Front Immunol. 2023 Jun 15;14:1183066. doi: 10.3389/fimmu.2023.1183066. eCollection 2023.

ABSTRACT

Dysregulated inflammation involving innate immune cells, particularly of the monocyte/macrophage lineage, is a key contributor to the pathogenesis of Duchenne muscular dystrophy (DMD). Trained immunity is an evolutionarily ancient protective mechanism against infection, in which epigenetic and metabolic alterations confer non-specific hyperresponsiveness of innate immune cells to various stimuli. Recent work in an animal model of DMD (mdx mice) has shown that macrophages exhibit cardinal features of trained immunity, including the presence of innate immune system "memory". The latter is reflected by epigenetic changes and durable transmissibility of the trained phenotype to healthy non-dystrophic mice by bone marrow transplantation. Mechanistically, it is suggested that a Toll-like receptor (TLR) 4-regulated, memory-like capacity of innate immunity is induced at the level of the bone marrow by factors released from the damaged muscles, leading to exaggerated upregulation of both pro- and anti-inflammatory genes. Here we propose a conceptual framework for the involvement of trained immunity in DMD pathogenesis and its potential to serve as a new therapeutic target.

PMID:37398642 | PMC:PMC10309206 | DOI:10.3389/fimmu.2023.1183066

bioRxiv. 2023 Jun 1:2023.05.29.542763. doi: 10.1101/2023.05.29.542763. Preprint.

ABSTRACT

Clot formation is a crucial process that prevents bleeding, but can lead to severe disorders when imbalanced. This process is regulated by the coagulation cascade, a biochemical network that controls the enzyme thrombin, which converts soluble fibrinogen into the fibrin fibers that constitute clots. Coagulation cascade models are typically complex and involve dozens of partial differential equations (PDEs) representing various chemical species' transport, reaction kinetics, and diffusion. Solving these PDE systems computationally is challenging, due to their large size and multi-scale nature. We propose a multi-fidelity strategy to increase the efficiency of coagulation cascade simulations. Leveraging the slower dynamics of molecular diffusion, we transform the governing PDEs into ordinary differential equations (ODEs) representing the evolution of species concentrations versus blood residence time. We then Taylor-expand the ODE solution around the zero-diffusivity limit to obtain spatiotemporal maps of species concentrations in terms of the statistical moments of residence time, , and provide the governing PDEs for . This strategy replaces a high-fidelity system of N PDEs representing the coagulation cascade of N chemical species by N ODEs and p PDEs governing the residence time statistical moments. The multi-fidelity order( p ) allows balancing accuracy and computational cost, providing a speedup of over N/p compared to high-fidelity models. Using a simplified coagulation network and an idealized aneurysm geometry with a pulsatile flow as a benchmark, we demonstrate favorable accuracy for low-order models of p = 1 and p = 2. These models depart from the high-fidelity solution by under 16% ( p = 1) and 5% ( p = 2) after 20 cardiac cycles. The favorable accuracy and low computational cost of multi-fidelity models could enable unprecedented coagulation analyses in complex flow scenarios and extensive reaction networks. Furthermore, it can be generalized to advance our understanding of other systems biology networks affected by blood flow.

PMID:37398367 | PMC:PMC10312426 | DOI:10.1101/2023.05.29.542763

Toxicol Res (Camb). 2023 Apr 17;12(3):369-380. doi: 10.1093/toxres/tfad016. eCollection 2023 Jun.

