Colon-specific deletion of epithelial sodium channel causes sodium loss and aldosterone resistance

Aldosterone promotes electrogenic sodium reabsorption through the amiloride-sensitive epithelial sodium channel (ENaC). Here, we investigated the importance of ENaC and its positive regulator channel-activating protease 1 (CAP1/Prss8) in colon. Mice lacking the αENaC subunit in colonic superficial cells (Scnn1a(KO)) were viable, without fetal or perinatal lethality. Control mice fed a regular or low-salt diet had a significantly higher amiloride-sensitive rectal potential difference (∆PDamil) than control mice fed a high-salt diet. In Scnn1a(KO) mice, however, this salt restriction-induced increase in ∆PDamil did not occur, and the circadian rhythm of ∆PDamil was blunted. Plasma and urinary sodium and potassium did not change with regular or high-salt diets or potassium loading in control or Scnn1a(KO) mice. However, Scnn1a(KO) mice fed a low-salt diet lost significant amounts of sodium in their feces and exhibited high plasma aldosterone and increased urinary sodium retention. Mice lacking the CAP1/Prss8 in colonic superficial cells (Prss8(KO)) were viable, without fetal or perinatal lethality. Compared with controls, Prss8(KO) mice fed regular or low-salt diets exhibited significantly reduced ∆PDamil in the afternoon, but the circadian rhythm was maintained. Prss8(KO) mice fed a low-salt diet also exhibited sodium loss through feces and higher plasma aldosterone levels. Thus, we identified CAP1/Prss8 as an in vivo regulator of ENaC in colon. We conclude that, under salt restriction, activation of the renin-angiotensin-aldosterone system in the kidney compensated for the absence of ENaC in colonic surface epithelium, leading to colon-specific pseudohypoaldosteronism type 1 with mineralocorticoid resistance without evidence of impaired potassium balance.

Splicing changes in SMA mouse motoneurons and SMN-depleted neuroblastoma cells: evidence for involvement of splicing regulatory proteins.

Spinal Muscular Atrophy (SMA) is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. The second gene copy, SMN2, produces some, but not enough, functional SMN protein. SMN is essential to assemble small nuclear ribonucleoproteins (snRNPs) that form the spliceosome. However, it is not clear whether SMA is caused by defects in this function that could lead to splicing changes in all tissues, or by the impairment of an additional, less well characterized, but motoneuron-specific SMN function. We addressed the first possibility by exon junction microarray analysis of motoneurons (MNs) isolated by laser capture microdissection from a severe SMA mouse model. This revealed changes in multiple U2-dependent splicing events. Moreover, splicing appeared to be more strongly affected in MNs than in other cells. By testing mutiple genes in a model of progressive SMN depletion in NB2a neuroblastoma cells, we obtained evidence that U2-dependent splicing changes occur earlier than U12-dependent ones. As several of these changes affect genes coding for splicing regulators, this may acerbate the splicing response induced by low SMN levels and induce secondary waves of splicing alterations.

Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung cancer.

Anticancer therapies currently used in the clinic often can neither eradicate the tumor nor prevent disease recurrence due to tumor resistance. In this study, we showed that chemoresistance to pemetrexed, a multi-target anti-folate (MTA) chemotherapeutic agent for non-small cell lung cancer (NSCLC), is associated with a stem cell-like phenotype characterized by an enriched stem cell gene signature, augmented aldehyde dehydrogenase activity and greater clonogenic potential. Mechanistically, chemoresistance to MTA requires activation of epithelial-to-mesenchymal transition (EMT) pathway in that an experimentally induced EMT per se promotes chemoresistance in NSCLC and inhibition of EMT signaling by kaempferol renders the otherwise chemoresistant cancer cells susceptible to MTA. Relevant to the clinical setting, human primary NSCLC cells with an elevated EMT signaling feature a significantly enhanced potential to resist MTA, whereas concomitant administration of kaempferol abrogates MTA chemoresistance, regardless of whether it is due to an intrinsic or induced activation of the EMT pathway. Collectively, our findings reveal that a bona fide activation of EMT pathway is required and sufficient for chemoresistance to MTA and that kaempferol potently regresses this chemotherapy refractory phenotype, highlighting the potential of EMT pathway inhibition to enhance chemotherapeutic response of lung cancer.

The Forgotten Archduke: The Funeral Monument for Ernest of Austria in Brussels

Archduke Ernest of Austria (1553–1595), second son of Emperor Maximilian II and younger brother of Emperor Rudolf II, was in his youth a possible candidate for the thrones of the Empire or the Spanish Kingdom. Instead, he became Governor-General of the Netherlands in 1593 and relocated to Brussels in 1594 where he was welcomed with lavish festivities as the bearer of hope and prosperity. Unfortunately, Ernest died only thirteen months later without having achieved any political success. His brother and successor Albert of Austria commissioned the funeral monument for Ernest in 1600 after it was settled that he would be buried in Brussels and not Vienna. Focusing on this monument, which draws stylistically from various dynasty-related models, it will be shown that Albert intended to use this monument – and thus his brother’s memoria – to make the Brussels Cathedral the primary location of Habsburg dynastic memory in the Low Countries.

