Prog Biophys Mol Biol. 2023 May 31:S0079-6107(23)00056-1. doi: 10.1016/j.pbiomolbio.2023.05.004. Online ahead of print.

ABSTRACT

Here we contrast several carcinogenesis models. The somatic-mutation-theory posits mutations as main causes of malignancy. However, inconsistencies led to alternative explanations. For example, the tissue-organization-field-theory considers disrupted tissue-architecture as main cause. Both models can be reconciled using systems-biology-approaches, according to which tumors hover in states of self-organized criticality between order and chaos, are emergent results of multiple deviations and are subject to general laws of nature: inevitable variation(mutation) explainable by increased entropy(second-law-of-thermodynamics) or indeterminate decoherence upon measurement of superposed quantum systems(quantum mechanics), followed by Darwinian-selection. Genomic expression is regulated by epigenetics. Both systems cooperate. So cancer is neither just a mutational nor an epigenetic problem. Rather, epigenetics links environmental cues to endogenous genetics engendering a regulatory machinery that encompasses specific cancer-metabolic-networks. Interestingly, mutations occur at all levels of this machinery (oncogenes/tumor-suppressors, epigenetic-modifiers, structure-genes, metabolic-genes). Therefore, in most cases, DNA mutations may be the initial and crucial cancer-promoting triggers.

PMID:37268024 | DOI:10.1016/j.pbiomolbio.2023.05.004

Biochim Biophys Acta Mol Cell Res. 2023 May 31:119502. doi: 10.1016/j.bbamcr.2023.119502. Online ahead of print.

ABSTRACT

Our study maps the classic nuclear localization signal (cNLS) domain within WRNIP that directs the protein's nuclear positioning.

PMID:37268023 | DOI:10.1016/j.bbamcr.2023.119502

Annu Rev Microbiol. 2023 Jun 2. doi: 10.1146/annurev-micro-032521-041554. Online ahead of print.

ABSTRACT

Plasmodium falciparum, the human malaria parasite, infects two hosts and various cell types, inducing distinct morphological and physiological changes in the parasite in response to different environmental conditions. These variations required the parasite to adapt and develop elaborated molecular mechanisms to ensure its spread and transmission. Recent findings have significantly improved our understanding of the regulation of gene expression in P. falciparum. Here, we provide an up-to-date overview of technologies used to highlight the transcriptomic adjustments occurring in the parasite throughout its life cycle. We also emphasize the complementary and complex epigenetic mechanisms regulating gene expression in malaria parasites. This review concludes with an outlook on the chromatin architecture, the remodeling systems, and how this 3D genome organization is critical in various biological processes. Expected final online publication date for the Annual Review of Microbiology, Volume 77 is September 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37268002 | DOI:10.1146/annurev-micro-032521-041554

Adv Sci (Weinh). 2023 Jun 2:e2205445. doi: 10.1002/advs.202205445. Online ahead of print.

ABSTRACT

The spread of coronavirus disease 2019 (COVID-19), caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2), has progressed into a global pandemic. To date, thousands of genetic variants have been identified among SARS-CoV-2 isolates collected from patients. Sequence analysis reveals that the codon adaptation index (CAI) values of viral sequences have decreased over time but with occasional fluctuations. Through evolution modeling, it is found that this phenomenon may result from the virus's mutation preference during transmission. Using dual-luciferase assays, it is further discovered that the deoptimization of codons in the viral sequence may weaken protein expression during virus evolution, indicating that codon usage may play an important role in virus fitness. Finally, given the importance of codon usage in protein expression and particularly for mRNA vaccines, it is designed several codon-optimized Omicron BA.2.12.1, BA.4/5, and XBB.1.5 spike mRNA vaccine candidates and experimentally validated their high levels of expression. This study highlights the importance of codon usage in virus evolution and provides guidelines for codon optimization in mRNA and DNA vaccine development.

PMID:37267926 | DOI:10.1002/advs.202205445

Cell Stem Cell. 2023 Jun 1;30(6):885-903.e10. doi: 10.1016/j.stem.2023.05.001.

