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Multidrug-resistant and highly virulent Klebsiella pneumoniae isolates are emerging, but the clonal groups (CGs) corresponding to these high-risk strains have remained imprecisely defined. We aimed to identify K. pneumoniae CGs on the basis of genome-wide sequence variation and to provide a simple bioinformatics tool to extract virulence and resistance gene data from genomic data. We sequenced 48 K. pneumoniae isolates, mostly of serotypes K1 and K2, and compared the genomes with 119 publicly available genomes. A total of 694 highly conserved genes were included in a core-genome multilocus sequence typing scheme, and cluster analysis of the data enabled precise definition of globally distributed hypervirulent and multidrug-resistant CGs. In addition, we created a freely accessible database, BIGSdb-Kp, to enable rapid extraction of medically and epidemiologically relevant information from genomic sequences of K. pneumoniae. Although drug-resistant and virulent K. pneumoniae populations were largely nonoverlapping, isolates with combined virulence and resistance features were detected.

In Poland we have varied ways of protection such as transformation or in situ protection. In the case of detached houses often with farming buildings they work, while in the area of rural complexes there are some difficulty with these matters. To be general and brief such endeavour seems to call for agreement of local community when it comes to keeping the idea in order to protect the design and architectural tradition.

Gaucher disease is a rare inherited disease caused by a deficiency in glucocerebrosidase leading to lipid accumulation in cells of mononuclear-macrophage lineage known as Gaucher cells. Visceral enlargement, bone involvement, mild anemia and thrombocytopenia are the major manifestations of Gaucher disease. We have previously demonstrated that the red blood cells from patients exhibit abnormal properties, which indicates a new role in Gaucher disease pathophysiology. To investigate whether erythroid progenitors are affected, we examined the in vitro erythropoiesis from the peripheral CD34+ cells of patients and controls. CD34− cells were differentiated into macrophages and co-cultivated with erythroblasts. We showed an accelerated differentiation of erythroid progenitors without maturation arrest from patients compared to controls. This abnormal differentiation persisted in the patients when the same experiments were performed without macrophages, which strongly suggested that dyserythropoiesis in Gaucher disease is secondary to an inherent defect in the erythroid progenitors. The accelerated differentiation was associated with reduced cell proliferation. As a result, less mature erythroid cells were generated in vitro in the Gaucher disease cultures compared to the control. We then compared the biological characteristics of untreated patients according to their anemic status. Compared to the non-anemic group, the anemic patients exhibit higher plasma levels of growth differentiation factor-15, a marker of ineffective erythropoiesis, but they had no indicators of hemolysis and similar reticulocyte counts. Taken together, these results demonstrated an unsuspected dyserythropoiesis that was independent of the macrophages and could participate, at least in part, to the basis of anemia in Gaucher disease.

Despite the recent advances in the development of antitumor therapies, the prognosis for patients with malignant gliomas remains dismal. Therapy with tumor-selective viruses is emerging as a treatment option for this devastating disease. In this study we characterize the anti-glioma effect of VCN-01, an improved hyaluronidase-armed pRB-pathway-selective oncolytic adenovirus that has proven safe and effective in the treatment of several solid tumors. VCN-01 displayed a significant cytotoxic effect on glioma cells in vitro. In vivo, in two different orthotopic glioma models, a single intra-tumoral administration of VCN-01 increased overall survival significantly and led to long-term survivors free of disease.

INTRODUCTION:Glioblastoma is the most malignant brain tumor in adults and is associated with poor survival despite multimodal treatments. Glioma stem-like cells (GSCs) are cells functionally defined by their self-renewal potential and the ability to reconstitute the original tumor upon orthotopic implantation. They have been postulated to be the culprit of glioma chemo- and radio-resistance ultimately leading to relapse. Understanding the molecular circuits governing the GSC compartment is essential. SOX2, a critical transcription regulator of embryonic and neural stem cell function, is deregulated in GSCs however; the precise molecular pathways regulated by this gene in GSCs remain poorly understood. RESULTS:We performed a genome-wide analysis of SOX2-regulated transcripts in GSCs, using a microarray. We identified a total of 2048 differentially expressed coding transcripts and 261 non-coding transcripts. Cell adhesion and cell-cell signaling are among the most enriched terms using Gene Ontology (GO) classification. The pathways altered after SOX2 down-modulation includes multiple cellular processes such as amino-acid metabolism and intercellular signaling cascades. We also defined and classified the set of non-coding transcripts differentially expressed regulated by SOX2 in GSCs, and validated two of them. CONCLUSIONS:We present a comprehensive analysis of the transcriptome controlled by SOX2 in GSCs, gaining insights in the understanding of the potential roles of SOX2 in glioblastoma.

[This corrects the article DOI: 10.1371/journal.pone.0147211.].