Variations of clinopyroxene/melt element partitioning during assimilation of olivine/peridotite by low-Mg diorite magma

The effects of crystal chemistry and melt composition on the control of clinopyroxene/melt element partitioning (D) during the assimilation of olivine/peridotite by felsic magma have been investigated in Mesozoic high-Mg diorites from North China. The assimilation resulted in significant increase of Mg, Cr and Ni and only slight (< 30%) decrease of incompatible elements of the magma, and the compositional variations have been mirrored by the normally and reversely zoned clinopyroxene microphenocrysts formed at the early stage of the magma evolution. The Mg# [100 × Mg / (Mg + Fe)] values of the reversely zoned clinopyroxenes increase from 65 to 75 in the core to 85–90 in the high-Mg midsection, and reduce back to 73–79 at the rim. Trace element profiles across all these clinopyroxene domains have been measured by LA-ICP-MS. The melt trace element composition has been constrained from bulk rock analyses of the fine-grained low- and high-Mg diorites. Clinopyroxene/melt partition coefficients for rare earth elements (REE) and Y in the high-Mg group zonings (Mg# > 73–79, DDy < 1.2) are positively correlated with tetrahedral IVAl and increase by a factor of 3–4 as tetrahedral IVAl increases from 0.01 to 0.1 per formula unit (pfu). These systematic variations are interpreted to be controlled by the clinopyroxene composition. In contrast, partition coefficients for low-Mg group zonings (Mg# < 75–79, DDy > 1.2) are elevated by up to an order of magnitude (for REE and Y) or more (for Zr and Hf) at similar IVAl, indicating dominant control of melt composition/structure. DZr and DHf show a larger sensitivity to the compositional change of crystal and melt than DREE. DTi values for the low- and high-Mg zonings show a uniform dependence on IVAl. DSr and DLi are insensitive to the compositional change of clinopyroxene and melt, resulting in Sr depletions in the clinopyroxene zonings with elevated REE without crystallization of plagioclase. Our observations show that crystal chemistry and melt composition/structure may alternatively control clinopyroxene/melt partitioning during the assimilation of peridotite by felsic magma, and may be useful for deciphering clinopyroxene compositions and related crust–mantle processes.

Potential for virus transfer between the honey bees Apis mellifera and A. cerana

Viruses seem to play a key role in European honey bee, Apis mellifera health, and have a much broader host spectrum than previously thought. Few studies have investigated interspecific virus transfer within the genus Apis. The introduction of A. mellifera into Asia exposed endemic Apis species to the risk of obtaining new viruses or viral strains and vice versa. To investigate the potential for host shifts, virus prevalence and sequences were monitored over three years in single and mixed-species apiaries hosting introduced A. mellifera and endemic Apis cerana. Deformed wing virus (DWV), Israeli acute paralysis virus (IAPV), black queen cell virus (BQCV), and sacbrood virus (SBV) were found, but not KBV, VDV-1, ABPV, or CBPV. Virus infections and prevalence were generally lower in A. cerana compared to A. mellifera, and varied over the years. The sequence data provided evidence for interspecific transfer of IAPV, BQCV, and DWV, but SBV strains seem to be species specific. Prevalence and sequence results taken together indicate that interspecific transfers of viruses are rare, even if honey bees are kept in close proximity. We discuss the pattern observed in the context host specificity and resistance. Our understanding of the extent of these exchanges is limited by a lack of knowledge on the mechanisms of adaptation of viruses to different hosts.

An empirical evaluation of the Random Forests classifier models for variable selection in a large-scale lung cancer case-control study

Random Forests™ is reported to be one of the most accurate classification algorithms in complex data analysis. It shows excellent performance even when most predictors are noisy and the number of variables is much larger than the number of observations. In this thesis Random Forests was applied to a large-scale lung cancer case-control study. A novel way of automatically selecting prognostic factors was proposed. Also, synthetic positive control was used to validate Random Forests method. Throughout this study we showed that Random Forests can deal with large number of weak input variables without overfitting. It can account for non-additive interactions between these input variables. Random Forests can also be used for variable selection without being adversely affected by collinearities. ^ Random Forests can deal with the large-scale data sets without rigorous data preprocessing. It has robust variable importance ranking measure. Proposed is a novel variable selection method in context of Random Forests that uses the data noise level as the cut-off value to determine the subset of the important predictors. This new approach enhanced the ability of the Random Forests algorithm to automatically identify important predictors for complex data. The cut-off value can also be adjusted based on the results of the synthetic positive control experiments. ^ When the data set had high variables to observations ratio, Random Forests complemented the established logistic regression. This study suggested that Random Forests is recommended for such high dimensionality data. One can use Random Forests to select the important variables and then use logistic regression or Random Forests itself to estimate the effect size of the predictors and to classify new observations. ^ We also found that the mean decrease of accuracy is a more reliable variable ranking measurement than mean decrease of Gini. ^

