Pegylated interferon alfa (pegIFN-α) can induce molecular remissions in patients with JAK2-V617F-positive myeloproliferative neoplasms (MPNs) by targeting long-term hematopoietic stem cells (LT-HSCs). Additional somatic mutations in genes regulating LT-HSC self-renewal, such as DNMT3A, have been reported to have poorer responses to pegIFN-α. We investigated whether DNMT3A loss leads to alterations in JAK2-V617F LT-HSC functions conferring resistance to pegIFN-α treatment in a mouse model of MPN and in hematopoietic progenitors from patients with MPN. Long-term treatment with pegIFN-α normalized blood parameters and reduced splenomegaly and JAK2-V617F chimerism in single-mutant JAK2-V617F (VF) mice. However, pegIFN-α in VF;Dnmt3aΔ/Δ (VF;DmΔ/Δ) mice worsened splenomegaly and failed to reduce JAK2-V617F chimerism. Furthermore, LT-HSCs from VF;DmΔ/Δ mice compared with VF were less prone to accumulate DNA damage and exit dormancy upon pegIFN-α treatment. RNA sequencing showed that IFN-α induced stronger upregulation of inflammatory pathways in LT-HSCs from VF;DmΔ/Δ than from VF mice, indicating that the resistance of VF;DmΔ/Δ LT-HSC was not due to failure in IFN-α signaling. Transplantations of bone marrow from pegIFN-α-treated VF;DmΔ/Δ mice gave rise to more aggressive disease in secondary and tertiary recipients. Liquid cultures of hematopoietic progenitors from patients with MPN with JAK2-V617F and DNMT3A mutation showed increased percentages of JAK2-V617F-positive colonies upon IFN-α exposure, whereas in patients with JAK2-V617F alone, the percentages of JAK2-V617F-positive colonies decreased or remained unchanged. PegIFN-α combined with 5-azacytidine only partially overcame resistance in VF;DmΔ/Δ mice. However, this combination strongly decreased the JAK2-mutant allele burden in mice carrying VF mutation only, showing potential to inflict substantial damage preferentially to the JAK2-mutant clone.

• MeSH
• Cell Self Renewal MeSH
• Drug Resistance, Neoplasm * genetics   MeSH
• DNA Methyltransferase 3A * genetics   MeSH
• DNA (Cytosine-5-)-Methyltransferases * genetics   metabolism   MeSH
• Hematopoietic Stem Cells * metabolism   pathology   drug effects   MeSH
• Interferon-alpha * pharmacology   MeSH
• Janus Kinase 2 * genetics   metabolism   MeSH
• Humans MeSH
• Myeloproliferative Disorders * genetics   pathology   drug therapy   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Polyethylene Glycols pharmacology   MeSH
• Recombinant Proteins MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Traditionally, anticancer therapies focus on restraining uncontrolled proliferation. However, these cytotoxic therapies expose cancer cells to direct killing, instigating the process of natural selection favoring survival of resistant cells that become the foundation for tumor progression and therapy failure. Recognizing this phenomenon has prompted the development of alternative therapeutic strategies. Here we propose strategies targeting cancer hallmarks beyond proliferation, aiming at re-educating cancer cells towards a less malignant phenotype. These strategies include controlling cell dormancy, transdifferentiation therapy, normalizing the cancer microenvironment, and using migrastatic therapy. Adaptive resistance to these educative strategies does not confer a direct proliferative advantage to resistant cells, as non-resistant cells are not subject to eradication, thereby delaying or preventing the development of therapy-resistant tumors.

• MeSH
• Drug Resistance, Neoplasm MeSH
• Humans MeSH
• Tumor Microenvironment * MeSH
• Neoplasms * therapy   MeSH
• Cell Proliferation MeSH
• Antineoplastic Agents therapeutic use   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Vysokoškolská učebnice, která se zaměřuje na různé druhy mikroorganismů a jejich ekologii a patogenitu.

