Elife. 2023 Apr 25;12:e74915. doi: 10.7554/eLife.74915. Online ahead of print.

ABSTRACT

The immune system plays a major role in maintaining many physiological processes in the reproductive system. However, a complete characterization of the immune milieu in the ovary, and particularly how it is affected by female aging, is still lacking. Here, we utilize single-cell RNA sequencing and flow cytometry to construct the complete description of the murine ovarian immune system. We show that the composition of the immune cells undergoes an extensive shift with age towards adaptive immunity. We analyze the effect of aging on gene expression and chemokine and cytokine networks and show an overall decreased expression of inflammatory mediators together with an increased expression of senescent cells recognition receptors. Our results suggest that the fertile female's ovarian immune aging differs from the suggested female post-menopause inflammaging as it copes with the inflammatory stimulations during repeated cycles and the increasing need for clearance of accumulating atretic follicles.

PMID:37096871 | DOI:10.7554/eLife.74915

Elife. 2023 Apr 25;12:e84360. doi: 10.7554/eLife.84360. Online ahead of print.

ABSTRACT

During the rapid and reductive cleavage divisions of early embryogenesis, subcellular structures such as the nucleus and mitotic spindle scale to decreasing cell size. Mitotic chromosomes also decrease in size during development, presumably to scale coordinately with mitotic spindles, but underlying mechanisms are unclear. Here we combine in vivo and in vitro approaches using eggs and embryos from the frog Xenopus laevis to show that mitotic chromosome scaling is mechanistically distinct from other forms of subcellular scaling. We found that mitotic chromosomes scale continuously with cell, spindle and nuclear size in vivo. However, unlike for spindles and nuclei, mitotic chromosome size cannot be re-set by cytoplasmic factors from earlier developmental stages. In vitro, increasing nuclear-cytoplasmic (N/C) ratio is sufficient to recapitulate mitotic chromosome scaling, but not nuclear or spindle scaling, through differential loading of maternal factors during interphase. An additional pathway involving importin a scales mitotic chromosomes to cell surface area/volume ratio (SA/V) during metaphase. Finally, single-chromosome immunofluorescence and Hi-C data suggest that mitotic chromosomes shrink during embryogenesis through decreased recruitment of condensin I, resulting in major rearrangements of DNA loop architecture to accommodate the same amount of DNA on a shorter axis. Together, our findings demonstrate how mitotic chromosome size is set by spatially and temporally distinct developmental cues in the early embryo.

PMID:37096661 | DOI:10.7554/eLife.84360

Arthritis Rheumatol. 2023 Apr 25. doi: 10.1002/art.42536. Online ahead of print.

ABSTRACT

OBJECTIVE: Systemic sclerosis (SSc) is a multifactorial autoimmune fibrotic disorder involving complex rewiring of cell-intrinsic and cell-extrinsic signaling co-expression networks involving a range of cell types. However, the rewired circuits as well as corresponding cell-cell interactions remain poorly understood. To address this, we first used a predictive machine learning framework to analyze single-cell RNA-seq data from 24 SSc patients across the severity (as quantified by the Modified Rodnan Skin Score) spectrum.

METHODS: We used a LASSO-based predictive machine learning approach on the scRNA-seq dataset to identify predictive biomarkers of SSc severity, both across and within cell types. The use of L1 regularization helps prevent overfitting on high-dimensional data. Correlation network analyses were coupled to the LASSO model to identify cell-intrinsic and cell-extrinsic co-correlates of the identified biomarkers of SSc severity.

RESULTS: We found that the uncovered cell-type-specific predictive biomarkers of MRSS included previously implicated genes in fibroblast and myeloid cell subsets (e.g., SFPR2+ fibroblasts and monocytes), as well as novel gene biomarkers of MRSS, especially in keratinocytes. Correlation network analyses unveiled novel cross-talk between immune pathways as well as implicated keratinocytes in addition to fibroblast and myeloid cells as key cell-types involved in SSc pathogenesis. We then validated the uncovered association of key gene expression and protein markers in keratinocytes, KRT6A and S100A8, with SSc skin disease severity.

