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The epithelial-mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they coregulate a set of cassette exon events, with the majority showing discordant splicing regulation. Discordant splicing events regulated by hnRNPM show a positive correlation with splicing during EMT; however, concordant events do not, indicating the role of hnRNPM in regulating alternative splicing during EMT is more complex than previously understood. Motif enrichment analysis near hnRNPM-ESRP1 coregulated exons identifies guanine-uridine rich motifs downstream from hnRNPM-repressed and ESRP1-enhanced exons, supporting a general model of competitive binding to these cis-elements to antagonize alternative splicing. The set of coregulated exons are enriched in genes associated with cell migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of coregulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtyping. This study identifies complex modes of interaction between hnRNPM and ESRP1 in regulation of splicing in disease-relevant contexts.

Background: Mental health disorders are the leading cause of disability in youth globally. China has the world's second largest youth population with growing urban-rural inequalities. Guizhou is China's poorest province, and its rural youth mental health is seldom studied. Aims: (1) to examine the prevalence and gender differences in drug use, depressive symptoms, social support, and externalizing behaviors in adolescents from an underserved rural Guizhou community; (2) to compare these measures between our sample and an urban Beijing sample. Subject and methods: A cross-sectional study was conducted among children 12–14 years-old from rural Guizhou using the Global School-based Student Health Survey. Prevalence of 19 mental health risk factors and behaviors were examined and compared to those from a public urban Beijing sample. Associations of mental health variables with gender and rural residence were examined using multivariable logistic regression models in a combined analysis. Results: Mental health risk factors and behaviors were more prevalent in our rural sample for 9/19 surveyed items. Rural adolescent in our sample had higher risks in experiencing troubles due to drinking, loneliness, insomnia, hopelessness, poor social support and poor parental understanding, injuries, and absenteeism. Girls compared to boys had lower risks of excessive drinking, smoking, fighting, injures and being bullied. Conclusion: Rural adolescents from an underserved Guizhou community were significantly more vulnerable to mental health risk factors and behaviors compared to urban Beijing peers and gender mattered. Research on context- and gender-informed interventions is needed.

Abstract Background Women with depression disorder outnumber men, and health care and social service providers are mostly female. Drawing on conservation of resources (COR) theory, this study aims to examine the association between role conflicts and depression among health care and social service providers, and further investigate the mediating effect of burnout, as well as the moderating effect of marital status and motherhood. Methods The data come from the baseline of the ‘China Social Work Longitudinal Study’ conducted in 2019, which contains 1,219 female social workers who reported work-family conflict. The five items of the scale in our model were extracted from the existing literature to ensure the construct validity of potential variables, and confirmatory factor analyses (CFAs) were also conducted to ensure the validity and reliability of the scale. Descriptive analyses and correlation analyses were performed with SPSS 24, while the path analysis was conducted using Amos 24. The moderating effects of marital status and motherhood were further tested using multiple-group analyses. Results Female health care and social service providers experienced a high level of depression. Work-to-family conflict (WFC), family-to-work conflict (FWC), and organizational role conflict (ORC) were significantly and positively associated with female social workers’ depression. Exhaustion and cynicism fully mediated the effects of ORC on depression and partially mediated the effects of WFC on depression. In addition, FWC had only a direct effect on depression. A multiple-group analysis further indicated that both marital status and motherhood status may have played a moderating role in the conflict-burnout-depression link and that being unmarried and having no child were risk factors for depression in female health care and social service providers. Conclusions Marriage and motherhood have both negative and positive effects on the depression of female health care and social service providers. This suggests that marriage and motherhood may act as a form of “family clientelism” for female health care and social service providers who marry and have children.