OBJETIVO: Estudo retrospectivo comparando resultados da IA e da IP em pacientes operados com o diagnóstico de EIA (tipo 1 de Lenke). MÉTODOS: Os resultados de 24 pacientes com idade de 11 a 18 anos com EIA tipo Lenke I e submetidos a tratamento cirúrgico por meio da abordagem anterior (12 pacientes) ou posterior (12 pacientes) foram comparados. Todos os pacientes foram operados pelo mesmo cirurgião e seguidos por um período mínimo de cinco anos. As variáveis de comparação incluíram: correção sagital e coronal, distância da vértebra apical a linha média, rotação da vértebra apical, número de vértebras instrumentadas e variáveis funcionais por meio do questionário SRS-22. Os dados obtidos foram analisados com a versão 9 do programa SAS. Os dois grupos foram comparados com o teste t de Student com um nível de significância de 5% (0,05). RESULTADOS: A correção da curva no plano frontal no pós-operatório imediato (p = 0,031), tardio (p = 0,043) e também a rotação da vértebra apical no pós-operatório imediato (p = 0,002) e tardio (p = 0,021) no grupo de pacientes submetidos à correção por meio da abordagem anterior. O número de vértebras instrumentadas foi 7,69 ± 1,38 no grupo de pacientes submetidos a IA e 11,38 ± 2,92 na IP (p = 0,021). A avaliação funcional (SRS-22) não demonstrou diferença significativa (p > 0,05) entre os grupos. CONCLUSÃO: O grupo de pacientes submetidos à correção da escoliose por instrumentação anterior apresentou maior correção no plano frontal, maior derrotação da vértebra apical e menor número de vértebras artrodesadas.OBJECTIVE: To evaluate and compare the results of AI and PI in patients diagnosed with Lenke type I curves who were treated surgically. METHODS: The results of 24 patients aged 11 to 18 years with Lenke type I idiopathic scoliosis who underwent surgery with anterior (12 patients) or posterior (12 patients) instrumentation were compared. All patients were operated by the same surgeon and were followed up for a minimum period of five years. Variables for comparison include: coronal and sagittal correction, distance from apical vertebra to midline, apical vertebral rotation, number of instrumented vertebrae and functional variables by means of the SRS-22 questionnaire. The data obtained were analyzed with the SAS program, version 9. The two groups were compared with a 2-tailed Student's t-test with a level of significance set at 5% (0.05). RESULTS: The correction of the curve on the frontal plane was higher at immediate (p=0.031) and late postoperative (p=0.043) as well the apical vertebral rotation during immediate (p=0.002) and late (p=0.019) evaluation in the anterior spinal fusion group. The number of instrumented vertebrae was 7.69±1.38 in the anterior spinal fusion patients and 11.38±2.92 in the posterior spine fusion patients (p=0.021). Functional assessment (SRS-22) showed no significant difference (p>0.05) between groups. CONCLUSION: Anterior spine fusion patients presented greater scoliosis correction on frontal plane, greater derotation of apical vertebrae and smaller number of fused vertebrae.

Despite the recent global spread of CTX-M β-lactamases in Escherichia coli isolates from community-acquired urinary tract infections (CA-UTIs), their dissemination has been little studied in developing countries. In a 2-year prospective study, we documented the prevalence of extended-spectrum β-lactamases (ESBLs) in E. coli that were responsible for CA-UTIs in Phnom-Penh, Cambodia. Ninety-three E. coli strains were included. We observed a high prevalence of resistance to amoxicillin (88.2% of strains), cotrimoxazole (75.3%), ciprofloxacin (67.7%), gentamicin (42.5%), and third-generation cephalosporins (37.7%). A total of 34 strains carried ESBLs, all of which were CTX-M type. CTX-M carriage was associated with resistance to fluoroquinolones and aminoglycosides. U using repetitive extragenic palindromic–PCR, we identified 4 clusters containing 9, 8, 3, and 2 strains. The prevalence of CTX-M β-lactamases has reached a critical level in Cambodia, which highlights the need for study of their spread in developing countries.

The activation of G-protein coupled receptors by agonist compounds results in diverse biological responses in cells, such as the endocytosis process consisting in the translocation of receptors from the plasma membrane to the cytoplasm within internalizing vesicles or endosomes. In order to functionally evaluate endocytosis events resulted from pharmacological responses, we have developed an image analysis method -the Q-Endosomes algorithm- that specifically discriminates the fluorescent signal originated at endosomes from that one observed at the plasma membrane in images obtained from living cells by fluorescence microscopy. Mu opioid (MOP) receptor tagged at the carboxy-terminus with yellow fluorescent protein (YFP) and permanently expressed in HEK293 cells was used as experimental model to validate this methodology. Time-course experiments performed with several agonists resulted in different sigmoid curves depending on the drug used to initiate MOP receptor endocytosis. Thus, endocytosis resulting from the simultaneous activation of co-expressed MOP and serotonin 5-HT2C receptors by morphine plus serotonin was significantly different, in kinetics as well as in maximal response parameters, from the one caused by DAMGO, sufentanyl or methadone. Therefore, this analytical tool permits the pharmacological characterization of receptor endocytosis in living cells with functional and temporal resolution.

We aimed to detect the extended-spectrum β-lactamases (ESBLs) secreted by clinical strains of Escherichia coli at Fann University Hospital in Dakar and to characterize them molecularly. We identified 32 isolates producing ESBLs. The CTX-M-15 gene was the most frequently detected ESBL gene, detected in 90.63% of the isolates studied.

La autarquía es un concepto del pensamiento clásico griego del que, traspapelado en la historia, se ha demeritado su sentido original, prescindiendo de toda sinergia posible a la que remitiría la autosuficiencia buscada por éste. Este artículo explora distintas reflexiones teóricas para repensar estadios evolutivos de la autarquía en el ámbito rural como una opción favorable al desarrollo regional vista desde el marco de los procesos migratorios, de las nuevas ruralidades, de la ruralización y expansión urbana y de la creación de redes sociales.

In humans, β-thalassemia dyserythropoiesis is characterized by expansion of early erythroid precursors and erythroid progenitors and then ineffective erythropoiesis. This ineffective erythropoiesis is defined as a suboptimal production of mature erythrocytes originating from a proliferating pool of immature erythroblasts. It is characterized by (1) accelerated erythroid differentiation, (2) maturation blockade at the polychromatophilic stage, and (3) death of erythroid precursors. Despite extensive knowledge of molecular defects causing β-thalassemia, less is known about the mechanisms responsible for ineffective erythropoiesis. In this paper, we will focus on the underlying mechanisms leading to premature death of thalassemic erythroid precursors in the bone marrow.