Bioinformatics. 2023 Jun 30;39(Supplement_1):i413-i422. doi: 10.1093/bioinformatics/btad271.

ABSTRACT

MOTIVATION: Sequence-based deep learning approaches have been shown to predict a multitude of functional genomic readouts, including regions of open chromatin and RNA expression of genes. However, a major limitation of current methods is that model interpretation relies on computationally demanding post hoc analyses, and even then, one can often not explain the internal mechanics of highly parameterized models. Here, we introduce a deep learning architecture called totally interpretable sequence-to-function model (tiSFM). tiSFM improves upon the performance of standard multilayer convolutional models while using fewer parameters. Additionally, while tiSFM is itself technically a multilayer neural network, internal model parameters are intrinsically interpretable in terms of relevant sequence motifs.

RESULTS: We analyze published open chromatin measurements across hematopoietic lineage cell-types and demonstrate that tiSFM outperforms a state-of-the-art convolutional neural network model custom-tailored to this dataset. We also show that it correctly identifies context-specific activities of transcription factors with known roles in hematopoietic differentiation, including Pax5 and Ebf1 for B-cells, and Rorc for innate lymphoid cells. tiSFM's model parameters have biologically meaningful interpretations, and we show the utility of our approach on a complex task of predicting the change in epigenetic state as a function of developmental transition.

AVAILABILITY AND IMPLEMENTATION: The source code, including scripts for the analysis of key findings, can be found at https://github.com/boooooogey/ATAConv, implemented in Python.

PMID:37387140 | DOI:10.1093/bioinformatics/btad271

Int J Sports Physiol Perform. 2023 Jun 28:1-4. doi: 10.1123/ijspp.2023-0042. Online ahead of print.

ABSTRACT

PURPOSE: The record power profile (RPP) has gained popularity as a method of monitoring endurance cycling performance. However, the expected variation of cyclists' performance between seasons remains unknown. We aimed to assess the between-seasons variability of peak performance (assessed through the RPP) in male professional cyclists.

METHODS: The study followed a longitudinal observational design. Sixty-one male professional cyclists (age 26 [5] y) with power output data from both training sessions and competitions were analyzed for a median of 4 consecutive seasons (range 2-12). The highest mean maximum power values attained for different durations (from 10 s to 30 min), as well as the resulting critical power, were determined for each season. Within-cyclist variability between seasons was assessed, and the upper threshold of expected changes (ie, twice the normal coefficient of variation) was determined.

RESULTS: All mean maximum power values showed an overall high agreement and low variability between seasons (intraclass correlation coefficient [ICC] = .76-.88 and coefficient of variation [CV] = 3.2%-5.9%), with the lowest variability observed for long efforts (>1 min). Critical power showed an ICC and CV of .79 (95% CI, .70-.85) and 3.3% (95% CI, 3.0%-3.7%), respectively. Upper thresholds of expected variation were <12% for short efforts (≤1 min) and <8% for long efforts.

CONCLUSIONS: "Real-world" peak performance assessed through the RPP shows a low variability between seasons in male professional cyclists-especially for long efforts-with expected variation being around 6% and 3% for short (≤1 min) and long efforts, respectively, and with changes >12% and >8%, respectively, being infrequent for these effort durations.

PMID:37385604 | DOI:10.1123/ijspp.2023-0042

Phytochemistry. 2023 Jun 27:113777. doi: 10.1016/j.phytochem.2023.113777. Online ahead of print.