Optimizing lanthanide catalyst performance with organic ligands often encounters significant challenges, including susceptibility to water or oxygen and complex synthesis pathways. To address these issues, our research focuses on developing inorganic lanthanide clusters with enhanced stability and functionality. In this study, we introduce the [Sm6O(OH)8(H2O)24]I8(H2O)8 cluster (Sm-OC) as a sustainable and efficient catalyst for the aerobic oxidation of thiols under heating conditions. The Sm-OC catalyst demonstrated remarkable stability, outstanding recyclability, and excellent chemoselectivity across a diverse range of functional groups in 38 different tests. Notably, it enables efficient unsymmetrical disulfide synthesis and prevents the formation of over-oxidized by-products, highlighting its superior performance. This Sm-OC catalyst provides a practical and robust tool for the precise construction of versatile disulfides, thus establishing a template for the broader use of lanthanide clusters in organic synthesis. [ABSTRACT FROM AUTHOR]

A sustainable bioeconomy in agricultural and agro-industrial production must inevitably involve the sustainable use of agricultural residues through zero-waste processes. Corn cob is considered crucial agricultural waste as 278 and 293 million tons were produced worldwide in 2022 and 2023, respectively. Corn cob hydrolysates, which are abundant in xylose and glucose, could be efficiently utilized for xylitol and ethanol production through the cultivation of recycling the yeast strain Candida magnoliae TISTR 5664 in the single-stage and sequential-stage co-production of these products. The statistically significant maxima (p ≤ 0.05) ethanol concentrations were improved by 7.8% (49.9–51.7 g/L or 91.3–95.6% of the theoretical) from the single stage of ethanol production employing recycled cells and 9.9% (50.9–54.1 g/L or 77.3–83.9% of the theoretical) from the second step of sequential-stage co-production using recycled cells without xylitol accumulation. Conversely, the single-stage xylitol production utilizing recycled cells under microaerobic conditions resulted in a statistically significant lower (p ≤ 0.05) xylitol concentration by two folds relative to the control, while ethanol concentration was elevated by almost double. The statistically significant maximum (p ≤ 0.05) xylitol was achieved at 25.9 g/L (58.6% of the theoretical) when sequential-stage co-production was initiated in the first step with fresh inoculum only and not recycled cells. The sequential-stage co-production of xylitol and ethanol presented the potential for statistically significant improvement (p ≤ 0.05) of both xylitol and ethanol production processes. [ABSTRACT FROM AUTHOR]

Conjugated polymers have attracted significant attention in the field of photocatalysis due to their exceptional properties, including versatile optimization, cost-effectiveness, and structure stability. Herein, two conjugated porous polymers, PhIN-CPP and ThIN-CPP, based on triazines, were meticulously designed and successfully synthesized using benzene and thiophene as building blocks. Based on UV diffuse reflection spectra, the photonic band gaps of PhIN-CPP and ThIN-CPP were calculated as 2.05 eV and 1.79 eV. The PhIN-CPP exhibited a high hydrogen evolution rate (HER) of 5359.92 μmol·g−1·h−1, which is 10 times higher than that of Thin-CPP (538.49 μmol·g−1·h−1). The remarkable disparity in the photocatalytic performance can be primarily ascribed to alterations in the band structure of the polymers, which includes its more stable benzene units, fluffier structure, larger specific surface area, most pronounced absorption occurring in the visible region and highly extended conjugation with a high density of electrons. The ΔEST values for PhIN-CPP and ThIN-CPP were calculated as 0.79 eV and 0.80 eV, respectively, based on DFT and TD-DFT calculations, which revealed that the incorporation of triazine units in the as-prepared CMPs could enhance the charge transfer via S1 ↔ T1 and was beneficial to the photocatalytic decomposition of H2O. This study presents a novel concept for developing a hybrid system for preparation of H2 by photocatalysis with effectiveness, sustainability, and economy. [ABSTRACT FROM AUTHOR]

