Human Monoclonal Antibodies Neutralizing Cytomegalovirus (CMV) for Prophylaxis of CMV Disease: Report of a Phase I Trial in Bone Marrow Transplant Recipients

The safety and pharmacokinetics of the two neutralizing human IgG1 monoclonal antibodies to cytomegalovirus (CMV) SDZ89-104 and 89-109 in bonemarrowtransplant (BM1)recipients was assessed in an open phase I trial. Thirteen patients, 8 seropositive and 5 seronegative for CMV, were treated with allogeneic or autologous bone marrow transplantation. SDZ 89-104 was given to 5 and SDZ 89-109 to 8 patients. Patients were divided into high-and low-dose groups. A fixed prestudy dose of 0.1 mg/kg was given 4 days before BMT. On days 3, 17, 31,45, 59, and 73, patients were treated with either 0.5 or 2 mg/kg of the respective antibody. Results indicate that doses of 2 mg/kg of SDZ 89-104 or SDZ 89-109 in alternating weeks can be safely administered to BMT patients. Serum trough levels measured by antiidiotype ELISA were ∼10 µg/ml after administration of 0.5 mg/kg and ∼50 µg/ml after treatment with 2 mg/kg of SDZ 89-104 or SDZ 89-109. High serum levels defined by antiidiotype ELISA techniques closely paralleled increased neutralizing activity. Serum half-lives calculatedfrom these data were ∼6 day

Point sets on the sphere S2\mathbb{S}^2 with small spherical cap discrepancy

In this paper we study the geometric discrepancy of explicit constructions of uniformly distributed points on the two-dimensional unit sphere. We show that the spherical cap discrepancy of random point sets, of spherical digital nets and of spherical Fibonacci lattices converges with order $N^{-1/2}$. Such point sets are therefore useful for numerical integration and other computational simulations. The proof uses an area-preserving Lambert map. A detailed analysis of the level curves and sets of the pre-images of spherical caps under this map is given

Transport by molecular motors in the presence of static defects

The transport by molecular motors along cytoskeletal filaments is studied theoretically in the presence of static defects. The movements of single motors are described as biased random walks along the filament as well as binding to and unbinding from the filament. Three basic types of defects are distinguished, which differ from normal filament sites only in one of the motors' transition probabilities. Both stepping defects with a reduced probability for forward steps and unbinding defects with an increased probability for motor unbinding strongly reduce the velocities and the run lengths of the motors with increasing defect density. For transport by single motors, binding defects with a reduced probability for motor binding have a relatively small effect on the transport properties. For cargo transport by motors teams, binding defects also change the effective unbinding rate of the cargo particles and are expected to have a stronger effect.Comment: 20 pages, latex, 7 figures, 1 tabl

Evolution of leaf-form in land plants linked to atmospheric CO2 decline in the Late Palaeozoic era

The widespread appearance of megaphyll leaves, with their branched veins and planate form, did not occur until the close of the Devonian period at about 360 Myr ago. This happened about 40 Myr after simple leafless vascular plants first colonized the land in the Late Silurian/Early Devonian, but the reason for the slow emergence of this common feature of present-day plants is presently unresolved. Here we show, in a series of quantitative analyses using fossil leaf characters and biophysical principles, that the delay was causally linked with a 90% drop in atmospheric pCO2 during the Late Palaeozoic era. In contrast to simulations for a typical Early Devonian land plant, possessing few stomata on leafless stems, those for a planate leaf with the same stomatal characteristics indicate that it would have suffered lethal overheating, because of greater interception of solar energy and low transpiration. When planate leaves first appeared in the Late Devonian and subsequently diversified in the Carboniferous period, they possessed substantially higher stomatal densities. This observation is consistent with the effects of the pCO2 on stomatal development and suggests that the evolution of planate leaves could only have occurred after an increase in stomatal density, allowing higher transpiration rates that were sufficient to maintain cool and viable leaf temperatures

A realtime observatory for laboratory simulation of planetary flows

Motivated by the large-scale circulation of the atmosphere and ocean, we develop a system that uses observations from a laboratory analog to constrain, in real time, a numerical simulation of the laboratory flow. This system provides a tool to rapidly prototype new methods for state and parameter estimation, and facilitates the study of prediction, predictability, and transport of geophysical fluids where observations or numerical simulations would not independently suffice. A computer vision system is used to extract measurements of the physical simulation. Observations are used to constrain the model-state of the MIT General Circulation Model in a probabilistic, ensemble based assimilation approach. Using a combination of parallelism, domain decomposition and an efficient scheme to select ensembles of model-states, we show that estimates that effectively track the fluid state can be produced. To the best of our knowledge this is the first such observatory for laboratory analogs of planetary circulation that functions in real time.National Science Foundation (U.S.) (CNS-0540259)National Science Foundation (U.S.) (grant CNS-0540248

Fibroblasts activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses

Background. Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders. Objectives. To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC. Methods. We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies. Results. Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB. Conclusions. Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS.This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2013-43475R, SAF2017-88908-R and SAF2017-86810-R); from Instituto de Salud Carlos III and CIBERER, cofunded with European Regional Development Funds (ERDF) (PT13/0001/0007, PI14/00931, PI15/00716, PI15/00956, PT17/0009/0006 and PI17/01747); and from the European Union (HEALTH-F2-2011-261392 and H2020-INFRADEV-1-2015-1/ELIXIR-EXCELERATEref. 676559). Additional funding from Comunidad de Madrid (AvanCell-CM S2017/BMD-3692); Catalan Government (AGAUR 2014_SGR_603); ‘Fundacio' La Marató de TV3, 01331-30’; CERCA Programme/Generalitat de Catalunya; and ‘Fundación Científica de la Asociación Española Contra el Cáncer’, Spain

Histological and immunohistochemical features of the spleen in persistent polyclonal B-cell lymphocytosis closely mimic splenic B-cell lymphoma

Persistent polyclonal B-cell lymphocytosis (PPBL) is rare and intriguing hematological disorder predominantly reported in young to middle- aged smoking women. It is characterized by persistent moderate polyclonal B-cell lymphocytosis with circulating hallmark binucleated lymphocytes and elevated polyclonal serum IgM. Most patients have benign clinical course on long-term follow-up. Some pathologic features of PPBL may resemble malignant lymphoma, including morphology as well as frequent cytogenetic and molecular abnormalities. Significant symptomatic splenomegaly requiring splenectomy is very unusual for this disorder; therefore there is a lack of descriptions of the morphologic features of the spleen in the literature. We present here one of the first detailed descriptions of the morphologic and immunohistochemical features of the spleen from a young female with PPBL who developed massive splenomegaly during 6-year follow up. Splenectomy was performed for symptomatic relief and suspicion of malignant process. The morphological and immunohistochemical features of the spleen closely mimicked involvement by B-cell lymphoma, however there was no monotypic surface light chain restriction seen by flow cytometry and no clonal rearrangement of IgH gene was detected by molecular analysis. Evaluating a splenectomy sample in cases like this may present a diagnostic challenge to pathologists. Therefore, correlation with B cell clonality studies (by flow cytometry and molecular analysis), clinical findings and peripheral blood morphology searching for characteristic binucleated lymphocytes is essential to avoid misdiagnosing this benign process as B-cell lymphoma. We also present here a literature review on pathogenesis of PPBL

Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom