Sonic Hedgehog Induces the Segregation of Patched and Smoothened in Endosomes

AbstractBackground: Sonic hedgehog (Shh) signal transduction involves the ligand binding Patched1 (Ptc1) protein and a signaling component, Smoothened (Smo). A select group of compounds inhibits both Shh signaling, regulated by Ptc1, and late endosomal lipid sorting, regulated by the Ptc-related Niemann-Pick C1 (NPC1) protein. This suggests that Ptc1 regulates Smo activity through a common late endosomal sorting pathway also utilized by NPC1. During signaling, Ptc accumulates in endosomal compartments, but it is unclear if Smo follows Ptc into the endocytic pathway.Results: We characterized the dynamic subcellular distributions of Ptc1, Smo, and activated Smo mutants individually and in combination. Ptc1 and Smo colocalize extensively in the absence of ligand and are internalized together after ligand binding, but Smo becomes segregated from Ptc1/Shh complexes destined for lysosomal degradation. In contrast, activated Smo mutants do not colocalize with nor are cotransported with Ptc1. Agents that block late endosomal transport and protein sorting inhibit the ligand-induced segregation of Ptc1 and Smo. We show that, like NPC1-regulated lipid sorting, Shh signal transduction is blocked by antibodies that specifically disrupt the internal membranes of late endosomes, which provide a platform for protein and lipid sorting.Conclusions: These data support a model in which Ptc1 inhibits Smo only when in the same compartment. Ligand-induced segregation allows Smo to signal independently of Ptc1 after becoming sorted from Ptc1/Shh complexes in the late endocytic pathway

Multiple Small Bowel Perforations Secondary to Cytomegalovirus in a Patient with Acquired Immunodeficiency Syndrome

Cytomegalovirus gastroenteritis can be a life-threatening infection in patients with the acquired immunodeficiency syndrome. Although gastrointestinal ulcerations from cytomegalovirus have been widely reported, our patient is only the second case reported with actual perforations in the small bowel

Chronic Idiopathic Thrombocytopenic Purpura: Effective preoperative preparation and long-term results of splenectomy

A retrospective review of 98 patients seen at Henry Ford Hospital from 1953 through 1977 demonstrated that splenectomy for chronic idiopathic thrombocytopenic purpura provided a good response which usually was sustained on long-term follow-up (72% at 15 years). Although splenectomy for this condition had a low mortality, morbidity was significant in patients older than 40 years. When compared to patients whose response to splenectomy was sustained, patients who relapsed had significantly lower platelet counts preoperatively both when they were untreated (mean: 9,194 per cc versus 18,524 per-cc) and/or when they were treated with steroids (mean: 85,647 per cc versus 142,590 per cc). Another significant risk factor for relapse was a longer interval from splenectomy to the maximum postoperative platelet count. In the immediate preoperative preparation of the patient for splenectomy, corticosteroids temporarily increased the platelet count, but high doses were necessary in many patients. A platelet count of greater than 40,000/cc usually was achieved with a dose of 60 to 80 mgs of prednisone per day for several days. Platelet infusion rarely was needed if patients were prepared adequately with steroids. There should be no hesitation to give large doses of steroids for a few days, and a delay in proceeding with the operation, once indicated, should be avoided. Because the response of the platelet count to splenectomy may be variable or fluctuating and late relapses can occur, patients should be re-evaluated periodically

Algorithmic decidability of Engel's property for automaton groups

We consider decidability problems associated with Engel's identity ($[\cdots[[x,y],y],\dots,y]=1$ for a long enough commutator sequence) in groups generated by an automaton. We give a partial algorithm that decides, given $x,y$, whether an Engel identity is satisfied. It succeeds, importantly, in proving that Grigorchuk's $2$-group is not Engel. We consider next the problem of recognizing Engel elements, namely elements $y$ such that the map $x\mapsto[x,y]$ attracts to $\{1\}$. Although this problem seems intractable in general, we prove that it is decidable for Grigorchuk's group: Engel elements are precisely those of order at most $2$. Our computations were implemented using the package FR within the computer algebra system GAP

