11 research outputs found
Memory in random bouncing ball dynamics
The bouncing of an inelastic ball on a vibrating plate is a popular model
used in various fields, from granular gases to nanometer-sized mechanical
contacts. For random plate motion, so far, the model has been studied using
Poincar{\'e} maps in which the excitation by the plate at successive bounces is
assumed to be a discrete Markovian (memoryless) process. Here, we investigate
numerically the behaviour of the model for continuous random excitations with
tunable correlation time. We show that the system dynamics are controlled by
the ratio of the Markovian mean flight time of the ball and the mean time
between successive peaks in the motion of the exciting plate. When this ratio,
which depends on the bandwidth of the excitation signal, exceeds a certain
value, the Markovian approach is appropriate; below, memory of preceding
excitations arises, leading to a significant decrease of the jump duration; at
the smallest values of the ratio, chattering occurs. Overall, our results open
the way for uses of the model in the low excitation regime, which is still
poorly understood.Comment: Final published version, 5 pages, 4 figure
Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23
SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24–q32. By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3′ UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23.The Centre for Dermatology and Genetic Medicine is supported by a Wellcome Trust Strategic Award (reference 098439/Z/12/Z). The work was supported by the MRC (MR/M018512/1) and the UK National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre (BRC) award to Guy’s and St. Thomas’ NHS Foundation Trust, in partnership with the King’s College London and King’s College Hospital NHS Foundation Trust. This study was also supported by UK Medical Research Council Project Grant (MR/M00046X/1) and Action Research grant SP3706 as well as medical student grants from the Jean Shanks Foundation and the British Association of Dermatologists
A new IV busulfan fixed dosing for better exposure targeting in children undergoing allogeneic or autologous hematopoietic stem cell transplantation
Ofatumumab in poor-prognosis chronic lymphocytic leukemia: A phase IV, non-interventional, observational study from the European research initiative on chronic lymphocytic leukemia
We report the largest retrospective, phase IV non-interventional, observational study of ofatumumab therapy in heavily pre-treated patients with poor-prognosis chronic lymphocytic leukemia. Total number of patients was 103; median age was 65 years (range 39-85). Median number of prior lines of therapy was 4 (range 1-13), including, in most cases, rituximab-, fludarabine-and alemtuzumab-based regimens; 13 patients had been allografted. Of 113 adverse events, 28 (29%) were considered to be directly related to ofatumumab. Grade 3-4 toxicities included neutropenia (10%), thrombocytopenia (5%), anemia (3%), pneumonia (17%), and fever (3%). Two heavily pre-treated patients developed progressive multifocal leukoencephalopathy. On an intention-to-treat analysis, the overall response rate was 22% (3 complete response, 1 incomplete complete response). Median progression-free and overall survival times were 5 and 11 months, respectively. This study confirms in a daily-life setting the feasibility and acceptable toxicity of ofatumumab treatment in advanced chronic lymphocytic leukemia. The complete response rate, however, was low. Therefore, treatment with ofatumumab should be moved to earlier phases of the disease. Ideally, this should be done in combination with other agents, as recently approved for ofatumumab plus chlorambucil as front-line treatment for patients unfit for fludarabine. © 2015 Ferrata Storti Foundation