Interaction of the Transcription Start Site Core Region and Transcription Factor YY1 Determine Ascorbate Transporter SVCT2 Exon 1a Promoter Activity

Transcription of the ascorbate transporter, SVCT2, is driven by two distinct promoters in exon 1 of the transporter sequence. The exon 1a promoter lacks a classical transcription start site and little is known about regulation of promoter activity in the transcription start site core (TSSC) region. Here we present evidence that the TSSC binds the multifunctional initiator-binding protein YY1. Electrophoresis shift assays using YY1 antibody showed that YY1 is present as one of two major complexes that specifically bind to the TSSC. The other complex contains the transcription factor NF-Y. Mutations in the TSSC that decreased YY1 binding also impaired the exon 1a promoter activity despite the presence of an upstream activating NF-Y/USF complex, suggesting that YY1 is involved in the regulation of the exon 1a transcription. Furthermore, YY1 interaction with NF-Y and/or USF synergistically enhanced the exon 1a promoter activity in transient transfections and co-activator p300 enhanced their synergistic activation. We propose that the TSSC plays a vital role in the exon 1a transcription and that this function is partially carried out by the transcription factor YY1. Moreover, co-activator p300 might be able to synergistically enhance the TSSC function via a “bridge” mechanism with upstream sequences

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

BACKGROUND: In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. METHODS: We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS: A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. CONCLUSIONS: Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety

Chronic myeloid leukemia mimicking primary myelofibrosis: A case report

Bone marrow fibrosis leading to dry tap aspiration and often associated with blast crisis has previously been reported in both Chronic myeloid leukemia and Primary myelofibrosis. The similarities between these two conditions in terms of clinical presentation and morphology can really create a diagnostic dilemma. Here we present a case of Chronic myeloid leukemia in fibrosis and blast crisis in a 32 year old lady which closely resembled Primary myelofibrosis in transformation. All myeloproliferative neoplasms can undergo blast transformation. In this case, the detection of Philadelphia chromosome helped to distinguish Chronic myeloid leukemia from other myeloproliferative neoplasms.</p

Boundary layer on a flat plate with suction

In this paper we have discussed the boundary layer on a plate with suction. The problem is solved near the leading edge as well as far downstream. A linear suction law is assumed near the leading edge for simplicity, whereas no restriction is placed on the suction law in the region downstream. An explict expression for boundary layer thickness in terms of suction speed and distance from leading edge is derived. It is found that the thickness of the boundary layer depends on the derivative of the suction speed. The skin friction also has been evaluated. Though near the leading edge a linear law of suction is assumed, the method used in the paper can be easily generalised for any other power law, for example, we may use a power series expansion for the function defining the suction velocity

COVID-19 diagnosis: A comprehensive review of pre-trained deep learning models based on feature extraction algorithm

Due to the augmented rise of COVID-19, clinical specialists are looking for fast faultless diagnosis strategies to restrict Covid spread while attempting to lessen the computational complexity. In this way, swift diagnosis techniques for COVID-19 with high precision can offer valuable aid to clinical specialists. RT- PCR test is an expensive and tedious COVID diagnosis technique in practice. Medical imaging is feasible to diagnose COVID-19 by X-ray chest radiography to get around the shortcomings of RT-PCR. Through a variety of Deep Transfer-learning models, this research investigates the potential of Artificial Intelligence -based early diagnosis of COVID-19 via X-ray chest radiographs. With 10,192 normal and 3616 Covid X-ray chest radiographs, the deep transfer-learning models are optimized to further the accurate diagnosis. The x-ray chest radiographs undergo a data augmentation phase before developing a modified dataset to train the Deep Transfer-learning models. The Deep Transfer-learning architectures are trained using the extracted features from the Feature Extraction stage. During training, the classification of X-ray Chest radiographs based on feature extraction algorithm values is converted into a feature label set containing the classified image data with a feature string value representing the number of edges detected after edge detection. The feature label set is further tested with the SVM, KNN, NN, Naive Bayes and Logistic Regression classifiers to audit the quality metrics of the proposed model. The quality metrics include accuracy, precision, F1 score, recall and AUC. The Inception-V3 dominates the six Deep Transfer-learning models, according to the assessment results, with a training accuracy of 84.79% and a loss function of 2.4%. The performance of Cubic SVM was superior to that of the other SVM classifiers, with an AUC score of 0.99, precision of 0.983, recall of 0.8977, accuracy of 95.8%, and F1 score of 0.9384. Cosine KNN fared better than the other KNN classifiers with an AUC score of 0.95, precision of 0.974, recall of 0.777, accuracy of 90.8%, and F1 score of 0.864. Wide NN fared better than the other NN classifiers with an AUC score of 0.98, precision of 0.975, recall of 0.907, accuracy of 95.5%, and F1 score of 0.939. According to the findings, SVM classifiers topped other classifiers in terms of performance indicators like accuracy, precision, recall, F1-score, and AUC. The SVM classifiers reported better mean optimal scores compared to other classifiers. The performance assessment metrics uncover that the proposed methodology can aid in preliminary COVID diagnosis

Surgical management of ureteropelvic junction obstruction in adults

Ureteropelvic junction (UPJ) obstruction is a well-recognized entity that may present at any time - in fetal life, infancy, childhood, or early or late adulthood. As the most common site of obstruction in the upper urinary tract, the UPJ is an area with which urologists should be well familiar. There has been an improved understanding of the pathophysiology of primary congenital UPJ obstruction that has been reflected in the evolution of surgical options, from open surgical repair to minimally invasive surgery. Although the primary scope of this review is the surgical management of this condition, we will briefly review the pathogenesis, clinical presentation, and diagnosis of UPJ obstruction