Analysis of Expression Pattern and Genetic Deletion of Netrin5 in the Developing Mouse

Boundary cap cells are a transient, neural-crest-derived population found at the motor exit point and dorsal root entry zone of the embryonic spinal cord. These cells contribute to the central/peripheral nervous system boundary, and in their absence neurons and glia from the CNS migrate into the PNS. We found Netrin5 (Ntn5), a previously unstudied member of the netrin gene family, to be robustly expressed in boundary cap cells. We generated Ntn5 knockout mice and examined neurodevelopmental and boundary-cap-cell-related phenotypes. No abnormalities in cranial nerve guidance, dorsal root organization, or sensory projections were found. However, Ntn5 mutant embryos did have ectopic motor neurons that migrated out of the ventral horn and into the motor roots. Previous studies have implicated semaphorin6A (Sema6A) in boundary cap cells signaling to plexinA2 (PlxnA2)/neuropilin2 (Nrp2) in motor neurons in restricting motor neuron cell bodies to the ventral horn, particularly in the caudal spinal cord. In Ntn5 mutants, ectopic motor neurons are likely to be a different population, as more ectopias were found rostrally. Furthermore, ectopic motor neurons in Ntn5 mutants were not immunoreactive for NRP2. The netrin receptor DCC is a potential receptor for NTN5 in motor neurons, as similar ectopic neurons were found in Dcc mutant mice, but not in mice deficient for other netrin receptors. Thus, Ntn5 is a novel netrin family member that is expressed in boundary cap cells, functioning to prevent motor neuron migration out of the CNS

A Deficiency of Ceramide Biosynthesis Causes Cerebellar Purkinje Cell Neurodegeneration and Lipofuscin Accumulation

Sphingolipids, lipids with a common sphingoid base (also termed long chain base) backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln) and toppler (to), with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydro)ceramide synthase 1 (CerS1), which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases

Pedestrian-level wind conditions around buildings for wind comfort assessment

The practice of investigating the pedestrian level wind environment, so called wind engineering, is now ubiquitous. Many city case studies exist in literature but few systematic studies of common urban architectural features exist. Among these common features is the simple channel which is common in large cities and has been well documented in literature as leading to significant wind speed increases. This study investigates the effects of adding a blockage at the channel inlet on observed velocities in the channel centerline on 1:100 scale with a view to applying the results to full scale. Time averaged velocity profiles were used to investigate the effect of blockage size and channel width on wind speed amplification. It was found that counter-intuitively, the size of the blockage at the inlet is not proportional to the size of the peak velocity reduction in the channel. The largest blockage created a minimum flow speed reduction (K = 0.98) for a channel width of 200mm. It was outperformed by the smallest blockage for a channel width of 300mm where a greater speed reduction was observed (K = 1.04). It was found that for buildings nearing the interaction flow regime the addition of a blockage has negligible effect on speed.J. Steer, S. W. Li, N. Morcom, S. Jucius, F. Ghanadi and M. Arjomand