Genomes shed light on the evolution of Begonia, a mega‐diverse genus

Clarifying the evolutionary processes underlying species diversification and adaptation is a key focus of evolutionary biology. Begonia (Begoniaceae) is one of the most species-rich angiosperm genera with ~2,000 species, most of which are shade-adapted. Here, we present chromosome-scale genome assemblies for four species of Begonia (B. loranthoides, B. masoniana, B. darthvaderiana, and B. peltatifolia), and whole genome shot-gun data for an additional 74 Begonia representatives to investigate lineage evolution and shade adaptation of the genus. The four genome assemblies range in size from 331.75 Mb (B. peltatifolia) to 799.83 Mb (B. masoniana), and harbor 22,059 - 23,444 protein-coding genes. Synteny analysis revealed a lineage specific whole-genome duplication (WGD) that occurred just before the diversification of the Begonia. Functional enrichment of gene families retained after WGD highlight the significance of modified carbohydrate metabolism and photosynthesis possibly linked to shade-adaptation in the genus, which is further supported by expansions of gene families involved in light perception and harvesting. Phylogenomic reconstructions and genomics studies indicate that genomic introgression has also played a role in the evolution of Begonia. Overall, this study provides valuable genomic resources for Begonia and suggests potential drivers underlying the diversity and adaptive evolution of this mega-diverse clade

The in vivo metabolic pathway of Deg-AZM and in vitro investigations into the contribution of drug metabolizing enzymes and drug transporters in the drug interactions of Deg-AZM, a clinical-stage new transgelin agonist

IntroductionDeglycosylated azithromycin (Deg-AZM), a new transgelin agonist with positive therapeutic effects on slow transit constipation, has been approved for clinical trials in 2024. This work investigated the drug metabolism and transport of Deg-AZM to provide research data for further development of Deg-AZM.MethodsA combination of UPLC-QTOF-MS was used to obtain metabolite spectra of Deg-AZM in plasma, urine, feces and bile. Caco-2 cells was used to investigate the permeability of Deg-AZM and whether it is a potential substrate of the efflux transporter P-glycoprotein. Human liver microsome phenotyping assays with chemical inhibition and recombinant CYPs phenotyping assays were used to investigate the CYP450 enzyme phenotype involved in Deg-AZM metabolism in vitro. A HLM inhibition reaction system was established to evaluate the inhibitory effect of Deg-AZM on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The mRNA expression of human primary hepatocytes incubated with Deg-AZM or not was evaluate the induction of Deg-AZM on CYP1A2, CYP2B6, and CYP3A4.Results44 metabolites of Deg-AZM were identified in rat urine, feces, bile, and plasma, the metabolic pathways included demethylation, monohydroxylation, dihydroxylation, dehydroxidation, hydroreduction, hydrolysis, methylation, glucuronidation and the combination of different metabolic pathways. Deg-AZM was a low permeability drug in the intestine and a potential substrate of the efflux transporter P-glycoprotein. CYP3A4 was the major CYP isoform responsible for Deg-AZM metabolism. Deg-AZM showed moderate inhibition with CYP2B6 and CYP2D6. Data in three batches of human primary hepatocytes disclosed induction potential of Deg-AZM on CYP2B6 and CYP3A4.ConclusionThe in vivo metabolic pathway of Deg-AZM and in vitro possibility of drug interaction for Deg-AZM with CYP enzymes and drug transporter were fully investigated. It was suggested that dose adjustments may be warranted depending on the potency of the corresponding modulators in clinical

Deglycosylated azithromycin alleviates cisplatin-evoked constipation in mice by altering host metabolome and gut microbiota composition

