Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus.

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straightforward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus

Toughening Immiscible Polymer Blends:The Role of Interface-Crystallization-Induced Compatibilization Explored Through Nanoscale Visualization

This study explores the novel approach of interface-crystallization-induced compatibilization (ICIC) via stereocomplexation as a promising method to improve the interfacial strength in thermodynamically immiscible polymers. Herein, two distinct reactive interfacial compatibilizers, poly(styrene-co-glycidyl methacrylate)-graft-poly(l-lactic acid) (SAL) and poly(styrene-co-glycidyl methacrylate)-graft-poly(d-lactic acid) (SAD) are synthesized via reactive melt blending in an integrated grafting and blending process. This approach is demonstrated to enhance the interfacial strength of immiscible polyvinylidene fluoride/poly l-lactic acid (PVDF/PLLA) 50/50 blends via ICIC. IR nanoimaging indicates a cocontinuous morphology in the blends. The blend compatibilized with SAD exhibits a higher storage modulus, as unveiled by small amplitude oscillatory shear (SAOS) in the melt state at a temperature below the melting temperature of the stereocomplex (SC) crystals and by DMTA measurements in the solid state. This increase is attributed to the formation of a 200-300 nm thick rigid interfacial SC crystalline layer that is directly visible using AFM imaging and chemically characterized via IR nanospectroscopy. This ICIC also results in a significant toughening of the blend, with the elongation at break increasing more than 20-fold. Moreover, the fracture toughness factor obtained from single edge-notch bending (SENB) tests is doubled with ICIC as compared to the uncompatibilized blend, indicating the strong crack-resistance capability as a result of ICIC. This improvement is also evident in SEM images, where thinner and longer fibrillation is observed on the fractured surface in the presence of ICIC.</p

Emergence and fate of stem cell-like Tcf7⁺ CD8⁺ T cells during a primary immune response to viral infection.

In response to infection, naïve CD8 &lt;sup&gt;+&lt;/sup&gt; T (T &lt;sub&gt;N&lt;/sub&gt; ) cells yield a large pool of short-lived terminal effector (T &lt;sub&gt;TE&lt;/sub&gt; ) cells that eliminate infected host cells. In parallel, a minor population of stem cell-like central memory (T &lt;sub&gt;CM&lt;/sub&gt; ) cells forms, which has the capacity to maintain immunity after pathogen clearance. It has remained uncertain whether stem-like T &lt;sub&gt;CM&lt;/sub&gt; cells arise by dedifferentiation from a subset of cytolytic T &lt;sub&gt;TE&lt;/sub&gt; cells or whether priming generates stem-like cells capable of seeding the T &lt;sub&gt;CM&lt;/sub&gt; compartment and, if so, when cytolytic T &lt;sub&gt;TE&lt;/sub&gt; cells branch off. Here, we show that CD8 &lt;sup&gt;+&lt;/sup&gt; T cells with stem-like properties, which are identified by the expression of TCF1 (encoded by Tcf7), are present across the primary response to infection. Priming programs T &lt;sub&gt;N&lt;/sub&gt; cells to undergo multiple cell divisions, over the course of which TCF1 expression is maintained. These TCF1 &lt;sup&gt;+&lt;/sup&gt; cells further expand relatively independently of systemic inflammation, antigen dose, or affinity, and they quantitatively yield TCF1 &lt;sup&gt;+&lt;/sup&gt; T &lt;sub&gt;CM&lt;/sub&gt; cells after pathogen clearance. Inflammatory signals suppress TCF1 expression in early divided TCF1 &lt;sup&gt;+&lt;/sup&gt; cells. TCF1 down-regulation is associated with the irreversible loss of self-renewal capacity and the silencing of stem/memory genes, which precedes the stable acquisition of a T &lt;sub&gt;TE&lt;/sub&gt; state. TCF1 expression restrains cell cycling, explaining in part the limited expansion of TCF1 &lt;sup&gt;+&lt;/sup&gt; relative to TCF1 &lt;sup&gt;-&lt;/sup&gt; cells during the primary response. Thus, our data are consistent with terminal differentiation of effector cells being a step-wise process that is initiated by inflammation in primed stem-like cells, which would otherwise become central memory cells by default

Engineering Robust Metallic Zero-Mode States in Olympicene Graphene Nanoribbons

Metallic graphene nanoribbons (GNRs) represent a critical component in the toolbox of low-dimensional functional materials technolo-gy serving as 1D interconnects capable of both electronic and quantum information transport. The structural constraints imposed by on-surface bottom-up GNR synthesis protocols along with the limited control over orientation and sequence of asymmetric monomer building blocks during the radical step-growth polymerization has plagued the design and assembly of metallic GNRs. Here we report the regioregular synthesis of GNRs hosting robust metallic states by embedding a symmetric zero-mode superlattice along the backbone of a GNR. Tight-binding electronic structure models predict a strong nearest-neighbor electron hopping interaction between adjacent zero-mode states resulting in a dispersive metallic band. First principles DFT-LDA calculations confirm this prediction and the robust, metallic zero-mode band of olympicene GNRs (oGNRs) is experimentally corroborated by scanning tunneling spectroscopy.Comment: 8 pages, 4 figure

