Formulation of Fast-Release Gastroretentive Solid Dispersion of Glibenclamide with Gelucire 50/13

Purpose: Fast-release gastroretentive solid dispersions of glibenclamide using gelucire were prepared to achieve improved bioavailability.Methods: Hot melt granulation technique was adopted to prepare solid dispersions (SDs) of glibenclamide in gelucire 50/13 and were compared with pure glibenclamide and physical mixtures of drug and gelucire using hot stage polarized microscopy, powder x-ray diffraction (PXRD), Fourier transform infrared spectroscopy FTIR, bouyancy as well as by in vitro release and in vivo studies. Further aging studies were carried out for the samples.Results: PXRD showed that glibenclamide was present in SD in an amorphous form while FTIR spectroscopy revealed the presence of hydrogen bonding in the SDs. In vitro buoyancy was found for 11 h and there was improvement in solubility and dissolution rate for all test formulations. Formulations were found to follow Zero order kinetic. During aging study, no decrease of in vitro drug dissolution was observed over 3-month period. Crystallinity in the SDs was observed following aging. A more pronounced lowering of blood glucose level in Wistar rats compared with the pure drug, suggests that the test formulations are superior.Conclusion: This study demonstrates the high potential of hot melt technique for obtaining stable fast release gastroretentive solid dispersions of poorly water soluble drug using polyglycolized glycerides as carriers

Direct torque control scheme for a six-phase induction motor with reduced torque ripple

This paper presents an improved direct torque control (DTC) method for an asymmetrical six-phase induction motor using a two-level six-phase inverter. As is well-known, a simple extension of three-phase direct torque control technique to an asymmetrical six-phase motor, using large vectors only, introduces significant current harmonics of the order 6n±1 (n = 1,3,5,…), which are mapped into the non-flux/torque producing (xy) plane. These harmonics cause only losses in the motor winding as they do not take part in torque production. Hence a number of different improved DTC techniques have been developed in the past for multiphase motor drives. The paper takes one such DTC method as the starting point and improves it further by using the concept of virtual voltage vectors. Developed vector selection algorithm, based on two virtual voltage vectors, requires the information on position of the flux in the auxiliary (xy) subspace and provides stator current quality commensurate with the currently available best DTC algorithm for six-phase drives. However, use of two virtual voltage vectors enables a substantial reduction of the torque ripple, which is achieved by means of a five-level torque comparator. Extensive experimentation is performed and it is shown that the reduction of the current harmonics is in essence almost the same as in another recently developed DTC scheme, based on the use of a single virtual voltage vector. However, the achieved torque ripple reduction, which is verified experimentally, makes the scheme superior when compared to the existing approaches. At the same time, developed scheme retains qualities of conventional DTC schemes, such as simple structure and fast response. Its additional beneficial feature is the easiness of implementation

Neurospora from natural populations: Population genomics insights into the Life history of a model microbial Eukaryote

The ascomycete filamentous fungus Neurospora crassa played a historic role in experimental biology and became a model system for genetic research. Stimulated by a systematic effort to collect wild strains initiated by Stanford geneticist David Perkins, the genus Neurospora has also become a basic model for the study of evolutionary processes, speciation, and population biology. In this chapter, we will first trace the history that brought Neurospora into the era of population genomics. We will then cover the major contributions of population genomic investigations using Neurospora to our understanding of microbial biogeography and speciation, and review recent work using population genomics and genome-wide association mapping that illustrates the unique potential of Neurospora as a model for identifying the genetic basis of (potentially adaptive) phenotypes in filamentous fungi. The advent of population genomics has contributed to firmly establish Neurospora as a complete model system and we hope our review will entice biologists to include Neurospora in their research

Advances in ophthalmic drug delivery

Various strategies for ocular drug delivery are considered; from basic formulation techniques for improving availability of drugs; viscosity enhancers and mucoadhesives aid drug retention and penetration enhancers promote drug transport into the eye. The use of drug loaded contact lenses and ocular inserts allows drugs to be better placed where they are needed for more direct delivery. Developments in ocular implants gives a means to overcome the physical barriers that traditionally prevented effective treatment. Implant technologies are under development allowing long term drug delivery from a single procedure, these devices allow posterior chamber diseases to be effectively treated. Future developments could bring artificial corneas to eliminate the need for donor tissue and one-off implantable drug depots lasting the patient’s lifetime