ABSTRACT

Chemical warfare victims suffer from bronchiolitis and chronic pulmonary obstruction caused by sulfur mustard (SM) toxicity. Despite the mesenchymal stem cells capacity to alleviate inflammation, their low survival rate under oxidative stress severely limits their effectiveness. This study aimed to examine how natural (Crocin) and synthetic (Dexamethasone) antioxidants might affect MSC efficacy. MSCs were treated with the optimal doses of Crocin (Cr.), Dexamethasone (Dex.), and their combination. The A549 cells line was pretreated with the optimal dose of the CEES to mimic the lung disease. Then, the affected A549 cells were exposed to the preconditioned MSCs and conditioned media, and then their survival rates were estimated by MTTor2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Annexin-V PI apoptosis test was conducted for MSCs and A549 cells. Reactive Oxygen Species (ROS) assay and Enzyme-linked immunosorbent assay (ELISA) test demonstrated the percentage of production of ROS and the cytokines levels in A549/CEES, respectively. The results revealed significant increases in Cr. + Dex. treated MSCs (P < .01) and A549 cells treated with MSCs-CM/Cr/Dex (P < .01) groups' survival. The apoptosis rate and ROS production were reduced in the MSCs-CM/Cr/Dex. Also, considerable decreases in IL-1β (P < .01) and IL-6 (P < .01) and a significant increase in IL-10 (P < .05) in treated A549/CEES by Cr/Dex and MSCs-CM/Cr/Dex supported the synergistic effects of Crocin and Dexamethasone.

PMID:37397913 | PMC:PMC10311171 | DOI:10.1093/toxres/tfad016

IEEE Trans Mol Biol Multiscale Commun. 2023 Mar;9(1):28-48. doi: 10.1109/tmbmc.2023.3246928. Epub 2023 Feb 22.

ABSTRACT

Electronic circuits intuitively visualize and quantitatively simulate biological systems with nonlinear differential equations that exhibit complicated dynamics. Drug cocktail therapies are a powerful tool against diseases that exhibit such dynamics. We show that just six key states, which are represented in a feedback circuit, enable drug-cocktail formulation: 1) healthy cell number; 2) infected cell number; 3) extracellular pathogen number; 4) intracellular pathogenic molecule number; 5) innate immune system strength; and 6) adaptive immune system strength. To enable drug cocktail formulation, the model represents the effects of the drugs in the circuit. For example, a nonlinear feedback circuit model fits measured clinical data, represents cytokine storm and adaptive autoimmune behavior, and accounts for age, sex, and variant effects for SARS-CoV-2 with few free parameters. The latter circuit model provided three quantitative insights on the optimal timing and dosage of drug components in a cocktail: 1) antipathogenic drugs should be given early in the infection, but immunosuppressant timing involves a tradeoff between controlling pathogen load and mitigating inflammation; 2) both within and across-class combinations of drugs have synergistic effects; 3) if they are administered sufficiently early in the infection, anti-pathogenic drugs are more effective at mitigating autoimmune behavior than immunosuppressant drugs.

PMID:37397625 | PMC:PMC10312325 | DOI:10.1109/tmbmc.2023.3246928

Genes Dis. 2022 Oct 6;10(4):1165-1168. doi: 10.1016/j.gendis.2022.09.011. eCollection 2023 Jul.

NO ABSTRACT

PMID:37397562 | PMC:PMC10311045 | DOI:10.1016/j.gendis.2022.09.011

Genes Dis. 2022 Sep 19;10(3):731-734. doi: 10.1016/j.gendis.2022.09.002. eCollection 2023 May.

NO ABSTRACT

PMID:37396524 | PMC:PMC10308156 | DOI:10.1016/j.gendis.2022.09.002

Front Microbiol. 2023 Jun 15;14:1187304. doi: 10.3389/fmicb.2023.1187304. eCollection 2023.

ABSTRACT

Coordination of cell cycle and metabolism exists in all cells. The building of a new cell is a process that requires metabolic commitment to the provision of both Gibbs energy and building blocks for proteins, nucleic acids, and membranes. On the other hand, the cell cycle machinery will assess and regulate its metabolic environment before it makes decisions on when to enter the next cell cycle phase. Furthermore, more and more evidence demonstrate that the metabolism can be regulated by cell cycle progression, as different biosynthesis pathways are preferentially active in different cell cycle phases. Here, we review the available literature providing a critical overview on how cell cycle and metabolism may be coupled with one other, bidirectionally, in the budding yeast Saccharomyces cerevisiae.

PMID:37396387 | PMC:PMC10309209 | DOI:10.3389/fmicb.2023.1187304

Microb Cell. 2023 Jun 1;10(7):141-144. doi: 10.15698/mic2023.07.799. eCollection 2023 Jul 3.