CONCLUSION: Our global systems analyses uncover previous uncharacterized cell-intrinsic and cell-extrinsic signaling co-expression networks underlying SSc severity that involve keratinocytes, myeloid cells and fibroblasts. This article is protected by copyright. All rights reserved.

PMID:37096444 | DOI:10.1002/art.42536

Elife. 2023 Apr 25;12:e84395. doi: 10.7554/eLife.84395.

ABSTRACT

Antimicrobial peptides (AMPs) offer a promising solution to the antibiotic resistance crisis. However, an unresolved serious concern is that the evolution of resistance to therapeutic AMPs may generate cross-resistance to host AMPs, compromising a cornerstone of the innate immune response. We systematically tested this hypothesis using globally disseminated mobile colistin resistance (MCR) that has been selected by the use of colistin in agriculture and medicine. Here, we show that MCR provides a selective advantage to Escherichia coli in the presence of key AMPs from humans and agricultural animals by increasing AMP resistance. Moreover, MCR promotes bacterial growth in human serum and increases virulence in a Galleria mellonella infection model. Our study shows how the anthropogenic use of AMPs can drive the accidental evolution of resistance to the innate immune system of humans and animals. These findings have major implications for the design and use of therapeutic AMPs and suggest that MCR may be difficult to eradicate, even if colistin use is withdrawn.

PMID:37094804 | DOI:10.7554/eLife.84395

J Labelled Comp Radiopharm. 2023 Apr 24. doi: 10.1002/jlcr.4025. Online ahead of print.

ABSTRACT

The beta-site amyloid precursor protein cleaving enzyme (BACE1) is responsible for initiating the generation of beta-amyloid, the major constituent of amyloid plaques in Alzheimer's disease (AD). The purpose of this study was to develop a specific BACE1 radioligand for visualization of the distribution pattern and quantification of the BACE1 protein in the rodent and monkey brain both in vitro by autoradiography and in vivo by positron emission tomography (PET). The BACE1 inhibitor RO6807936 originating from an in-house chemical drug optimization program was selected based on its PET tracer like physicochemical properties and a favorable pharmacokinetic profile. Saturation binding analysis of [3 H]RO6807936 revealed specific and high affinity binding (KD = 2.9 nM) and a low Bmax value (4.3 nM) of the BACE1 protein in native rat brain membranes. [3 H]RO6807936 binding showed a ubiquitous distribution on rat brain slices in vitro with higher levels in the CA3 8 cell layer and the granule cell layer of the hippocampus. In a next step, RO6807936 was successfully radiolabelled with carbon-11 and showed acceptable uptake in the baboon brain as well as a widespread and rather homogeneous distribution consistent with rodent data. In vivo blockade studies with a specific BACE1 inhibitor reduced uptake of the tracer to homogenous levels across brain regions and demonstrated specificity of the signal. Our data warrant further profiling of this PET tracer candidate in humans to investigate BACE1 expression in normal individuals and those with AD and as an imaging biomarker for target occupancy studies in clinical drug trials.

PMID:37095603 | DOI:10.1002/jlcr.4025

Microbiome. 2023 Apr 24;11(1):88. doi: 10.1186/s40168-023-01506-0.

ABSTRACT

BACKGROUND: Psychological health risk is one of the most severe and complex risks in manned deep-space exploration and long-term closed environments. Recently, with the in-depth research of the microbiota-gut-brain axis, gut microbiota has been considered a new approach to maintain and improve psychological health. However, the correlation between gut microbiota and psychological changes inside long-term closed environments is still poorly understood. Herein, we used the "Lunar Palace 365" mission, a 1-year-long isolation study in the Lunar Palace 1 (a closed manned Bioregenerative Life Support System facility with excellent performance), to investigate the correlation between gut microbiota and psychological changes, in order to find some new potential psychobiotics to maintain and improve the psychological health of crew members.

