Latent rank change detection for analysis of splice-junction microarrays with nonlinear effects

Alternative splicing of gene transcripts greatly expands the functional capacity of the genome, and certain splice isoforms may indicate specific disease states such as cancer. Splice junction microarrays interrogate thousands of splice junctions, but data analysis is difficult and error prone because of the increased complexity compared to differential gene expression analysis. We present Rank Change Detection (RCD) as a method to identify differential splicing events based upon a straightforward probabilistic model comparing the over- or underrepresentation of two or more competing isoforms. RCD has advantages over commonly used methods because it is robust to false positive errors due to nonlinear trends in microarray measurements. Further, RCD does not depend on prior knowledge of splice isoforms, yet it takes advantage of the inherent structure of mutually exclusive junctions, and it is conceptually generalizable to other types of splicing arrays or RNA-Seq. RCD specifically identifies the biologically important cases when a splice junction becomes more or less prevalent compared to other mutually exclusive junctions. The example data is from different cell lines of glioblastoma tumors assayed with Agilent microarrays.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS389 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Over-represented sequences located on UTRs are potentially involved in regulatory functions

Eukaryotic gene expression must be coordinated for the proper functioning of biological processes. This coordination can be achieved both at the transcriptional and post-transcriptional levels. In both cases, regulatory sequences placed at either promoter regions or on UTRs function as markers recognized by regulators that can then activate or repress different groups of genes according to necessity. While regulatory sequences involved in transcription are quite well documented, there is a lack of information on sequence elements involved in post-transcriptional regulation. We used a statistical over-representation method to identify novel regulatory elements located on UTRs. An exhaustive search approach was used to calculate the frequency of all possible n-mers (short nucleotide sequences) in 16,160 human genes of NCBI RefSeq sequences and to identify any peculiar usage of n-mers on UTRs. After a stringent filtering process, we identified circa 4,000 highly over-represented n-mers on UTRs. We provide evidence that these n-mers are potentially involved in regulatory functions. Identified n-mers overlap with previously identified binding sites for HuR and Tia1 and, AU-rich and GU-rich sequences. We determined also that over-represented n-mers are particularly enriched in a group of 159 genes directly involved in tumor formation. Finally, a method to cluster n-mer groups allowed the identification of putative gene networks.Over-represented sequences, UTRs, regulatory functions

O Grupo Pinhal na região nordeste do estado de São Paulo e áreas vizinhas do estado de Minas Gerais

