Estado, sociedad civil y hegemonía en el pensamiento político de Gramsci

En el presente artículo analizamos el concepto de hegemonía de Gramsci y su relación con los conceptos políticos fundamentales de su pensamiento. Nos confrontamos con las interpretaciones que sitúan la hegemonía exclusivamente en el ámbito de la sociedad civil y mostramos la complejidad teórica de concepto gramsciano de Estado, que integra dialécticamente la sociedad civil con la sociedad política. Con ello se pone de manifiesto el modo en que se articulan coerción y consenso en el pensamiento político de Gramsci, así como la necesidad de dominar las estructuras políticas del Estado para consolidar la hegemonía conquistada en la sociedad civil.

Estado, sociedad civil y hegemonía en el pensamiento político de Gramsci

En el presente artículo analizamos el concepto de hegemonía de Gramsci y su relación con los conceptos políticos fundamentales de su pensamiento. Nos confrontamos con las interpretaciones que sitúan la hegemonía exclusivamente en el ámbito de la sociedad civil y mostramos la complejidad teórica de concepto gramsciano de Estado, que integra dialécticamente la sociedad civil con la sociedad política. Con ello se pone de manifiesto el modo en que se articulan coerción y consenso en el pensamiento político de Gramsci, así como la necesidad de dominar las estructuras políticas del Estado para consolidar la hegemonía conquistada en la sociedad civil.

Estado, sociedad civil y hegemonía en el pensamiento político de Gramsci

En el presente artículo analizamos el concepto de hegemonía de Gramsci y su relación con los conceptos políticos fundamentales de su pensamiento. Nos confrontamos con las interpretaciones que sitúan la hegemonía exclusivamente en el ámbito de la sociedad civil y mostramos la complejidad teórica de concepto gramsciano de Estado, que integra dialécticamente la sociedad civil con la sociedad política. Con ello se pone de manifiesto el modo en que se articulan coerción y consenso en el pensamiento político de Gramsci, así como la necesidad de dominar las estructuras políticas del Estado para consolidar la hegemonía conquistada en la sociedad civil.

Hospital without dyspnea: Rationale and design of a multidisciplinary intervention

Dyspnea is a common and disabling symptom of respiratory and heart diseases, which is growing in incidence. During hospital admission, breathlessness is under-diagnosed and under-treated, although there are treatments available for controlling the symptom. We have developed a tailored implementation strategy directed to medical staff to promote the application of these pharmacological and non-pharmacological tools in dealing with dyspnea. The primary aim is to decrease the rate of patients that do not receive an adequate relief of dyspnea. This is a four-stage quasi-experimental study. The intervention consists in two teaching talks that will be taught in Cardiology and Respiratory Medicine Departments. The contents will be prepared by Palliative Care specialists, based on available tools for management of dyspnea and patients' needs. A cross-sectional study of dyspnea in hospitalized patients will be performed before and after the intervention to ascertain an improvement in dyspnea intensity due to changes in medical practices. The last phase consists in the creation of consensus protocols for dyspnea management based in our experience. The results of this study are expected to be of great value and may change clinical practice in the near future and promote a changing for the better of dyspnea care.

África Austral: Los minerales como recurso estratégico para los intereses de Estados Unidos y China, período 2000-2010

La región de África Austral emerge como un nuevo escenario geopolítico complejo, en el que la lucha por la adquisición de los derechos de exploración, extracción y distribución de minerales estratégicos ha intensificado la presencia del número de actores estratégicos en esta zona. En este sentido, es interesante analizar el juego de poder que se desarrolla entre Estados Unidos y China con el fin de neutralizar la debilidad estratégica que representa la carencia de estos recursos naturales, esenciales para el desarrollo de sus industrias, así como también la oportunidad que representan como mecanismo para ampliar las esferas de influencia extra continental. Así pues, la presente investigación analiza a partir de la explotación de los minerales como recursos estratégicos, los efectos de la geoestrategia reciente de estos dos jugadores activos del sistema internacional contemporáneo en la relación con los Estados que conforman la región meridional del continente africano, durante el periodo 2000-2010.

Maestría en educación rural centroamericana: hacia un modelo pedagógico flexible

Program in Rural Education” is presented to the national and international community as a high level graduate program, whose purpose is to improve the quality of formal and informal educational processes within the area through an innovative pedagogical model that includes itinerancy along the isthmus, as well as in site and distance learning with a virtual component. Furthermore, this program bases its practice on the development of a flexible model, on inclusiveness and also on a differentiated methodological and evaluative proposal that recovers the knowledge produced in every country around de issue of rural education.