• MeSH
• Ecology MeSH
• Communicable Diseases MeSH
• Microbiological Phenomena MeSH
• Environmental Microbiology MeSH
• Molecular Biology MeSH
• Publication type
• Monograph MeSH

• Conspectus
• Mikrobiologie
• Učební osnovy. Vyučovací předměty. Učebnice
• NML Fields
• mikrobiologie, lékařská mikrobiologie
• NML Publication type
• učebnice vysokých škol

BACKGROUND: The advancement of sequencing technologies today has made a plethora of whole-genome re-sequenced (WGRS) data publicly available. However, research utilizing the WGRS data without further configuration is nearly impossible. To solve this problem, our research group has developed an interactive Allele Catalog Tool to enable researchers to explore the coding region allelic variation present in over 1,000 re-sequenced accessions each for soybean, Arabidopsis, and maize. RESULTS: The Allele Catalog Tool was designed originally with soybean genomic data and resources. The Allele Catalog datasets were generated using our variant calling pipeline (SnakyVC) and the Allele Catalog pipeline (AlleleCatalog). The variant calling pipeline is developed to parallelly process raw sequencing reads to generate the Variant Call Format (VCF) files, and the Allele Catalog pipeline takes VCF files to perform imputations, functional effect predictions, and assemble alleles for each gene to generate curated Allele Catalog datasets. Both pipelines were utilized to generate the data panels (VCF files and Allele Catalog files) in which the accessions of the WGRS datasets were collected from various sources, currently representing over 1,000 diverse accessions for soybean, Arabidopsis, and maize individually. The main features of the Allele Catalog Tool include data query, visualization of results, categorical filtering, and download functions. Queries are performed from user input, and results are a tabular format of summary results by categorical description and genotype results of the alleles for each gene. The categorical information is specific to each species; additionally, available detailed meta-information is provided in modal popups. The genotypic information contains the variant positions, reference or alternate genotypes, the functional effect classes, and the amino-acid changes of each accession. Besides that, the results can also be downloaded for other research purposes. CONCLUSIONS: The Allele Catalog Tool is a web-based tool that currently supports three species: soybean, Arabidopsis, and maize. The Soybean Allele Catalog Tool is hosted on the SoyKB website ( https://soykb.org/SoybeanAlleleCatalogTool/ ), while the Allele Catalog Tool for Arabidopsis and maize is hosted on the KBCommons website ( https://kbcommons.org/system/tools/AlleleCatalogTool/Zmays and https://kbcommons.org/system/tools/AlleleCatalogTool/Athaliana ). Researchers can use this tool to connect variant alleles of genes with meta-information of species.

• MeSH
• Alleles * MeSH
• Arabidopsis * genetics   MeSH
• Data Mining * methods   MeSH
• Datasets as Topic * MeSH
• Gene Frequency MeSH
• Genotype MeSH
• Glycine max * genetics   MeSH
• Internet * MeSH
• Zea mays * genetics   MeSH
• Metadata MeSH
• Mutation MeSH
• Pigmentation genetics   MeSH
• Genes, Plant genetics   MeSH
• Software * MeSH
• Amino Acid Substitution MeSH
• Plant Dormancy genetics   MeSH
• Data Visualization MeSH
• Publication type
• Journal Article MeSH

Circulating tumor cells (CTCs) are released from primary tumors and transported through the body via blood or lymphatic vessels before settling to form micrometastases under suitable conditions. Accordingly, several studies have identified CTCs as a negative prognostic factor for survival in many types of cancer. CTCs also reflect the current heterogeneity and genetic and biological state of tumors; so, their study can provide valuable insights into tumor progression, cell senescence, and cancer dormancy. Diverse methods with differing specificity, utility, costs, and sensitivity have been developed for isolating and characterizing CTCs. Additionally, novel techniques with the potential to overcome the limitations of existing ones are being developed. This primary literature review describes the current and emerging methods for enriching, detecting, isolating, and characterizing CTCs.