ABSTRACT

The undifferentiated cambial meristematic cell (CMC) has been recognized as a value-added production platform for plant natural products in comparison to the dedifferentiated plant cell line (DDC). In a time-based approach at 0, 24, 48, and 72 h, the present study aimed at investigating the phytochemical metabolome of methyl jasmonate (MeJA)-elicited CMC cultures derived from sweet basil (Ocimum basilicum L.), including primary and secondary metabolites analyzed using GC/TOF-MS post-silylation and RP-UPLC-C18-FT-MS/MS, respectively, as well as the analysis of aroma composition using headspace SPME-GC-MS. The results revealed a stress response in primary metabolism manifested by an increase in amino and organic acids reaching their maximum levels after 48 (1.3-fold) and 72 (1.7-fold) h, respectively. In addition, phenolic acids (e.g., sagerinic acid, rosmarinic acid, and 3-O-methylrosmarinic acid) followed by flavonoid aglycones (e.g., salvigenin and 5,6,4'-trihydroxy-7,3'-dimethoxyflavone) were the most abundant with prominent increases at 48 (1.2-fold) and 72 (2.1-fold) h, respectively. The aroma was intensified by the elicitation along the time, especially after 48 and 72 h. Furthermore, multivariate data analyses, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) confirmed elicitation effect, especially post 48 and 72 h. The study further assessed the effect of MeJA elicitation on the antioxidant and polyphenolic content. The cultures at 48 h demonstrated a significant (p < 0.05) antioxidant activity concurrently with correlation with total polyphenolic content using Pearson's correlation. Our study provides new insights to the elicitation impact on primary and secondary metabolism, in addition to aroma profile, to orchestrate the stress response and in relation to antioxidant effect.

PMID:37385363 | DOI:10.1016/j.phytochem.2023.113777

Lancet Diabetes Endocrinol. 2023 Jun 26:S2213-8587(23)00131-6. doi: 10.1016/S2213-8587(23)00131-6. Online ahead of print.

ABSTRACT

BACKGROUND: Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype.

METHODS: In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation.

FINDINGS: Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice.

INTERPRETATION: We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process.

FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.

PMID:37385287 | DOI:10.1016/S2213-8587(23)00131-6

Comput Methods Programs Biomed. 2023 Jun 17;240:107681. doi: 10.1016/j.cmpb.2023.107681. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Mechanistic-based Model simulations (MM) are an effective approach commonly employed, for research and learning purposes, to better investigate and understand the inherent behavior of biological systems. Recent advancements in modern technologies and the large availability of omics data allowed the application of Machine Learning (ML) techniques to different research fields, including systems biology. However, the availability of information regarding the analyzed biological context, sufficient experimental data, as well as the degree of computational complexity, represent some of the issues that both MMs and ML techniques could present individually. For this reason, recently, several studies suggest overcoming or significantly reducing these drawbacks by combining the above-mentioned two methods. In the wake of the growing interest in this hybrid analysis approach, with the present review, we want to systematically investigate the studies available in the scientific literature in which both MMs and ML have been combined to explain biological processes at genomics, proteomics, and metabolomics levels, or the behavior of entire cellular populations.

METHODS: Elsevier Scopus®, Clarivate Web of Science™ and National Library of Medicine PubMed® databases were enquired using the queries reported in Table 1, resulting in 350 scientific articles.

RESULTS: Only 14 of the 350 documents returned by the comprehensive search conducted on the three major online databases met our search criteria, i.e. present a hybrid approach consisting of the synergistic combination of MMs and ML to treat a particular aspect of systems biology.

CONCLUSIONS: Despite the recent interest in this methodology, from a careful analysis of the selected papers, it emerged how examples of integration between MMs and ML are already present in systems biology, highlighting the great potential of this hybrid approach to both at micro and macro biological scales.

PMID:37385142 | DOI:10.1016/j.cmpb.2023.107681

BMC Res Notes. 2023 Jun 29;16(1):126. doi: 10.1186/s13104-023-06404-0.

ABSTRACT

PURPOSE: This study investigates the applicability of optimized machine learning (ML) approach for the prediction of Medial tibial stress syndrome (MTSS) using anatomic and anthropometric predictors.

METHOD: To this end, 180 recruits were enrolled in a cross-sectional study of 30 MTSS (30.36 ± 4.80 years) and 150 normal (29.70 ± 3.81 years). Twenty-five predictors/features, including demographic, anatomic, and anthropometric variables, were selected as risk factors. Bayesian optimization method was used to evaluate the most applicable machine learning algorithm with tuned hyperparameters on the training data. Three experiments were performed to handle the imbalances in the data set. The validation criteria were accuracy, sensitivity, and specificity.

RESULTS: The highest performance (even 100%) was observed for the Ensemble and SVM classification models while using at least 6 and 10 most important predictors in undersampling and oversampling experiments, respectively. In the no-resampling experiment, the best performance (accuracy = 88.89%, sensitivity = 66.67%, specificity = 95.24%, and AUC = 0.8571) was achieved for the Naive Bayes classifier with the 12 most important features.