ABSTRACT

The bacterial stringent response and its effector alarmone guanosine penta- or tetra - phosphates (p)ppGpp are vital for bacterial tolerance and survival of various stresses in environments (including antibiotics) and host cells (virulence). (p)ppGpp does so by binding to its numerous target proteins and reprograming bacterial transcriptome to tune down the synthesis of nucleotides and rRNA/tRNA, and up-regulate amino acid biosynthesis genes. Recent identification of more novel (p)ppGpp direct binding proteins in Escherichia coli and their deep studies have unveiled unprecedented details of how (p)ppGpp coordinates the nucleotide and amino acid metabolic pathways upon stringent response; however, the mechanistic link between nucleotide and amino acid metabolisms remains still incompletely understood. Here we propose the metabolite ribose 5'-phosphate as the key link between nucleotide and amino acid metabolisms and a working model integrating both the transcriptional and metabolic effects of (p)ppGpp on E. coli physiological adaptation during the stringent response.

PMID:37395996 | PMC:PMC10311079 | DOI:10.15698/mic2023.07.799

Biotechnol Lett. 2023 Jul 3. doi: 10.1007/s10529-023-03406-7. Online ahead of print.

ABSTRACT

Metabolic engineering has shown that optimizing metabolic pathways' fluxes for industrial purposes requires a methodical approach. Accordingly, in this study, in silico metabolic modeling was utilized to characterize the lesser-known strain Basfia succiniciproducens under different environmental conditions, followed by the use of industrially relevant substrates for succinic acid synthesis. Based on RT-qPCR carried out in flask experiments, we discovered a relatively large difference in the expression levels of ldhA gene compared to glucose in both xylose and glycerol cultures. In bioreactor-scale fermentations, the impact of different gas phases (CO2, CO2/AIR) on biomass yield, substrate consumption, and metabolite profiles was also investigated. In the case of glycerol, the addition of CO2 increased biomass as well as target product formation, while using CO2/AIR gas phase resulted in higher target product yield (0.184 mM⋅mM-1). In case of xylose, using CO2 alone would result in higher succinic acid production (0.277 mM⋅mM-1). The promising rumen bacteria, B. succiniciproducens, has shown to be suitable for succinic acid production from both xylose and glycerol. As a result, our findings present new opportunities for broadening the range of raw materials used in this significant biochemical process. Our study also sheds light on fermentation parameter optimization for this strain, namely that, CO2/AIR supply has a positive effect on target product formation.

PMID:37395870 | DOI:10.1007/s10529-023-03406-7

Plant Physiol. 2023 Jul 3:kiad382. doi: 10.1093/plphys/kiad382. Online ahead of print.

ABSTRACT

During transgenic plant production, tissue culture often carries epigenetic and genetic changes that underlie somaclonal variations, leading to unpredictable phenotypes. Additionally, specific treatments for rice (Oryza sativa) transformation processes may individually or jointly contribute to somaclonal variations, but their specific impacts on rice epigenomes towards transcriptional variations remain unknown. Here, the impact from individual transformation treatments on genome-wide DNA methylation and the transcriptome were examined. In addition to activating stress-responsive genes, individual transformation components targeted different gene expression modules that were enriched in specific functional categories. The transformation treatments strongly impacted DNA methylation and expression; 75% were independent of tissue culture. Furthermore, our genome-wide analysis showed that the transformation treatments consistently resulted in global hypo-CHH methylation enriched at promoters highly associated with downregulation, particularly when the promoters were co-localized with miniature inverted-repeat transposable elements. Our results clearly highlight the specificity of impacts triggered by individual transformation treatments during rice transformation with the potential association between DNA methylation and gene expression. These changes in gene expression and DNA methylation resulting from rice transformation treatments explain a significant portion of somaclonal variations, that is way beyond the tissue culture effect.

PMID:37394940 | DOI:10.1093/plphys/kiad382

J Biomol Struct Dyn. 2023 Jul 2:1-19. doi: 10.1080/07391102.2023.2230293. Online ahead of print.