• MeSH
• Humans MeSH
• Neoplastic Cells, Circulating * pathology   MeSH
• Cell Separation methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Dormant cells of Mycobacterium tuberculosis, in addition to low metabolic activity and a high level of drug resistance, are characterized by 'non-culturability'-a specific reversible state of the inability of the cells to grow on solid media. The biochemical characterization of this physiological state of the pathogen is only superficial, pending clarification of the metabolic processes that may exist in such cells. In this study, applying LC-MS proteomic profiling, we report the analysis of proteins accumulated in dormant, 'non-culturable' M. tuberculosis cells in an in vitro model of self-acidification of mycobacteria in the post-stationary phase, simulating the in vivo persistence conditions-the raw data are available via ProteomeXchange with identifier PXD028849. This approach revealed the preservation of 1379 proteins in cells after 5 months of storage in dormancy; among them, 468 proteins were statistically different from those in the actively growing cells and bore a positive fold change (FC). Differential analysis revealed the proteins of the pH-dependent regulatory system PhoP and allowed the reconstruction of the reactions of central carbon/glycerol metabolism, as well as revealing the salvaged pathways of mycothiol and UMP biosynthesis, establishing the cohort of survival enzymes of dormancy. The annotated pathways mirror the adaptation of the mycobacterial metabolic machinery to life within lipid-rich macrophages: especially the involvement of the methyl citrate and glyoxylate pathways. Thus, the current in vitro model of M. tuberculosis self-acidification reflects the biochemical adaptation of these bacteria to persistence in vivo. Comparative analysis with published proteins displaying antigenic properties makes it possible to distinguish immunoreactive proteins among the proteins bearing a positive FC in dormancy, which may include specific antigens of latent tuberculosis. Additionally, the biotransformatory enzymes (oxidoreductases and hydrolases) capable of prodrug activation and stored up in the dormant state were annotated. These findings may potentially lead to the discovery of immunodiagnostic tests for early latent tuberculosis and trigger the discovery of efficient drugs/prodrugs with potency against non-replicating, dormant populations of mycobacteria.

• MeSH
• Mass Spectrometry MeSH
• Latent Tuberculosis * MeSH
• Humans MeSH
• Mycobacterium tuberculosis * metabolism   MeSH
• Proteomics MeSH
• Tuberculosis, Lymph Node * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The universal nine-amino-acid transactivation domains (9aaTADs) have been identified in numerous transcription activators. Here, we identified the conserved 9aaTAD motif in all nine members of the specificity protein (SP) family. Previously, the Sp1 transcription factor has been defined as a glutamine-rich activator. We showed by amino acid substitutions that the glutamine residues are completely dispensable for 9aaTAD function and are not conserved in the SP family. We described the origin and evolutionary history of 9aaTADs. The 9aaTADs of the ancestral Sp2 gene became inactivated in early chordates. We next discovered that an accumulation of valines in 9aaTADs inactivated their transactivation function and enabled their strict conservation during evolution. Subsequently, in chordates, Sp2 has duplicated and created new paralogs, Sp1, Sp3, and Sp4 (the SP1-4 clade). During chordate evolution, the dormancy of the Sp2 activation domain lasted over 100 million years. The dormant but still intact ancestral Sp2 activation domains allowed diversification of the SP1-4 clade into activators and repressors. By valine substitution in the 9aaTADs, Sp1 and Sp3 regained their original activator function found in ancestral lower metazoan sea sponges. Therefore, the vertebrate SP1-4 clade could include both repressors and activators. Furthermore, we identified secondary 9aaTADs in Sp2 introns present from fish to primates, including humans. In the gibbon genome, introns containing 9aaTADs were used as exons, which turned the Sp2 gene into an activator. Similarly, we identified introns containing 9aaTADs used conditionally as exons in the (SP family-unrelated) transcription factor SREBP1, suggesting that the intron-9aaTAD reservoir is a general phenomenon.

• MeSH
• Transcriptional Activation MeSH
• Gene Duplication MeSH
• Phylogeny MeSH
• Introns * genetics   MeSH
• Humans MeSH
• Evolution, Molecular * MeSH
• Gene Expression Regulation * MeSH
• Amino Acid Sequence MeSH
• Sequence Homology MeSH
• Sp2 Transcription Factor * antagonists & inhibitors   genetics   metabolism   MeSH
• Valine genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH

The universal nine-amino-acid transactivation domains (9aaTADs) have been identified in numerous transcription activators. Here, we identified the conserved 9aaTAD motif in all nine members of the specificity protein (SP) family. Previously, the Sp1 transcription factor has been defined as a glutamine-rich activator. We showed by amino acid substitutions that the glutamine residues are completely dispensable for 9aaTAD function and are not conserved in the SP family. We described the origin and evolutionary history of 9aaTADs. The 9aaTADs of the ancestral Sp2 gene became inactivated in early chordates. We next discovered that an accumulation of valines in 9aaTADs inactivated their transactivation function and enabled their strict conservation during evolution. Subsequently, in chordates, Sp2 has duplicated and created new paralogs, Sp1, Sp3, and Sp4 (the SP1-4 clade). During chordate evolution, the dormancy of the Sp2 activation domain lasted over 100 million years. The dormant but still intact ancestral Sp2 activation domains allowed diversification of the SP1-4 clade into activators and repressors. By valine substitution in the 9aaTADs, Sp1 and Sp3 regained their original activator function found in ancestral lower metazoan sea sponges. Therefore, the vertebrate SP1-4 clade could include both repressors and activators. Furthermore, we identified secondary 9aaTADs in Sp2 introns present from fish to primates, including humans. In the gibbon genome, introns containing 9aaTADs were used as exons, which turned the Sp2 gene into an activator. Similarly, we identified introns containing 9aaTADs used conditionally as exons in the (SP family-unrelated) transcription factor SREBP1, suggesting that the intron-9aaTAD reservoir is a general phenomenon.

• MeSH
• Transcriptional Activation MeSH
• Gene Duplication MeSH
• Phylogeny MeSH
• Introns genetics   MeSH
• Humans MeSH
• Evolution, Molecular * MeSH
• Gene Expression Regulation * MeSH
• Amino Acid Sequence MeSH
• Sequence Homology MeSH
• Sp2 Transcription Factor antagonists & inhibitors   genetics   metabolism   MeSH
• Valine genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The role of trees in the nitrous oxide (N2O) balance of boreal forests has been neglected despite evidence suggesting their substantial contribution. We measured seasonal changes in N2O fluxes from soil and stems of boreal trees in Finland, showing clear seasonality in stem N2O flux following tree physiological activity, particularly processes of CO2 uptake and release. Stem N2O emissions peak during the vegetation season, decrease rapidly in October, and remain low but significant to the annual totals during winter dormancy. Trees growing on dry soils even turn to consumption of N2O from the atmosphere during dormancy, thereby reducing their overall N2O emissions. At an annual scale, pine, spruce and birch are net N2O sources, with spruce being the strongest emitter. Boreal trees thus markedly contribute to the seasonal dynamics of ecosystem N2O exchange, and their species-specific contribution should be included into forest emission inventories.

• MeSH
• Atmosphere chemistry   MeSH
• Ecosystem * MeSH
• Methane metabolism   MeSH
• Nitrous Oxide metabolism   MeSH
• Carbon Dioxide metabolism   MeSH
• Soil chemistry   MeSH
• Seasons * MeSH
• Plant Stems metabolism   MeSH
• Trees physiology   MeSH
• Taiga * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Finland MeSH

Heteromorphic diaspores (fruits and seeds) are an adaptive bet-hedging strategy to cope with spatiotemporally variable environments, particularly fluctuations in favourable temperatures and unpredictable precipitation regimes in arid climates. We conducted comparative analyses of the biophysical and ecophysiological properties of the two distinct diaspores (mucilaginous seed (M+ ) vs indehiscent (IND) fruit) in the dimorphic annual Aethionema arabicum (Brassicaceae), linking fruit biomechanics, dispersal aerodynamics, pericarp-imposed dormancy, diaspore abscisic acid (ABA) concentration, and phenotypic plasticity of dimorphic diaspore production to its natural habitat and climate. Two very contrasting dispersal mechanisms of the A. arabicum dimorphic diaspores were revealed. Dehiscence of large fruits leads to the release of M+ seed diaspores, which adhere to substrata via seed coat mucilage, thereby preventing dispersal (antitelechory). IND fruit diaspores (containing nonmucilaginous seeds) disperse by wind or water currents, promoting dispersal (telechory) over a longer range. The pericarp properties confer enhanced dispersal ability and degree of dormancy on the IND fruit morph to support telechory, while the M+ seed morph supports antitelechory. Combined with the phenotypic plasticity to produce more IND fruit diaspores in colder temperatures, this constitutes a bet-hedging survival strategy to magnify the prevalence in response to selection pressures acting over hilly terrain.

• MeSH
• Biophysical Phenomena * MeSH
• Biomechanical Phenomena MeSH
• Brassicaceae physiology   MeSH
• Ecosystem MeSH
• Adaptation, Physiological * MeSH
• Germination physiology   MeSH
• Fruit physiology   MeSH
• Soil MeSH
• Seeds physiology   MeSH
• Seed Dispersal physiology   MeSH
• Wind MeSH
• Water MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH