Science. 2023 Apr 28;380(6643):eabn3943. doi: 10.1126/science.abn3943. Epub 2023 Apr 28.

ABSTRACT

Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.

PMID:37104599 | DOI:10.1126/science.abn3943

Science. 2023 Apr 28;380(6643):eabn1430. doi: 10.1126/science.abn1430. Epub 2023 Apr 28.

ABSTRACT

We examined transposable element (TE) content of 248 placental mammal genome assemblies, the largest de novo TE curation effort in eukaryotes to date. We found that although mammals resemble one another in total TE content and diversity, they show substantial differences with regard to recent TE accumulation. This includes multiple recent expansion and quiescence events across the mammalian tree. Young TEs, particularly long interspersed elements, drive increases in genome size, whereas DNA transposons are associated with smaller genomes. Mammals tend to accumulate only a few types of TEs at any given time, with one TE type dominating. We also found association between dietary habit and the presence of DNA transposon invasions. These detailed annotations will serve as a benchmark for future comparative TE analyses among placental mammals.

PMID:37104570 | DOI:10.1126/science.abn1430

PLoS One. 2023 Apr 27;18(4):e0281470. doi: 10.1371/journal.pone.0281470. eCollection 2023.

ABSTRACT

Biotic stresses are pests and pathogens that cause a variety of crop diseases and damages. In response to these agents, crops trigger specific defense signal transduction pathways in which hormones play a central role. To recognize hormonal signaling, we integrated barley transcriptome datasets related to hormonal treatments and biotic stresses. In the meta-analysis of each dataset, 308 hormonal and 1232 biotic DEGs were identified respectively. According to the results, 24 biotic TFs belonging to 15 conserved families and 6 hormonal TFs belonging to 6 conserved families were identified, with the NF-YC, GNAT, and WHIRLY families being the most prevalent. Additionally, gene enrichment and pathway analyses revealed that over-represented cis-acting elements were recognized in response to pathogens and hormones. Based on the co-expression analysis, 6 biotic and 7 hormonal modules were uncovered. Finally, the hub genes of PKT3, PR1, SSI2, LOX2, OPR3, and AOS were candidates for further study in JA- or SA-mediated plant defense. The qPCR confirmed that the expression of these genes was induced from 3 to 6 h following exposure to 100 μM MeJA, with peak expression occurring between 12 h and 24 h and decreasing after 48 h. Overexpression of PR1 was one of the first steps toward SAR. As well as regulating SAR, NPR1 has also been shown to be involved in the activation of ISR by the SSI2. LOX2 catalyzes the first step of JA biosynthesis, PKT3 plays an important role in wound-activated responses, and OPR3 and AOS are involved in JA biosynthesis. In addition, many unknown genes were introduced that can be used by crop biotechnologists to accelerate barley genetic engineering.

PMID:37104505 | DOI:10.1371/journal.pone.0281470

Cell Tissue Bank. 2023 Apr 27. doi: 10.1007/s10561-023-10090-4. Online ahead of print.

ABSTRACT

Mesenchymal stem cells with tissue repair capacity involve in regenerative medicine. MSCs can promote bone repair when employed with nano scaffolds/particles. Here, the MTT and Acridine Orange assay enabled the cytotoxic concentration of Zinc oxide nanoparticles and Polyurethane evaluation. Following culturing adipose tissue-derived MSCs, ADSCs' proliferation, growth, and osteogenic differentiation in the presence of PU with and without ZnO NPs is tracked by a series of biological assays, including Alkaline Phosphatase activity, Calcium deposition, alizarin red staining, RT-PCR, scanning electron microscope, and immunohistochemistry. The results showed boosted osteogenic differentiation of ADSCs in the presence of 1% PU scaffold and ZnO NPS and can thus apply as a new bone tissue engineering matrix. The expression level of Osteonectin, Osteocalcin, and Col1 increased in PU-ZnO 1% on the 7th and 14th days. There was an increase in the Runx2 gene expression on the 7th day of differentiation in PU-ZnO 1%, while it decreased on day 14th. In conclusion, Polyurethane nano scaffolds supported the MSCs' growth and rapid osteogenic differentiation. The PU-ZnO helps not only with cellular adhesion and proliferation but also with osteogenic differentiation.

PMID:37103688 | DOI:10.1007/s10561-023-10090-4

J Mol Model. 2023 Apr 27;29(5):160. doi: 10.1007/s00894-023-05562-z.

ABSTRACT

CONTEXT: Breast cancer is the most prevalent type of malignancies among women worldwide and is associated with serious physical and mental consequences. Current chemotherapies may lack successful outcomes; thus, the development of targeted recombinant immunotoxins is plausible. The predicted B cell and T cell epitopes of arazyme of the fusion protein are able to elicit immune response. The results of codon adaptation tool of herceptin-arazyme have improved from 0.4 to 1. The in silico immune simulation results showed significant response for immune cells. In conclusion, our findings show that the known multi-epitope fusion protein may activate humoral and cellular immune responses and maybe a possible candidate for breast cancer treatment.

METHODS: In this study, the selected monoclonal antibody constituting herceptin and the bacterial metalloprotease, arazyme, was used with different peptide linkers to design a novel fusion protein to predict different B cell and T cell epitopes by the means of the relevant databases. Modeler 10.1 and I-TASSER online server were used to predict and validate the 3D structure and then docked to HER2-receptor using HADDOCK2.4 web server. The molecular dynamics (MD) simulations of the arazyme-linker-herceptin-HER2 complex were performed by GROMACS 2019.6 software. The sequence of arazyme-herceptin was optimized for the expression in prokaryotic host using online servers and cloned into pET-28a plasmid. The recombinant pET28a was transferred into the Escherichia coli BL21DE3. Expression and binding affinity of arazyme-herceptin and arazyme to human breast cancer cell lines (SK-BR-3/HER2 + and MDA-MB-468/HER2 -) were validated by the SDS-PAGE and cell‑ELISA, respectively.

PMID:37103612 | DOI:10.1007/s00894-023-05562-z

Genome Biol Evol. 2023 Apr 27:evad066. doi: 10.1093/gbe/evad066. Online ahead of print.

ABSTRACT

Admixture, the genetic merging of parental populations resulting in mixed ancestry, has occurred frequently throughout the course of human history. Numerous admixture events have occurred between human populations across the world, which have shaped genetic ancestry in modern humans. For example, populations in the Americas are often mosaics of different ancestries due to recent admixture events as part of European colonization. Admixed individuals also often have introgressed DNA from Neanderthals and Denisovans that may have come from multiple ancestral populations, which may affect how archaic ancestry is distributed across an admixed genome. In this study, we analyzed admixed populations from the Americas to assess whether the proportion and location of admixed segments due to recent admixture impact an individual's archaic ancestry. We identified a positive correlation between non-African ancestry and archaic alleles, as well as a slight enrichment of Denisovan alleles in Indigenous American segments relative to European segments in admixed genomes. We also identify several genes as candidates for adaptive introgression, based on archaic alleles present at high frequency in admixed American populations but low frequency in East Asian populations. These results provide insights into how recent admixture events between modern humans redistributed archaic ancestry in admixed genomes.

PMID:37103242 | DOI:10.1093/gbe/evad066

Insects. 2023 Apr 16;14(4):386. doi: 10.3390/insects14040386.

ABSTRACT

Eusociality represents the higher degree of interaction in insects. This complex social structure is maintained through a multimodal communication system that allows colony members to be flexible in their responses, fulfilling the overall society's needs. The colony plasticity is supposedly achieved by combining multiple biochemical pathways through the neuromodulation of molecules such as biogenic amines, but the mechanisms through which these regulatory compounds act are far from being fully disentangled. Here, we review the potential function of major bioamines (dopamine, tyramine, serotine, and octopamine) on the behavioral modulation of principal groups of eusocial Hymenoptera, with a special focus on ants. Because functional roles are species- and context-dependent, identifying a direct causal relationship between a biogenic amine variation and behavioral changes is extremely challenging. We also used a quantitative and qualitative synthesis approach to summarize research trends and interests in the literature related to biogenic amines of social insects. Shedding light on the aminergic regulation of behavioral responses will pave the way for an entirely new approach to understanding the evolution of sociality in insects.

