Drug Dissolution in Oral Drug Absorption: Workshop Report.

The in-person workshop "Drug Dissolution in Oral Drug Absorption" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk.

Enrichment of intrinsically disordered residues in ohnologs facilitates abiotic stress resilience in Brassica rapa.

Arabidopsis thaliana and Brassica rapa are in the same evolutionary lineage, although the latter experienced an additional whole genome triplication event. Therefore, it would be intriguing to investigate the traits that gene duplication imposes to mediate plant stress tolerance. Here, we noticed that B.

Interplay between gene expression and gene architecture as a consequence of gene and genome duplications: evidence from metabolic genes of .

Unlabelled: Gene and genome duplications have been widespread during the evolution of flowering plant which resulted in the increment of biological complexity as well as creation of plasticity of a genome helping the species to adapt to changing environments. Duplicated genes with higher evolutionary rates can act as a mechanism of generating novel functions in secondary metabolism. In this study, we explored duplication as a potential factor governing the expression heterogeneity and gene architecture of Primary Metabolic Genes (PMGs) and Secondary Metabolic Genes (SMGs) of .

Chaperone client proteins evolve slower than non-client proteins.

Chaperones are important molecular machinery that assists proteins to attain their native three-dimensional structure crucial for function. Earlier studies using experimental evolution showed that chaperones impose a relaxation of sequence constraints on their "client" proteins, which may lead to the fixation of slightly deleterious mutations on the latter. However, we hypothesized that such a phenomenon might be harmful to the organism in a natural physiological condition.

The combined influence of codon composition and tRNA copy number regulates translational efficiency by influencing synonymous nucleotide substitution.

Codon usage bias is an important genomic phenomenon, where highly expressed genes use optimal codons for smoother translation with high yield, facilitated by the cognate tRNAs. Here, we presented the tRNA co-adaptation index (co-AI) by correlating tRNA gene copy number and codon composition in Saccharomyces cerevisiae. We observed that this co-AI is positively correlated with protein abundance and translation rate.

Deciphering the intrinsic properties of fungal proteases in optimizing phytopathogenic interaction.

Phytopathogenic fungi secrete a wide range of enzymes to penetrate and colonize host tissues. Of them protease activity is reported to increase disease aggressiveness in the plant. With the aim to explore the reason of the higher infection potential of proteases, we have compared several genomic and proteomic attributes among different hydrolytic enzymes coded by five pathogenic fungal species which are the potent infectious agents of plant.

Exploring the major cross-talking edges of competitive endogenous RNA networks in human Chronic and Acute Myeloid Leukemia.

Background: Human Chronic and Acute Myeloid Leukemia are myeloproliferative disorders in myeloid lineage of blood cells characterized by accumulation of aberrant white blood cells. In cancer, the anomalous transcriptome includes deregulated expression of non-coding RNAs in conjunction with protein-coding mRNAs in human genome. The coding or non-coding RNA transcripts harboring miRNA-binding sites can converse with and regulate each other by explicitly contending for a limited pool of shared miRNAs and act as competitive endogenous RNAs (ceRNAs).

The role of introns in the conservation of the metabolic genes of Arabidopsis thaliana.

In Arabidopsis thaliana, primary metabolic genes (PMGs) are more evolutionarily conserved and intron-rich than secondary metabolic genes. We observed that PMGs are more primitive and pan-taxonomically persistent as compared to secondary (SMGs) and non-metabolic genes (NMGs). This difference in primitiveness and persistence is primarily correlated with intron number and is independent of gene expression level.

Evolutionary rate heterogeneity between multi- and single-interface hubs across human housekeeping and tissue-specific protein interaction network: Insights from proteins' and its partners' properties.

Integrating gene expression into protein-protein interaction network (PPIN) leads to the construction of tissue-specific (TS) and housekeeping (HK) sub-networks, with distinctive TS- and HK-hubs. All such hub proteins are divided into multi-interface (MI) hubs and single-interface (SI) hubs, where MI hubs evolve slower than SI hubs. Here we explored the evolutionary rate difference between MI and SI proteins within TS- and HK-PPIN and observed that this difference is present only in TS, but not in HK-class.

Impact of the US FDA "Biopharmaceutics Classification System" (BCS) Guidance on Global Drug Development.

The FDA guidance on application of the biopharmaceutics classification system (BCS) for waiver of in vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created worldwide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry toward its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided.

Systematic Analyses and Prediction of Human Drug Side Effect Associated Proteins from the Perspective of Protein Evolution.

Identification of various factors involved in adverse drug reactions in target proteins to develop therapeutic drugs with minimal/no side effect is very important. In this context, we have performed a comparative evolutionary rate analyses between the genes exhibiting drug side-effect(s) (SET) and genes showing no side effect (NSET) with an aim to increase the prediction accuracy of SET/NSET proteins using evolutionary rate determinants. We found that SET proteins are more conserved than the NSET proteins.

