Fizikokemijska karakterizacija čvrstih disperzijskih sustava tadalafila s poloksamerom 407

Dissolution behaviour of a poorly water-soluble drug, tadalafil, from its solid dispersion systems with poloxamer 407 has been investigated. Solid dispersion systems of tadalafil were prepared with poloxamer 407 in 1:0.5, 1:1.5 and 1:2.5 ratios using the melting method. Characterization of binary systems with FTIR and powder XRPD studies demonstrated the presence of strong hydrogen bonding interactions, a significant decrease in crystallinity and the possibility of existence of amorphous entities of the drug. In the binary systems tested, 1:0.5 proportion of tadalafil/poloxamer 407 showed rapid dissolution of tadalafil (DE30 70.9 ± 3.6 %). In contrast, higher proportions of poloxamer 407 (1:1.5 and 1:2.5) offered no advantage towards dissolution enhancement of the drug from corresponding binary systems indicating altered rheological characteristics of the polymer, at its higher concentration, which might have retarded the release rate of tadalafil.U radu je ispitivano oslobađanje u vodi teško topljivog lijeka tadalafila iz čvrstih disperzijskih sustava. Ti sustavi pripravljeni su s poloksamerom 407 u omjeru lijeka i polimera 1:0,5, 1:1,5 i 1:2,5, koristeći metodu taljenja. Karakterizacija binarnih sustava s FTIR i rendgenskom difrakcijom praha XRD ukazuje na prisutnost snažnih vodikovih veza, značajno smanjenje kristaliničnosti i moguću prisutnost amorfnog lijeka. Iz binarnog sustava tadalafil/poloksamer 1:0,5 oslobađanje ljekovite tvari je brzo (DE30 70,9 ± 3,6 %). Nasuprot tome, iz pripravaka s višim omjerima lijeka i polimera (1:1,5 i 1:2,5) oslobađanje ljekovite tvari nije povećano. Usporavanje oslobađanja tadalafila moglo bi biti posljedicom promjene reoloških svojstava polimera pri višim koncentracijama

CPP-ZFN: A potential DNA-targeting anti-malarial drug

<p>Abstract</p> <p>Background</p> <p>Multidrug-resistant <it>Plasmodium </it>is of major concern today. Effective vaccines or successful applications of RNAi-based strategies for the treatment of malaria are currently unavailable. An unexplored area in the field of malaria research is the development of DNA-targeting drugs that can specifically interact with parasitic DNA and introduce deleterious changes, leading to loss of vital genome function and parasite death.</p> <p>Presentation of the hypothesis</p> <p>Advances in the development of zinc finger nuclease (ZFN) with engineered DNA recognition domains allow us to design and develop nuclease of high target sequence specificity with a mega recognition site that typically occurs only once in the genome. Moreover, cell-penetrating peptides (CPP) can cross the cell plasma membrane and deliver conjugated protein, nucleic acid, or any other cargo to the cytoplasm, nucleus, or mitochondria. This article proposes that a drug from the combination of the CPP and ZFN systems can effectively enter the intracellular parasite, introduce deleterious changes in its genome, and eliminate the parasite from the infected cells.</p> <p>Testing the hypothesis</p> <p>Availability of a DNA-binding motif for more than 45 triplets and its modular nature, with freedom to change number of fingers in a ZFN, makes development of customized ZFN against diverse target DNA sequence of any gene feasible. Since the <it>Plasmodium </it>genome is highly AT rich, there is considerable sequence site diversity even for the structurally and functionally conserved enzymes between <it>Plasmodium </it>and humans. CPP can be used to deliver ZFN to the intracellular nucleus of the parasite. Signal-peptide-based heterologous protein translocation to <it>Plasmodium</it>-infected RBCs (iRBCs) and different <it>Plasmodium </it>organelles have been achieved. With successful fusion of CPP with mitochondrial- and nuclear-targeting peptides, fusion of CPP with 1 more <it>Plasmodium </it>cell membrane translocation peptide seems achievable.</p> <p>Implications of the hypothesis</p> <p>Targeting of the <it>Plasmodium </it>genome using ZFN has great potential for the development of anti-malarial drugs. It allows the development of a single drug against all malarial infections, including multidrug-resistant strains. Availability of multiple ZFN target sites in a single gene will provide alternative drug target sites to combat the development of resistance in the future.</p