ABSTRACT

Dengue virus is a mosquito-borne pathogen that causes a variety of illnesses ranging from mild fever to severe and fatal dengue haemorrhagic fever or dengue shock syndrome. One of the major clinical manifestations of severe dengue infection is thrombocytopenia. The dengue non-structural protein 1 (NS1) is the primary protein that stimulates immune cells via toll-like receptor 4 (TLR4), induces platelets, and promotes aggregation, which could result in thrombocytopenia. The leaf extracts of Carica papaya seem to have therapeutic benefits in managing thrombocytopenia associated with dengue. The present study focuses on understanding the underlying mechanism of the use of papaya leaf extracts in treating thrombocytopenia. We have identified 124 phytocompounds that are present in the papaya leaf extract. The pharmacokinetics, molecular docking, binding free energy calculations, and molecular dynamic simulations were performed to investigate the drug-like properties, binding affinities, and interaction of phytocompounds with NS1 protein as well as the interactions of NS1 with TLR4. Three phytocompounds were found to bind with the ASN130, a crucial amino acid residue in the active site of the NS1 protein. Thus, we conclude that Rutin, Myricetin 3-rhamnoside, or Kaempferol 3-(2''-rhamnosylrutinoside) may serve as promising molecules by ameliorating thrombocytopenia in dengue-infected patients by interfering the interaction of NS1 with TLR4. These molecules can serve as drugs in the management of dengue-associated thrombocytopenia after verifying their effectiveness and assessing the drug potency, through additional in-vitro assays.Communicated by Ramaswamy H. Sarma.

PMID:37394810 | DOI:10.1080/07391102.2023.2230293

Signal Transduct Target Ther. 2023 Jul 3;8(1):256. doi: 10.1038/s41392-023-01500-w.

NO ABSTRACT

PMID:37394666 | DOI:10.1038/s41392-023-01500-w

Cancer Metastasis Rev. 2023 Jul 3. doi: 10.1007/s10555-023-10101-6. Online ahead of print.

ABSTRACT

Carcinoma of unknown primary (CUP) is a heterogeneous group of metastatic cancers in which the site of origin is not identifiable. These carcinomas have a poor outcome due to their late presentation with metastatic disease, difficulty in identifying the origin and delay in treatment. The aim of the pathologist is to broadly classify and subtype the cancer and, where possible, to confirm the likely primary site as this information best predicts patient outcome and guides treatment. In this review, we provide histopathologists with diagnostic practice points which contribute to identifying the primary origin in such cases. We present the current clinical evaluation and management from the point of view of the oncologist. We discuss the role of the pathologist in the diagnostic pathway including the control of pre-analytical conditions, assessment of sample adequacy, diagnosis of cancer including diagnostic pitfalls, and evaluation of prognostic and predictive markers. An integrated diagnostic report is ideal in cases of CUP, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. This highly specialized evolving area ultimately leads to personalized oncology and potentially improved outcomes for patients.

PMID:37394540 | DOI:10.1007/s10555-023-10101-6

Genome Biol. 2023 Jul 3;24(1):147. doi: 10.1186/s13059-023-02986-x.

ABSTRACT

Sequencing has revealed hundreds of millions of human genetic variants, and continued efforts will only add to this variant avalanche. Insufficient information exists to interpret the effects of most variants, limiting opportunities for precision medicine and comprehension of genome function. A solution lies in experimental assessment of the functional effect of variants, which can reveal their biological and clinical impact. However, variant effect assays have generally been undertaken reactively for individual variants only after and, in most cases long after, their first observation. Now, multiplexed assays of variant effect can characterise massive numbers of variants simultaneously, yielding variant effect maps that reveal the function of every possible single nucleotide change in a gene or regulatory element. Generating maps for every protein encoding gene and regulatory element in the human genome would create an 'Atlas' of variant effect maps and transform our understanding of genetics and usher in a new era of nucleotide-resolution functional knowledge of the genome. An Atlas would reveal the fundamental biology of the human genome, inform human evolution, empower the development and use of therapeutics and maximize the utility of genomics for diagnosing and treating disease. The Atlas of Variant Effects Alliance is an international collaborative group comprising hundreds of researchers, technologists and clinicians dedicated to realising an Atlas of Variant Effects to help deliver on the promise of genomics.

PMID:37394429 | DOI:10.1186/s13059-023-02986-x

Trends Plant Sci. 2023 Jul 1:S1360-1385(23)00198-X. doi: 10.1016/j.tplants.2023.06.006. Online ahead of print.

ABSTRACT

Histone deacetylases (HDACs) are important chromatin regulators essential for plant tolerance to adverse environments. In addition to histone deacetylation and epigenetic regulation, HDACs deacetylate non-histone proteins and thereby regulate multiple pathways. Like other post-translational modifications (PTMs), acetylation/deacetylation is a reversible switch regulating different cellular processes in plants. Here, by focusing on results obtained in arabidopsis (Arabidopsis thaliana) and rice plants, we analyze the different aspects of HDAC functions and the underlying regulatory mechanisms in modulating plant responses to stress. We hypothesize that, in addition to epigenetic regulation of gene expression, HDACs can also control plant tolerance to stress by regulating transcription, translation, and metabolic activities and possibly assembly-disassembly of stress granules (SGs) through lysine deacetylation of non-histone proteins.

PMID:37394308 | DOI:10.1016/j.tplants.2023.06.006

Cells Dev. 2023 Jun 30:203866. doi: 10.1016/j.cdev.2023.203866. Online ahead of print.

ABSTRACT

The pharyngula stage of vertebrate development is characterized by stereotypical arrangement of ectoderm, mesoderm, and neural tissues from the anterior spinal cord to the posterior, yet unformed tail. While early embryologists over-emphasized the similarity between vertebrate embryos at the pharyngula stage, there is clearly a common architecture upon which subsequent developmental programs generate diverse cranial structures and epithelial appendages such as fins, limbs, gills, and tails. The pharyngula stage is preceded by two morphogenetic events: gastrulation and neurulation, which establish common shared structures despite the occurrence of cellular processes that are distinct to each of the species. Even along the body axis of a singular organism, structures with seemingly uniform phenotypic characteristics at the pharyngula stage have been established by different processes. We focus our review on the processes underlying integration of posterior axial tissue formation with the primary axial tissues that creates the structures laid out in the pharyngula. Single cell sequencing and novel gene targeting technologies have provided us with new insights into the differences between the processes that form the anterior and posterior axis, but it is still unclear how these processes are integrated to create a seamless body. We suggest that the primary and posterior axial tissues in vertebrates form through distinct mechanisms and that the transition between these mechanisms occur at different locations along the anterior-posterior axis. Filling gaps that remain in our understanding of this transition could resolve ongoing problems in organoid culture and regeneration.

PMID:37394035 | DOI:10.1016/j.cdev.2023.203866

J Biochem Mol Toxicol. 2023 Jul 2:e23451. doi: 10.1002/jbt.23451. Online ahead of print.

ABSTRACT

Sanguinarine is an alkaloid with diverse biological activities, nevertheless, whether it can target epigenetic modifiers remains unknown. In this study, sanguinarine was characterized as a strong BRD4 inhibitor with IC50 = 361.3 nM against BRD4 (BD1) and IC50 = 302.7 nM against BRD4 (BD2) that can inactivate BRD4 reversibly. Additional cellular assays suggested that sanguinarine can bind BRD4 in human clear cell renal cell carcinoma (ccRCC) cell line 786-O and inhibit cell growth with IC50 (24 h) = 0.6752 μM and IC50 (48 h) = 0.5959 μM in a BRD4 dependent manner partially. Meanwhile, sanguinarine can inhibit the migration of 786-O cells in vitro and in vivo, and reverse epithelial-mesenchymal transition. Moreover, it can inhibit 786-O cells proliferation in vivo in a BRD4 dependent manner partially. In sum, our study identified BRD4 as a new target of sanguinarine, and sanguinarine may serve as a potential therapeutic agent against ccRCC.

PMID:37393519 | DOI:10.1002/jbt.23451

Biosystems. 2023 Jun 29:104961. doi: 10.1016/j.biosystems.2023.104961. Online ahead of print.

ABSTRACT

Primary myelofibrosis is an untreatable age-related disorder of haematopoiesis in which a break in the crosstalk between progenitor Haematopoietic Stem Cells (HSCs) and neighbouring mesenchymal stem cells causes HSCs to rapidly proliferate and migrate out of the bone marrow. Around 90% of patients harbour mutations in driver genes that all converge to overactivate haematopoietic JAK-STAT signalling, which is thought to be critical for disease progression, as well as microenvironment modification induced by chronic inflammation. The trigger to the initial event is unknown but dysregulated thrombopoietin (TPO) and Toll-Like Receptor (TLR) signalling are hypothesised to initiate chronic inflammation which then disrupts stem cell crosstalk. Using a systems biology approach, we have constructed an intercellular logical model that captures JAK-STAT signalling and key crosstalk channels between haematopoietic and mesenchymal stem cells. The aim of the model is to decipher how TPO and TLR stimulation can perturb the bone marrow microenvironment and dysregulate stem cell crosstalk. The model predicted conditions in which the disease was averted and established for both wildtype and ectopically JAK mutated simulations. The presence of TPO and TLR are both required to disturb stem cell crosstalk and result in the disease for wildtype. TLR signalling alone was sufficient to perturb the crosstalk and drive disease progression for JAK mutated simulations. Furthermore, the model predicts probabilities of disease onset for wildtype simulations that match clinical data. These predictions might explain why patients who test negative for the JAK mutation can still be diagnosed with PMF, in which continual exposure to TPO and TLR receptor activation may trigger the initial inflammatory event that perturbs the bone marrow microenvironment and induce disease onset.

PMID:37392989 | DOI:10.1016/j.biosystems.2023.104961

Talanta. 2023 Jun 24;265:124878. doi: 10.1016/j.talanta.2023.124878. Online ahead of print.

ABSTRACT

Recent advances in proteomics technologies have enabled the analysis of thousands of proteins in a high-throughput manner. Mass spectrometry (MS) based proteomics uses a peptide-centric approach where biological samples undergo specific proteolytic digestion and then only unique peptides are used for protein identification and quantification. Considering the fact that a single protein may have multiple unique peptides and a number of different forms, it becomes essential to understand dynamic protein-peptide relationships to ensure robust and reliable peptide-centric protein analysis. In this study, we investigated the correlation between protein concentration and corresponding unique peptide responses under a conventional proteolytic digestion condition. Protein-peptide correlation, digestion efficiency, matrix-effect, and concentration-effect were evaluated. Twelve unique peptides of alpha-2-macroglobulin (A2MG) were monitored using a targeted MS approach to acquire insights into protein-peptide dynamics. Although the peptide responses were reproducible between replicates, protein-peptide correlation was moderate in protein standards and low in complex matrices. The results suggest that reproducible peptide signal could be misleading in clinical studies and a peptide selection could dramatically change the outcome at protein level. This is the first study investigating quantitative protein-peptide correlations in biological samples using all unique peptides representing the same protein and opens a discussion on peptide-based proteomics.

PMID:37392709 | DOI:10.1016/j.talanta.2023.124878

Anal Bioanal Chem. 2023 Jul 1. doi: 10.1007/s00216-023-04806-4. Online ahead of print.

ABSTRACT

Droplet microfluidics is a rapidly advancing area of microfluidic technology, which offers numerous advantages for cell analysis, such as isolation and accumulation of signals, by confining cells within droplets. However, controlling cell numbers in droplets is challenging due to the uncertainty of random encapsulation which result in many empty droplets. Therefore, more precise control techniques are needed to achieve efficient encapsulation of cells within droplets. Here, an innovative microfluidic droplet manipulation platform had been developed, which employed positive pressure as a stable and controllable driving force for manipulating fluid within chips. The air cylinder, electro-pneumatics proportional valve, and the microfluidic chip were connected through a capillary, which enabled the formation of a fluid wall by creating a difference in hydrodynamic resistance between two fluid streams at the channel junction. Lowering the pressure of the driving oil phase eliminates hydrodynamic resistance and breaks the fluid wall. Regulating the duration of the fluid wall breakage controls the volume of the introduced fluid. Several important droplet microfluidic manipulations were demonstrated on this microfluidic platform, such as sorting of cells/droplets, sorting of droplets co-encapsulated cells and hydrogels, and active generation of droplets encapsulated with cells in a responsive manner. The simple, on-demand microfluidic platform was featured with high stability, good controllability, and compatibility with other droplet microfluidic technologies.

PMID:37392212 | DOI:10.1007/s00216-023-04806-4