Rhesus factors and ammonium: a function in efflux?

Completion of fungal, plant and human genomes paved the way to the identification of erythrocytic rhesus proteins and their kidney homologs as ammonium transporters. Ammonium is the preferred nitrogen source of bacteria and fungi, and plants acquire nitrogen from the soil in the form of ammonium [1]. In animals and humans, assimilated forms of nitrogen - amino acids - are much preferred for nutrition, and, in the case of ammonotelic animals, ammonium is used for the excretion of nitrogen instead. In the human kidney, ammonium is produced, reabsorbed and excreted as a means to maintain pH balance and to get rid of surplus inorganic nitrogen. Whether ammonium transport also has a role in the pH regulation of other organs is not known and the molecular mechanisms were not, up to now, understood.

Die Küstenebene Palästinas : mit geologischer Übersichtskarte 1:250000

von Paul Range

CHARACTERIZATION OF DIFFERENTIATION AND PROGNOSTIC BIOMARKERS ON CD8+ TUMOR-INFILTRATING LYMPHOCYTES IN METASTATIC MELANOMA

CD8+ cytotoxic T lymphocytes (CTL) frequently infiltrate tumors, yet most melanoma patients fail to undergo tumor regression. We studied the differentiation of the CD8+ tumor-infiltrating lymphocytes (TIL) from 44 metastatic melanoma patients using known T-cell differentiation markers. We also compared CD8+ TIL against the T cells from matched melanoma patients’ peripheral blood. We discovered a novel subset of CD8+ TIL co-expressing early-differentiation markers, CD27, CD28, and a late/senescent CTL differentiation marker, CD57. This CD8+CD57+ TIL expressed a cytolytic enzyme, granzyme B (GB), yet did not express another cytolytic pore-forming molecule, perforin (Perf). In contrast, the CD8+CD57+ T cells in the periphery were CD27-CD28-, and GBHi and PerfHi. We found this TIL subset was not senescent and could be induced to proliferate and differentiate into CD27-CD57+, perforinHi, mature CTL. This further differentiation was arrested by TGF-β1, an immunosuppressive cytokine known to be produced by many different kinds of tumors. Therefore, we have identified a novel subset of incompletely differentiated CD8+ TIL that resembled those found in patients with uncontrolled chronic viral infections. In a related study, we explored prognostic biomarkers in metastatic melanoma patients treated in a Phase II Adoptive Cell Therapy (ACT) trial, in which autologous TIL were expanded ex vivo with IL-2 and infused into lymphodepleted patients. We unexpectedly found a significant positive clinical association with the infused CD8+ TIL expressing B- and T- lymphocyte attentuator (BTLA), an inhibitory T-cell receptor. We found that CD8+BTLA+ TIL had a superior proliferative response to IL-2, and were more capable of autocrine IL-2 production in response to TCR stimulation compared to the CD8+BTLA- TIL. The CD8+BTLA+ TIL were less differentiated and resembled the incompletely differentiated CD8+ TIL described above. In contrast, CD8+BTLA- TIL were poorly proliferative, expressed CD45RA and killer-cell immunoglobulin-like receptors (KIRs), and exhibited a gene expression signature of T cell deletion. Surprisingly, ligation of BTLA by its cognate receptor, HVEM, enhanced the survival of CD8+BTLA+ TIL by activating Akt/PKB. Our studies provide a comprehensive characterization of CD8+ TIL differentiation in melanoma, and revealed BTLA as a novel T-cell differentiation marker along with its role in promoting T cell survival.

Deuterium analysis of ice core GISP2

The Greenland Ice Sheet Project 2 (GISP2) core can enhance our understanding of the relationship between parameters measured in the ice in central Greenland and variability in the ocean, atmosphere, and cryosphere of the North Atlantic Ocean and adjacent land masses. Seasonal (summer, winter) to annual responses of dD and deuterium excess isotopic signals in the GISP2 core to the seesaw in winter temperatures between West Greenland and northern Europe from A.D. 1840 to 1970 are investigated. This seesaw represents extreme modes of the North Atlantic Oscillation, which also influences sea surface temperatures (SSTs), atmospheric pressures, geostrophic wind strength, and sea ice extents beyond the winter season. Temperature excursions inferred from the dD record during seesaw/extreme NAO mode years move in the same direction as the West Greenland side of the seesaw. Symmetry with the West Greenland side of the seesaw suggests a possible mechanism for damping in the ice core record of the lowest decadal temperatures experienced in Europe from A.D. 1500 to 1700. Seasonal and annual deuterium excess excursions during seesaw years show negative correlation with dD. This suggests an isotopic response to a SST/ land temperature seesaw. The isotopic record from GISP2 may therefore give information on both ice sheet and sea surface temperature variability. Cross-plots of dD and d show a tendency for data to be grouped according to the prevailing mode of the seesaw, but do not provide unambiguous identification of individual seesaw years. A combination of ice core and tree ring data sets may allow more confident identification of GA and GB (extreme NAO mode) years prior to 1840.