Global Methylation Patterns in Idiopathic Pulmonary Fibrosis

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is characterized by profound changes in the lung phenotype including excessive extracellular matrix deposition, myofibroblast foci, alveolar epithelial cell hyperplasia and extensive remodeling. The role of epigenetic changes in determining the lung phenotype in IPF is unknown. In this study we determine whether IPF lungs exhibit an altered global methylation profile.\ud \ud METHODOLOGY/PRINCIPAL FINDINGS: Immunoprecipitated methylated DNA from 12 IPF lungs, 10 lung adenocarcinomas and 10 normal histology lungs was hybridized to Agilent human CpG Islands Microarrays and data analysis was performed using BRB-Array Tools and DAVID Bioinformatics Resources software packages. Array results were validated using the EpiTYPER MassARRAY platform for 3 CpG islands. 625 CpG islands were differentially methylated between IPF and control lungs with an estimated False Discovery Rate less than 5%. The genes associated with the differentially methylated CpG islands are involved in regulation of apoptosis, morphogenesis and cellular biosynthetic processes. The expression of three genes (STK17B, STK3 and HIST1H2AH) with hypomethylated promoters was increased in IPF lungs. Comparison of IPF methylation patterns to lung cancer or control samples, revealed that IPF lungs display an intermediate methylation profile, partly similar to lung cancer and partly similar to control with 402 differentially methylated CpG islands overlapping between IPF and cancer. Despite their similarity to cancer, IPF lungs did not exhibit hypomethylation of long interspersed nuclear element 1 (LINE-1) retrotransposon while lung cancer samples did, suggesting that the global hypomethylation observed in cancer was not typical of IPF.\ud \ud CONCLUSIONS/SIGNIFICANCE: Our results provide evidence that epigenetic changes in IPF are widespread and potentially important. The partial similarity to cancer may signify similar pathogenetic mechanisms while the differences constitute IPF or cancer specific changes. Elucidating the role of these specific changes will potentially allow better understanding of the pathogenesis of IPF.\ud \u

PPS, a Large Multidomain Protein, Functions with Sex-Lethal to Regulate Alternative Splicing in Drosophila

Alternative splicing controls the expression of many genes, including the Drosophila sex determination gene Sex-lethal (Sxl). Sxl expression is controlled via a negative regulatory mechanism where inclusion of the translation-terminating male exon is blocked in females. Previous studies have shown that the mechanism leading to exon skipping is autoregulatory and requires the SXL protein to antagonize exon inclusion by interacting with core spliceosomal proteins, including the U1 snRNP protein Sans-fille (SNF). In studies begun by screening for proteins that interact with SNF, we identified PPS, a previously uncharacterized protein, as a novel component of the machinery required for Sxl male exon skipping. PPS encodes a large protein with four signature motifs, PHD, BRK, TFS2M, and SPOC, typically found in proteins involved in transcription. We demonstrate that PPS has a direct role in Sxl male exon skipping by showing first that loss of function mutations have phenotypes indicative of Sxl misregulation and second that the PPS protein forms a complex with SXL and the unspliced Sxl RNA. In addition, we mapped the recruitment of PPS, SXL, and SNF along the Sxl gene using chromatin immunoprecipitation (ChIP), which revealed that, like many other splicing factors, these proteins bind their RNA targets while in close proximity to the DNA. Interestingly, while SNF and SXL are specifically recruited to their predicted binding sites, PPS has a distinct pattern of accumulation along the Sxl gene, associating with a region that includes, but is not limited to, the SxlPm promoter. Together, these data indicate that PPS is different from other splicing factors involved in male-exon skipping and suggest, for the first time, a functional link between transcription and SXL–mediated alternative splicing. Loss of zygotic PPS function, however, is lethal to both sexes, indicating that its role may be of broad significance

A Constructive Perspective on Signcryption Security

Signcryption is a public-key cryptographic primitive, originally introduced by Zheng (Crypto \u2797), that allows parties to establish secure communication without the need of prior key agreement. Instead, a party registers its public key at a certificate authority (CA), and only needs to retrieve the public key of the intended partner from the CA before being able to protect the communication. Signcryption schemes provide both authenticity and confidentiality of sent messages and can offer a simpler interface to applications and better performance compared to generic compositions of signature and encryption schemes. Although introduced two decades ago, the question which security notions of signcryption are adequate in which applications has still not reached a fully satisfactory answer. To resolve this question, we conduct a constructive analysis of this public-key primitive. Similar to previous constructive studies for other important primitives, this treatment allows to identify the natural goal that signcryption schemes should achieve and to formalize this goal in a composable framework. More specifically, we capture the goal of signcryption as a gracefully-degrading secure network, which is basically a network of independent parties that allows secure communication between any two parties. However, when a party is compromised, its respective security guarantees are lost, while all guarantees for the remaining users remain unaffected. We show which security notions for signcryption are sufficient to construct this kind of secure network from a certificate authority (or key registration resource) and insecure communication. Our study does not only unveil that it is the so-called insider-security notion that enables this construction, but also that a weaker version thereof would already be sufficient. This may be of interest in the context of practical signcryption schemes that do not achieve the stronger notions. Last but not least, we observe that the graceful-degradation property is actually an essential feature of signcryption that stands out in comparison to alternative and more standard constructions that achieve secure communication from the same assumptions. This underlines the vital importance of the insider security notion for signcryption and strongly supports, in contrast to the initial belief, the recent trend to consider the insider security notion as the standard notion for signcryption

Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

Background: Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care. Methods: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg–cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab–cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing. Findings: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab–cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab–cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97–1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97–1·34]; p=0·13). Mortality was lower in the tixagevimab–cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50–0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab–cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68–1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab–cilgavimab group and 38 (5%) in the placebo group. Interpretation: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower. Funding: US National Institutes of Health (NIH) and Operation Warp Speed