The Pinhal Group is a very important lithostratigraphic unit that border the São Francisco Craton, in the NE of the State of São Paulo and SSW of the State of Minas Gerais, southern Brazil. The Pinhal and Socorro Complexes are the main granitic-migmatitic areas of this unit, including "migmatites forming granites", migmatites, "normal granites" and several medium to high grade metamorphic country rocks. The granitic suite include various equigranular and porphyroid types and porphyritic, pegmatitic and aplitic dikes. Geochronologic age determinations indicate their relation with "Brazilian Cycle" (Baikalian Cycle, of Upper Precambrian age); the country rocks belong to the Amparo Group (Middle Precambriam), which rocks underwent an intensive remobilization during the Brazilian Cycle. The "migmatites forming granites" are surrounded by an aureole of migmatites composed of 3 zones: the outer zone is formed by layered migmatites, the medium one by agmatitic and "schollen" migmatites; and the inner one by "schlieren", nebulitic and homophanic migmatites. The central granitic core is equigranular or porphyroid. The migmatitic aureole is frequently disturbed by faults, by "normal granite" instrusions or by the interference of adjacent aureoles; these disturbances lead to very complex (polyphasic) migmatites. Strong metassomatic phenomena affected the rocks of the Pinhal Group, at two distinct phases. The first one, of potassic character, in characterized by an intensive development of microcline mega-crystals; and the second one, of sodic nature, by the formation of pure albite. In each phase, distinct metassomatic pulsations have been observed, linked with the several intrusion and tectonic events which have affected the complexes which form megadiapirs of polydiapiric nature. The big granite plutons have arisen from the base of the sialic crust along "thermal channels" related to zones of tectonic weakness. During this slow ascension these bodies have undergone deep modifications (remobilization, subsolidus recrystalization, metasomatism, assimilation and fractional crystalization), without significative changes in their chemical character. From the regional point of view the Pinhal Group is correlated to the Serra dos Órgãos Group, in the Rio de Janeiro State. Economic geology in the investigated region is mainly related to pegmatites exploitation.O Grupo Pinhal é uma importante unidade litoestratigráfica, aflorante na região NE do Estado de São Paulo e SSW do Estado de Minas Gerais, no Brasil meridional. Os Complexos de Pinhal e Socorro são as principais áreas granítico-migmatíticas desta unidade, incluindo "granitos formadores de migmatitos", "granitos normais", migmatitos e vários tipos de metamorfitos regionais, de médio a alto grau de metamorfismo. O conjunto de rochas graníticas inclui diversos tipos equigranulares e porfiroides, bem como diques aplíticos, porfiríticos e pegmatíticos. A geocronologia indicou idades que relacionam essas rochas com o Ciclo Brasiliano (Ciclo Baikaliano, do Pré-Cambriano Superior); as rochas encaixantes pertencem ao Grupo Amparo (do Pré-Cambriano Médio), as quais sofreram uma intensa remobilização durante o Ciclo Brasiliano. Os "granitos formadores de migmatitos" sâo circundados por uma auréola de migmatitos, composta por três zonas: a externa é formada por migmatito acamado; a intermediária, por migmatitos agmatitico e "schollen", e a interna por migmatito do tipo "schlieren", nebulitico e homofânico. O núcleo granítico central é equigranular ou porfiroide. A auréola migmatítica é, com freqüência, perturbada por falhamentos, pela intrusão de "granitos normais" ou pela interferência de auréolas adjacentes; essas perturbações levam ao aparecimento de migmatitos complexos, polifásicos. Intensa atividade metassomática afetou as rochas do Grupo Pinhal, em duas dases distintas. A primeira, de natureza potássica, é caracterizada pelo abundante desenvolvimento de megacristais de microlina, e a segunda, de natureza sódica, pela formação de albita pura. Em cada uma dessas fases observou-se pulsações metassomáticas distintas, relacionadas com as diversas intrusões e eventos tectónicos que afetaram os complexos que constituem megadiápiros de natureza polidiapírica. Os grandes corpos graníticos plutônicos ascenderam, da base da crosta siálica, através de "canais térmicos" relacionados com zonas de fraqueza tectônica. Durante essa lenta ascensão, esses corpos sofreram profundas modificações (remobilizações, recristalização sub-sólida, metassomatismo, assimilação e cristalização fracionada). Do ponto de vista regional o Grupo Pinhal é correlacionável ao Grupo Serrados Órgãos, no Estado do Rio de Janeiro. Os recursos econômicos na região investigada constituem-se essencialmente de material para construção civil e minerais de pegmatito

Lesão expansiva cerebral devida a citomegalovírus: relato de caso e revisão da literatura