PMID:37103201 | DOI:10.3390/insects14040386

Insects. 2023 Mar 31;14(4):347. doi: 10.3390/insects14040347.

ABSTRACT

Bombyx mori is a model lepidopteran insect of great economic value. Mulberry leaves are its only natural food source. The development of artificial diets can not only resolve the seasonal shortage of mulberry leaves but also enable changes to be made to the feed composition according to need. Metabolomic differences between the midguts of male and female silkworms fed either on fresh mulberry leaves or an artificial diet were studied using liquid chromatography-mass spectrography (LC-MS/MS) analysis. A total of 758 differential metabolites were identified. Our analysis showed that they were mainly involved in disease resistance and immunity, silk quality, and silkworm growth and development. These experimental results provide insights into the formulation of optimized artificial feed for silkworms.

PMID:37103160 | DOI:10.3390/insects14040347

In Vivo. 2023 May-Jun;37(3):1022-1027. doi: 10.21873/invivo.13176.

ABSTRACT

BACKGROUND/AIM: 1,5-Anhydro-d-fructose (1,5-AF, saccharide) and 1,5-anhydro-d-glucitol (1,5-AG) converted from 1,5-AF via the glycemic pathway have health benefits. However, this metabolism has not been sufficiently elucidated. To clarify the in vivo metabolism of 1,5-AF to 1,5-AG, porcine (blood kinetics) and human (urinary excretion) studies were conducted.

MATERIALS AND METHODS: Microminipigs were administrated 1,5-AF orally or intravenously. Blood samples were obtained to analyse the kinetics of 1,5-AF and 1,5-AG. Urine samples were collected from human subjects who had orally ingested 1,5-AF, and the amounts of 1,5-AF and 1,5-AG excreted in the urine were analysed.

RESULTS: In blood kinetics analysis, the time to the maximum concentration of 1,5-AF after intravenous administration was 0.5 h, whereas 1,5-AF was not observed after oral administration. The times to the maximum concentration of 1,5-AG after intravenous and oral administration were 1.5 h and 2 h, respectively. In urinary excretion, the concentration of 1,5-AG in urine rapidly increased after the administration of 1,5-AF, peaked at 2 h, whereas 1,5-AF was not detected.

CONCLUSION: 1,5-AF was rapidly metabolized to 1.5-AG in vivo in swine and human.

PMID:37103066 | DOI:10.21873/invivo.13176

Gels. 2023 Mar 29;9(4):278. doi: 10.3390/gels9040278.

ABSTRACT

In recent years, the antimicrobial activity of chitosan-based hydrogels has been at the forefront of research in wound healing and the prevention of medical device contamination. Anti-infective therapy is a serious challenge given the increasing prevalence of bacterial resistance to antibiotics as well as their ability to form biofilms. Unfortunately, hydrogel resistance and biocompatibility do not always meet the demands of biomedical applications. As a result, the development of double-network hydrogels could be a solution to these issues. This review discusses the most recent techniques for creating double-network chitosan-based hydrogels with improved structural and functional properties. The applications of these hydrogels are also discussed in terms of tissue recovery after injuries, wound infection prevention, and biofouling of medical devices and surfaces for pharmaceutical and medical applications.

PMID:37102890 | DOI:10.3390/gels9040278

Haematologica. 2023 Apr 27. doi: 10.3324/haematol.2022.282160. Online ahead of print.

ABSTRACT

Not available.

PMID:37102614 | DOI:10.3324/haematol.2022.282160

Elife. 2023 Apr 27;12:e84757. doi: 10.7554/eLife.84757.