Cetoacidosis inducida por corticoides y gatifloxacina en una mujer joven no diabética

Objetivo: Comunicar un caso de cetoacidosis inducida por corticoides y gatifloxacina y discutir los mecanismos de esta inusual y seria complicación. Caso clínico: Mujer de 32 años, ingresa por neumonía adquirida en la comunidad de 5 días de evolución. Antecedentes: AR probable diagnosticada 4 meses antes tratada con metotrexate y corticoides intermitente. Examen físico: regular estado general, IMC 21, Tº 38ºC, FR 32/min, derrame pleural derecho, FC 96/min, PA 110/70, artralgias sin artritis. Exámenes complementarios: Hto 23%, GB 16300/mm3, VSG 96mm/1ºh, glucemia 0.90mg/dl, función hepática y amilasa normales, uremia 1.19g/l, creatinina 19mg/l. Hemocultivos (2) y esputo positivos para Neumococo penicilina-sensible. La neumonía responde a gatifloxacina. Deteriora la función renal hasta la anuria con acidosis metabólica. Se interpreta como glomerulonefritis lúpica rápidamente progresiva por proteinuria de 2g/24hs, FR (+) 1/1280, FAN (+) 1/320 homogéneo, Anti ADN (+) , complemento bajo: C3 29.4mg/dl y C4 10mg/dl, Ac anti Ro, La, Scl70, RNP y anticardiolipinas positivos. Se indica metilprednisolona EV (3 bolos 1g), complicándose con hiperglucemias de >6 g/l y cetoacidosis con cetonuria (+); Ac anti ICA y antiGAD negativos con HbA1C 5.2%. Es tratada en UTI (insulina y hemodiálisis). La paciente mejora, se desciende la dosis de corticoides, con normalización de la glucemia sin tratamiento hipoglucemiante. Comentarios 1) La presencia de HbA1C nomal, Ac anti ICA y GAD negativos permite descartar con razonable grado de certeza una diabetes tipo1 asociada al lupus. 2) El desarrollo de la cetoacidosis durante el tratamiento con corticoides y gatifloxacina y su resolución posterior avalan el rol etiológico de los mismos. 3) La cetoacidosis puede explicarse por estimulación de la gluconeogénesis y la insulinoresistencia a nivel de receptor y post-receptor generada por los fármacos potenciado por el estado inflamatorio relacionado con el lupus y la sepsis.

Cayó la yuta : Basta de contrabando en la pasiva

El presente trabajo esboza una crítica con base empírica y conceptual al análisis de la construcción pasiva basado en la operación contrabando (smuggling) propuesto por Collins (2005). En primer lugar, se exponen los argumentos de tipo empírico, los cuales se basan en aspectos de la construcción pasiva española (y de otras lenguas romance de sujeto nulo) que la derivación de Collins no permite explicar. Los fenómenos más salientes que se discuten son: (i) la imposibilidad de dar cuenta de los sujetos postverbales en la pasiva de lenguas romance de sujeto nulo (e.g. fueron detenidos los asaltantes) dado el ascenso del Sintagma de Participio a la posición de especificador de Voz (contra Belletti 2009); (ii) el obligatorio tratamiento como argumento verbal del complemento agente que impide dar cuenta de su comportamiento ante islas de extracción débiles (e.g. *por el docente, no sabe Juan por qué fue desaprobada María); (iii) y la imposibilidad de explicar el arrastre de la preposición (pied-piping) ante movimiento del nominal que recibe interpretación de argumento externo a la periferia izquierda (e.g. ¿por quién fueron arrestados los asaltantes?). Los argumentos conceptuales se basan, principalmente, en la inexistencia de requerimientos gramaticales para varias de las suboperaciones y movimientos de los que depende esta derivación de la pasiva. Además, se defienden las observaciones de Gehrke y Grillo (2007) con respecto a la naturaleza ad-hoc del análisis (que, en términos técnicos, se reducen a que las computaciones propuestas por Collins requieren "ver hacia adelante" (look-ahead) en la derivación). Ante estas consideraciones, se defiende el análisis de la construcción pasiva presentado durante el auge del modelo GB (Jaeggli 1986, Baker et al. 1989), el cual, sin ser perfecto, resulta mucho más consistente con respecto al requerimiento de adecuación descriptiva de toda teoría gramatical