CONCLUSION: The Naive Bayes, Ensemble, and SVM methods could be the primary choices to apply the machine learning approach in MTSS risk prediction. These predictive methods, alongside the eight common proposed predictors, might help to more accurately calculate the individual risk of developing MTSS at the point of care.

PMID:37386606 | DOI:10.1186/s13104-023-06404-0

Nat Genet. 2023 Jun 29. doi: 10.1038/s41588-023-01433-8. Online ahead of print.

ABSTRACT

Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.

PMID:37386249 | DOI:10.1038/s41588-023-01433-8

Nat Plants. 2023 Jun 29. doi: 10.1038/s41477-023-01452-7. Online ahead of print.

ABSTRACT

The leaf epidermis represents a multifunctional tissue consisting of trichomes, pavement cells and stomata, the specialized cellular pores of the leaf. Pavement cells and stomata both originate from regulated divisions of stomatal lineage ground cells (SLGCs), but whereas the ontogeny of the stomata is well characterized, the genetic pathways activating pavement cell differentiation remain relatively unexplored. Here, we reveal that the cell cycle inhibitor SIAMESE-RELATED1 (SMR1) is essential for timely differentiation of SLGCs into pavement cells by terminating SLGC self-renewal potency, which depends on CYCLIN A proteins and CYCLIN-DEPENDENT KINASE B1. By controlling SLGC-to-pavement cell differentiation, SMR1 determines the ratio of pavement cells to stomata and adjusts epidermal development to suit environmental conditions. We therefore propose SMR1 as an attractive target for engineering climate-resilient plants.

PMID:37386150 | DOI:10.1038/s41477-023-01452-7

Commun Biol. 2023 Jun 29;6(1):678. doi: 10.1038/s42003-023-05041-4.

ABSTRACT

Genome-wide association studies identified several disease-causing mutations in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the contribution of genetic variants to pathway disturbances and their cell type-specific variations, especially in glia, is poorly understood. We integrated ALS GWAS-linked gene networks with human astrocyte-specific multi-omics datasets to elucidate pathognomonic signatures. It predicts that KIF5A, a motor protein kinesin-1 heavy-chain isoform, previously detected only in neurons, can also potentiate disease pathways in astrocytes. Using postmortem tissue and super-resolution structured illumination microscopy in cell-based perturbation platforms, we provide evidence that KIF5A is present in astrocyte processes and its deficiency disrupts structural integrity and mitochondrial transport. We show that this may underly cytoskeletal and trafficking changes in SOD1 ALS astrocytes characterised by low KIF5A levels, which can be rescued by c-Jun N-terminal Kinase-1 (JNK1), a kinesin transport regulator. Altogether, our pipeline reveals a mechanism controlling astrocyte process integrity, a pre-requisite for synapse maintenance and suggests a targetable loss-of-function in ALS.

PMID:37386082 | DOI:10.1038/s42003-023-05041-4

Nat Commun. 2023 Jun 29;14(1):3851. doi: 10.1038/s41467-023-39242-6.

ABSTRACT

The interplay of positive and negative interactions between drug-sensitive and resistant cells influences the effectiveness of treatment in heterogeneous cancer cell populations. Here, we study interactions between estrogen receptor-positive breast cancer cell lineages that are sensitive and resistant to ribociclib-induced cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition. In mono- and coculture, we find that sensitive cells grow and compete more effectively in the absence of treatment. During treatment with ribociclib, sensitive cells survive and proliferate better when grown together with resistant cells than when grown in monoculture, termed facilitation in ecology. Molecular, protein, and genomic analyses show that resistant cells increase metabolism and production of estradiol, a highly active estrogen metabolite, and increase estrogen signaling in sensitive cells to promote facilitation in coculture. Adding estradiol in monoculture provides sensitive cells with increased resistance to therapy and cancels facilitation in coculture. Under partial inhibition of estrogen signaling through low-dose endocrine therapy, estradiol supplied by resistant cells facilitates sensitive cell growth. However, a more complete blockade of estrogen signaling, through higher-dose endocrine therapy, diminished the facilitative growth of sensitive cells. Mathematical modeling quantifies the strength of competition and facilitation during CDK4/6 inhibition and predicts that blocking facilitation has the potential to control both resistant and sensitive cancer cell populations and inhibit the emergence of a refractory population during cell cycle therapy.