Estela de Tuiia, arquero del rey : Traducción de una estela egipcia de la dinastía XVIII al castellano

Este trabajo tiene como objetivo la presentación, transliteración y traducción de una estela egipcia de la Dinastía XVIII creada en honor a Tuiia, un arquero y sirviente personal del rey. La estela nos ofrece una puerta de acceso a los ritos funerarios y las relaciones familiares en el contexto del universo cultural del Reino Nuevo. El documento se encuentra preservado en el Museo Británico

La realeza egipcia : Dios padre- hijo Rey : Algunas consideraciones míticas literarias sobre el faraón como Hijo de Ra

La relación filial entre el dios-padre y el hijo-rey en la monarquía egipcia expresó una de las principales condiciones que el faraón debía cumplir para asumir el trono en las Dos Tierras. Asimismo este vínculo dentro del Estado se simbolizó a partir del Reino Antiguo con el título real Hijo de Ra, pero también en diversas expresiones que lo relacionaban con el dios Ra y una realeza solarizada. Por ejemplo los dos últimos cuentos del papiro Westcar narran el origen divino de la dinastía V como hijos del dios Ra, texto literario que se vincula con los Mitos de Origen de un Rey. En el presente trabaja analizamos estas referencias que dan cuenta de uno de los rasgos esenciales de la realeza egipcia, su divinidad

La representación política en la España peninsular entre el final de la dinastía Habsburgo y el comienzo de la era Borbónica

Este trabajo propone abordar el problema de la representación política, expresada en la vecindad y la naturaleza, entre el fin de la dinastía de Habsburgo y los primeros años del reinado de Felipe V. Los decretos de Nueva Planta impulsados por Felipe V proponían la desaparición del criterio locativo para la definición de la naturaleza y conllevaban una innovación de las relaciones Rey-súbdito. Esto suponía la supresión de las naturalezas particulares de todos los reinos en favor de una naturaleza común

Amistades paganas y persecución de los cristianos : La epístola de Bruno de Querfurt al emperador Enrique II

La carta que presentamos traducida al español fue escrita en el año 1008 por el obispo misionero Bruno de Querfurt. El destinatario era el rey sajón Enrique II (1002-1024), emperador desde el año 1014. El contexto de la epístola está marcado por los vínculos cambiantes entre diversos actores políticos. La dinastía polaca piasta había cooperado con el Imperio desde mediados del siglo x. Por otra parte, los liutizos, una confederación de pueblos eslavos paganos, se habían levantado contra las estructuras eclesiásticas e imperiales en la región del Elba en 983, en el marco de un floreciente paganismo. Sin embargo, al iniciarse el nuevo milenio, el piasta Boleslao el Bravo se había convertido en una amenaza más atemorizadora para el Imperio, debido particularmente a la expansión territorial que encabezaba. Así, el rey Enrique II pactó en el año 1003 en Quedlinburg con los liutizos frente al piasta: se sellaba una alianza entre un rey cristiano y una confederación pagana para hacer frente a otro gobernante cristiano. Bruno de Querfurt, que había dedicado su vida a la misión y recibía apoyo de Boleslao, escribió esta misiva, con el objeto de señalar las contradicciones de la alianza citada arriba

Estela de Tuiia, arquero del rey : Traducción de una estela egipcia de la dinastía XVIII al castellano

Este trabajo tiene como objetivo la presentación, transliteración y traducción de una estela egipcia de la Dinastía XVIII creada en honor a Tuiia, un arquero y sirviente personal del rey. La estela nos ofrece una puerta de acceso a los ritos funerarios y las relaciones familiares en el contexto del universo cultural del Reino Nuevo. El documento se encuentra preservado en el Museo Británico

La realeza egipcia : Dios padre- hijo Rey : Algunas consideraciones míticas literarias sobre el faraón como Hijo de Ra

La relación filial entre el dios-padre y el hijo-rey en la monarquía egipcia expresó una de las principales condiciones que el faraón debía cumplir para asumir el trono en las Dos Tierras. Asimismo este vínculo dentro del Estado se simbolizó a partir del Reino Antiguo con el título real Hijo de Ra, pero también en diversas expresiones que lo relacionaban con el dios Ra y una realeza solarizada. Por ejemplo los dos últimos cuentos del papiro Westcar narran el origen divino de la dinastía V como hijos del dios Ra, texto literario que se vincula con los Mitos de Origen de un Rey. En el presente trabaja analizamos estas referencias que dan cuenta de uno de los rasgos esenciales de la realeza egipcia, su divinidad

La representación política en la España peninsular entre el final de la dinastía Habsburgo y el comienzo de la era Borbónica

Este trabajo propone abordar el problema de la representación política, expresada en la vecindad y la naturaleza, entre el fin de la dinastía de Habsburgo y los primeros años del reinado de Felipe V. Los decretos de Nueva Planta impulsados por Felipe V proponían la desaparición del criterio locativo para la definición de la naturaleza y conllevaban una innovación de las relaciones Rey-súbdito. Esto suponía la supresión de las naturalezas particulares de todos los reinos en favor de una naturaleza común