RESULTS: We report some altered gut microbiota that were associated with psychological changes in the long-term closed environment. Four potential psychobiotics (Bacteroides uniformis, Roseburia inulinivorans, Eubacterium rectale, and Faecalibacterium prausnitzii) were identified. On the basis of metagenomic, metaproteomic, and metabolomic analyses, the four potential psychobiotics improved mood mainly through three pathways related to nervous system functions: first, by fermenting dietary fibers, they may produce short-chain fatty acids, such as butyric and propionic acids; second, they may regulate amino acid metabolism pathways of aspartic acid, glutamic acid, tryptophan, etc. (e.g., converting glutamic acid to gamma-aminobutyric acid; converting tryptophan to serotonin, kynurenic acid, or tryptamine); and third, they may regulate other pathways, such as taurine and cortisol metabolism. Furthermore, the results of animal experiments confirmed the positive regulatory effect and mechanism of these potential psychobiotics on mood.

CONCLUSIONS: These observations reveal that gut microbiota contributed to a robust effect on the maintenance and improvement of mental health in a long-term closed environment. Our findings represent a key step towards a better understanding the role of the gut microbiome in mammalian mental health during space flight and provide a basis for future efforts to develop microbiota-based countermeasures that mitigate risks to crew mental health during future long-term human space expeditions on the moon or Mars. This study also provides an essential reference for future applications of psychobiotics to neuropsychiatric treatments. Video Abstract.

PMID:37095530 | DOI:10.1186/s40168-023-01506-0

Nat Med. 2023 Apr 24. doi: 10.1038/s41591-023-02317-4. Online ahead of print.

ABSTRACT

Recent studies proposed a general psychopathology factor underlying common comorbidities among psychiatric disorders. However, its neurobiological mechanisms and generalizability remain elusive. In this study, we used a large longitudinal neuroimaging cohort from adolescence to young adulthood (IMAGEN) to define a neuropsychopathological (NP) factor across externalizing and internalizing symptoms using multitask connectomes. We demonstrate that this NP factor might represent a unified, genetically determined, delayed development of the prefrontal cortex that further leads to poor executive function. We also show this NP factor to be reproducible in multiple developmental periods, from preadolescence to early adulthood, and generalizable to the resting-state connectome and clinical samples (the ADHD-200 Sample and the Stratify Project). In conclusion, we identify a reproducible and general neural basis underlying symptoms of multiple mental health disorders, bridging multidimensional evidence from behavioral, neuroimaging and genetic substrates. These findings may help to develop new therapeutic interventions for psychiatric comorbidities.

PMID:37095248 | DOI:10.1038/s41591-023-02317-4

Nat Commun. 2023 Apr 24;14(1):2359. doi: 10.1038/s41467-023-38119-y.

ABSTRACT

Synthetic sRNAs allow knockdown of target genes at translational level, but have been restricted to a limited number of bacteria. Here, we report the development of a broad-host-range synthetic sRNA (BHR-sRNA) platform employing the RoxS scaffold and the Hfq chaperone from Bacillus subtilis. BHR-sRNA is tested in 16 bacterial species including commensal, probiotic, pathogenic, and industrial bacteria, with >50% of target gene knockdown achieved in 12 bacterial species. For medical applications, virulence factors in Staphylococcus epidermidis and Klebsiella pneumoniae are knocked down to mitigate their virulence-associated phenotypes. For metabolic engineering applications, high performance Corynebacterium glutamicum strains capable of producing valerolactam (bulk chemical) and methyl anthranilate (fine chemical) are developed by combinatorial knockdown of target genes. A genome-scale sRNA library covering 2959 C. glutamicum genes is constructed for high-throughput colorimetric screening of indigoidine (natural colorant) overproducers. The BHR-sRNA platform will expedite engineering of diverse bacteria of both industrial and medical interest.

PMID:37095132 | DOI:10.1038/s41467-023-38119-y

Aliment Pharmacol Ther. 2023 May;57(10):1180-1182. doi: 10.1111/apt.17491.

NO ABSTRACT

PMID:37094315 | DOI:10.1111/apt.17491

Eur J Sport Sci. 2023 Apr 24:1-27. doi: 10.1080/17461391.2023.2207082. Online ahead of print.

