Cornelia-de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect

Cornelia de Lange syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a missense mutation in BRD4 associated with a Cornelia de Lange-like syndrome that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers it does not affect transcription of the pluripotency network in mouse embryonic stem cells. Rather, it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange syndrome

Usefulness of molecular biology performed with formaldehyde-fixed paraffin embedded tissue for the diagnosis of combined pulmonary invasive mucormycosis and aspergillosis in an immunocompromised patient

Immunocompromised patients who develop invasive filamentous mycotic infections can be efficiently treated if rapid identification of the causative fungus is obtained. We report a case of fatal necrotic pneumonia caused by combined pulmonary invasive mucormycosis and aspergillosis in a 66 year-old renal transplant recipient. Aspergillus was first identified during the course of the disease by cytological examination and culture (A. fumigatus) of bronchoalveolar fluid. Hyphae of Mucorales (Rhizopus microsporus) were subsequently identified by culture of a tissue specimen taken from the left inferior pulmonary lobe, which was surgically resected two days before the patient died. Histological analysis of the lung parenchyma showed the association of two different filamentous mycoses for which the morphological features were evocative of aspergillosis and mucormycosis. However, the definitive identification of the associative infection was made by polymerase chain reaction (PCR) performed on deparaffinized tissue sections using specific primers for aspergillosis and mucormycosis. This case demonstrates that discrepancies between histological, cytological and mycological analyses can occur in cases of combined mycotic infection. In this regard, it shows that PCR on selected paraffin blocks is a very powerful method for making or confirming the association of different filamentous mycoses and that this method should be made available to pathology laboratories

Activity of Deferasirox in Mucorales: Influences of Species and Exogenous Iron

Differences in deferasirox susceptibility among members of the order Mucorales are unknown. Here we show that Cunninghamella bertholletiae (four isolates) and Mucor species (five isolates) display higher deferasirox MICs and minimal fungicidal concentrations compared to Rhizopus species (six isolates). Exogenous iron further attenuated the deferasirox susceptibility of Mucorales isolates with low MICs. Vital staining revealed damage to subapical compartments in susceptible strains

Bounding on Rough Terrain with the LittleDog Robot

A motion planning algorithm is described for bounding over rough terrain with the LittleDog robot. Unlike walking gaits, bounding is highly dynamic and cannot be planned with quasi-steady approximations. LittleDog is modeled as a planar five-link system, with a 16-dimensional state space; computing a plan over rough terrain in this high-dimensional state space that respects the kinodynamic constraints due to underactuation and motor limits is extremely challenging. Rapidly Exploring Random Trees (RRTs) are known for fast kinematic path planning in high-dimensional configuration spaces in the presence of obstacles, but search efficiency degrades rapidly with the addition of challenging dynamics. A computationally tractable planner for bounding was developed by modifying the RRT algorithm by using: (1) motion primitives to reduce the dimensionality of the problem; (2) Reachability Guidance, which dynamically changes the sampling distribution and distance metric to address differential constraints and discontinuous motion primitive dynamics; and (3) sampling with a Voronoi bias in a lower-dimensional “task space” for bounding. Short trajectories were demonstrated to work on the robot, however open-loop bounding is inherently unstable. A feedback controller based on transverse linearization was implemented, and shown in simulation to stabilize perturbations in the presence of noise and time delays.United States. Defense Advanced Research Projects Agency. Learning Locomotion Program (AFRL contract # FA8650-05-C-7262