ABSTRACT

Morphogen gradients can instruct cells about their position in a patterned tissue. Non-linear morphogen decay has been suggested to increase gradient precision by reducing the sensitivity to variability in the morphogen source. Here, we use cell-based simulations to quantitatively compare the positional error of gradients for linear and non-linear morphogen decay. While we confirm that non-linear decay reduces the positional error close to the source, the reduction is very small for physiological noise levels. Far from the source, the positional error is much larger for non-linear decay in tissues that pose a flux barrier to the morphogen at the boundary. In light of this new data, a physiological role of morphogen decay dynamics in patterning precision appears unlikely.

PMID:37102505 | DOI:10.7554/eLife.84757

iScience. 2023 Mar 31;26(4):106541. doi: 10.1016/j.isci.2023.106541. eCollection 2023 Apr 21.

ABSTRACT

Skeletal muscle dysfunction or reprogramming due to the effects of the cancer secretome is observed in multiple malignancies. Although mouse models are routinely used to study skeletal muscle defects in cancer, because of species specificity of certain cytokines/chemokines in the secretome, a human model system is required. Here, we establish simplified multiple skeletal muscle stem cell lines (hMuSCs), which can be differentiated into myotubes. Using single nuclei ATAC-seq (snATAC-seq) and RNA-seq (snRNA-seq), we document chromatin accessibility and transcriptomic changes associated with the transition of hMuSCs to myotubes. Cancer secretome accelerated stem to myotube differentiation, altered the alternative splicing machinery and increased inflammatory, glucocorticoid receptor, and wound healing pathways in hMuSCs. Additionally, cancer secretome reduced metabolic and survival pathway associated miR-486, AKT, and p53 signaling in hMuSCs. hMuSCs underwent myotube differentiation when engrafted into NSG mice and thus providing a humanized in vivo skeletal muscle model system to study cancer cachexia.

PMID:37102148 | PMC:PMC10123345 | DOI:10.1016/j.isci.2023.106541

Biomed Res Int. 2023 Apr 17;2023:3728131. doi: 10.1155/2023/3728131. eCollection 2023.

ABSTRACT

PURPOSE: As a scientific field, bioinformatics has drawn remarkable attention from various fields, such as information technology, mathematics, and modern biological sciences, in recent years. The topic models originating from the field of natural language processing have become the focus of attention with the rapid accumulation of biological datasets. Thus, this research is aimed at modeling the topic content of the bioinformatics literature presented by Iranian researchers in the Scopus Citation Database. Methodology. This research was a descriptive-exploratory study, and the studied population included 3899 papers indexed in the Scopus database, which had been indexed in this database until March 9, 2022. The topic modeling was then performed on the abstracts and titles of the papers. A combination of LDA and TF-IDF was utilized for topic modeling. Findings. The data analysis with topic modeling resulted in identifying seven main topics "Molecular Modeling," "Gene Expression," "Biomarker," "Coronavirus," "Immunoinformatics," "Cancer Bioinformatics," and "Systems Biology." Moreover, "Systems Biology" and "Coronavirus" had the largest and smallest clusters, respectively.

CONCLUSION: The present investigation demonstrated an acceptable performance for the LDA algorithm in classifying the topics included in this field. The extracted topic clusters indicated excellent consistency and topic connection with each other.

PMID:37101687 | PMC:PMC10125747 | DOI:10.1155/2023/3728131

ACS Bio Med Chem Au. 2022 Feb 16;2(3):196-204. doi: 10.1021/acsbiomedchemau.1c00061. eCollection 2022 Jun 15.