PMID:37386030 | DOI:10.1038/s41467-023-39242-6

PLoS Pathog. 2023 Jun 29;19(6):e1011468. doi: 10.1371/journal.ppat.1011468. Online ahead of print.

ABSTRACT

Controlled human malaria infections (CHMI) are a valuable tool to study parasite gene expression in vivo under defined conditions. In previous studies, virulence gene expression was analyzed in samples from volunteers infected with the Plasmodium falciparum (Pf) NF54 isolate, which is of African origin. Here, we provide an in-depth investigation of parasite virulence gene expression in malaria-naïve European volunteers undergoing CHMI with the genetically distinct Pf 7G8 clone, originating in Brazil. Differential expression of var genes, encoding major virulence factors of Pf, PfEMP1s, was assessed in ex vivo parasite samples as well as in parasites from the in vitro cell bank culture that was used to generate the sporozoites (SPZ) for CHMI (Sanaria PfSPZ Challenge (7G8)). We report broad activation of mainly B-type subtelomeric located var genes at the onset of a 7G8 blood stage infection in naïve volunteers, mirroring the NF54 expression study and suggesting that the expression of virulence-associated genes is generally reset during transmission from the mosquito to the human host. However, in 7G8 parasites, we additionally detected a continuously expressed single C-type variant, Pf7G8_040025600, that was most highly expressed in both pre-mosquito cell bank and volunteer samples, suggesting that 7G8, unlike NF54, maintains expression of some previously expressed var variants during transmission. This suggests that in a new host, the parasite may preferentially express the variants that previously allowed successful infection and transmission. Trial registration: ClinicalTrials.gov - NCT02704533; 2018-004523-36.

PMID:37384799 | DOI:10.1371/journal.ppat.1011468

PLoS Pathog. 2023 Jun 29;19(6):e1011416. doi: 10.1371/journal.ppat.1011416. eCollection 2023 Jun.

ABSTRACT

Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from naïve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population "arms" that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes.

PMID:37384622 | DOI:10.1371/journal.ppat.1011416

Cell Rep. 2023 Jun 28;42(7):112680. doi: 10.1016/j.celrep.2023.112680. Online ahead of print.

ABSTRACT

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. To explore microbial influences on susceptibility, we screened 85 microbiota-associated metabolites for their effects on Cryptosporidium parvum growth in vitro. We identify eight inhibitory metabolites in three main classes: secondary bile salts/acids, a vitamin B6 precursor, and indoles. Growth restriction of C. parvum by indoles does not depend on the host aryl hydrocarbon receptor (AhR) pathway. Instead, treatment impairs host mitochondrial function and reduces total cellular ATP, as well as directly reducing the membrane potential in the parasite mitosome, a degenerate mitochondria. Oral administration of indoles, or reconstitution of the gut microbiota with indole-producing bacteria, delays life cycle progression of the parasite in vitro and reduces the severity of C. parvum infection in mice. Collectively, these findings indicate that microbiota metabolites impair mitochondrial function and contribute to colonization resistance to Cryptosporidium infection.

PMID:37384526 | DOI:10.1016/j.celrep.2023.112680

STAR Protoc. 2023 Jun 28;4(3):102380. doi: 10.1016/j.xpro.2023.102380. Online ahead of print.

ABSTRACT

Since the start of mass-spectrometry-based proteomics, proteins from non-referenced open reading frames or alternative proteins (AltProts) have been overlooked. Here, we present a protocol to identify human subcellular AltProt and decipher some interactions using cross-linking mass spectrometry. We describe steps for cell culture, in cellulo cross-link, subcellular extraction, and sequential digestion. We then detail both liquid chromatography-tandem mass spectrometry and cross-link data analyses. The implementation of a single workflow allows the non-targeted identification of signaling pathways involving AltProts. For complete details on the use and execution of this protocol, please refer to Garcia-del Rio et al.1.

PMID:37384523 | DOI:10.1016/j.xpro.2023.102380

Front Plant Sci. 2023 Jun 13;14:1181529. doi: 10.3389/fpls.2023.1181529. eCollection 2023.