Mounting epidemiology studies have reported the potential associations between ambient air pollution exposure and colorectal cancer (CRC). However, the genetic association between ambient air pollution and CRC remains unclear. Using the Genome-wide association study (GWAS) data from UK biobank, we explored the genetic association of CRC (5,657 cases and 372,016 controls) with four ambient air pollutants (PM2.5, PM10, NO2, NOx; n = 423,796 to 456,380) under the framework of Mendelian randomization (MR). Our results revealed a significant association between long-term NO2 exposure (per 10 µg/m3) and increased CRC risk, with an odds ratio (OR) of 1.02 (95% confidence interval [CI]: 1.00–1.03), while no statistical association was found between CRC risk and the other air pollutants. Sensitivity analysis confirmed the robustness of the results. It is imperative to consider the impact of air pollution, particularly NO2, in mitigating the risk of CRC. [ABSTRACT FROM AUTHOR]

Polyether amines are versatile compounds characterized by a flexible structure, consisting of polyoxypropylene and polyoxyethylene as the backbone, with amine groups at each end. They have widespread applications in various industrial processes and daily life. Despite their versatility, the utilization of polyether amines as base catalysts is rare. In this study, one kind of three-arm polyether amine 1 was employed as an environmentally friendly, cost-effective catalyst for the aerobic oxidation of thiophenols, leading to the synthesis of disulfides. The oxidative coupling of thiols serves as a fundamental pathway for the production of disulfides, which are vital in both chemical and biological processes. In contrast to known methods for thiol oxidation, this polyether amine-based catalytic process eliminates the need for expensive stoichiometric oxidants and minimizes the formation of over-oxidized by-products. Using a mere 0.5 mol % of the polyether amine 1 as the catalyst, a remarkable > 96% yield was achieved for all 16 tested substrates, encompassing a diverse range of functional groups, under the catalytic aerobic oxidation conditions. Furthermore, it is noteworthy that over 90% of the polyether amine catalyst can be efficiently recovered for reuse without loss of activity, making this a sustainable and cost-effective catalytic approach. [ABSTRACT FROM AUTHOR]

[Objective] The Prydz Bay belt in East Antarctica recorded two significant tectono-thermal events, the Grenvillian event and the Pan-African event, which are considered to be closely related to the evolution of the Rodinia and Gondwana supercontinents. However, the geological history and the tectonic nature of the two events remain controversial. [Methods] Mineralogical and petrological analyses, phase equilibria modelling and zircon geochronology are combined to investigate the spinel-cordierite granulite from the Mirror Peninsula in order to better understand the tectono-thermal history of the Prydz Bay belt. [Results] The spinel-cordierite granulite contains different stages of mineral assemblages. The major stage of mineral assemblage involves cordierite, spinel, biotite, sillimanite, K-feldspar and minor garnet and ilmenite. The later stage of mineral assemblage is indicated by the emergence of magnetite as the increasing volumes of biotite and cordierite. Minor garnet and corundum are locally preserved, implying the mineral reaction 'g+cor→sp+sill' and more garnet and corundum in the peak stage. The garnet grains consist of 70%-72% almandine, 20%-22% pyrope, -4% grossularite and -4% spessartine. The XFe (Fe2+/(Fe2++Mg2+)) of representative garnet grains ranges from 0.77 to 0.80. The spinel exhibits an XFe range from 0.80 to 0.86. Different cordierite grains have similar compositions with Al of 3.89-3.93 a.p.f.u (atoms per formula unit) and XFe of 0.32-0.36. Biotite has high TiO2 (4.13%-5.23%) and Ti (0.23-0.30 a.p.f.u). K-feldspar grains consist of 78%-85% orthoclase, 15%-23% albite and -1% anorthite. Based on the mineral compositions and phase equilibrium modelling, the pressure-temperature (P-T) conditions of the major stage of mineral assemblage are constrained to 870-910 °C and 0.64-0.69 GPa, followed by later retrogression to 810-820°C and 0.49-0.53 GPa. A peak stage with higher P-T conditions (T>910 °C, P>0.69 GPa) can be inferred based on the relict peak minerals and characteristic mineral compositions (e.g. Ti in biotite). Zircon grains commonly show core-mantle-rim structures in cathodoluminescence (CL) images. The LA-ICP-MS zircon U-Pb dating analyses reveal a wide age range from 613±7 Ma to 877±9 Ma (except a maximum of 916±11 Ma) for the cores. The zircon bright rims yield a weighted mean age of 526±8 Ma with a wide range of Th/U (0.06-1.23), mostly higher than 0.1. [Conclusion] Based on the results, a few conclusions can be drawn: (1) The spinel-cordierite granulite recorded medium-low pressure/high-ultrahigh temperature metamorphism with a clockwise P-T evolution path and high dT/dP. (2) The results of zircon geochronological analysis show that zircon cores mainly record U-Pb ages in the range of 800--600 Ma, younger than typical ages of Grenvillian events, which may reflect younger inherited zircon cores or significant isotopic resetting. (3) The age of -530 Ma of zircon rims is interpreted to represent the post-peak cooling stage of the Pan-African tectono-thermal event. [Significance] This study examined the P-T conditions and the zircon ages of the spinel-cordierite granulite in the Mirror Peninsula. In combination with previous results, the P-T-t path constructed for the spinel-cordierite granulite provides new constraints on the evolution of the Prydz Bay belt during the Pan-African period. [ABSTRACT FROM AUTHOR]