ABSTRACT

The anaerobic biosyntheses of heme, heme d 1, and bacteriochlorophyll all require the action of radical SAM enzymes. During heme biosynthesis in some bacteria, coproporphyrinogen III dehydrogenase (CgdH) catalyzes the decarboxylation of two propionate side chains of coproporphyrinogen III to the corresponding vinyl groups of protoporphyrinogen IX. Its solved crystal structure was the first published structure for a radical SAM enzyme. In bacteria, heme is inserted into enzymes by the cytoplasmic heme chaperone HemW, a radical SAM enzyme structurally highly related to CgdH. In an alternative heme biosynthesis route found in archaea and sulfate-reducing bacteria, the two radical SAM enzymes AhbC and AhbD catalyze the removal of two acetate groups (AhbC) or the decarboxylation of two propionate side chains (AhbD). NirJ, a close homologue of AhbC, is required for propionate side chain removal during the formation of heme d 1 in some denitrifying bacteria. Biosynthesis of the fifth ring (ring E) of all chlorophylls is based on an unusual six-electron oxidative cyclization step. The sophisticated conversion of Mg-protoporphyrin IX monomethylester to protochlorophyllide is facilitated by an oxygen-independent cyclase termed BchE, which is a cobalamin-dependent radical SAM enzyme. Most of the radical SAM enzymes involved in tetrapyrrole biosynthesis were recognized as such by Sofia et al. in 2001 (Nucleic Acids Res.2001, 29, 1097-1106) and were biochemically characterized thereafter. Although much has been achieved, the challenging tetrapyrrole substrates represent a limiting factor for enzyme/substrate cocrystallization and the ultimate elucidation of the corresponding enzyme mechanisms.

PMID:37101575 | PMC:PMC10114771 | DOI:10.1021/acsbiomedchemau.1c00061

Aging Cell. 2023 Apr 26:e13852. doi: 10.1111/acel.13852. Online ahead of print.

ABSTRACT

Perturbed metabolism of ammonia, an endogenous cytotoxin, causes mitochondrial dysfunction, reduced NAD+ /NADH (redox) ratio, and postmitotic senescence. Sirtuins are NAD+ -dependent deacetylases that delay senescence. In multiomics analyses, NAD metabolism and sirtuin pathways are enriched during hyperammonemia. Consistently, NAD+ -dependent Sirtuin3 (Sirt3) expression and deacetylase activity were decreased, and protein acetylation was increased in human and murine skeletal muscle/myotubes. Global acetylomics and subcellular fractions from myotubes showed hyperammonemia-induced hyperacetylation of cellular signaling and mitochondrial proteins. We dissected the mechanisms and consequences of hyperammonemia-induced NAD metabolism by complementary genetic and chemical approaches. Hyperammonemia inhibited electron transport chain components, specifically complex I that oxidizes NADH to NAD+ , that resulted in lower redox ratio. Ammonia also caused mitochondrial oxidative dysfunction, lower mitochondrial NAD+ -sensor Sirt3, protein hyperacetylation, and postmitotic senescence. Mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX), but not NAD+ precursor nicotinamide riboside, reversed ammonia-induced oxidative dysfunction, electron transport chain supercomplex disassembly, lower ATP and NAD+ content, protein hyperacetylation, Sirt3 dysfunction and postmitotic senescence in myotubes. Even though Sirt3 overexpression reversed ammonia-induced hyperacetylation, lower redox status or mitochondrial oxidative dysfunction were not reversed. These data show that acetylation is a consequence of, but is not the mechanism of, lower redox status or oxidative dysfunction during hyperammonemia. Targeting NADH oxidation is a potential approach to reverse and potentially prevent ammonia-induced postmitotic senescence in skeletal muscle. Since dysregulated ammonia metabolism occurs with aging, and NAD+ biosynthesis is reduced in sarcopenia, our studies provide a biochemical basis for cellular senescence and have relevance in multiple tissues.

PMID:37101412 | DOI:10.1111/acel.13852

Mol Cancer. 2023 Apr 26;22(1):76. doi: 10.1186/s12943-023-01777-z.

NO ABSTRACT

PMID:37101282 | DOI:10.1186/s12943-023-01777-z

Orphanet J Rare Dis. 2023 Apr 26;18(1):95. doi: 10.1186/s13023-023-02683-9.

