples, and using molecular sequencing of three different genes (the large subunit rRNA gene [LSU], internal transcribed spacer [ITS], and beta-tubulin gene), they were conclusively identified as Aspergillus sydowii, an organism circumstantially associated with gorgonian coral fan disease in the Caribbean. Surprisingly, no human health or marine ecosystem impacts were associated with this Australian dust storm event. Australian fungal cultures were nontoxic to fish gills and caused a minor reduction in the motility of Alexandrium or Chattonella algal cultures but had their greatest impacts on Symbiodinium dinoflagellate coral symbiont motility, with hyphae being more detrimental than spores. While we have not yet seen any soft coral disease outbreaks on the Australian Great Barrier Reef similar to those observed in the Caribbean and while this particular fungal population was non-or weakly pathogenic, our observations raise the possibility of future marine ecosystem pathogen impacts from similar dust storms harboring more pathogenic strains

Deformable Model for 3D Intramodal Nonrigid Breast Image Registration with Fiducial Skin Markers

We implemented a new approach to intramodal non-rigid 3D breast image registration. Our method uses fiducial skin markers (FSM) placed on the breast surface. After determining the displacements of FSM, finite element method (FEM) is used to distribute the markers’ displacements linearly over the entire breast volume using the analogy between the orthogonal components of the displacement field and a steady state heat transfer (SSHT). It is valid because the displacement field in x, y and z direction and a SSHT problem can both be modeled using LaPlace’s equation and the displacements are analogous to temperature differences in SSHT. It can be solved via standard heat conduction FEM software with arbitrary conductivity of surface elements significantly higher than that of volume elements. After determining the displacements of the mesh nodes over the entire breast volume, moving breast volume is registered to target breast volume using an image warping algorithm. Very good quality of the registration was obtained. Following similarity measurements were estimated: Normalized Mutual Information (NMI), Normalized Correlation Coefficient (NCC) and Sum of Absolute Valued Differences (SAVD). We also compared our method with rigid registration technique

Considerations for maintaining family diversity in commercially mass-spawned penaeid shrimp: a case study on Penaeus monodon

Skewed family distributions are common in aquaculture species that are highly fecund, communally (mass) spawned, and/or communally reared. The magnitude of skews pose challenges for maintaining family-specific genetic diversity, as increased resources are required to detect individuals from underrepresented families, or reliably determine relative survival as a measure of family performance. There is limited understanding of family skews or changes in family proportion of communally reared shrimp under commercial rearing conditions and particularly how this may affect genotyping strategies to recover family performance data in breeding programs. In this study, three separate batches of shrimp, Penaeus monodon, were communally spawned and reared, and then sampled as larvae when ponds were stocked at 30 days of culture (DOC) and as juveniles from commercial ponds during harvest at 150 DOC. A total of 199 broodstock contributed to the 5,734 progeny that were genotyped with a custom multiplex single nucleotide polymorphism (SNP) panel, and family assignments were cross-referenced using two parentage assignment methods, CERVUS and COLONY. A total of 121 families were detected, with some families contributing up to 11% of progeny at 30 DOC and up to 18% of progeny at harvest. Significant changes were detected for 20% of families from 30 to 150 DOC, with up to a 9% change in relative contribution. Family skew data was applied in several models to determine the optimal sample size to detect families, along with the ability to detect changes in relative family contribution over time. Results showed that an order of magnitude increase in sampling was required to capture the lowest represented 25% of families, as well as significantly improve the accuracy to determine changes in family proportion from 30 to 150 DOC. Practical measures may be implemented at the hatchery to reduce family skews; a cost-effective measure may be to address the initial magnitude differences in viable progeny produced among families, by pooling equal quantities of hatched larvae from each family. This study demonstrates the relationships between skews in families under commercial conditions, the ability to accurately detect families, and the balance of sampling effort and genotyping cost in highly fecund species such as shrimp

Exclusive electroproduction of K+ Lambda and K+ Sigma^0 final states at Q^2 = 0.030-0.055 (GeV/c)^2

Cross section measurements of the exclusive p(e,e'K+)Lambda,Sigma^0 electroproduction reactions have been performed at the Mainz Microtron MAMI in the A1 spectrometer facility using for the first time the Kaos spectrometer for kaon detection. These processes were studied in a kinematical region not covered by any previous experiment. The nucleon was probed in its third resonance region with virtual photons of low four-momenta, Q^2= 0.030-0.055 (GeV/c)^2. The MAMI data indicate a smooth transition in Q^2 from photoproduction to electroproduction cross sections. Comparison with predictions of effective Lagrangian models based on the isobar approach reveal that strong longitudinal couplings of the virtual photon to the N* resonances can be excluded from these models.Comment: 16 pages, 7 figure

