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Lens epithelium derived growth factor (LEDGF), also known as PC4 and SFRS1 interacting protein 1 (PSIP1) and transcriptional co-activator p75, is the cellular binding partner of lentiviral integrase (IN) proteins. LEDGF accounts for the characteristic propensity of Lentivirus to integrate within active transcription units and is required for efficient viral replication. We now present a crystal structure containing the N-terminal and catalytic core domains (NTD and CCD) of HIV-2 IN in complex with the IN binding domain (IBD) of LEDGF. The structure extends the known IN-LEDGF interface, elucidating primarily charge-charge interactions between the NTD of IN and the IBD. A constellation of acidic residues on the NTD is characteristic of lentiviral INs, and mutations of the positively charged residues on the IBD severely affect interaction with all lentiviral INs tested. We show that the novel NTD-IBD contacts are critical for stimulation of concerted lentiviral DNA integration by LEDGF in vitro and for its function during the early steps of HIV-1 replication. Furthermore, the new structural details enabled us to engineer a mutant of HIV-1 IN that primarily functions only when presented with a complementary LEDGF mutant. These findings provide structural basis for the high affinity lentiviral IN-LEDGF interaction and pave the way for development of LEDGF-based targeting technologies for gene therapy.

A sensitive approach to quantitative analysis of transcriptional regulation in diploid organisms is analysis of allelic imbalance (AI) in RNA sequencing (RNA-seq) data. A near-universal practice in such studies is to prepare and sequence only one library per RNA sample. We present theoretical and experimental evidence that data from a single RNA-seq library is insufficient for reliable quantification of the contribution of technical noise to the observed AI signal; consequently, reliance on one-replicate experimental design can lead to unaccounted-for variation in error rates in allele-specific analysis. We develop a computational approach, Qllelic, that accurately accounts for technical noise by making use of replicate RNA-seq libraries. Testing on new and existing datasets shows that application of Qllelic greatly decreases false positive rate in allele-specific analysis while conserving appropriate signal, and thus greatly improves reproducibility of AI estimates. We explore sources of technical overdispersion in observed AI signal and conclude by discussing design of RNA-seq studies addressing two biologically important questions: quantification of transcriptome-wide AI in one sample, and differential analysis of allele-specific expression between samples. Allele-specific expression in diploid organisms can be quantified by RNA-seq and it is common practice to rely on a single library. Here, the authors show that the standard approach has variable error rate and present Qllelic as a tool to improve reproducibility of allele-specific RNA-seq analysis.

Background Crohn’s disease of the small intestine typically causes abdominal symptoms and nutritional problems, but renal consequences are rare. Case presentation We report a 70 year-old British Caucasian man with longstanding Crohn’s disease of the small intestine complicated by multiple fibrotic strictures, who developed a rapid deterioration in his renal function around the same time as initiation of biologic therapy. Following investigation into the cause of his renal deterioration and eventually a renal biopsy, he was diagnosed with oxalate nephropathy leading to end-stage renal failure with creatinine peaking at 604 umol/l. The pathophysiology of enteric hyperoxaluria in Crohn’s disease is discussed. Conclusion Awareness of hyperoxaluria and potential oxalate nephrotoxicity in patients with small intestinal Crohn’s and an intact colon should help clinicians advise such patients on dietary and fluid intake modification at an early stage.

Documented symptomatic hypoglycemia is defined as “event during which typical symptoms of hypoglycemia are accompanied by measured blood glucose of ≤70 mg/dL. Most of the studies and recommendations for the unconscious hypoglycemic adult advocate the use of 25 g of glucose as 50 mL of 50% dextrose solution intravenous or 1 mg of intramuscular glucagon. To compare the efficacy and safety of 5 g boluses of 10%, 25% and 50% dextrose in the treatment of hypoglycemic patients presenting to our emergency department. This was a randomized controlled single blinded study. Hypoglycemic patients in altered mental status were randomized into three treatment arms to be administered 10%, 25% or 50% dextrose. 5 g aliquots of intravenous 10%,25% or 50% dextrose were administered over 1 min. Time taken to achieve a Glasgow Coma Scale (GCS) of 15 and median total doses (g) were the primary outcomes. Data of 204 patients were analysed in the study. There was no difference in the median time to achieve a GCS of 15 in all three treatment arms (6 min). Total median dose administered in the 10% and 25% groups was lower than 50% (10 g vs 15 g). Proportion of patients who received the maximum dose of 25 g was higher in the 50% group as compared to 10% and 25% groups (12%, 3%, 4%). There was no difference in 10% dextrose and 25% dextrose as compared to 50% dextrose in achieving the baseline mental status (or GCS 15) in the treatment of hypoglycemia in the ED.