ABSTRACT

Tissue repair responses in metazoans are highly coordinated by different cell types over space and time. However, comprehensive single-cell-based characterization covering this coordination is lacking. Here, we captured transcriptional states of single cells over space and time during skin wound closure, revealing choreographed gene-expression profiles. We identified shared space-time patterns of cellular and gene program enrichment, which we call multicellular "movements" spanning multiple cell types. We validated some of the discovered space-time movements using large-volume imaging of cleared wounds and demonstrated the value of this analysis to predict "sender" and "receiver" gene programs in macrophages and fibroblasts. Finally, we tested the hypothesis that tumors are like "wounds that never heal" and found conserved wound healing movements in mouse melanoma and colorectal tumor models, as well as human tumor samples, revealing fundamental multicellular units of tissue biology for integrative studies.

PMID:37267918 | DOI:10.1016/j.stem.2023.05.001

Cell Stem Cell. 2023 Jun 1;30(6):832-850.e6. doi: 10.1016/j.stem.2023.05.002.

ABSTRACT

Remodeling of the tissue niche is often evident in diseases, yet, the stromal alterations and their contribution to pathogenesis are poorly characterized. Bone marrow fibrosis is a maladaptive feature of primary myelofibrosis (PMF). We performed lineage tracing and found that most collagen-expressing myofibroblasts were derived from leptin-receptor-positive (LepR+) mesenchymal cells, whereas a minority were from Gli1-lineage cells. Deletion of Gli1 did not impact PMF. Unbiased single-cell RNA sequencing (scRNA-seq) confirmed that virtually all myofibroblasts originated from LepR-lineage cells, with reduced expression of hematopoietic niche factors and increased expression of fibrogenic factors. Concurrently, endothelial cells upregulated arteriolar-signature genes. Pericytes and Sox10+ glial cells expanded drastically with heightened cell-cell signaling, suggesting important functional roles in PMF. Chemical or genetic ablation of bone marrow glial cells ameliorated fibrosis and improved other pathology in PMF. Thus, PMF involves complex remodeling of the bone marrow microenvironment, and glial cells represent a promising therapeutic target.

PMID:37267917 | DOI:10.1016/j.stem.2023.05.002

Mol Cell. 2023 Jun 1;83(11):1839-1855.e13. doi: 10.1016/j.molcel.2023.05.012.

ABSTRACT

Localized translation is vital to polarized cells and requires precise and robust distribution of different mRNAs and ribosomes across the cell. However, the underlying molecular mechanisms are poorly understood and important players are lacking. Here, we discovered a Rab5 effector, the five-subunit endosomal Rab5 and RNA/ribosome intermediary (FERRY) complex, that recruits mRNAs and ribosomes to early endosomes through direct mRNA-interaction. FERRY displays preferential binding to certain groups of transcripts, including mRNAs encoding mitochondrial proteins. Deletion of FERRY subunits reduces the endosomal localization of transcripts in cells and has a significant impact on mRNA levels. Clinical studies show that genetic disruption of FERRY causes severe brain damage. We found that, in neurons, FERRY co-localizes with mRNA on early endosomes, and mRNA loaded FERRY-positive endosomes are in close proximity of mitochondria. FERRY thus transforms endosomes into mRNA carriers and plays a key role in regulating mRNA distribution and transport.

PMID:37267905 | DOI:10.1016/j.molcel.2023.05.012

Tissue Cell. 2023 May 20;82:102117. doi: 10.1016/j.tice.2023.102117. Online ahead of print.

ABSTRACT

Keratocytes are the main cellular components of the corneal stroma. This cell is quiescent and cannot be cultured easily. The aim of this study was to investigate differentiate human adipose mesenchymal stem cells (hADSCs) into corneal keratocyte cells by combining natural scaffolds and conditioned medium (CM) and evaluating their safety in the rabbit's cornea. Keratocytes were cultured in an optimal culture medium and this medium was collected and kept as a CM. hADSCs were cultured on the decellularized human small incision lenticule extraction (SMILE) lenticule (SL), amniotic membrane (AM), and collagen-coated plates, and were exposed to keratocyte-CM (KCM) for 7, 14, and 21 days. Differentiation was evaluated using Real-time PCR and immunocytochemistry (ICC). hADSCs were cultured on the SL scaffolds and implanted in the corneal stroma of 8 New Zealand male rabbits. Rabbits were followed for 3 months and the safety was evaluated by clinical and histological variables. Real-time PCR results showed a significant increase in the expression of keratocyte-specific markers on the 21 day of differentiation compared to the control group. ICC also confirmed the induction of differentiation. Implantation of SLs containing differentiated cells in the cornea of animals showed no serious complications including neovascularization, corneal opacity, inflammation, or signs of tissue rejection. Furthermore, the evaluation of the presence of keratocyte-like cells after three months in the rabbit stroma was confirmed by Real-time PCR and immunohistochemistry (IHC) analysis. Our results showed that combination of combination of corneal extracellular matrix and KCM can induced keratocytes differentiation of hADSC and can be introduced as a alternative method to supply the required keratocytes in corneal tissue engineering.