ABSTRACT

Industrial chicory (Cichorium intybus var. sativum) is a biannual crop mostly cultivated for extraction of inulin, a fructose polymer used as a dietary fiber. F1 hybrid breeding is a promising breeding strategy in chicory but relies on stable male sterile lines to prevent self-pollination. Here, we report the assembly and annotation of a new industrial chicory reference genome. Additionally, we performed RNA-Seq on subsequent stages of flower bud development of a fertile line and two cytoplasmic male sterile (CMS) clones. Comparison of fertile and CMS flower bud transcriptomes combined with morphological microscopic analysis of anthers, provided a molecular understanding of anther development and identified key genes in a range of underlying processes, including tapetum development, sink establishment, pollen wall development and anther dehiscence. We also described the role of phytohormones in the regulation of these processes under normal fertile flower bud development. In parallel, we evaluated which processes are disturbed in CMS clones and could contribute to the male sterile phenotype. Taken together, this study provides a state-of-the-art industrial chicory reference genome, an annotated and curated candidate gene set related to anther development and male sterility as well as a detailed molecular timetable of flower bud development in fertile and CMS lines.

PMID:37384353 | PMC:PMC10298185 | DOI:10.3389/fpls.2023.1181529

F1000Res. 2023 Jun 26;12:376. doi: 10.12688/f1000research.133220.2. eCollection 2023.

ABSTRACT

RNA-binding protein Fused-in Sarcoma (FUS) plays an essential role in various cellular processes. Mutations in the C-terminal domain region, where the nuclear localization signal (NLS) is located, causes the redistribution of FUS from the nucleus to the cytoplasm. In neurons, neurotoxic aggregates are formed as a result, contributing to neurogenerative diseases. Well-characterized anti-FUS antibodies would enable the reproducibility of FUS research, thereby benefiting the scientific community. In this study, we characterized ten FUS commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.

PMID:37384305 | PMC:PMC10293799 | DOI:10.12688/f1000research.133220.2

Front Oncol. 2023 Jun 13;13:1200897. doi: 10.3389/fonc.2023.1200897. eCollection 2023.

ABSTRACT

INTRODUCTION: Resistance in anti-cancer treatment is a result of clonal evolution and clonal selection. In chronic myeloid leukemia (CML), the hematopoietic neoplasm is predominantly caused by the formation of the BCR::ABL1 kinase. Evidently, treatment with tyrosine kinase inhibitors (TKIs) is tremendously successful. It has become the role model of targeted therapy. However, therapy resistance to TKIs leads to loss of molecular remission in about 25% of CML patients being partially due to BCR::ABL1 kinase mutations, while for the remaining cases, various other mechanisms are discussed.

METHODS: Here, we established an in vitro-TKI resistance model against the TKIs imatinib and nilotinib and performed exome sequencing.

RESULTS: In this model, acquired sequence variants in NRAS, KRAS, PTPN11, and PDGFRB were identified in TKI resistance. The well-known pathogenic NRAS p.(Gln61Lys) variant provided a strong benefit for CML cells under TKI exposure visible by increased cell number (6.2-fold, p < 0.001) and decreased apoptosis (-25%, p < 0.001), proving the functionality of our approach. The transfection of PTPN11 p.(Tyr279Cys) led to increased cell number (1.7-fold, p = 0.03) and proliferation (2.0-fold, p < 0.001) under imatinib treatment.

DISCUSSION: Our data demonstrate that our in vitro-model can be used to study the effect of specific variants on TKI resistance and to identify new driver mutations and genes playing a role in TKI resistance. The established pipeline can be used to study candidates acquired in TKI-resistant patients, thereby providing new options for the development of new therapy strategies to overcome resistance.

PMID:37384296 | PMC:PMC10294234 | DOI:10.3389/fonc.2023.1200897

Front Cell Dev Biol. 2023 Jun 13;11:1169962. doi: 10.3389/fcell.2023.1169962. eCollection 2023.