Real-time monitoring of cellular dynamics using a microfluidic cell culture system with integrated electrode array and potentiostat

A versatile microfluidic, multichamber cell culture and analysis system with an integrated electrode array and potentiostat suitable for electrochemical detection and microscopic imaging is presented in this paper. The system, which allows on-line electrode cleaning and modification, was developed for real-time monitoring of cellular dynamics, exemplified in this work by monitoring of redox metabolism inside living yeast cells and dopamine release from PC12 cell

Identification of Clinical Isolates of Candida albicans with Increased Fitness in Colonization of the Murine Gut

The commensal and opportunistic pathogen Candida albicans is an important cause of fungal diseases in humans, with the gastrointestinal tract being an important reservoir for its infections. The study of the mechanisms promoting the C. albicans commensal state has attracted considerable attention over the last few years, and several studies have focused on the identification of the intestinal human mycobiota and the characterization of Candida genes involved in its establishment as a commensal. In this work, we have barcoded 114 clinical C. albicans isolates to identify strains with an enhanced fitness in a murine gastrointestinal commensalism model. The 114 barcoded clinical isolates were pooled in four groups of 28 to 30 strains that were inoculated by gavage in mice previously treated with antibacterial therapy. Eight strains that either exhibited higher colonization load and/or remained in the gut after antibiotic removal were selected. The phenotypic analysis of these strains compared to an RFP-tagged SC5314 wild type strain did not reveal any specific trait associated with its increased colonization; all strains were able to filament and six of the eight strains displayed invasive growth on Spider medium. Analysis of one of these strains, CaORAL3, revealed that although mice required previous bacterial microbiota reduction with antibiotics to be able to be colonized, removal of this procedure could take place the same day (or even before) Candida inoculation. This strain was able to colonize the intestine of mice already colonized with Candida without antibiotic treatment in co-housing experiments. CaORAL3 was also able to be established as a commensal in mice previously colonized by another (CaHG43) or the same (CaORAL3) C. albicans strain. Therefore, we have identified C. albicans isolates that display higher colonization load than the standard strain SC5314 which will surely facilitate the analysis of the factors that regulate fungal colonization

Spatio-temporal insights into microbiology of the freshwater-to-hypersaline, oxic-hypoxic-euxinic waters of Ursu Lake

Ursu Lake is located in the Middle Miocene salt deposit of Central Romania. It is stratified, and the water column has three distinct water masses: an upper freshwater-to-moderately saline stratum (0–3 m), an intermediate stratum exhibiting a steep halocline (3–3.5 m), and a lower hypersaline stratum (4 m and below) that is euxinic (i.e. anoxic and sulphidic). Recent studies have characterized the lake's microbial taxonomy and given rise to intriguing ecological questions. Here, we explore whether the communities are dynamic or stable in relation to taxonomic composition, geochemistry, biophysics, and ecophysiological functions during the annual cycle. We found: (i) seasonally fluctuating, light-dependent communities in the upper layer (≥0.987–0.990 water-activity), a stable but phylogenetically diverse population of heterotrophs in the hypersaline stratum (water activities down to 0.762) and a persistent plate of green sulphur bacteria that connects these two (0.958–0.956 water activity) at 3–3.5 to 4 m; (ii) communities that might be involved in carbon- and sulphur-cycling between and within the lake's three main water masses; (iii) uncultured lineages including Acetothermia (OP1), Cloacimonetes (WWE1), Marinimicrobia (SAR406), Omnitrophicaeota (OP3), Parcubacteria (OD1) and other Candidate Phyla Radiation bacteria, and SR1 in the hypersaline stratum (likely involved in the anaerobic steps of carbon- and sulphur-cycling); and (iv) that species richness and habitat stability are associated with high redox-potentials. Ursu Lake has a unique and complex ecology, at the same time exhibiting dynamic fluctuations and stability, and can be used as a modern analogue for ancient euxinic water bodies and comparator system for other stratified hypersaline systems

Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey

Purpose: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. Methods: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. Results: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. Conclusions: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia