Software Review of Risk*Assistant (Version 1.1) and RiskEZ (Version 1), both for Windows

RiskEZ and Risk*Assistant both make site risk assessment more accessible to many users and provide a relatively efficient means for performing screening level risk assessments. The programs perform basic site risk assessment calcu lations for users and provide point estimates of incremental individual cancer risks and non cancer hazard quotients following standard Environmental Pro tection Agency risk assessment guidance documents. Risk*Assistant allows the user to input raw data from which it can perform some dispersion modeling and calculate exposure point concentrations, while RiskEZ takes the exposure point concentrations as inputs. RiskEZ includes features that allow multiple network users to work on the same site and to deal with radioactive contami nants as well as chemical ones, while Risk*Assistant limits access to a site to one user at a time and it includes non radioactive substances. Neither program currently has the capability to perform probabilistic risk analyses, although Risk*Assistant allows the user to peform some sensitivity analysis. This review highlights differences between the programs and demonstrates how selection of a particular program might influence the results.     

Interaction between Foxc1 and Fgf8 during Mammalian Jaw Patterning and in the Pathogenesis of Syngnathia

Syngnathia (bony fusion of the upper and lower jaw) is a rare human congenital condition, with fewer than sixty cases reported in the literature. Syngnathia typically presents as part of a complex syndrome comprising widespread oral and maxillofacial anomalies, but it can also occur in isolation. Most cartilage, bone, and connective tissue of the head and face is derived from neural crest cells. Hence, congenital craniofacial anomalies are often attributed to defects in neural crest cell formation, survival, migration, or differentiation. The etiology and pathogenesis of syngnathia however remains unknown. Here, we report that Foxc1 null embryos display bony syngnathia together with defects in maxillary and mandibular structures, and agenesis of the temporomandibular joint (TMJ). In the absence of Foxc1, neural crest cell derived osteogenic patterning is affected, as osteoblasts develop ectopically in the maxillary prominence and fuse with the dentary bone. Furthermore, we observed that the craniofacial musculature is also perturbed in Foxc1 null mice, which highlights the complex tissue interactions required for proper jaw development. We present evidence that Foxc1 and Fgf8 genetically interact and that Fgf8 dosage is associated with variation in the syngnathic phenotype. Together our data demonstrates that Foxc1 – Fgf8 signaling regulates mammalian jaw patterning and provides a mechanistic basis for the pathogenesis of syngnathia. Furthermore, our work provides a framework for understanding jaw patterning and the etiology of other congenital craniofacial anomalies, including temporomandibular joint agenesis.     

Inducing the liver: Understanding the signals that promote murine liver budding

The endoderm emerges as an epithelial sheet that covers the surface of the developing murine embryo. This tissue will produce the entire gut tube as well as associated digestive and respiratory organs including the thyroid, thymus, lung, liver, and pancreas. The emergence of each endodermal organ occurs in a temporally distinct manner that is dependant upon reciprocal inductive interactions between the endoderm and the underlying mesoderm. The emergence of the hepatic endoderm, which occurs using a morphological process termed liver budding, initiates during early somitogenesis in the mouse at approximately 8.25 days post‐coitum (dpc). Explant and transplant studies performed in chicken and mouse have demonstrated that secreted signals from adjacent mesodermal tissues initiate the hepatic gene program from ventral‐fated endoderm. Here, we review the data in support of the roles of members of the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and Wnt signaling pathways in liver budding and discover that little is known about the precise endogenous signals involved in the molecular and morphological induction of liver budding in the mouse. J. Cell. Physiol. 226: 1727–1731, 2011. © 2010 Wiley‐Liss, Inc.     

Damping capacity is evolutionarily conserved in the radial silk of orb-weaving spiders

Orb-weaving spiders depend upon their two-dimensional silk traps to stop insects in mid flight. While the silks used to construct orb webs must be extremely tough to absorb the tremendous kinetic energy of insect prey, webs must also minimize the return of that energy to prey to prevent insects from bouncing out of oscillating webs. We therefore predict that the damping capacity of major ampullate spider silk, which forms the supporting frames and radial threads of orb webs, should be evolutionarily conserved among orb-weaving spiders. We test this prediction by comparing silk from six diverse species of orb spiders. Silk was taken directly from the radii of orb webs and a Nano Bionix test system was used either to sequentially extend the silk to 25% strain in 5% increments while relaxing it fully between each cycle, or to pull virgin silk samples to 15% strain. Damping capacity was then calculated as the percent difference in loading and unloading energies. Damping capacity increased after yield for all species and typically ranged from 40 to 50% within each cycle for sequentially pulled silk and from 50 to 70% for virgin samples. Lower damping at smaller strains may allow orb webs to withstand minor perturbations from wind and small prey while still retaining the ability to capture large insects. The similarity in damping capacity of silk from the radii spun by diverse spiders highlights the importance of energy absorption by silk for orb-weaving spiders.     

Conjunctival melanoma copy number alterations and correlation with mutation status,tumor features,and clinical outcome

Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation‐specific copy number alterations. Deletions on chr 10q11.21‐26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann–Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.     

Diverse lineages of pathogenic Leptospira species are widespread in the environment in Puerto Rico,USA

BackgroundLeptospirosis, caused by Leptospira bacteria, is a common zoonosis worldwide, especially in the tropics. Reservoir species and risk factors have been identified but surveys for environmental sources are rare. Furthermore, understanding of environmental Leptospira containing virulence associated genes and possibly capable of causing disease is incomplete, which may convolute leptospirosis diagnosis, prevention, and epidemiology.Methodology/Principal findingsWe collected environmental samples from 22 sites in Puerto Rico during three sampling periods over 14-months (Dec 2018-Feb 2020); 10 water and 10 soil samples were collected at each site. Samples were screened for DNA from potentially pathogenic Leptospira using the lipL32 PCR assay and positive samples were sequenced to assess genetic diversity. One urban site in San Juan was sampled three times over 14 months to assess persistence in soil; live leptospires were obtained during the last sampling period. Isolates were whole genome sequenced and LipL32 expression was assessed in vitro.We detected pathogenic Leptospira DNA at 15/22 sites; both soil and water were positive at 5/15 sites. We recovered lipL32 sequences from 83/86 positive samples (15/15 positive sites) and secY sequences from 32/86 (10/15 sites); multiple genotypes were identified at 12 sites. These sequences revealed significant diversity across samples, including four novel lipL32 phylogenetic clades within the pathogenic P1 group. Most samples from the serially sampled site were lipL32 positive at each time point. We sequenced the genomes of six saprophytic and two pathogenic Leptospira isolates; the latter represent a novel pathogenic Leptospira species likely belonging to a new serogroup.Conclusions/SignificanceDiverse and novel pathogenic Leptospira are widespread in the environment in Puerto Rico. The disease potential of these lineages is unknown but several were consistently detected for >1 year in soil, which could contaminate water. This work increases understanding of environmental Leptospira diversity and should improve leptospirosis surveillance and diagnostics.     

Novel Staphylococcal Glycosyltransferases SdgA and SdgB Mediate Immunogenicity and Protection of Virulence-Associated Cell Wall Proteins

Infection of host tissues by Staphylococcus aureus and S. epidermidis requires an unusual family of staphylococcal adhesive proteins that contain long stretches of serine-aspartate dipeptide-repeats (SDR). The prototype member of this family is clumping factor A (ClfA), a key virulence factor that mediates adhesion to host tissues by binding to extracellular matrix proteins such as fibrinogen. However, the biological siginificance of the SDR-domain and its implication for pathogenesis remain poorly understood. Here, we identified two novel bacterial glycosyltransferases, SdgA and SdgB, which modify all SDR-proteins in these two bacterial species. Genetic and biochemical data demonstrated that these two glycosyltransferases directly bind and covalently link N-acetylglucosamine (GlcNAc) moieties to the SDR-domain in a step-wise manner, with SdgB appending the sugar residues proximal to the target Ser-Asp repeats, followed by additional modification by SdgA. GlcNAc-modification of SDR-proteins by SdgB creates an immunodominant epitope for highly opsonic human antibodies, which represent up to 1% of total human IgG. Deletion of these glycosyltransferases renders SDR-proteins vulnerable to proteolysis by human neutrophil-derived cathepsin G. Thus, SdgA and SdgB glycosylate staphylococcal SDR-proteins, which protects them against host proteolytic activity, and yet generates major eptopes for the human anti-staphylococcal antibody response, which may represent an ongoing competition between host and pathogen.