La perdita di chance nel prisma del danno non patrimoniale

Il danno da perdita di chance rappresenta la categoria giuridica di cui la giurisprudenza si serve per ampliare i confini della tutela risarcitoria, in diversi casi in cui, alla stregua dell’impostazione dogmatica tradizionale, non potrebbe dirsi configurabile un danno-conseguenza (né sotto forma di danno emergente, né sotto forma di lucro cessante). Lo studio, una volta delimitato il campo dell’indagine e dato conto delle opinioni dottrinali sulla ricostruzione della figura, ha preso le mosse dall’illustrazione degli orientamenti della giurisprudenza, la quale, a partire dagli anni ’80 del secolo scorso, è andata via via applicando l’istituto nei settori del diritto del lavoro, della responsabilità professionale (in particolare dell’avvocato), e del danno alla persona (nel quale ultimo si è messo in luce come il danno da perdita di chance possa rivestire funzione unicamente descrittiva di tipologie di pregiudizio riconducibili alle “tradizionali” voci di danno). Nel secondo capitolo si è analiticamente esaminata la fattispecie del danno da perdita di chance, alla luce delle categorie e dei principi generali della responsabilità civile, vagliando i margini di “armonizzabilità” dell’istituto rispetto alle classificazioni in termini di danno emergente/lucro cessante, danno presente/futuro, danno-evento/danno-conseguenza, nonché rispetto alle regole sulla causalità, al requisito dell’ingiustizia del danno, e alle tecniche di liquidazione del danno. Nell’ultimo capitolo, si è proceduto, poi, a “calare” l’istituto del danno da perdita di chance nel “sottosettore” della responsabilità sanitaria, sottoponendo a verifica la “tenuta teorica” della sua “variante” non patrimoniale al cospetto della recente novella legislativa rappresentata dalla l. n. 24/17, nonché degli orientamenti giurisprudenziali che, negli ultimi due anni, hanno interessato i temi dell’onere della prova del nesso causale e dello stesso danno da perdita di chance non patrimoniale. A conclusione dello studio, si sono svolte, infine, alcune considerazioni sulle criticità che precludono un’armonica “riconduzione a sistema” dell’istituto, consigliandone il definitivo abbandono.

Human GC-AG alternative intron isoforms with weak donor sites show enhanced consensus at acceptor exon positions

It has been previously observed that the intrinsically weak variant GC donor sites, in order to be recognized by the U2-type spliceosome, possess strong consensus sequences maximized for base pair formation with U1 and U5/U6 snRNAs. However, variability in signal strength is a fundamental mechanism for splice site selection in alternative splicing. Here we report human alternative GC-AG introns (for the first time from any species), and show that while constitutive GC-AG introns do possess strong signals at their donor sites, a large subset of alternative GC-AG introns possess weak consensus sequences at their donor sites. Surprisingly, this subset of alternative isoforms shows strong consensus at acceptor exon positions 1 and 2. The improved consensus at the acceptor exon can facilitate a strong interaction with U5 snRNA, which tethers the two exons for ligation during the second step of splicing. Further, these isoforms nearly always possess alternative acceptor sites and always possess alternative acceptor sites and exhibit particularly weak polypyrimidine tracts characteristic of AG-dependent introns. The acceptor exon nucleotides are part of the consensus required for the U2AF(35)-mediated recognition of AG in such introns. Such improved consensus at acceptor exons is not found in either normal or alternative GT-AG introns having weak donor sites or weak polypyrimidine,tracts. The changes probably reflect mechanisms that allow GC-AG alternative intron isoforms to cope with two conflicting requirements, namely an apparent need for differential splice strength to direct the choice of alternative sites and a need for improved donor signals to compensate for the central mismatch base pair (C-A) in the RNA duplex of U1 snRNA and the pre-mRNA. The other important findings include (i) one in every twenty alternative introns is a GC-AG intron, and (ii) three of every five observed GC-AG introns are alternative isoforms.

A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism

Context: Loss-of-function mutations of the kisspeptin-1 receptor gene, KISS1R, have been identified in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH). Objective: To investigate KISS1R defects in patients with absent or delayed puberty. Patients: We investigated KISS1R gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP). Methods: The entire coding region of KISS1R was amplified by PCR followed by automatic sequencing. In addition, screening for KISS1R exonic deletions was performed by multiplex ligation-dependent probe amplification. Results: One novel homozygous KISS1R mutation was identified in two siblings with nIHH. This variant was an insertion/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position -2 to -4, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 30 splice acceptor site of intron 2 of KISS1R. The brothers who carried this KISS1R mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous KISS1R variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, in vitro studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP. Conclusion: Loss-of-function mutations of KISS1R represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel KISS1R homozygous splice acceptor site mutation in the familial form of nIHH.