An Efficient Bet-GCN Approach for Link Prediction

The task of determining whether or not a link will exist between two entities, given the current position of the network, is called link prediction. The study of predicting and analyzing links between entities in a network is emerging as one of the most interesting research areas to explore. In the field of social network analysis, finding mutual friends, predicting the friendship status between two network individuals in the near future, etc., contributes significantly to a better understanding of the underlying network dynamics. The concept has many applications in biological networks, such as finding possible connections (possible interactions) between genes and predicting protein-protein interactions. Apart from these, the concept has applications in many other areas of network science. Exploration based on Graph Neural Networks (GNNs) to accomplish such tasks is another focus that is attracting a lot of attention these days. These approaches leverage the strength of the structural information of the network along with the properties of the nodes to make efficient predictions and classifications. In this work, we propose a network centrality based approach combined with Graph Convolution Networks (GCNs) to predict the connections between network nodes. We propose an idea to select training nodes for the model based on high edge betweenness centrality, which improves the prediction accuracy of the model. The study was conducted using three benchmark networks: CORA, Citeseer, and PubMed. The prediction accuracies for these networks are: 95.08%, 95.07%, and 95.3%. The performance of the model is comprehensive and comparable to the other prior art methods and studies. Moreover, the performance of the model is evaluated with 90.13% for WikiCS and 87.7% for Amazon Product network to show the generalizability of the model. The paper discusses in detail the reason for the improved predictive ability of the model both theoretically and experimentally. Our results are generalizable and our model has the potential to provide good results for link prediction tasks in any domain

Genome analysis and genetic enhancement of tomato

The Solanaceae is an important family of vegetable crops, ornamentals and medicinal plants. Tomato has served as a model member of this family largely because of its enriched cytogenetic, genetic, as well as physical, maps. Mapping has helped in cloning several genes of importance such as Pto, responsible for resistance against bacterial speck disease, Mi-1.2 for resistance against nematodes, and fw2.2 QTL for fruit weight. A high-throughput genome-sequencing program has been initiated by an international consortium of 10 countries. Since heterochromatin has been found to be concentrated near centromeres, the consortium is focusing on sequencing only the gene-rich euchromatic region. Genomes of the members of Solanaceae show a significant degree of synteny, suggesting that the tomato genome sequence would help in the cloning of genes for important traits from other Solanaceae members as well. ESTs from a large number of cDNA libraries have been sequenced, and microarray chips, in conjunction with wide array of ripening mutants, have contributed immensely to the understanding of the fruit-ripening phenomenon. Work on the analysis of the tomato proteome has also been initiated. Transgenic tomato plants with improved abiotic stress tolerance, disease resistance and insect resistance, have been developed. Attempts have also been made to develop tomato as a bioreactor for various pharmaceutical proteins. However, control of fruit quality and ripening remains an active and challenging area of research. Such efforts should pave the way to improve not only tomato, but also other solanaceous crops

Parathyroid Hormone Secretion and Receptor Expression Determine the Age-Related Degree of Osteogenic Differentiation in Dental Pulp Stem Cells

