In vitro functional correction of Hermansky-Pudlak Syndrome type-1 by lentiviral-mediated gene transfer.

Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism, bleeding tendency and susceptibility to pulmonary fibrosis. No curative therapy is available. Genetic correction directed to the lungs, bone marrow and/or gastro-intestinal tract might provide alternative forms of treatment for the diseases multi-systemic complications. We demonstrate that lentiviral-mediated gene transfer corrects the expression and function of the HPS1 gene in patient dermal melanocytes, which opens the way to development of gene therapy for HPS

Variational formulas of higher order mean curvatures

In this paper, we establish the first variational formula and its Euler-Lagrange equation for the total $2p$-th mean curvature functional $\mathcal {M}_{2p}$ of a submanifold $M^n$ in a general Riemannian manifold $N^{n+m}$ for $p=0,1,...,[\frac{n}{2}]$. As an example, we prove that closed complex submanifolds in complex projective spaces are critical points of the functional $\mathcal {M}_{2p}$, called relatively $2p$-minimal submanifolds, for all $p$. At last, we discuss the relations between relatively $2p$-minimal submanifolds and austere submanifolds in real space forms, as well as a special variational problem.Comment: 13 pages, to appear in SCIENCE CHINA Mathematics 201

Resolvent estimates for normally hyperbolic trapped sets

We give pole free strips and estimates for resolvents of semiclassical operators which, on the level of the classical flow, have normally hyperbolic smooth trapped sets of codimension two in phase space. Such trapped sets are structurally stable and our motivation comes partly from considering the wave equation for Kerr black holes and their perturbations, whose trapped sets have precisely this structure. We give applications including local smoothing effects with epsilon derivative loss for the Schr\"odinger propagator as well as local energy decay results for the wave equation.Comment: Further changes to erratum correcting small problems with Section 3.5 and Lemma 4.1; this now also corrects hypotheses, explicitly requiring trapped set to be symplectic. Erratum follows references in this versio

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse

Total energy calculation of high pressure selenium: The origin of incommensurate modulations in Se-IV and the instability of proposed Se-II

We present calculation of the high pressure crystal structures in selenium, including rational approximants to the recently reported incommensurate phases. We show how the incommensurate phases can be intuitively explained in terms of imaginary phonon frequencies arising from Kohn anomalies in the putative undistorted phase. We also find inconsistencies between the calculated and experimental Se-II phase - the calculations show it to be a metastable metal while the experiment finds a stable semiconductor. We propose that the experimentally reported structure is probably in error.Comment: 4 pages 4 figure

Invasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series

BACKGROUND: Opportunistic invasive fungal infections are increasingly frequent in intensive care patients. Their clinical spectrum goes beyond the patients with malignancies, and for example invasive pulmonary aspergillosis has recently been described in critically ill patients without such condition. Liver failure has been suspected to be a risk factor for aspergillosis. CASE PRESENTATION: We describe three cases of adult respiratory distress syndrome with sepsis, shock and multiple organ failure in patients with severe liver failure among whom two had positive Aspergillus antigenemia and one had a positive Aspergillus serology. In all cases bronchoalveolar lavage fluid was positive for Aspergillus fumigatus. Outcome was fatal in all cases despite treatment with voriconazole and agressive symptomatic treatment. CONCLUSION: Invasive aspergillosis should be among rapidly raised hypothesis in cirrhotic patients developing acute respiratory symptoms and alveolar opacities

Deep sequencing analysis of mutations resulting from the incorporation of dNTP analogs

Next-generation DNA sequencing technology was used to score >100 000 mutations resulting from exposure of a nucleic acid template to a mutagenic dNTP analog during a single pass of a DNA polymerase. An RNA template of known secondary structure was reverse transcribed in the presence of 8-oxo-dGTP, dPTP or both, followed by forward transcription in the presence of standard NTPs. Each mutagen, whether used alone or in combination, resulted in a highly characteristic mutation profile. Mutations were generated at a mean frequency of 1–2% per eligible nucleotide position, but there was substantial variation in the frequency of mutation at different positions, with a SD close to the mean. This variation was partly due to the identity of the immediately surrounding nucleotides and was not significantly influenced by the secondary structure of the RNA template. Most of the variation appears to result from idiosyncratic features that derive from local sequence context, demonstrating how different genetic sequences have different chemical phenotypes

Extensive central nervous system involvement in Merkel cell carcinoma: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Merkel cell carcinoma is a rare malignant cutaneous neoplasm that is locally invasive and frequently metastasizes to lymph nodes, liver, lungs, bone and brain. The incidence of Merkel cell carcinoma has increased in the past three decades.</p> <p>Case presentation</p> <p>A 65-year-old Caucasian man presented with a sudden onset of severe headache and a three-month history of balance disturbance. Magnetic resonance imaging revealed a large meningeal metastasis. The radiologic workup showed retroperitoneal and inguinal lymph node metastases. Biopsy of the inguinal lymph nodes showed metastases of Merkel cell carcinoma. Biopsy from three different suspected skin lesions revealed no Merkel cell carcinoma, and the primary site of Merkel cell carcinoma remained unknown. Leptomeningeal metastases, new axillary lymph node metastases, and intraspinal (epidural and intradural) metastases were detected within six, seven and eight months, respectively, from the start of symptoms despite treating the intracranial metastasis with gamma knife and the abdominal metastases with surgical dissection and external radiotherapy. This indicates the aggressive nature of the disease.</p> <p>Conclusion</p> <p>To the best of our knowledge, this is the first report in the literature of an intracranial meningeal metastasis of Merkel cell carcinoma treated with gamma knife and of intraspinal intradural metastases of Merkel cell carcinoma. Despite good initial response to radiotherapy, recurrence and occurrence of new metastases are common in Merkel cell carcinoma.</p

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future