RNA polymerase I promoter and splice acceptor site recognition affect gene expression in non-pathogenic Leishmania species

Leishmania (Sauroleishmania) tarentolae has biotechnological potential for use as live vaccine against visceral leishmaniasis and as a system for the over expression of eukaryotic proteins that possess accurate post-translational modifications. For both purposes, new systems for protein expression in this non-pathogenic protozoan are necessary. The ribosomal RNA promoter proved to be a stronger transcription driver since its use yielded increased levels of recombinant protein in organisms of both genera Trypanosoma or Leishmania. We have evaluated heterologous expression systems using vectors with two different polypyrimidine tracts in the splice acceptor site by measuring a reporter gene transcribed from L. tarentolae RNA polymerase I promoter. Our data indicate that the efficiency of chloramphenicol acetyl transferase expression changed drastically with homologous or heterologous sequences, depending on the polypyrimidine tract used in the construct and differences in size and/or distance from the AG dinucleotide. In relation to the promoter sequence the reporter expression was higher in heterologous lizard-infecting species than in the homologous L. tarentolae or in the mammalian-infecting L. (Leishmania) amazonensis.

Mechanism of resistance to tyrosine kinase inhibitors in philadelphia-positive acute lymphblastic leukaemia (all): from genetic alterations to impaired RNA editing

The Ph chromosome is the most frequent cytogenetic aberration associated with adult ALL and it represents the single most significant adverse prognostic marker. Despite imatinib has led to significant improvements in the treatment of patients with Ph+ ALL, in the majority of cases resistance developed quickly and disease progressed. Some mechanisms of resistance have been widely described but the full knowledge of contributing factors, driving both the disease and resistance, remains to be defined. The observation of rapid development of lymphoblastic leukemia in mice expressing altered Ikaros (Ik) isoforms represented the background of this study. Ikaros is a zinc finger transcription factor required for normal hemopoietic differentiation and proliferation, particularly in the lymphoid lineages. By means of alternative splicing, Ikaros encodes several proteins that differ in their abilities to bind to a consensus DNA-binding site. Shorter, DNA nonbinding isoforms exert a dominant negative effect, inhibiting the ability of longer heterodimer partners to bind DNA. The differential expression pattern of Ik isoforms in Ph+ ALL patients was analyzed in order to determine if molecular abnormalities involving the Ik gene could associate with resistance to imatinib and dasatinib. Bone marrow and peripheral blood samples from 46 adult patients (median age 55 yrs, 18-76) with Ph+ ALL at diagnosis and during treatment with imatinib (16 pts) or dasatinib (30 pts) were collected. We set up a fast, high-throughput method based on capillary electrophoresis technology to detect and quantify splice variants. 41% Ph+ ALL patients expressed high levels of the non DNA-binding dominant negative Ik6 isoform lacking critical N-terminal zinc-fingers which display abnormal subcellular compartmentalization pattern. Nuclear extracts from patients expressed Ik6 failed to bind DNA in mobility shift assay using a DNA probe containing an Ikaros-specific DNA binding sequence. In 59% Ph+ ALL patients there was the coexistence in the same PCR sample and at the same time of many splice variants corresponded to Ik1, Ik2, Ik4, Ik4A, Ik5A, Ik6, Ik6 and Ik8 isoforms. In these patients aberrant full-length Ikaros isoforms in Ph+ ALL characterized by a 60-bp insertion immediately downstream of exon 3 and a recurring 30-bp in-frame deletion at the end of exon 7 involving most frequently the Ik2, Ik4 isoforms were also identified. Both the insertion and deletion were due to the selection of alternative splice donor and acceptor sites. The molecular monitoring of minimal residual disease showed for the first time in vivo that the Ik6 expression strongly correlated with the BCR-ABL transcript levels suggesting that this alteration could depend on the Bcr-Abl activity. Patient-derived leukaemia cells expressed dominant-negative Ik6 at diagnosis and at the time of relapse, but never during remission. In order to mechanistically demonstrated whether in vitro the overexpression of Ik6 impairs the response to tyrosine kinase inhibitors (TKIs) and contributes to resistance, an imatinib-sensitive Ik6-negative Ph+ ALL cell line (SUP-B15) was transfected with the complete Ik6 DNA coding sequence. The expression of Ik6 strongly increased proliferation and inhibited apoptosis in TKI sensitive cells establishing a previously unknown link between specific molecular defects that involve the Ikaros gene and the resistance to TKIs in Ph+ ALL patients. Amplification and genomic sequence analysis of the exon splice junction regions showed the presence of 2 single nucleotide polymorphisms (SNPs): rs10251980 [A/G] in the exon2/3 splice junction and of rs10262731 [A/G] in the exon 7/8 splice junction in 50% and 36% of patients, respectively. A variant of the rs11329346 [-/C], in 16% of patients was also found. Other two different single nucleotide substitutions not recognized as SNP were observed. Some mutations were predicted by computational analyses (RESCUE approach) to alter cis-splicing elements. In conclusion, these findings demonstrated that the post-transcriptional regulation of alternative splicing of Ikaros gene is defective in the majority of Ph+ ALL patients treated with TKIs. The overexpression of Ik6 blocking B-cell differentiation could contribute to resistance opening a time frame, during which leukaemia cells acquire secondary transforming events that confer definitive resistance to imatinib and dasatinib.