ABSTRACT

AbstractEvidence suggests that preterm birth is associated with an impaired physical fitness later in life, but whether these effects are already visible since early childhood remains unknown. We aimed to compare the physical fitness of preterm preschoolers with that of children born at term. Children aged three to six years and born preterm (<35 weeks) were recruited from a Neonatal Intensive Care Unit, and children born at term (>37 weeks) were included as controls. A variety of physical fitness indicators (strength, cardiorespiratory fitness, agility, flexibility, and balance) were assessed with the PREFIT battery and the adapted sit and reach test. Physical activity levels were measured through the PrePAQ questionnaire. A total of 98 preterm children (gestational age 32.4 ± 2.3 weeks, age 5.1 ± 0.8 years) and 74 controls (gestational age 39.9 ± 1.0 weeks, age 4.8 ± 0.9 years) were analyzed. Despite no significant differences in physical activity levels (p > 0.05), preterm children showed an overall poorer physical fitness compared to controls. Specifically, preterm children had an impaired handgrip strength (-13.95%, p < 0.001), lower-limb muscle strength (-12.67%, p = 0.003), agility (-14.9%, p = 0.001), cardiorespiratory fitness (-12.73% p = 0.005) and flexibility (-17.04%, p = 0.001) compared to controls. An inverse dose-response association was observed between the level of prematurity and physical fitness, with very preterm children (gestational age ≤32 weeks) presenting the poorest fitness levels. In summary, prematurity seems to impair physical fitness since early childhood, which might support the need for promoting preventive strategies (e.g., fitness monitoring and applying exercise interventions).

PMID:37093663 | DOI:10.1080/17461391.2023.2207082

Microbiol Spectr. 2023 Apr 24:e0488122. doi: 10.1128/spectrum.04881-22. Online ahead of print.

ABSTRACT

The increased transmissibility of SARS-CoV-2 variants of concern (VOCs) has raised questions regarding the environmental stability of these viruses. Although a prolonged survival time has been reported for SARS-CoV-2, how long new variants can persist on contaminated surfaces and how environmental factors affect the persistence time are not fully characterized. The present study provides a comprehensive assessment of the stability of Omicron variants BA.1 and BA.5, which are currently circulating strains, on the surfaces of widely used transport packaging materials. By monitoring viable virus detection over a 7-day period under different environmental conditions, it was found that the environmental stability of SARS-CoV-2 Omicron variants depended heavily on the surface type, temperature, and virus concentration. In addition, virus nucleic acid exhibited high stability on the material surface independent of whether viable virus was detected. These findings provide useful information for logistics practitioners and the general public to appropriately deal with transport items under different conditions to minimize the risk of epidemic transmission. IMPORTANCE This study shows the environmental stability of SARS-CoV-2 Variants Omicron BA.1 and BA.5 on surfaces of widely used transport packaging materials. The findings demonstrate that the environmental stability of the SARS-CoV-2 Omicron variants varies based on material type. The viability of SARS-CoV-2 on material surfaces depends heavily on temperature and viral titer. Low temperatures and high viral titers promote virus survival. Moreover, in contrast to virus viability, virus nucleic acid exhibits high stability on the surfaces of widely used materials, making the detection of virus nucleic acid unsuitable for evaluating the risk of epidemic transmission.

PMID:37092817 | DOI:10.1128/spectrum.04881-22

J Proteome Res. 2023 Apr 24. doi: 10.1021/acs.jproteome.3c00178. Online ahead of print.

ABSTRACT

A recent paper in Science Advances by Sun et al. claims that intra-chloroplast proteins in the model plant Arabidopsis can be polyubiquitinated and then extracted into the cytosol for subsequent degradation by the proteasome. Most of this conclusion hinges on several sets of mass spectrometry (MS) data. If the proposed results and conclusion are true, this would be a major change in the proteolysis/proteostasis field, breaking the long-standing dogma that there are no polyubiquitination mechanisms within chloroplast organelles (nor in mitochondria). Given its importance, we reanalyzed their raw MS data using both open and closed sequence database searches and encountered many issues not only with the results but also discrepancies between stated methods (e.g., use of alkylating agent iodoacetamide (IAA)) and observed mass modifications. Although there is likely enrichment of ubiquitination signatures in a subset of the data (probably from ubiquitination in the cytosol), we show that runaway alkylation with IAA caused extensive artifactual modifications of N termini and lysines to the point that a large fraction of the desired ubiquitination signatures is indistinguishable from artifactual acetamide signatures, and thus, no intra-chloroplast polyubiquitination conclusions can be drawn from these data. We provide recommendations on how to avoid such perils in future work.