PMID:37267821 | DOI:10.1016/j.tice.2023.102117

Sci Immunol. 2023 Jun 8;8(84):eabq7991. doi: 10.1126/sciimmunol.abq7991. Epub 2023 Jun 2.

ABSTRACT

Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.

PMID:37267384 | DOI:10.1126/sciimmunol.abq7991

Sci Adv. 2023 Jun 2;9(22):eadf1814. doi: 10.1126/sciadv.adf1814. Epub 2023 Jun 2.

ABSTRACT

Embryonic development proceeds as a series of orderly cell state transitions built upon noisy molecular processes. We defined gene expression and cell motion states using single-cell RNA sequencing data and in vivo time-lapse cell tracking data of the zebrafish tailbud. We performed a parallel identification of these states using dimensional reduction methods and a change point detection algorithm. Both types of cell states were quantitatively mapped onto embryos, and we used the cell motion states to study the dynamics of biological state transitions over time. The time average pattern of cell motion states is reproducible among embryos. However, individual embryos exhibit transient deviations from the time average forming left-right asymmetries in collective cell motion. Thus, the reproducible pattern of cell states and bilateral symmetry arise from temporal averaging. In addition, collective cell behavior can be a source of asymmetry rather than a buffer against noisy individual cell behavior.

PMID:37267354 | DOI:10.1126/sciadv.adf1814

PLoS One. 2023 Jun 2;18(6):e0286599. doi: 10.1371/journal.pone.0286599. eCollection 2023.

ABSTRACT

To reduce the genome sequence representation, restriction site-associated DNA sequencing (RAD-seq) protocols is being widely used either with single-digest or double-digest methods. In this study, we genotyped the sesame population (48 sample size) in a pilot scale to compare single and double-digest RAD-seq (sd and ddRAD-seq) methods. We analysed the resulting short-read data generated from both protocols and assessed their performance impacting the downstream analysis using various parameters. The distinct k-mer count and gene presence absence variation (PAV) showed a significant difference between the sesame samples studied. Additionally, the variant calling from both datasets (sdRAD-seq and ddRAD-seq) exhibits a significant difference between them. The combined variants from both datasets helped in identifying the most diverse samples and possible sub-groups in the sesame population. The most diverse samples identified from each analysis (k-mer, gene PAV, SNP count, Heterozygosity, NJ and PCA) can possibly be representative samples holding major diversity of the small sesame population used in this study. The best possible strategies with suggested inputs for modifications to utilize the RAD-seq strategy efficiently on a large dataset containing thousands of samples to be subjected to molecular analysis like diversity, population structure and core development studies were discussed.

PMID:37267340 | DOI:10.1371/journal.pone.0286599

G3 (Bethesda). 2023 Jun 2:jkad105. doi: 10.1093/g3journal/jkad105. Online ahead of print.

ABSTRACT

The COVID-19 pandemic has catalyzed unprecedented scientific data and reagent sharing and collaboration, which enabled understanding the virology of the SARS-CoV-2 virus and vaccine development at record speed. The pandemic, however, has also raised awareness of the danger posed by the family of coronaviruses, of which 7 are known to infect humans and dozens have been identified in reservoir species, such as bats, rodents, or livestock. To facilitate understanding the commonalities and specifics of coronavirus infections and aspects of viral biology that determine their level of lethality to the human host, we have generated a collection of freely available clones encoding nearly all human coronavirus proteins known to date. We hope that this flexible, Gateway-compatible vector collection will encourage further research into the interactions of coronaviruses with their human host, to increase preparedness for future zoonotic viral outbreaks.

PMID:37267226 | DOI:10.1093/g3journal/jkad105

IEEE/ACM Trans Comput Biol Bioinform. 2023 Jun 2;PP. doi: 10.1109/TCBB.2023.3282212. Online ahead of print.

