The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1

The dynamic regulation of histone modifications is important for modulating transcriptional programs during development. Aberrant H3K4 methylation is associated with neurological disorders, but how the levels and the recognition of this modification affect specific neuronal processes is unclear. Here we show that RBR-2, the sole homolog of the KDM5 family of H3K4me3/me2 demethylases in Caenorhabditis elegans, ensures correct axon guidance by controlling the expression of the actin regulator wsp-1. Loss of rbr-2 results in increased levels of H3K4me3 at the transcriptional start site of wsp-1, with concomitant higher wsp-1 expression responsible for defective axon guidance. In agreement, overexpression of WSP-1 mimics rbr-2 loss, while its depletion restores normal axon guidance in rbr-2 mutants. NURF-1, an H3K4me3-binding protein and member of the chromatin-remodeling complex NURF, is required for promoting aberrant wsp-1 transcription in rbr-2 mutants and its ablation restores wild type expression of wsp-1 and axon guidance. Thus, our results establish a precise role for epigenetic regulation in neuronal development by demonstrating a functional link between RBR-2 activity, H3K4me3 levels, the NURF complex and the expression of WSP-1.</jats:p

Intravascular myopericytoma in the heel: Case report and literature review

Intravascular myopericytoma (IVMP), regarded as a variant of myopericytoma, is a rare tumor. Very few cases have been described, none in the foot. The first case of IVMP located in the heel of the foot is described in this article. A literature review is reported of all cases of IVMP published in the English literature. A 48-year-old man possessed an IVMP on the heel of the right foot. The physical examination and histopathological and ultrasound studies are described. The literature review yielded 5 cases of IVMP, 2 of which were in the thigh and 1 each in the oral mucosa, the periorbital region, and the leg. The possibility that these lesions may be malignant suggests that the histopathological study of vascular tumors should include immunohistochemical tests

A clathrin coat assembly role for the muniscin protein central linker revealed by TALEN-mediated gene editing

Clathrin-mediated endocytosis is an evolutionarily ancient membrane transport system regulating cellular receptivity and responsiveness. Plasmalemma clathrin-coated structures range from unitary domed assemblies to expansive planar constructions with internal or flanking invaginated buds. Precisely how these morphologically-distinct coats are formed, and whether all are functionally equivalent for selective cargo internalization is still disputed. We have disrupted the genes encoding a set of early arriving clathrin-coat constituents, FCHO1 and FCHO2, in HeLa cells. Endocytic coats do not disappear in this genetic background; rather clustered planar lattices predominate and endocytosis slows, but does not cease. The central linker of FCHO proteins acts as an allosteric regulator of the prime endocytic adaptor, AP-2. By loading AP-2 onto the plasma membrane, FCHO proteins provide a parallel pathway for AP-2 activation and clathrin-coat fabrication. Further, the steady-state morphology of clathrin-coated structures appears to be a manifestation of the availability of the muniscin linker during lattice polymerization. DOI: http://dx.doi.org/10.7554/eLife.04137.00

A new surgical procedure for hallux limitus treatment: Double-V osteotomy on the base of the proximal phalanx of the hallux

The purpose of this study was to evaluate the effectiveness of the new Double-V osteotomy of the first metatarsophalangeal joint (1 st MPJ) in patients with hallux limitus (HL). A study of 66 patients was performed, 33 patients were treated Cheilectomy and 33 were treated Double-V. All patients underwent an assessment of the passive mobility of the 1 st MPJ before the procedure, reevaluated 12 months later evaluating dorsiflexion, plantarflexion, and patients status using both the American Orthopaedic Foot and Ankle Society (AOFAS) for Hallux Metatarsophalangeal-Interphalangeal Scale. In comparing the improvement achieved regarding the increase of mobility obtained with surgical treatment, the feet operated with procedure Double-V gained significant degrees of movement increased in all analyzed parameters (P<.05). We achieved 13.33° more than average in dorsiflexion motion and 2.12° more than average in plantarflexion with regard to the feet that were operated with Cheilectomy procedure. Double-V scores on the AOFAS scale improved significantly (P=.000) 91.48 points postoperative, while with the following Cheilectomy only 79.30 points. This new surgical technique, easy to perform and with low complexity in surgical execution and a minimum of complications, produces better clinical and functional results that Cheilectomy alone

The Eps15 Homology (Eh) Domain-Based Interaction between Eps15 and Hrb Connects the Molecular Machinery of Endocytosis to That of Nucleocytosolic Transport