New High Field State of Flux Line Lattice in Unconventional Superconductor CeCoIn_5

Ultrasound velocity measurements of the unconventional superconductor CeCoIn_5 with extremely large Pauli paramagnetic susceptibility reveal an unusual structural transformation of the flux line lattice (FLL) in the vicinity of the upper critical field. The transition field coincides with that at which heat capacity measurements reveal a second order phase transition. The lowering of the sound velocity at the transition is consistent with the collapse of the FLL tilt modulus and a crossover to quasi two-dimensional FLL pinning. These results provide a strong evidence that the high field state is the Fulde-Ferrel-Larkin-Ovchinikov phase, in which the order parameter is spatially modulated and has planar nodes aligned perpendicular to the vortices.Comment: 5 pages, 4 figure

Late Endosomal Cholesterol Accumulation Leads to Impaired Intra-Endosomal Trafficking

Background Pathological accumulation of cholesterol in late endosomes is observed in lysosomal storage diseases such as Niemann-Pick type C. We here analyzed the effects of cholesterol accumulation in NPC cells, or as phenocopied by the drug U18666A, on late endosomes membrane organization and dynamics. Methodology/Principal Findings Cholesterol accumulation did not lead to an increase in the raft to non-raft membrane ratio as anticipated. Strikingly, we observed a 2–3 fold increase in the size of the compartment. Most importantly, properties and dynamics of late endosomal intralumenal vesicles were altered as revealed by reduced late endosomal vacuolation induced by the mutant pore-forming toxin ASSP, reduced intoxication by the anthrax lethal toxin and inhibition of infection by the Vesicular Stomatitis Virus. Conclusions/Significance These results suggest that back fusion of intralumenal vesicles with the limiting membrane of late endosomes is dramatically perturbed upon cholesterol accumulation

Temperature dependence of the upper critical field of an anisotropic singlet superconductivity in a square lattice tight-binding model in parallel magnetic fields

Upper critical field parallel to the conducting layer is studied in anisotropic type-II superconductors on square lattices. We assume enough separation of the adjacent layers, for which the orbital pair-breaking effect is suppressed for exactly aligned parallel magnetic field. In particular, we examine the temperature dependence of the critical field H_c(T) of the superconductivity including the Fulde-Ferrell-Larkin-Ovchinnikov (FFLO or LOFF) state, in which the Cooper pairs have non-zero center-of-mass momentum q. In the system with the cylindrically symmetric Fermi-surface, it is known that H_c(T) of the d-wave FFLO state exhibits a kink at a low temperature due to a change of the direction of q in contrast to observations in organic superconductors. It is shown that the kink disappears when the Fermi-surface is anisotropic to some extent, since the direction of q is locked in an optimum direction independent of the temperature.Comment: 5 pages, 5 figures, revtex.sty, submitted to J.Phys.Soc.Jp

SNX12 Role in Endosome Membrane Transport

In this paper, we investigated the role of sorting nexin 12 (SNX12) in the endocytic pathway. SNX12 is a member of the PX domain-containing sorting nexin family and shares high homology with SNX3, which plays a central role in the formation of intralumenal vesicles within multivesicular endosomes. We found that SNX12 is expressed at very low levels compared to SNX3. SNX12 is primarily associated with early endosomes and this endosomal localization depends on the binding to 3-phosphoinositides. We find that overexpression of SNX12 prevents the detachment (or maturation) of multivesicular endosomes from early endosomes. This in turn inhibits the degradative pathway from early to late endosomes/lysosomes, much like SNX3 overexpression, without affecting endocytosis, recycling and retrograde transport. In addition, while previous studies showed that Hrs knockdown prevents EGF receptor sorting into multivesicular endosomes, we find that overexpression of SNX12 restores the sorting process in an Hrs knockdown background. Altogether, our data show that despite lower expression level, SNX12 shares redundant functions with SNX3 in the biogenesis of multivesicular endosomes