MotivationThe length of the 3' untranslated region (3' UTR) of an mRNA is essential for many biological activities such as mRNA stability, sub-cellular localization, protein translation, protein binding and translation efficiency. Moreover, correlation between diseases and the shortening (or lengthening) of 3' UTRs has been reported in the literature. This length is largely determined by the polyadenylation cleavage site in the mRNA. As alternative polyadenylation (APA) sites are common in mammalian genes, several tools have been published recently for detecting APA sites from RNA-Seq data or performing shortening/lengthening analysis. These tools consider either up to only two APA sites in a gene or only APA sites that occur in the last exon of a gene, although a gene may generally have more than two APA sites and an APA site may sometimes occur before the last exon. Furthermore, the tools are unable to integrate the analysis of shortening/lengthening events with APA site detection.ResultsWe propose a new tool, called TAPAS, for detecting novel APA sites from RNA-Seq data. It can deal with more than two APA sites in a gene as well as APA sites that occur before the last exon. The tool is based on an existing method for finding change points in time series data, but some filtration techniques are also adopted to remove change points that are likely false APA sites. It is then extended to identify APA sites that are expressed differently between two biological samples and genes that contain 3' UTRs with shortening/lengthening events. Our extensive experiments on simulated and real RNA-Seq data demonstrate that TAPAS outperforms the existing tools for APA site detection or shortening/lengthening analysis significantly.Availability and implementationhttps://github.com/arefeen/TAPAS.Supplementary informationSupplementary data are available at Bioinformatics online.

BackgroundIt was recently discovered that abundant and stable extracellular RNA (exRNA) species exist in bodily fluids. Saliva is an emerging biofluid for biomarker development for noninvasive detection and screening of local and systemic diseases. Use of RNA-Sequencing (RNA-Seq) to profile exRNA is rapidly growing; however, no single preparation and analysis protocol can be used for all biofluids. Specifically, RNA-Seq of saliva is particularly challenging owing to high abundance of bacterial contents and low abundance of salivary exRNA. Given the laborious procedures needed for RNA-Seq library construction, sequencing, data storage, and data analysis, saliva-specific and optimized protocols are essential.MethodsWe compared different RNA isolation methods and library construction kits for long and small RNA sequencing. The role of ribosomal RNA (rRNA) depletion also was evaluated.ResultsThe miRNeasy Micro Kit (Qiagen) showed the highest total RNA yield (70.8 ng/mL cell-free saliva) and best small RNA recovery, and the NEBNext library preparation kits resulted in the highest number of detected human genes [5649-6813 at 1 reads per kilobase RNA per million mapped (RPKM)] and small RNAs [482-696 microRNAs (miRNAs) and 190-214 other small RNAs]. The proportion of human RNA-Seq reads was much higher in rRNA-depleted saliva samples (41%) than in samples without rRNA depletion (14%). In addition, the transfer RNA (tRNA)-derived RNA fragments (tRFs), a novel class of small RNAs, were highly abundant in human saliva, specifically tRF-4 (4%) and tRF-5 (15.25%).ConclusionsOur results may help in selection of the best adapted methods of RNA isolation and small and long RNA library constructions for salivary exRNA studies.

