Prenatal ultrasonographic diagnosis and successful management of mediastinal teratoma A case report

A case of mediastinal teratoma, diagnosed in utero by realtime ultrasonography during a late 3rd trimester evaluation of polyhydramnios, is described. Prompt respiratory assistance to the infant at birth and early surgical intervention led to a successful outcome

Genetic disorders in the Indian community of South Africa

Objectives. To determine the range of genetic disorders in the Indian population of South Africa, assess relevant historical and demographical factors, and discuss the implications for medical and genetic care. Methods. WSW reviewed the archived data pertaining to patients seen in his paediatric practice in Durban during the past 45 years. Likewise, PB reviewed case details of persons encountered since 1972 in Cape Town, at outreach clinics, and in special institutions for the handicapped throughout South Africa. Additional information was accessed through the Cape Genetic Heritage archive. Results. In addition to the common ubiquitous worldwide genetic disorders, several rare heritable conditions are present in the Indian community of South Africa. These disorders are the consequence of the founder effect and reflect the biological heritage of the early immigrants. Demographic factors (notably endogamy) are also relevant in this respect. As a result of these processes, thalassaemia is by far the most common and important genetic disorder in the Indian population in the country. Conclusion. Awareness of the presence of specific genetic conditions in the Indian community of South Africa is important in the diagnostic process. In turn, diagnostic precision facilitates accurate prognostication and optimal medical and genetic management

Community-Based Participatory Research and Sustainability: The Petersburg Wellness Consortium

The principle and practice of sustainability is critical in community-based participatory research. Actively planning for and building community capacity to ensure sustainability is even more critical in research involving underserved populations and underrepresented minorities. The perception of researchers engaging with the community until their research needs have been met, then leaving the community with minimal, if any benefits, has all too often been the reality in these communities. This paper offers a case study of how an independent community consortium was borne from an academic/community research partnership in Petersburg, Virginia. We discuss lessons learned and practice implications as we describe the evolution of, and challenges associated with, cultivating a sustainable independent coalition

Proteolysis of HCF-1 by Ser/Thr glycosylation-incompetent O-GlcNAc transferase:UDP-GlcNAc complexes

In complex with the cosubstrate UDP-N-acetylglucosamine (UDP-GlcNAc),O-linked-GlcNAc transferase (OGT) catalyzes Ser/ThrO-GlcNAcylation of many cellular proteins and proteolysis of the transcriptional coregulator HCF-1. Such a dual glycosyltransferase-protease activity, which occurs in the same active site, is unprecedented and integrates both reversible and irreversible forms of protein post-translational modification within one enzyme. Although occurring within the same active site, we show here that glycosylation and proteolysis occur through separable mechanisms. OGT consists of tetratricopeptide repeat (TPR) and catalytic domains, which, together with UDP-GlcNAc, are required for both glycosylation and proteolysis. Nevertheless, a specific TPR domain contact with the HCF-1 substrate is critical for proteolysis but not Ser/Thr glycosylation. In contrast, key catalytic domain residues and even a UDP-GlcNAc oxygen important for Ser/Thr glycosylation are irrelevant for proteolysis. Thus, from a dual glycosyltransferase-protease, essentially single-activity enzymes can be engineered both in vitro and in vivo. Curiously, whereas OGT-mediated HCF-1 proteolysis is limited to vertebrate species, invertebrate OGTs can cleave human HCF-1. We present a model for the evolution of HCF-1 proteolysis by OGT

Evaluating strategies for managing anthropogenic mortality on marine mammals : an R implementation with the package RLA

Funding: ADERA provided support for salaries (MA).Bycatch, the undesirable and non-intentional catch of non-target species in marine fisheries, is one of the main causes of mortality of marine mammals worldwide. When quantitative conservation objectives and management goals are clearly defined, computer-based procedures can be used to explore likely population dynamics under different management scenarios and estimate the levels of anthropogenic removals, including bycatch, that marine mammal populations may withstand. Two control rules for setting removal limits are the Potential Biological Removal (PBR) established under the US Marine Mammal Protection Act and the Removals Limit Algorithm (RLA) inspired from the Catch Limit Algorithm (CLA) developed under the Revised Management Procedure of the International Whaling Commission. The PBR and RLA control rules were tested in a Management Strategy Evaluation (MSE) framework. A key feature of PBR and RLA is to ensure conservation objectives are met in the face of the multiple uncertainties or biases that plague real-world data on marine mammals. We built a package named RLA in the R software to carry out MSE of control rules to set removal limits in marine mammal conservation. The package functionalities are illustrated by two case studies carried out under the auspices of the Oslo and Paris convention (OSPAR) (the Convention for the Protection of the Marine Environment of the North-East Atlantic) Marine Mammal Expert Group (OMMEG) in the context of the EU Marine Strategy Framework Directive. The first case study sought to tune the PBR control rule to the conservation objective of restoring, with a probability of 0.8, a cetacean population to 80% of carrying capacity after 100 years. The second case study sought to further develop a RLA to set removals limit on harbor porpoises in the North Sea with the same conservation objective as in the first case study. Estimation of the removals limit under the RLA control rule was carried out within the Bayesian paradigm. Outputs from the functions implemented in the package RLA allows the assessment of user-defined performance metrics, such as time to reach a given fraction of carrying capacity under a given level of removals compared to the time needed given no removals.Publisher PDFPeer reviewe

The conserved threonine-rich region of the HCF-1PRO repeat activates promiscuous OGT:UDP-GlcNAc glycosylation and proteolysis activities

O-Linked GlcNAc transferase (OGT) possesses dual glycosyltransferase-protease activities. OGT thereby stably glycosylates serines and threonines of numerous proteins and, via a transient glutamate glycosylation, cleaves a single known substrate-the so-called HCF-1 <sub>PRO</sub> repeat of the transcriptional co-regulator host-cell factor 1 (HCF-1). Here, we probed the relationship between these distinct glycosylation and proteolytic activities. For proteolysis, the HCF-1 <sub>PRO</sub> repeat possesses an important extended threonine-rich region that is tightly bound by the OGT tetratricopeptide-repeat (TPR) region. We report that linkage of this HCF-1 <sub>PRO</sub> -repeat, threonine-rich region to heterologous substrate sequences also potentiates robust serine glycosylation with the otherwise poor R <sub>p</sub> -αS-UDP-GlcNAc diastereomer phosphorothioate and UDP-5S-GlcNAc OGT co-substrates. Furthermore, it potentiated proteolysis of a non-HCF-1 <sub>PRO</sub> -repeat cleavage sequence, provided it contained an appropriately positioned glutamate residue. Using serine- or glutamate-containing HCF-1 <sub>PRO</sub> -repeat sequences, we show that proposed OGT-based or UDP-GlcNAc-based serine-acceptor residue activation mechanisms can be circumvented independently, but not when disrupted together. In contrast, disruption of both proposed activation mechanisms even in combination did not inhibit OGT-mediated proteolysis. These results reveal a multiplicity of OGT glycosylation strategies, some leading to proteolysis, which could be targets of alternative molecular regulatory strategies

A Framework for Dynamic Modelling of Railway Track Switches Considering the Switch Blades, Actuators and Control Systems

The main contribution of this paper is the development and demonstration a novel methodology that can be followed to develop a simulation twin of a railway track switch system to test the functionality in a digital environment. This is important because, globally, railway track switches are used to allow trains to change routes; they are a key part of all railway networks. However, because track switches are single points of failure, and safety-critical, their inability to operate correctly can cause significant delays and concomitant costs. In order to better understand the dynamic behaviour of switches during operation, this paper has developed a full simulation twin of a complete track switch system. The approach fuses FE for the rail bending and motion, with physics-based models of the electromechanical actuator system and the control system. Hence it provides researchers and engineers the opportunity to explore and understand the design space around the dynamic operation of new switches and switch machines before they are built. This is useful for looking at the modification or monitoring of existing switches, and it becomes even more important when new switch concepts are being considered and evaluated. The simulation is capable of running in real-time or faster meaning designs can be iterated and checked interactively. The paper describes the modelling approach and demonstrates the methodology by developing the system model for a novel “REPOINT” switch system and evaluating the system level performance against the switch’s dynamic performance requirements. In the context of that case study, it is found that the proposed new actuation system as designed can meet (and exceed) the system performance requirements and that the fault tolerance built into the actuation ensures continued operation after a single actuator failure

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated. © 2012 Cicek et al