Objective: To demonstrate the levels of parathyroid hormone secretion and genetic expressions of parathyroid hormone (PTH) and PTH1 receptor (PTH1R) genes in the dental pulp stem cells (DPSCs) from different age groups before and after induction of osteogenic differentiation. In addition, we also wanted to check their correlation with the degree of osteogenic differentiation. Methods: Human primary DPSCs from three age groups (milk tooth (SHEDs), 7–12 years old; young DPSCs (yDPSCs), 20–40 years old; old DPSCs (oDPSCs), 60+ years old) were characterized for mesenchymal stem cell (MSC) markers. DPSCs were subjected to osteogenic differentiation and functional staining. Gene expression levels were analyzed by qRT-PCR. Surface receptor analysis was done by flow cytometry. Comparative protein levels were evaluated by ELISA. Results: All SHEDs, yDPSCs, and oDPSCs were found to be expressing mesenchymal stem cell markers. SHEDs showed more mineralization than yDPSCs and oDPSCs after osteogenic induction. SHEDs exhibited higher expression of PTH and PTH1R before and after osteogenic induction, and after osteogenic induction, SHEDs showed more expression for RUNX2, ALPL, and OCN. Higher levels of PTH were observed in SHEDs and yDPSCs, and the number of PTH1R positive cells was relatively lower in yDPSCs and oDPSCs than in SHEDs. After osteogenic induction, SHEDs were superior in the secretion of OPG, and the secretions of ALPL and PTH and the number of PTH1R positive cells were relatively low in the oDPSCs. Conclusions: The therapeutic quality of dental pulp stem cells is largely based on their ability to retain their stemness characteristics. This study emphasizes the criterion of aging, which affects the secretion of PTH by these cells, which in turn attenuates their osteogenic potential

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update

10.1007/s12072-019-09946-3HEPATOLOGY INTERNATIONAL134353-39

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update (vol 13, pg 353, 2019)

10.1007/s12072-019-09980-1HEPATOLOGY INTERNATIONAL136826-82

A Snapshot of the Emerging Tomato Genome Sequence

The genome of tomato (Solanum lycopersicum L.) is being sequenced by an international consortium of 10 countries (Korea, China, the United Kingdom, India, the Netherlands, France, Japan, Spain, Italy, and the United States) as part of the larger \u201cInternational Solanaceae Genome Project (SOL): Systems Approach to Diversity and Adaptation\u201d initiative. The tomato genome sequencing project uses an ordered bacterial artificial chromosome (BAC) approach to generate a high-quality tomato euchromatic genome sequence for use as a reference genome for the Solanaceae and euasterids. Sequence is deposited at GenBank and at the SOL Genomics Network (SGN). Currently, there are around 1000 BACs finished or in progress, representing more than a third of the projected euchromatic portion of the genome. An annotation effort is also underway by the International Tomato Annotation Group. The expected number of genes in the euchromatin is 3c40,000, based on an estimate from a preliminary annotation of 11% of finished sequence. Here, we present this first snapshot of the emerging tomato genome and its annotation, a short comparison with potato (Solanum tuberosum L.) sequence data, and the tools available for the researchers to exploit this new resource are also presented. In the future, whole-genome shotgun techniques will be combined with the BAC-by-BAC approach to cover the entire tomato genome. The high-quality reference euchromatic tomato sequence is expected to be near completion by 2010

The tomato genome sequence provides insights into fleshy fruit evolution

Tomato (Solanum lycopersicum) is a major crop plant and a model system for fruit development. Solanum is one of the largest angiosperm genera1 and includes annual and perennial plants from diverse habitats. Here we present a high-quality genome sequence of domesticated tomato, a draft sequence of its closest wild relative, Solanum pimpinellifolium2, and compare them to each other and to the potato genome (Solanum tuberosum). The two tomato genomes show only 0.6% nucleotide divergence and signs of recent admixture, but show more than 8% divergence from potato, with nine large and several smaller inversions. In contrast to Arabidopsis, but similar to soybean, tomato and potato small RNAs map predominantly to gene-rich chromosomal regions, including gene promoters. The Solanum lineage has experienced two consecutive genome triplications: one that is ancient and shared with rosids, and a more recent one. These triplications set the stage for the neofunctionalization of genes controlling fruit characteristics, such as colour and fleshiness