Enhancing reductive cleavage of aromatic carboxamides

[GRAPHICS] A set of aromatic and especially heteroaromatic N-benzyl carboxamides, derived from naphthalene, pyridine, pyrazine, and quinoline, and the corresponding tert-butyl acylcarbamates have been synthesized and studied by cyclic voltammetry with respect to facilitated reduction. The latter undergo regiospecific cleavage of their C(O)-N bonds under very mild reductive conditions with formation of Boc-protected (benzyl)amine in most cases in nearly quantitative yields, Examples of preparative cleavage by controlled potential electrolysis, activated aluminum, and NaBH4 are given

Precis of epistemic angst:Book Symposium: Duncan Pritchard, Epistemic Angst (Princeton University Press, 2015, xiii + 236 pages)

ABSTRACT This book symposium features three critical pieces dealing with Duncan Pritchard's book, 'Epistemic Angst'; the symposium also contains Pritchard's replies to his critics

Diagnostic approach to inherited thrombocytopenias in a low-income setting

Background: Inherited thrombocytopenias (IT) remain a diagnostic challenge due to clinical and genetic heterogeneity. Although more than 30 genes have been identified, the underlying abnormality is unknown in half of the patients. Advent of next-generation technologies represented significant advances although access is limited in low-income economies. Aims:To rationalize resources for IT diagnosis in Argentina. Methods:First, we applied a diagnostic algorithm (Balduini, 2003) based on phenotypic characterization followed by candidate gene sequencing and, second, whole exome sequencing (WES) was performed in an international center in undiagnosed patients after this algorithm. Results:We included 114 patients from 50 pedigrees, 25 (0-73) years old, 68 (4-172) x109/L platelets; 68%, 30% and 2% had large, normal-sized and small platelets; 21% had syndromic forms: 11% hearing loss, 6% nephropathy, 7% hematologic malignancy, 2% myelofibrosis. By applying the algorithm, a conclusive diagnosis was reached in 27/50 (54%) pedigrees, 38% MYH9-RD; 4% Bernard-Soulier syndrome (1 monoallelic, 1 classic); 4% Gray Platelet Syndrome; 4% ANKRD26-RT; 2% FPD/AML; 2% Wiskott-Aldrich Syndrome. WES was undertaken in 8/23 (35%) pedigrees without diagnosis following the algorithm and known disorders were identified in 4 (1 FPD/AML, 1 ANKRD26-RT, 2 BSS:1 monoallelic, 1 biallelic), whereas no pathogenic variants in either known or new genes were detected in 4. Undiagnosed patients after the algorithm in whom WES was not performed suffered from mild isolated macrothrombocytopenia without distinctive features. Altogether, by this combined approach (algorithm+WES), a definitive diagnosis was identified in 31/50 (62%) pedigrees, which does not differ from the yield of NGS panels. ConclusionsIn conclusion, careful clinical phenotyping allowed diagnosis in a substantial proportion of patients and MYH9-RD was the disorder most easily recognized by the algorithm. Restricting the application of NGS to patients with negative results after the algorithm allowed to optimize resources and improved the diagnostic yield, representing a feasible approach in low-income settings.Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Goette, Nora Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Baroni Pietto, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Ayala, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Altuna, D.. Hospital Italiano; ArgentinaFil: Arrieta, M. E.. Hospital Público Descentralizado Dr. Guillermo Rawson.; ArgentinaFil: Bazak, N.. Hospital Zonal General de Agudos doctor Ricardo Gutierrez ; Gobierno de la Provincia de Buenos Aires;Fil: Bonaccorso, S.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Brodsky, A.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Donato, H.. Municipalidad de la Matanza (Buenos Aires). Hospital Municipal del Niño de San Justo; ArgentinaFil: Korin, J. D.. No especifíca;Fil: Lagrotta, P.. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Negro, Fernando Javier. Sanatorio Sagrado Corazón, Buenos Aires; ArgentinaFil: Ponzinibbio, Carlos. Hospital Italiano de La Plata; ArgentinaFil: Veber, E.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Savoia, A.. Università degli Studi di Trieste; ItaliaFil: Pecci, A.. Universita degli Studi di Pavia; ItaliaFil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaVirtual Congress of the International Society on Thrombosis and HaemostasisItaliaInternational Society on Thrombosis and Haemostasi

Near infrared photoluminescence of the univalent bismuth impurity center in leucite and pollucite crystal hosts

The bismuth doped aluminosilicate phases leucite (KAlSi2O6), gallium leucite (KGaSi2O6) and pollucite (CsAlSi2O6) display broadband NIR photoluminescence. The active center, responsible for this luminescence, is the Bi+ monocation, which substitutes for the large alkali metal cations. The Al,Si-disorder in the aluminosilicate framework of studied crystal phases results in the heterogeneity of Bi+ luminescent center population, which manifests itself in the characteristic dependency of the luminescence spectrum shape on the excitation wavelength. The relation of NIR emission in Bi+-doped leucite and pollucite phases to the luminescent properties of bismuth-doped glasses is also discussed