Cytomegalovirus (CMV) disease in acquired immunodeficiency syndrome (AIDS) patients most commonly presents as chorioretinitis and gastro-intestinal infection. Neurological involvement due to CMV may cause several clinical presentations: polyradiculitis, myelitis, encephalitis, ventriculo-encephalitis, and mononeuritis multiplex. Rarely, cerebral mass lesion is described. We report a 39 year-old woman with AIDS and previous cerebral toxoplasmosis. She presented with fever, seizures, and vulval ulcers. Her chest X-ray showed multiple lung nodules, and a large frontal lobe lesion was seen in a brain computed tomography scan. She underwent a brain biopsy through a frontal craniotomy, but her condition deteriorated and she died in the first postoperative day. Histopathological studies and immunohistochemistry disclosed CMV disease, and there was no evidence of cerebral toxoplasmosis, bacterial, mycobacterial or fungal infection. CMV disease should be considered in the differential diagnosis of cerebral mass lesion in AIDS patients. High suspicion index, timely diagnostic procedures (surgical or minimally invasive), and proper utilization of prophylactic and therapeutic medication could improve outcome of these patients.As doenças causadas pelo citomegalovírus (CMV) em pacientes com a síndrome da imunodeficiência adquirida apresentam-se principalmente como corioretinite ou comprometimento gastrointestinal. No sistema nervoso central, o CMV pode causar diversas síndromes clínicas: poliradiculite, mielite, encefalite, ventrículo-encefalite e mononeurite múltipla. Raramente, lesões expansivas cerebrais são descritas. Os autores relatam o caso de uma paciente de 39 anos com antecedentes de infecção pelo HIV e toxoplasmose cerebral, que apresentou-se com febre, convulsões e úlceras vulvares. O raios-X de tórax demonstrou múltiplos nódulos pulmonares e a tomografia computadorizada de crânio evidenciou extensa lesão no lobo frontal esquerdo. Após ser submetida à craniotomia, evoluiu com piora clínica, falecendo no primeiro dia de pós-operatório. Os estudos histopatológicos e imunohistoquímicos demonstraram doença citomegálica. Foram excluídas toxoplasmose cerebral e infecção bacteriana, micobacteriana ou fúngica. Concluímos que, embora seja extremamente raro, o CMV deve ser considerado no diagnóstico diferencial das lesões expansivas cerebrais em pacientes com infecção pelo HIV. Um elevado índice de suspeita, procedimentos diagnósticos oportunos (cirúrgicos ou minimamente invasivos), e o adequado uso de antivirais (terapêuticos e profiláticos) podem melhorar o prognóstico desta letal manifestação

Before It Gets Started: Regulating Translation at the 5′ UTR

Translation regulation plays important roles in both normal physiological conditions and diseases states. This regulation requires cis-regulatory elements located mostly in 5′ and 3′ UTRs and trans-regulatory factors (e.g., RNA binding proteins (RBPs)) which recognize specific RNA features and interact with the translation machinery to modulate its activity. In this paper, we discuss important aspects of 5′ UTR-mediated regulation by providing an overview of the characteristics and the function of the main elements present in this region, like uORF (upstream open reading frame), secondary structures, and RBPs binding motifs and different mechanisms of translation regulation and the impact they have on gene expression and human health when deregulated

Lesão intracraniana que respondeu ao tratamento anti-tuberculoso em paciente infectado pelo HIV

Cerebral tuberculomas constitute a major differential diagnosis of cerebral toxoplasmosis in human immunodeficiency virus (HIV)-infected patients in developing countries. We report the case of a 34-year old woman co-infected with HIV and possible disseminated tuberculosis (hepatitis, lymphadenopathy, and pleural effusion) who presented a large and solitary intracranial mass lesion. Despite extensive diagnostic efforts, including brain, ganglionar, and liver biopsies, no definitive diagnosis was reached. However, a trial with first-line antituberculous drugs led to a significant clinical and radiological improvement. Atypical presentations of cerebral tuberculomas should always be considered in the differential diagnosis of intracranial mass lesions in HIV-infected patients and a trial with antituberculous drugs is a valuable strategy to infer the diagnosis in a subset of patients.Os tuberculomas cerebrais constituem diagnóstico diferencial importante da toxoplasmose cerebral em pacientes infectados pelo vírus da imunodeficiência humana (HIV) de países em desenvolvimento. Os autores relatam o caso de uma mulher HIV positiva de 34 anos de idade, que apresentou provável tuberculose disseminada (hepatite, adenomegalia, e derrame pleural) associada à lesão expansiva cerebral única e gigante. Apesar dos esforços diagnósticos realizados, incluindo biópsia cerebral, ganglionar e hepática, o diagnóstico etiológico não foi confirmado. Porém, a resposta clínico-radiológica ao tratamento tuberculostático permitiu definir o diagnóstico de tuberculoma cerebral e a paciente teve alta hospitalar. Apresentações atípicas de tuberculomas cerebrais devem ser sempre consideradas no diagnóstico diferencial das lesões expansivas cerebrais em pacientes infectados pelo HIV e o uso do tratamento tuberculostático constitui ferramenta útil na definição diagnóstica em um sub-grupo de paciente