In eukaryotes, nascent RNA transcripts undergo an intricate series of RNA processing steps to achieve mRNA maturation. RNA editing and alternative splicing are two major RNA processing steps that can introduce significant modifications to the final gene products. By tackling these processes in isolation, recent studies have enabled substantial progress in understanding their global RNA targets and regulatory pathways. However, the interplay between individual steps of RNA processing, an essential aspect of gene regulation, remains poorly understood. By sequencing the RNA of different subcellular fractions, we examined the timing of adenosine-to-inosine (A-to-I) RNA editing and its impact on alternative splicing. We observed that >95% A-to-I RNA editing events occurred in the chromatin-associated RNA prior to polyadenylation. We report about 500 editing sites in the 3' acceptor sequences that can alter splicing of the associated exons. These exons are highly conserved during evolution and reside in genes with important cellular function. Furthermore, we identified a second class of exons whose splicing is likely modulated by RNA secondary structures that are recognized by the RNA editing machinery. The genome-wide analyses, supported by experimental validations, revealed remarkable interplay between RNA editing and splicing and expanded the repertoire of functional RNA editing sites.

To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal-specific gene expression changes, including induction of a senescence-associated secretory phenotype (SASP) program. Patient-derived neurons made without MECP2 showed signs of stress, including induction of P53, and senescence. The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendritic complexity. The induction of P53 targets was also detectable in analyses of human Rett patient brain, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder.

Human speech is one of the few examples of vocal learning among mammals yet ~half of avian species exhibit this ability. Its neurogenetic basis is largely unknown beyond a shared requirement for FoxP2 in both humans and zebra finches. We manipulated FoxP2 isoforms in Area X, a song-specific region of the avian striatopallidum analogous to human anterior striatum, during a critical period for song development. We delineate, for the first time, unique contributions of each isoform to vocal learning. Weighted gene coexpression network analysis of RNA-seq data revealed gene modules correlated to singing, learning, or vocal variability. Coexpression related to singing was found in juvenile and adult Area X whereas coexpression correlated to learning was unique to juveniles. The confluence of learning and singing coexpression in juvenile Area X may underscore molecular processes that drive vocal learning in young zebra finches and, by analogy, humans.

MotivationAnalysis of RNA sequencing (RNA-Seq) data in human saliva is challenging. Lack of standardization and unification of the bioinformatic procedures undermines saliva's diagnostic potential. Thus, it motivated us to perform this study.ResultsWe applied principal pipelines for bioinformatic analysis of small RNA-Seq data of saliva of 98 healthy Korean volunteers including either direct or indirect mapping of the reads to the human genome using Bowtie1. Analysis of alignments to exogenous genomes by another pipeline revealed that almost all of the reads map to bacterial genomes. Thus, salivary exRNA has fundamental properties that warrant the design of unique additional steps while performing the bioinformatic analysis. Our pipelines can serve as potential guidelines for processing of RNA-Seq data of human saliva.Availability and implementationProcessing and analysis results of the experimental data generated by the exceRpt (v4.6.3) small RNA-seq pipeline (github.gersteinlab.org/exceRpt) are available from exRNA atlas (exrna-atlas.org). Alignment to exogenous genomes and their quantification results were used in this paper for the analyses of small RNAs of exogenous origin.Contactdtww@ucla.edu.

