Defective platelet function in Niemann-Pick disease type C1

Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in either NPC1 (95% of cases) or NPC2. Reduced late endosome/lysosome calcium (Ca2+) levels and the accumulation of unesterified cholesterol and sphingolipids within the late endocytic system characterize this disease. We previously reported impaired lysosome-related organelle (LRO) function in Npc1−/− Natural Killer cells; however, the potential contribution of impaired acid compartment Ca2+ flux and LRO function in other cell types has not been determined. Here, we investigated LRO function in NPC1 disease platelets. We found elevated numbers of circulating platelets, impaired platelet aggregation and prolonged bleeding times in a murine model of NPC1 disease. Electron microscopy revealed abnormal ultrastructure in murine platelets, consistent with that seen in a U18666A (pharmacological inhibitor of NPC1) treated megakaryocyte cell line (MEG-01) exhibiting lipid storage and acidic compartment Ca2+ flux defects. Furthermore, platelets from NPC1 patients across different ages were found to cluster at the lower end of the normal range when platelet numbers were measured and had platelet volumes that were clustered at the top of the normal range. Taken together, these findings highlight the role of acid compartment Ca2+ flux in the function of platelet LROs

Lepton flavor violation in the Simplest Little Higgs model

The flavor sector of Little Higgs models based on product groups, notably the Littlest Higgs with T parity (LHT), has been extensively studied and some amount of fine tuning was found to be required to meet the experimental constraints. However, no such attention has been paid to other classes of models. Here we analyze the phenomenology of flavor mixing in the lepton sector of a simple group model, the Simplest Little Higgs (SLH). We obtain the Feynman rules of the SLH in the 't Hooft-Feynman gauge up to the necessary order and calculate the leading contributions to the rare processes mu -> e gamma, mu -> eee and mu-e conversion in nuclei. We find results comparable to those of the LHT model, because in both cases they arise at the one-loop level. These require the flavor alignment of the Yukawa couplings of light and heavy leptons at the per cent level or an effective scale of around 10 TeV.Comment: 41 pages, 8 figures; minor changes and one reference added, version to appear in JHE

Defective platelet function in Niemann‐Pick disease type C1

Niemann‐Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in either NPC1 (95% of cases) or NPC2. Reduced late endosome/lysosome calcium (Ca2+) levels and the accumulation of unesterified cholesterol and sphingolipids within the late endocytic system characterize this disease. We previously reported impaired lysosome‐related organelle (LRO) function in Npc1−/− Natural Killer cells; however, the potential contribution of impaired acid compartment Ca2+ flux and LRO function in other cell types has not been determined. Here, we investigated LRO function in NPC1 disease platelets. We found elevated numbers of circulating platelets, impaired platelet aggregation and prolonged bleeding times in a murine model of NPC1 disease. Electron microscopy revealed abnormal ultrastructure in murine platelets, consistent with that seen in a U18666A (pharmacological inhibitor of NPC1) treated megakaryocyte cell line (MEG‐01) exhibiting lipid storage and acidic compartment Ca2+ flux defects. Furthermore, platelets from NPC1 patients across different ages were found to cluster at the lower end of the normal range when platelet numbers were measured and had platelet volumes that were clustered at the top of the normal range. Taken together, these findings highlight the role of acid compartment Ca2+ flux in the function of platelet LROs