The Eps15 homology (EH) module is a protein–protein interaction domain that establishes a network of connections involved in various aspects of endocytosis and sorting. The finding that EH-containing proteins bind to Hrb (a cellular cofactor of the Rev protein) and to the related protein Hrbl raised the possibility that the EH network might also influence the so-called Rev export pathway, which mediates nucleocytoplasmic transfer of proteins and RNAs. In this study, we demonstrate that Eps15 and Eps15R, two EH-containing proteins, synergize with Hrb and Hrbl to enhance the function of Rev in the export pathway. In addition, the EH-mediated association between Eps15 and Hrb is required for the synergistic effect. The interaction between Eps15 and Hrb occurs in the cytoplasm, thus pointing to an unexpected site of action of Hrb, and to a possible role of the Eps15–Hrb complex in regulating the stability of Rev

Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffold

AbstractThe molecular coupling of CAS and Crk in response to integrin activation is an evolutionary conserved signaling module that controls cell proliferation, survival and migration. However, when deregulated, CAS/Crk signaling also contributes to cancer progression and developmental defects in humans. Here we highlight recent advances in our understanding of how CAS/Crk complexes assemble in cells to modulate the actin cytoskeleton, and the molecular mechanisms that regulate this process. We discuss in detail the spatiotemporal dynamics of CAS/Crk assembly and how this scaffold recruits specific effector proteins that couple integrin signaling networks to the migration machinery of cells. We also highlight the importance of CAS/Crk signaling in the dual regulation of cell migration and survival mechanisms that operate in invasive cells during development and pathological conditions associated with cancer metastasis

Radioguided adrenal surgery access in complex situations: Technical notes

The laparoscopic adrenalectomy is considered as the procedure of choice for the treatment of adrenal hyperplasia and tumor lesions. However, some special situations may limit the use of this method due to the difficulty to locate the gland and perform the lesion excision. We analyze 2 patients of a left adrenal tumor, explaining how they have overcome the difficulties in both situations. The first case was a patient with a history of intra-abdominal surgery and the other patient suffered from severe obesity. We performed with the use of the gamma probe, and the 2 cases, was of great help to access and glandular localization. The help of gamma probe test was achieved in the surgical bed, that removal was complete. The use of the portable gamma probe facilitated the access to the left adrenal gland as well as conducting the glandular excision without delay, despite the difficulties due to the intra abdominal surgery caused by the previous surgery, and in the case of severe obesity

Rescue radioguided laparoscopy surgery for meckel's diverticulum

The extirpation of Meckel's diverticulum (MD) via conventional or laparoscopic surgery is the definitive treatment. However, certain circumstances may modify or alter this situation and require the application of exceptional measures. We report a case under our observation who previously had an exploratory abdominal laparotomy for a suspected MD; however, the findings were negative. At that time, the diagnosis was established based on low-level gastrointestinal bleeding and isotopic tests that confirmed the existence of the diverticulum. Given the findings of gamma-graphic exploration and the previous negative surgical exploration, a decision was made to remove the lesion by laparoscopic radioguided surgery. The patient underwent bilateral laparoscopic radioguided surgery using a gamma radiation detection probe. The exploration of the abdominal cavity noted the existence of the diverticulum about 60 to 70 cm from the ileocecal valve. In this way, it was possible to proceed with the resection of the bowel loop and perform an intracorporeal anastomosis termino lateral. The postoperative course was uneventful, and the patient was discharged on the fifth postoperative day. We believe that the combination of radioguided surgery and single photon emission computed tomography/computed tomography could be useful for treating lesions in locations that are surgically difficult because of the characteristics of the lesion itself or the peculiarities of an individual patient

Tyrosine Phosphorylation of Eps15 Is Required for Ligand-Regulated, but Not Constitutive, Endocytosis

Membrane receptors are internalized either constitutively or upon ligand engagement. Whereas there is evidence for differential regulation of the two processes, little is known about the molecular machinery involved. Previous studies have shown that an unidentified kinase substrate is required for endocytosis of the epidermal growth factor receptor (EGFR), the prototypical ligand-inducible receptor, but not of the transferrin receptor (TfR), the prototypical constitutively internalized receptor. Eps15, an endocytic protein that is tyrosine phosphorylated by EGFR, is a candidate for such a function. Here, we show that tyrosine phosphorylation of Eps15 is necessary for internalization of the EGFR, but not of the TfR. We mapped Tyr 850 as the major in vivo tyrosine phosphorylation site of Eps15. A phosphorylation-negative mutant of Eps15 acted as a dominant negative on the internalization of the EGFR, but not of the TfR. A phosphopeptide, corresponding to the phosphorylated sequence of Eps15, inhibited EGFR endocytosis, suggesting that phosphotyrosine in Eps15 serves as a docking site for a phosphotyrosine binding protein. Thus, tyrosine phosphorylation of Eps15 represents the first molecular determinant, other than those contained in the receptors themselves, which is involved in the differential regulation of constitutive vs. regulated endocytosis