The common tetratricopeptide repeat acceptor site for steroid receptor-associated immunophilins and Hop is located in the dimerization domain of hsp90

Structurally related tetratricopeptide repeat motifs in steroid receptor-associated immunophilins and the STI1 homolog, Hop, mediate the interaction with a common cellular target, hsp90, We have identified the binding domain in hsp90 for cyclophilin 40 (CyP40) using a two-hybrid system screen of a mouse cDNA library. All isolated clones encoded the intact carboxyl terminus of hsp90 and overlapped with a common region corresponding to amino acids 558-724 of murine hsp84, The interaction was confirmed in vitro with bacterially expressed CyP40 and deletion mutants of hsp90 beta and was delineated further to a 124-residue COOH-terminal segment of hsp90, Deletion of the conserved MEEVD sequence at the extreme carboxyl terminus of hsp90 precludes interaction with CyP40, signifying an important role for this motif in hsp90 function. We show that CyP40 and Hop display similar interaction profiles with hsp90 truncation mutants and present evidence for the direct competition of Hop and FK506-binding protein 52 with CyP40 for binding to the hsp90 COOH-terminal region. Our results are consistent with a common tetratricopeptide repeat interaction site for Hop and steroid receptor associated immunophilins within a discrete COOH-terminal domain of hsp90. This region of hsp90 mediates ATP-independent chaperone activity, overlaps the hsp90 dimerization domain, and includes structural elements important for steroid receptor interaction.

Identification of SL addition trans-splicing acceptor sites in the internal transcribed spacer I region of pre-rRNA in Leishmania (Leishmania) amazonensis

Trypanosomatidae is a family of early branching eukaryotes harbouring a distinctive repertoire of gene expression strategies. Functional mature messenger RNA is generated via the trans-splicing and polyadenylation processing of constitutively transcribed polycistronic units. Recently, trans-splicing of pre-small subunit ribosomal RNA in the 5' external transcribed spacer region and of precursor tRNAsec have been described. Here, we used a previously validated semi-nested reverse transcription-polymerase chain reaction strategy to investigate internal transcribed spacer (ITS) I acceptor sites in total RNA from Leishmania (Leishmania) amazonensis. Two distinct spliced leader-containing RNAs were detected indicating that trans-splicing reactions occur at two AG acceptor sites mapped in this ITS region. These data provide further evidence of the wide spectrum of RNA molecules that act as trans-splicing acceptors in trypanosomatids.

Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A.

Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors. Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.

The consensus sequence of FAMLF alternative splice variants is overexpressed in undifferentiated hematopoietic cells

The familial acute myeloid leukemia related factor gene (FAMLF) was previously identified from a familial AML subtractive cDNA library and shown to undergo alternative splicing. This study used real-time quantitative PCR to investigate the expression of the FAMLF alternative-splicing transcript consensus sequence (FAMLF-CS) in peripheral blood mononuclear cells (PBMCs) from 119 patients with de novo acute leukemia (AL) and 104 healthy controls, as well as in CD34+cells from 12 AL patients and 10 healthy donors. A 429-bp fragment from a novel splicing variant of FAMLF was obtained, and a 363-bp consensus sequence was targeted to quantify total FAMLF expression. Kruskal-Wallis, Nemenyi, Spearman's correlation, and Mann-Whitney U-tests were used to analyze the data. FAMLF-CS expression in PBMCs from AL patients and CD34+ cells from AL patients and controls was significantly higher than in control PBMCs (P<0.0001). Moreover,FAMLF-CS expression in PBMCs from the AML group was positively correlated with red blood cell count (rs=0.317, P=0.006), hemoglobin levels (rs=0.210, P=0.049), and percentage of peripheral blood blasts (rs=0.256, P=0.027), but inversely correlated with hemoglobin levels in the control group (rs=–0.391, P<0.0001). AML patients with high CD34+ expression showed significantly higherFAMLF-CS expression than those with low CD34+ expression (P=0.041). Our results showed thatFAMLF is highly expressed in both normal and malignant immature hematopoietic cells, but that expression is lower in normal mature PBMCs.