Bigdata becomes a significant sector and academics research topic. Bigdata is a two-edged sword. The rising volume of information together will increase the likelihood of blundering non-public data privacy. Due to many new technologies and innovations that pervade our everyday lives, like smartphones and social networking apps, and the Internet of Things-based intelligent-world systems, the large amount of data generated in our world has exploded. During this data processing, storage, and the use of the information it can quickly cause personal information exposure and the difficulty of interpreting the information. The aim is to incorporate this range of information into one framework for big data management and to recognize problems regarding privacy. This paper begins with the introduction of bigdata, its process, protection issues, and tools which are used to solve its problems

In this research, a complex wideband antenna with different applications in wireless communication devices is proposed. The proposed wideband antenna resonates at different four frequencies, which include the wireless devices band, an Ultra-Wideband (UWB), and an X-band. This rectangle-shaped antenna with additional stub antennas has FR4 material used as a substrate with dimensions of (26 × 40 × 1.6 mm3). The resulting resonant frequencies cover Wireless Local-Area Network (WLAN) at 2 GHz and 5.3 GHz, Multiple Input Multiple Output (MIMO) at 6.7 GHz, and X-band at 8.7 GHz. The implementation of Defected Ground Structure (DGS) facilitates the reduction in size and increase in antenna performance, and by using the additional stubs, it provides a multi-sharpened band. It has an omnidirectional radiation pattern. Simulation results show that the proposed antenna provides a wide range of frequencies (4-9 GHz).

Transportin 3 (Tnpo3, Transportin-SR2) is implicated in nuclear import of splicing factors and HIV-1 replication. Herein, we show that the majority of cellular Tnpo3 binding partners contain arginine-serine (RS) repeat domains and present crystal structures of human Tnpo3 in its free as well as GTPase Ran- and alternative splicing factor/splicing factor 2 (ASF/SF2)-bound forms. The flexible β-karyopherin fold of Tnpo3 embraces the RNA recognition motif and RS domains of the cargo. A constellation of charged residues on and around the arginine-rich helix of Tnpo3 HEAT repeat 15 engage the phosphorylated RS domain and are critical for the recognition and nuclear import of ASF/SF2. Mutations in the same region of Tnpo3 impair its interaction with the cleavage and polyadenylation specificity factor 6 (CPSF6) and its ability to support HIV-1 replication. Steric incompatibility of the RS domain and RanGTP engagement by Tnpo3 provides the mechanism for cargo release in the nucleus. Our results elucidate the structural bases for nuclear import of splicing factors and the Tnpo3–CPSF6 nexus in HIV-1 biology.

Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants' effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression.

In mammalian cells, maternal and paternal alleles usually have similar transcriptional activity. Epigenetic mechanisms such as X-chromosome inactivation (XCI) and imprinting were historically viewed as rare exceptions to this rule. Discovery of autosomal monoallelic autosomal expression (MAE) a decade ago revealed an additional allele-specific mode regulating thousands of mammalian genes. Despite MAE prevalence, its mechanistic basis remains unknown. Using an RNA sequencing-based screen for reactivation of silenced alleles, we identified DNA methylation as key mechanism of MAE mitotic maintenance. In contrast with the all-or-nothing allelic choice in XCI, allele-specific expression in MAE loci is tunable, with exact allelic imbalance dependent on the extent of DNA methylation. In a subset of MAE genes, allelic imbalance was insensitive to DNA demethylation, implicating additional mechanisms in MAE maintenance in these loci. Our findings identify a key mechanism of MAE maintenance and provide basis for understanding the biological role of MAE.

The effects of formulation of leavened bread by using varying levels (for 50 g base flour) of soy flour–barnyard millet blends (with 5.74, 6.25, 7, 7.75 and 8.26 g of soy flour), yeast (1.83, 2, 2.25, 2.5 and 2.67 g) and salt (0.63, 0.8, 1.05, 1.30 and 1.47 g) on textural, colour and specific volume were determined. A central composite rotatable design of response surface methodology was used to plan the experiments. The second order models obtained were observed to be statistically significant and capable of demonstrating the effects input variables on responses. All the textural properties were affected significantly by amount of soy flour and yeast in the dough. Soy flour had a significant effect on the colour of the bread making it more brown. Interaction of soy flour and yeast affected the specific volume to maximum extent. Two-tailed t test established that the efficacy of the models as no significant was observed between the predicted and the actual values.