ABSTRACT

Aggregation of the Tar DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia and likely contributes to disease by loss of nuclear function. Analysis of TDP-43 function in knockout zebrafish identified an endothelial directional migration and hypersprouting phenotype during development prior lethality. In human umbilical vein cells (HUVEC) the loss of TDP-43 leads to hyperbranching. We identified elevated expression of FIBRONECTIN 1 (FN1), the VASCULAR CELL ADHESION MOLECULE 1 (VCAM1), as well as their receptor INTEGRIN α4β1 (ITGA4B1) in HUVEC cells. Importantly, reducing the levels of ITGA4, FN1, and VCAM1 homologues in the TDP-43 loss-of-function zebrafish rescues the angiogenic defects indicating the conservation of human and zebrafish TDP-43 function during angiogenesis. Our study identifies a novel pathway regulated by TDP-43 important for angiogenesis during development.

PMID:37384248 | PMC:PMC10299809 | DOI:10.3389/fcell.2023.1169962

Front Artif Intell. 2023 Jun 13;6:1201002. doi: 10.3389/frai.2023.1201002. eCollection 2023.

ABSTRACT

INTRODUCTION: Climate change is already affecting ecosystems around the world and forcing us to adapt to meet societal needs. The speed with which climate change is progressing necessitates a massive scaling up of the number of species with understood genotype-environment-phenotype (G×E×P) dynamics in order to increase ecosystem and agriculture resilience. An important part of predicting phenotype is understanding the complex gene regulatory networks present in organisms. Previous work has demonstrated that knowledge about one species can be applied to another using ontologically-supported knowledge bases that exploit homologous structures and homologous genes. These types of structures that can apply knowledge about one species to another have the potential to enable the massive scaling up that is needed through in silico experimentation.

METHODS: We developed one such structure, a knowledge graph (KG) using information from Planteome and the EMBL-EBI Expression Atlas that connects gene expression, molecular interactions, functions, and pathways to homology-based gene annotations. Our preliminary analysis uses data from gene expression studies in Arabidopsis thaliana and Populus trichocarpa plants exposed to drought conditions.

RESULTS: A graph query identified 16 pairs of homologous genes in these two taxa, some of which show opposite patterns of gene expression in response to drought. As expected, analysis of the upstream cis-regulatory region of these genes revealed that homologs with similar expression behavior had conserved cis-regulatory regions and potential interaction with similar trans-elements, unlike homologs that changed their expression in opposite ways.

DISCUSSION: This suggests that even though the homologous pairs share common ancestry and functional roles, predicting expression and phenotype through homology inference needs careful consideration of integrating cis and trans-regulatory components in the curated and inferred knowledge graph.

PMID:37384147 | PMC:PMC10298150 | DOI:10.3389/frai.2023.1201002

Front Aging. 2023 Jun 13;4:1196648. doi: 10.3389/fragi.2023.1196648. eCollection 2023.

ABSTRACT

Aging-related hypoxia, oxidative stress, and inflammation pathophysiology are closely associated with human age-related carcinogenesis and chronic diseases. However, the connection between hypoxia and hormonal cell signaling pathways is unclear, but such human age-related comorbid diseases do coincide with the middle-aging period of declining sex hormonal signaling. This scoping review evaluates the relevant interdisciplinary evidence to assess the systems biology of function, regulation, and homeostasis in order to discern and decipher the etiology of the connection between hypoxia and hormonal signaling in human age-related comorbid diseases. The hypothesis charts the accumulating evidence to support the development of a hypoxic milieu and oxidative stress-inflammation pathophysiology in middle-aged individuals, as well as the induction of amyloidosis, autophagy, and epithelial-to-mesenchymal transition in aging-related degeneration. Taken together, this new approach and strategy can provide the clarity of concepts and patterns to determine the causes of declining vascularity hemodynamics (blood flow) and physiological oxygenation perfusion (oxygen bioavailability) in relation to oxygen homeostasis and vascularity that cause hypoxia (hypovascularity hypoxia). The middle-aging hypovascularity hypoxia hypothesis could provide the mechanistic interface connecting the endocrine, nitric oxide, and oxygen homeostasis signaling that is closely linked to the progressive conditions of degenerative hypertrophy, atrophy, fibrosis, and neoplasm. An in-depth understanding of these intrinsic biological processes of the developing middle-aged hypoxia could provide potential new strategies for time-dependent therapies in maintaining healthspan for healthy lifestyle aging, medical cost savings, and health system sustainability.

PMID:37384143 | PMC:PMC10293850 | DOI:10.3389/fragi.2023.1196648