PMID:37092802 | DOI:10.1021/acs.jproteome.3c00178

Epigenetics. 2023 Dec;18(1):2201517. doi: 10.1080/15592294.2023.2201517.

ABSTRACT

Age-associated changes in DNA methylation have been characterized across various animals, but not yet in amphibians, which are of particular interest because they include widely studied model organisms. In this study, we present clear evidence that the aquatic vertebrate species Xenopus tropicalis displays patterns of age-associated changes in DNA methylation. We have generated whole-genome bisulfite sequencing (WGBS) profiles from skin samples of nine frogs representing young, mature, and old adults and characterized the gene- and chromosome-scale DNA methylation changes with age. Many of the methylation features and changes we observe are consistent with what is known in mammalian species, suggesting that the mechanism of age-related changes is conserved. Moreover, we selected a few thousand age-associated CpG sites to build an assay based on targeted DNA methylation analysis (TBSseq) to expand our findings in future studies involving larger cohorts of individuals. Preliminary results of a pilot TBSeq experiment recapitulate the findings obtained with WGBS setting the basis for the development of an epigenetic clock assay. The results of this study will allow us to leverage the unique resources available for Xenopus to study how DNA methylation relates to other hallmarks of ageing.

PMID:37092296 | DOI:10.1080/15592294.2023.2201517

EMBO J. 2023 Apr 24:e112869. doi: 10.15252/embj.2022112869. Online ahead of print.

ABSTRACT

Translation initiates when the eIF4F complex binds the 5' mRNA cap, followed by 5' untranslated region scanning for the start codon by scanning ribosomes. Here, we demonstrate that the ASC-1 complex (ASCC), which was previously shown to promote the dissociation of colliding 80S ribosomes, associates with scanning ribosomes to regulate translation initiation. Selective translation complex profiling (TCP-seq) analysis revealed that ASCC3, a helicase domain-containing subunit of ASCC, localizes predominantly to the 5' untranslated region of mRNAs. Ribo-seq, TCP-seq, and luciferase reporter analyses showed that ASCC3 knockdown impairs 43S preinitiation complex loading and scanning dynamics, thereby reducing translation efficiency. Whereas eIF4A, an RNA helicase in the eIF4F complex, is important for global translation, ASCC was found to regulate the scanning process for a specific subset of transcripts. Our results have thus revealed that ASCC is required not only for dissociation of colliding 80S ribosomes but also for efficient translation initiation by scanning ribosomes at a subset of transcripts.

PMID:37092320 | DOI:10.15252/embj.2022112869

Chembiochem. 2023 Apr 23:e202300141. doi: 10.1002/cbic.202300141. Online ahead of print.

ABSTRACT

Focal adhesion kinase (FAK) is an attractive drug target due to its overexpression in cancer. FAK functions as a non-receptor tyrosine kinase and scaffolding protein, coordinating several downstream signaling effectors and cellular processes. While drug discovery efforts have largely focused on targeting FAK kinase activity, FAK inhibitors have failed to show efficacy as single agents in clinical trials. Here, using structure-guided design, we report the development of a selective FAK inhibitor (BSJ-04-175) and degrader (BSJ-04-146) to evaluate the consequences and advantages of abolishing all FAK activity in cancer models. BSJ-04-146 achieves rapid and potent FAK degradation with high proteome-wide specificity in cancer cells and induces durable degradation in mice. Compared to kinase inhibition, targeted degradation of FAK exhibits pronounced improved activity on downstream signaling and cancer cell viability and migration. Together, BSJ-04-175 and BSJ-04-146 are valuable chemical tools to dissect the specific consequences of targeting FAK through small molecule inhibition or degradation.

PMID:37088717 | DOI:10.1002/cbic.202300141

Life Sci Space Res (Amst). 2023 May;37:25-38. doi: 10.1016/j.lssr.2023.02.002. Epub 2023 Feb 17.