ABSTRACT

Gene regulatory networks (GRNs) participate in many biological processes, and reconstructing them plays an important role in systems biology. Although many advanced methods have been proposed for GRN reconstruction, their predictive performance is far from the ideal standard, so it is urgent to design a more effective method to reconstruct GRN. Moreover, most methods only consider the gene expression data, ignoring the network structure information contained in GRN. In this study, we propose a supervised model named CNNGRN, which infers GRN from bulk time-series expression data via convolutional neural network (CNN) model, with a more informative feature. Bulk time series gene expression data imply the intricate regulatory associations between genes, and the network structure feature of ground-truth GRN contains rich neighbor information. Hence, CNNGRN integrates the above two features as model inputs. In addition, CNN is adopted to extract intricate features of genes and infer the potential associations between regulators and target genes. Moreover, feature importance visualization experiments are implemented to seek the key features. Experimental results show that CNNGRN achieved competitive performance on benchmark datasets compared to the state-of-the-art computational methods. Finally, hub genes identified based on CNNGRN have been confirmed to be involved in biological processes through literature.

PMID:37267145 | DOI:10.1109/TCBB.2023.3282212

Elife. 2023 Jun 2;12:e86032. doi: 10.7554/eLife.86032.

ABSTRACT

Colorectal cancer (CRC) remains a challenging and deadly disease with high tumor microenvironment (TME) heterogeneity. Using an integrative multi-omics analysis and artificial intelligence-enabled spatial analysis of whole-slide images, we performed a comprehensive characterization of TME in colorectal cancer (CCCRC). CRC samples were classified into four CCCRC subtypes with distinct TME features, namely, C1 as the proliferative subtype with low immunogenicity; C2 as the immunosuppressed subtype with the terminally exhausted immune characteristics; C3 as the immune-excluded subtype with the distinct upregulation of stromal components and a lack of T cell infiltration in the tumor core; and C4 as the immunomodulatory subtype with the remarkable upregulation of anti-tumor immune components. The four CCCRC subtypes had distinct histopathologic and molecular characteristics, therapeutic efficacy, and prognosis. We found that the C1 subtype may be suitable for chemotherapy and cetuximab, the C2 subtype may benefit from a combination of chemotherapy and bevacizumab, the C3 subtype has increased sensitivity to the WNT pathway inhibitor WIKI4, and the C4 subtype is a potential candidate for immune checkpoint blockade treatment. Importantly, we established a simple gene classifier for accurate identification of each CCCRC subtype. Collectively our integrative analysis ultimately established a holistic framework to thoroughly dissect the TME of CRC, and the CCCRC classification system with high biological interpretability may contribute to biomarker discovery and future clinical trial design.

PMID:37267125 | DOI:10.7554/eLife.86032

Cell Rep. 2023 Jun 1;42(6):112588. doi: 10.1016/j.celrep.2023.112588. Online ahead of print.

ABSTRACT

Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.

PMID:37267101 | DOI:10.1016/j.celrep.2023.112588

Microb Genom. 2023 Jun;9(6). doi: 10.1099/mgen.0.001028.

ABSTRACT

We delineate the evolutionary plasticity of the ecologically and biotechnologically important genus Streptomyces, by analysing the genomes of 213 species. Streptomycetes genomes demonstrate high levels of internal homology, whereas the genome of their last common ancestor was already complex. Importantly, we identify the species-specific fingerprint proteins that characterize each species. Even among closely related species, we observed high interspecies variability of chromosomal protein-coding genes, species-level core genes, accessory genes and fingerprints. Notably, secondary metabolite biosynthetic gene clusters (smBGCs), carbohydrate-active enzymes (CAZymes) and protein-coding genes bearing the rare TTA codon demonstrate high intraspecies and interspecies variability, which emphasizes the need for strain-specific genomic mining. Highly conserved genes, such as those specifying genus-level core proteins, tend to occur in the central region of the chromosome, whereas those encoding proteins with evolutionarily volatile species-level fingerprints, smBGCs, CAZymes and TTA-codon-bearing genes are often found towards the ends of the linear chromosome. Thus, the chromosomal arms emerge as the part of the genome that is mainly responsible for rapid adaptation at the species and strain level. Finally, we observed a moderate, but statistically significant, correlation between the total number of CAZymes and three categories of smBGCs (siderophores, e-Polylysin and type III lanthipeptides) that are related to competition among bacteria.

PMID:37266990 | DOI:10.1099/mgen.0.001028

Genes Genomics. 2023 Jun 2. doi: 10.1007/s13258-023-01404-7. Online ahead of print.