ABSTRACT

BACKGROUND: Inherited Metabolic Disorders (IMDs) are rare diseases where one impaired protein leads to a cascade of changes in the adjacent chemical conversions. IMDs often present with non-specific symptoms, a lack of a clear genotype-phenotype correlation, and de novo mutations, complicating diagnosis. Furthermore, products of one metabolic conversion can be the substrate of another pathway obscuring biomarker identification and causing overlapping biomarkers for different disorders. Visualization of the connections between metabolic biomarkers and the enzymes involved might aid in the diagnostic process. The goal of this study was to provide a proof-of-concept framework for integrating knowledge of metabolic interactions with real-life patient data before scaling up this approach. This framework was tested on two groups of well-studied and related metabolic pathways (the urea cycle and pyrimidine de-novo synthesis). The lessons learned from our approach will help to scale up the framework and support the diagnosis of other less-understood IMDs.

METHODS: Our framework integrates literature and expert knowledge into machine-readable pathway models, including relevant urine biomarkers and their interactions. The clinical data of 16 previously diagnosed patients with various pyrimidine and urea cycle disorders were visualized on the top 3 relevant pathways. Two expert laboratory scientists evaluated the resulting visualizations to derive a diagnosis.

RESULTS: The proof-of-concept platform resulted in varying numbers of relevant biomarkers (five to 48), pathways, and pathway interactions for each patient. The two experts reached the same conclusions for all samples with our proposed framework as with the current metabolic diagnostic pipeline. For nine patient samples, the diagnosis was made without knowledge about clinical symptoms or sex. For the remaining seven cases, four interpretations pointed in the direction of a subset of disorders, while three cases were found to be undiagnosable with the available data. Diagnosing these patients would require additional testing besides biochemical analysis.

CONCLUSION: The presented framework shows how metabolic interaction knowledge can be integrated with clinical data in one visualization, which can be relevant for future analysis of difficult patient cases and untargeted metabolomics data. Several challenges were identified during the development of this framework, which should be resolved before this approach can be scaled up and implemented to support the diagnosis of other (less understood) IMDs. The framework could be extended with other OMICS data (e.g. genomics, transcriptomics), and phenotypic data, as well as linked to other knowledge captured as Linked Open Data.

PMID:37101200 | DOI:10.1186/s13023-023-02683-9

Cell Death Differ. 2023 Apr 26. doi: 10.1038/s41418-023-01153-w. Online ahead of print.

ABSTRACT

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

PMID:37100955 | DOI:10.1038/s41418-023-01153-w

Nature. 2023 Apr 26. doi: 10.1038/s41586-023-05990-0. Online ahead of print.

ABSTRACT

The approximately 120 MDa mammalian nuclear pore complex (NPC) acts as a gatekeeper for the transport between the nucleus and cytosol1. The central channel of the NPC is filled with hundreds of intrinsically disordered proteins (IDPs) called FG-nucleoporins (FG-NUPs)2,3. Although the structure of the NPC scaffold has been resolved in remarkable detail, the actual transport machinery built up by FG-NUPs-about 50 MDa-is depicted as an approximately 60-nm hole in even highly resolved tomograms and/or structures computed with artificial intelligence4-11. Here we directly probed conformations of the vital FG-NUP98 inside NPCs in live cells and in permeabilized cells with an intact transport machinery by using a synthetic biology-enabled site-specific small-molecule labelling approach paired with highly time-resolved fluorescence microscopy. Single permeabilized cell measurements of the distance distribution of FG-NUP98 segments combined with coarse-grained molecular simulations of the NPC allowed us to map the uncharted molecular environment inside the nanosized transport channel. We determined that the channel provides-in the terminology of the Flory polymer theory12-a 'good solvent' environment. This enables the FG domain to adopt expanded conformations and thus control transport between the nucleus and cytoplasm. With more than 30% of the proteome being formed from IDPs, our study opens a window into resolving disorder-function relationships of IDPs in situ, which are important in various processes, such as cellular signalling, phase separation, ageing and viral entry.

PMID:37100914 | DOI:10.1038/s41586-023-05990-0