ABSTRACT

During spaceflight, multiple unique hazardous factors, particularly microgravity and space radiation, can induce different types of DNA damage, which pose a constant threat to genomic integrity and stability of living organisms. Although organisms have evolved different kinds of conserved DNA repair pathways to eliminate this DNA damage on Earth, the impact of space microgravity on the expressions of these DNA repair genes and their regulatory miRNAs has not been fully explored. In this study, we integrated all existing datasets, including both transcriptional and miRNA microarrays in wild-type (WT) Caenorhabditis elegans that were exposed to the treatments of spaceflight (SF), spaceflight control with a 1g centrifugal device (SC), and ground control (GC) in three space experiments with the periods of 4, 8 and 16.5 days. The results of principal component analysis showed the gene expression patterns for five major DNA repair pathways (i.e., non-homologous end joining (NHEJ), homologous recombination (HR), mismatch repair (MMR), nucleotide excision repair (NER), and base excision repair (BER)) were well separated and clustered between SF/GC and SC/GC treatments after three spaceflights. In the 16.5-days space experiment, we also selected the datasets of dys-1 mutant and ced-1 mutant of C. elegans, which respectively presented microgravity-insensitivity and radiosensitivity. Compared to the WT C. elegans flown in the 16.5-days spaceflight, the separation distances between SF and SC samples were significantly reduced in the dys-1 mutant, while greatly enhanced in the ced-1 mutant for five DNA repair pathways. By comparing the results of differential expression analysis in SF/GC versus SC/GC samples, we found the DNA repair genes annotated in the pathways of BER and NER were prominently down-regulated under microgravity during both the 4- and 8-days spaceflights. While, under microgravity, the genes annotated in MMR were dominatingly up-regulated during the 4-days spaceflight, and those annotated in HR were mainly up-regulated during the 8-days spaceflight. And, most of the DNA repair genes annotated in the pathways of BER, NER, MMR, and HR were up-regulated under microgravity during the 16.5-days spaceflight. Using miRNA-mRNA integrated analysis, we determined the regulatory networks of differentially expressed DNA repair genes and their regulatory miRNAs in WT C. elegans after three spaceflights. Compared to GC conditions, the differentially expressed miRNAs were analyzed under SF and SC treatments of three spaceflights, and some altered miRNAs that responded to SF and SC could regulate the expressions of corresponding DNA repair genes annotated in different DNA repair pathways. In summary, these findings indicate that microgravity can significantly alter the expression patterns of DNA repair genes and their regulatory miRNAs in space-flown C. elegans. The alterations of the expressions of DNA repair genes and the dominating DNA repair pathways under microgravity are possibly related to the spaceflight period. In addition, the key miRNAs are identified as the post-transcriptional regulators to regulate the expressions of various DNA repair genes under microgravity. These altered miRNAs that responded to microgravity can be implicated in regulating diverse DNA repair processes in space-flown C. elegans.

PMID:37087176 | DOI:10.1016/j.lssr.2023.02.002

Naunyn Schmiedebergs Arch Pharmacol. 2023 Apr 22. doi: 10.1007/s00210-023-02461-1. Online ahead of print.