ABSTRACT

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that arises from malignant transformation of B lymphocytes. Outcome of patients with DLBCL has been significantly improved by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, which is regarded "gold standard" of DLBCL therapy. It is unfortunate that febrile neutropenia, a decrease of the neutrophil count in the blood accompanying fever, is one of the most common complications that DLBCL patients receiving R-CHOP regimen experience. Given the critical role of neutrophils against bacterial and fungal infections, neutropenia could be deadly. While the association between R-CHOP therapy and neutropenia has been well-established, the negative effect of DLBCL cells on the survival of neutrophils has not been clearly understood. Our previous study have shown that conditioned medium (CM) derived from Ly1 DLBCL cells induces apoptosis in murine neutrophils ex vivo. Additionally, Ly1 CM and doxorubicin synergize to further enhance apoptotic rate in neutrophils, possibly contributing to neutropenia in DLBCL patients.

OBJECTIVE: We investigated the mechanism and genes that regulate neutrophil apoptosis induced by secretome of DLBCL cells, which would give insight into the potential role of DLBCL in neutropenia.

METHOD: Murine neutrophils were isolated from bone marrow in C57BL6/J mice using flow cytometry. QuantSeq 3' mRNA-sequencing was conducted on neutrophils following exposure to CM derived from Ly1 DLBCL cells or murine bone marrow cells (control). Quantseq 3'mRNA sequencing data were aligned to identify differentially expressed mRNAs. Next, the expression of genes related to neutrophil apoptosis and proliferation were analyzed and Gene classification and ontology were analyzed.

RESULT: We identified 1196 (198 upregulated and 998 downregulated) differentially expressed genes (DEGs) in Ly1 DLBCL co-culture group compared to the control group. The functional enrichment analyses of DEGs in co-culture group revealed significant enriched in apoptosis process, and immune system process in gene ontology and the highly enriched pathway of various bacterial infection, leukocyte transendothelial migration, apoptosis, and cell cycle in KEGG pathway. Importantly, Bcl7b, Bnip3, Bmx, Mcl1, and Pim1 were identified as critical regulators of neutrophil apoptosis, which may be potential drug targets for the treatment of neutropenia. We are currently testing the efficacy of the activators/inhibitors of the proteins encoded by these genes to investigate whether they would block DLBCL-induced neutrophil apoptosis.

CONCLUSION: In the present study, bioinformatic analyses of gene expression profiling data revealed the crucial genes involved in neutrophil apoptosis and gave insight into the underlying mechanism. Given our data, it may be likely that novel opportunities for the treatment of neutropenia, and eventually improvement of prognosis of DLBCL patients, might emerge.

PMID:37266765 | DOI:10.1007/s13258-023-01404-7

Front Genet. 2023 May 17;14:1215326. doi: 10.3389/fgene.2023.1215326. eCollection 2023.

NO ABSTRACT

PMID:37265964 | PMC:PMC10230049 | DOI:10.3389/fgene.2023.1215326

Front Plant Sci. 2023 May 17;14:1176553. doi: 10.3389/fpls.2023.1176553. eCollection 2023.

ABSTRACT

Fungal plant infections result in substantial losses to the agricultural sector. A range of fungicide seed dressings are available to control seed-borne fungal diseases; however, they lack sufficient efficacy because of intrinsic tolerance and acquired resistance. Moreover, many fungicide seed dressings can also penetrate plants, negatively affecting plant growth owing to their toxic effects on endophytes, as well as contributing to the spread of antibiotic resistance. Here, we evaluated the efficacy of M451, a member of a new class of antimicrobial agents that are not relevant to human healthcare. As a seed dressing for wheat seeds, M451 exhibited significant antifungal activity against one of the most devastating plant fungal pathogens, Fusarium spp. Furthermore, M451 was more active than the commercially used fungicide Maxim XL against both seed-borne and soil-borne F. oxysporum infection. Importantly, and unlike other antifungals, M451 seed dressing did not inhibit any of the major characteristics of wheat grains and seedlings, such as germination percentage, germination time, grain vigor, shoot- and root weight and length, but rather improved some of these parameters. The results also demonstrated that M451 had no negative impacts on endophytes and did not accumulate in grains. Thus, M451 may have potential applications as an antifungal agent in wheat cultivation.

PMID:37265634 | PMC:PMC10229829 | DOI:10.3389/fpls.2023.1176553

Front Cell Neurosci. 2023 May 17;17:1190804. doi: 10.3389/fncel.2023.1190804. eCollection 2023.

NO ABSTRACT

PMID:37265579 | PMC:PMC10230948 | DOI:10.3389/fncel.2023.1190804