IntroductionChemotherapy induced constipation (CIC) is a gastrointestinal side effect that occurs in patients receiving chemotherapy, which can further deteriorate the living quality of cancer patients. Deglycosylated azithromycin (Deg-AZM), a newly developed Class I drug with good therapeutic effects on chronic constipation, has been approved for clinical trials in 2024. However, it is unclear whether Deg-AZM has any impact on gut microbiota of CIC mice. The purpose of this study was to explore the role of Deg-AZM in treating CIC by modulating the gut microbiota.MethodsThe therapeutic effects of Deg-AZM on intestinal motility were assessed in a cisplatin-induced CIC mouse model. The gut microbiota composition was analyzed using 16S rRNA sequencing, and metabolic changes were evaluated through untargeted metabolomics of fecal samples.ResultsDeg-AZM significantly enhanced intestinal motility in the mice with cisplatin-evoked constipation. Gut microbiota analysis revealed that Deg-AZM altered the community composition by decreasing Deferribacterota and Pseudomonadota and increasing Bacteroidota, Lactobacillus and Muribaculaceae. The feces metabolomics revealed that alanine, aspartate and glutamate metabolism, citrate cycle (TCA cycle), purine metabolism, primary bile acid biosynthesis and taurine and hypotaurine metabolism in CIC model were modulated by Deg-AZM.ConclusionDeg-AZM could alleviate cisplatin-evoked constipation in mice by reshaping the structure of gut microbial community, which may provide a potential basis for the use and clinical development of Deg-AZM for CIC treatment

Radiative transfer modeling: Numerical techniques and applications in fiber optics manufacturing

Radiative transfer is an important heat transfer mode for many scientific and engineering applications. For example, radiative heat transfer can be orders of magnitude higher than other modes of heat transfer in optical fiber drawing process. Therefore, modeling of radiative transfer is very important to understand the physical phenomena as well as process control and optimization. However, accurate modeling of radiative transfer in semitransparent media has been proven to be extremely challenging. Solving the radiative transfer equation requires solution for an integral-differential equation with five independent variables (three in spatial domain and two in directional domain) even for gray media. Analytical solutions for the radiative transfer equation are limited to only a few extremely simplified cases and numerical modelings are sometimes prohibitively expensive. ^ This dissertation proposes several numerical techniques to improve the efficiency and accuracy in radiative transfer modeling. Two numerical techniques are proposed and demonstrated to reduce the computational cost of evaluating direct exchange areas for the zonal method. A modified scheme is proposed for modeling axisymmetric radiative transfer using finite volume method to improve compatibility with finite volume method in CFD analysis, as well as to remove sources of error in existing schemes. Numerical models to investigate radiative transfer related to fiber optics manufacturing are also presented. The radiative transfer in laser heating of fused silica rods and microstructured optical fiber fabrication is investigated to gain physical insights of processes involved. The effects of radiative heat transfer modeling and Fresnel boundary conditions are demonstrated. Finally, the thermal radiative properties of a submicron thick film coated semi-transparent fiber is determined using the ray tracing method and wave optics. The predicted radiative properties are incorporated into a detailed conjugate heat transfer model to study chemical vapor deposition carbon coating of optical fiber.

Phonon Transport and Thermal Conductivity Percolation in Random Nanoparticle Composites

In this paper, we investigated the effective thermal conductivity of three dimensional nanocomposites composed of randomly distributed binary nanoparticles with large differences (contrast ratio) in their intrinsic (bulk) thermal conductivity. When random composites are made from particles with very different thermal conductivity (large contrast ratio), a continuous phase of high thermal conductivity constituent is formed when its volumetric concentration reaches beyond the percolation threshold. Such a continuous phase of material can provide a potentially low resistance pathway for thermal transport in random composites. The percolation theory predicts the thermal conductivity of the random composites to increase according to a scaling law with increasing concentration of the high thermal conductivity constituent after percolation. However, when the characteristic size of the particles in the nanocomposites is comparable to or smaller than the phonon mean free path, the phonon scattering at interfaces between two materials can introduce significant thermal resistance in the highly conductive phonon pathway. Such interfacial thermal resistance can reduce the thermal conductivity of the nanoparticle composites. The thermal conductivity of the random nanoparticle composites thus deviates significantly from the predictions of the percolation theory. In this study, the Monte Carlo simulation was employed to generate random distribution of nanoparticles and to simulate the phonon transport in random nanoparticle composites. The effects of particle size, thermal conductivity contrast ratio, and the phonon-interface scattering characteristics on the effective thermal conductivity of random nanoparticle composites are scrutinized. The effective thermal conductivity of the random nanoparticle composites are mainly controlled by the interface density (interfacial area per unit volume) in the composites. The percolating pathway formed by the high thermal conductivity constituents is not as effective in improving the thermal conductivity of the random nanoparticle composites for a wide range of volumetric concentrations compared to a random composite with larger particle dimensions. Similarly, the thermal conductivity contrast ratio of the constituents only plays a limited role in determining the thermal conductivity of the composites studied. This study can be important in studying flexible thermoelectric materials and thermal interface materials