82 research outputs found
The recurrent pathogenic Pro890Leu substitution in CLTC causes a generalized defect in synaptic transmission in Caenorhabditis elegans
De novo CLTC mutations underlie a spectrum of early-onset neurodevelopmental phenotypes having developmental delay/intellectual disability (ID), epilepsy, and movement disorders (MD) as major clinical features. CLTC encodes the widely expressed heavy polypeptide of clathrin, a major component of the coated vesicles mediating endocytosis, intracellular trafficking, and synaptic vesicle recycling. The underlying pathogenic mechanism is largely unknown. Here, we assessed the functional impact of the recurrent c.2669C > T (p.P890L) substitution, which is associated with a relatively mild ID/MD phenotype. Primary fibroblasts endogenously expressing the mutated protein show reduced transferrin uptake compared to fibroblast lines obtained from three unrelated healthy donors, suggesting defective clathrin-mediated endocytosis. In vitro studies also reveal a block in cell cycle transition from G0/G1 to the S phase in patient's cells compared to control cells. To demonstrate the causative role of the p.P890L substitution, the pathogenic missense change was introduced at the orthologous position of the Caenorhabditis elegans gene, chc-1 (p.P892L), via CRISPR/Cas9. The resulting homozygous gene-edited strain displays resistance to aldicarb and hypersensitivity to PTZ, indicating defective release of acetylcholine and GABA by ventral cord motor neurons. Consistently, mutant animals show synaptic vesicle depletion at the sublateral nerve cords, and slightly defective dopamine signaling, highlighting a generalized deficit in synaptic transmission. This defective release of neurotransmitters is associated with their secondary accumulation at the presynaptic membrane. Automated analysis of C. elegans locomotion indicates that chc-1 mutants move slower than their isogenic controls and display defective synaptic plasticity. Phenotypic profiling of chc-1 (+/P892L) heterozygous animals and transgenic overexpression experiments document a mild dominant-negative behavior for the mutant allele. Finally, a more severe phenotype resembling that of chc-1 null mutants is observed in animals harboring the c.3146 T > C substitution (p.L1049P), homologs of the pathogenic c.3140 T > C (p.L1047P) change associated with a severe epileptic phenotype. Overall, our findings provide novel insights into disease mechanisms and genotype-phenotype correlations of CLTC-related disorders
Design and experimental evaluation of a low-complexity spatial combiner for LTE distributed antenna systems
On the Selection of Adaptive Modulation and Coding Modes over OFDM
In this paper we address the problem of how best
selecting the smallest set of transmission modes (i.e. modulation
and channel code formats) to be employed in adaptive modulation
and coding (AMC) schemes for OFDM. In fact, by decreasing the
number of allowable modes, the complexity of the ACM scheme is
greatly reduced. The method makes use of an optimum throughput
maximization algorithm for the bit and power allocation. We
start with a large set of possible transmission modes. Then, for
a given channel, we iterate the loading algorithm with mode sets
having successive removal of the mode which yields the smallest
contribution to the overall throughput. By using this method in a
Rayleigh fading channel, we are able to show that in the test case
of the HIPERLAN/2 modes, up to five modes out of seven can
be removed with a very small impact on the average achievable
throughput
[Special problems in the surgical treatment of megaesophageal cardial achalasia. A clinical case].
The paper report the case of a patient brought to the Authors' attention suffering from megaesophageal cardial achalasia who had already undergone gastroduodenal resection according to BII. It was considered worthwhile to report this case due to the problems which arose concerning the choice of a thoracic rather than abdominal route owing to the impossibility of associating cardiomyotomy with anti-reflux plastica surgery because of the reduced dimensions of the stomach
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