ABSTRACT

Skin cutaneous melanoma (SKCM) has a low early detection rate and a high mortality rate. There are many problems such as side effects and drug resistance in existing therapeutic drugs. Current studies have confirmed that SKCM pathogenesis-related genes promote the invasion and metastasis of cutaneous melanoma, but their roles in the tumor microenvironment (TME) remain unclear. Network pharmacology provides new opportunities for drug repurposing and repositioning, and is a fast, safe, and inexpensive drug discovery method to find new drugs for the treatment of SKCM. In this study, based on 3 databases (KEGG, OMIM, and Genotype) to obtain SKCM-related genes, and TCGA SKCM dataset, SKCM differential genes in GSE3189 and GSE46517 were intersected to identify SKCM pathogenesis-related differential genes, and the differential genes were immune infiltration and analysis, For survival analysis, a prognostic nomogram risk model was constructed based on the results of multivariate Cox regression analysis for risk stratification and prognosis prediction, then focused on the differential expression of ZC3H12A and its effect on TME. Finally, the protein interaction network method was used to quantify the similarity between 684 drug targets and skin melanoma, and to screen out drugs similar to skin melanoma. Based on 3 databases of KEGG, OMIM, and Genotype, 294 SKCM-related genes and 18 SKCM pathogenesis-related differential genes were obtained, and 18 SKCM pathogenesis-related differential genes were significantly correlated with TME. The constructed prognostic nomogram risk model predicted performance better and provided valuable information for immunotherapy. Multivariate Cox regression analysis and K-M analysis showed that ZC3H12A was a differentially expressed gene affecting the prognosis of SKCM and promoted the infiltration of anti-tumor immune cells CD8 + T cells, B cells, and DC cells. Based on the analysis of the protein interaction network method, 43 drugs were found to have high potential in the treatment of SKCM, and the literature search of these 43 drugs was carried out, and 21 drugs were found to have experimental verification for the treatment of SKCM. Taken together, the differential genes associated with the pathogenesis of SKCM have important roles in the tumor immune microenvironment, clinicopathological features, and prognosis, especially ZC3H12A has a potential role in identifying early SKCM patients. At the same time, it provides a new strategy for the drug development of SKCM and provides a basis for the reuse of SKCM drugs.

PMID:37086280 | DOI:10.1007/s00210-023-02461-1

Wiley Interdiscip Rev RNA. 2023 Apr 22:e1791. doi: 10.1002/wrna.1791. Online ahead of print.

ABSTRACT

Gastrointestinal (GI) cancer includes many cancer types, such as esophageal, liver, gastric, pancreatic, and colorectal cancer. As the cornerstone of personalized medicine for GI cancer, liquid biopsy based on noninvasive biomarkers provides promising opportunities for early diagnosis and dynamic treatment management. Recently, a growing number of studies have demonstrated the potential of cell-free RNA (cfRNA) as a new type of noninvasive biomarker in body fluids, such as blood, saliva, and urine. Meanwhile, transcriptomes based on high-throughput RNA detection technologies keep discovering new cfRNA biomarkers. In this review, we introduce the origins and applications of cfRNA, describe its detection and qualification methods in liquid biopsy, and summarize a comprehensive list of cfRNA biomarkers in different GI cancer types. Moreover, we also discuss perspective studies of cfRNA to overcome its current limitations in clinical applications. This article is categorized under: RNA in Disease and Development > RNA in Disease.

PMID:37086051 | DOI:10.1002/wrna.1791

Eur J Immunol. 2023 Apr 22:e2250162. doi: 10.1002/eji.202250162. Online ahead of print.

ABSTRACT

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. Disease etiology remains largely unknown, however a key role in JIA pathogenesis is surely mediated by T cells. T lymphocytes activity is controlled via signals, known as immune-checkpoints (IC). Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of IC in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at single cell level the feature of T cells in JIA chronic inflammation both at transcriptome level via single-cell RNA sequencing and at protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4+ and CD8+ T cells, those characterized by PD-1 expression were clonally expanded Trm-like cells and displayed the highest pro-inflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD-1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T regardless of their cytokine production profile. This article is protected by copyright. All rights reserved.

PMID:37086046 | DOI:10.1002/eji.202250162

STAR Protoc. 2023 Apr 21;4(2):102244. doi: 10.1016/j.xpro.2023.102244. Online ahead of print.

ABSTRACT

Variations in N-glycosylation, which is crucial to glycoprotein functions, impact many diseases and the safety and efficacy of biotherapeutic drugs. Here, we present a protocol for using GlycoMME (Glycosylation Markov Model Evaluator) to study N-glycosylation biosynthesis from glycomics data. We describe steps for annotating glycomics data and quantifying perturbations to N-glycan biosynthesis with interpretable models. We then detail procedures to predict the impact of mutations in disease or potential glycoengineering strategies in drug development. For complete details on the use and execution of this protocol, please refer to Liang et al. (2020).1.

PMID:37086409 | DOI:10.1016/j.xpro.2023.102244