Codon degeneracy and amino acid abundance influence the measures of codon usage bias: improved Nc (N̂ ) and ENCprime (N̂ ) measures.

Effective number of codons (N^c) and its variant N^'c (effective number of codons prime) are the two widely used methods for measuring unequal usage of synonymous codons in coding sequences, known as the codon usage bias (CUB). The mathematical formula used in calculating N^c and N^'c values is giving inappropriate measures of CUB in case of low abundance of amino acids. In addition, the magnitude of error also varies according to codon degeneracy.

Overlapping Regions in HIV-1 Genome Act as Potential Sites for Host-Virus Interaction.

More than a decade, overlapping genes in RNA viruses became a subject of research which has explored various effect of gene overlapping on the evolution and function of viral genomes like genome size compaction. Additionally, overlapping regions (OVRs) are also reported to encode elevated degree of protein intrinsic disorder (PID) in unspliced RNA viruses. With the aim to explore the roles of OVRs in HIV-1 pathogenesis, we have carried out an in-depth analysis on the association of gene overlapping with PID in 35 HIV1- M subtypes.

Deciphering the cross-talking of human competitive endogenous RNAs in K562 chronic myelogenous leukemia cell line.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation or abnormal accumulation of granulocytic cell line without the depletion of their capacity to differentiate. A reciprocal chromosomal translocation proceeding to the 'Philadelphia chromosome', involving the ABL proto-oncogene and BCR gene residing on Chromosome 9 and 22 respectively, is observed to be attributed to CML pathogenesis. Recent studies have been unraveling the crucial role of genomic 'dark matter' or the non-coding repertoire in cancer initiation and progression.

Insights into the dN/dS ratio heterogeneity between brain specific genes and widely expressed genes in species of different complexity.

In mammals, it has long been suggested that brain-specific genes (BSGs) and widely expressed genes (WEGs) have seemingly lower dN/dS ratio than any other gene sets. However, to what extent these genes differ in their dN/dS ratio has still remained controversial. Here, we have revealed lower dN/dS ratio of BSGs than WEGs in human-mouse, human-orangutan, human-chimpanzee and mouse-rat orthologous pair.

Navigating sticky areas in transdermal product development.

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits.

Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications.

Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non-proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles.

Overlapping genes: A significant genomic correlate of prokaryotic growth rates.

Elucidating the genomic features influencing prokaryotic growth rates has always been a study of interest. Previously, it was observed that overlapping genes (OGs) play a crucial role in the prokaryotic genome size reduction. This study is focused to explore whether OGs act as a potential correlate of prokaryotic growth rates.

Global analysis of human duplicated genes reveals the relative importance of whole-genome duplicates originated in the early vertebrate evolution.

Background: Gene duplication is a genetic mutation that creates functionally redundant gene copies that are initially relieved from selective pressures and may adapt themselves to new functions with time. The levels of gene duplication may vary from small-scale duplication (SSD) to whole genome duplication (WGD). Studies with yeast revealed ample differences between these duplicates: Yeast WGD pairs were functionally more similar, less divergent in subcellular localization and contained a lesser proportion of essential genes.

Exploring the evolutionary rate differences between human disease and non-disease genes.

Comparisons of evolutionary features between human disease and non-disease genes have a wide implication to understand the genetic basis of human disease genes. However, it has not yet been resolved whether disease genes evolve at slower or faster rate than the non-disease genes. To resolve this controversy, here we integrated human disease genes from several databases and compared their protein evolutionary rates with non-disease genes in both housekeeping and tissue-specific group.

Evolutionary Rate Heterogeneity of Primary and Secondary Metabolic Pathway Genes in Arabidopsis thaliana.

Primary metabolism is essential to plants for growth and development, and secondary metabolism helps plants to interact with the environment. Many plant metabolites are industrially important. These metabolites are produced by plants through complex metabolic pathways.

Elucidating evolutionary features and functional implications of orphan genes in Leishmania major.

Orphan genes are protein coding genes that lack recognizable homologs in other organisms. These genes were reported to comprise a considerable fraction of coding regions in all sequenced genomes and thought to be allied with organism's lineage-specific traits. However, their evolutionary persistence and functional significance still remain elusive.

Investigating different duplication pattern of essential genes in mouse and human.

Gene duplication is one of the major driving forces shaping genome and organism evolution and thought to be itself regulated by some intrinsic properties of the gene. Comparing the essential genes among mouse and human, we observed that the essential genes avoid duplication in mouse while prefer to remain duplicated in humans. In this study, we wanted to explore the reasons behind such differences in gene essentiality by cross-species comparison of human and mouse.