Aspergilosis cerebral causada por Aspergillus fumigatus en paciente con SIDA: primer reporte de caso demostrado por cultivo en Brasil

Cerebral aspergillosis is a rare cause of brain expansive lesion in AIDS patients. We report the first culture-proven case of brain abscess due to Aspergillus fumigatus in a Brazilian AIDS patient. The patient, a 26 year-old male with human immunodeficiency virus (HIV) infection and history of pulmonary tuberculosis and cerebral toxoplasmosis, had fever, cough, dyspnea, and two episodes of seizures. The brain computerized tomography (CT) showed a bi-parietal and parasagittal hypodense lesion with peripheral enhancement, and significant mass effect. There was started anti-Toxoplasma treatment. Three weeks later, the patient presented mental confusion, and a new brain CT evidenced increase in the lesion. He underwent brain biopsy, draining 10 mL of purulent material. The direct mycological examination revealed septated and hyaline hyphae. There was started amphotericin B deoxycholate. The culture of the material demonstrated presence of the Aspergillus fumigatus. The following two months, the patient was submitted to three surgeries, with insertion of drainage catheter and administration of amphotericin B intralesional. Three months after hospital admission, his neurological condition suffered discrete changes. However, he died due to intrahospital pneumonia. Brain abscess caused by Aspergillus fumigatus must be considered in the differential diagnosis of the brain expansive lesions in AIDS patients in Brazil.La aspergilosis cerebral es una causa rara de lesión expansiva cerebral en pacientes con SIDA. Presentamos el primer reporte de un absceso cerebral causado por Aspergillus fumigatus en un paciente brasileño con SIDA. El paciente, de 26 años de edad, presentaba antecedentes de infección por el virus de la inmunodeficiencia humana (VIH), tuberculosis pulmonar y toxoplasmosis cerebral. Manifestó fiebre, tos, disnea y dos episódios de convulsiones. La tomografía computadorizada (TC) demostró una lesión hipodensa parasagital y bi-parietal con realce periférico e importante efecto de masa. Se inició tratamiento anti-Toxoplasma. Tres semanas después, el paciente evidenció confusión mental y una nueva TC de cráneo mostró aumento de la lesión. Se realizó biopsia cerebral con drenaje de 10 mL de material purulento. El examen micológico directo reveló hifas hialinas septadas. Se inició anfotericina B deoxicolato. La cultura del material demostró presencia de Aspergillus fumigatus. En los siguientes dos meses el paciente fue sometido a otras tres cirugías, insertándose un catéter de drenaje y administrándose anfotericina B intralesional. Tres meses después de la admisión hospitalaria, la condición neurológica del paciente sufrió discretos cambios. Sin embargo, falleció debido a neumonia intrahospitalaria. Aunque muy raros, los abscesos cerebrales causados por Aspergillus fumigatus deben ser considerados en el diagnóstico diferencial de las lesiones expansivas cerebrales en pacientes con SIDA

BK virus associated meningoencephalitis in an AIDS patient treated with HAART

A severely immune-suppressed AIDS patient was suspected of suffering from BK virus (BKV) meningoencephalitis, after being studied for common causes of neurological complications of co-infectious origin. Polymerase chain reaction (PCR) and sequence analysis of cerebrospinal fluid and brain samples, confirmed the presence of BKV. His clinical condition improved along with the regression of brain lesions, after modifications on his antiretroviral regime. Five months after discharge, the patient was readmitted because of frequent headaches, and a marked inflammatory reaction was evidenced by a new magnetic resonance imaging (MRI). The symptoms paralleled a rising CD4+ lymphocyte count, and immune reconstitution syndrome was suspected. This is the first non-postmortem report of BKV meningoencephalitis in an AIDS patient, showing clinical and radiographic improvement solely under HAART