microRNAs (miRNAs) are small non-coding RNAs that play critical roles in gene regulation. The presence of miRNAs in extracellular biofluids is increasingly recognized. However, most previous characterization of extracellular miRNAs focused on their overall expression levels. Alternative sequence isoforms and modifications of miRNAs were rarely considered in the extracellular space. Here, we developed a highly accurate bioinformatic method, called miNTA, to identify 3’ non-templated additions (NTAs) of miRNAs using small RNA-sequencing data. Using miNTA, we conducted an in-depth analysis of miRNA 3’ NTA profiles in 1047 extracellular RNA-sequencing data sets of 4 types of biofluids. This analysis identified hundreds of miRNAs with 3’ uridylation or adenylation, with the former being more prevalent. Among these miRNAs, up to 53% (22%) had an average 3’ uridylation (adenylation) level of at least 10% in a specific biofluid. Strikingly, we found that 3’ uridylation levels enabled segregation of different types of biofluids, more effectively than overall miRNA expression levels. This observation suggests that 3’ NTA levels possess fluid-specific information relatively robust to batch effects. In addition, we observed that extracellular miRNAs with 3’ uridylations are enriched in processes related to angiogenesis, apoptosis, and inflammatory response, and this type of modification may stabilize base-pairing between miRNAs and their target genes. Together, our study provides a comprehensive landscape of miRNA NTAs in human biofluids, which paves way for further biomarker discoveries. The insights generated in our work built a foundation for future functional, mechanistic, and translational discoveries.

Immobilization is considered as a promising strategy toward the practical applications of powdered adsorbent. Herein, three dimensional (3D) printing cylindrical capsules with cross-linked PVA hydrogels membrane in encapsulate Chlorella pyrenoidosa (Cp) were utilized for removal of lead ions. The chemical compositions, hydrogels performance and morphologies of the membranes were determined by Fourier transformed infrared spectroscopy (FTIR), cross-linking degree, swelling degree, membrane flux and scanning electron microscopy (SEM). It is found that PVA cross-linking structure is successfully synthesized on the surface of capsule body and cap due to the presence of PVA in the filament. The lead ions adsorption capacity related to initial concentration of 50 mg/L in 48 h is reached 75.61%, revealing a good removal ability. The self-floating 3D printed capsules device also shows an excellent recovering property. After 7 runs of adsorption experiment, the lead ions adsorption ratio remains 78.56%, which will bring a broad prospect in wastewater treatment, chemical slow release along with sample preparation and separation.

Background: Hearing loss (HL) is the most common form of sensory disorder in humans. Molecular diagnosis of HL is important for genetic counseling for the affected individuals and their families.Methods: To identify potential genetic causes, we performed whole-exome sequencing and related biomedical informatics for 351 non-syndromic HL patients and their family members.Results: In the present study, we report the identification of four compound heterozygous variants in the CDH23 gene from four affected families, including four novel variants (c.995C>A, p.T332K; c.2159G>A, p.R720Q; c.5534A>G, p.N1845S, and c.7055-1G>C) and two frequently reported variants (c.719C>T, p.P240L and c.4762C>T, p.R1588W).Conclusion: Our findings significantly expanded the mutation spectrum of CDH23-associated autosomal recessive hearing loss.

BackgroundIn the past decade, patient-accessible electronic health record (PAEHR) systems have emerged as an important tool for health management both at the hospital level and individual level. However, little is known about the effects of PAEHR portals on the survivorship of patients with chronic health conditions (eg, cancer). ObjectiveThis study aims to investigate the effects of the use of PAEHR portals on cancer survivors’ health outcomes and to examine the mediation pathways through patient-centered communication (PCC) and health self-efficacy. MethodsData for this study were derived from the Health Information National Trends Survey (HINTS 5, Cycle 4) collected from February 2020 to June 2020. This study only involved respondents who reported having been diagnosed with cancer (N=626). Descriptive analyses were performed, and the mediation models were tested using Model 6 from the SPSS macro PROCESS. Statistically significant relationships among PAEHR portal use, PCC, health self-efficacy, and physical and psychological health were examined using bootstrapping procedures. In this study, we referred to the regression coefficients generated by min-max normalization as percentage coefficients (bp). The 95% bootstrapped CIs were used with 10,000 resamplings. ResultsNo positive direct associations between PAEHR portal use and cancer survivors’ health outcomes were found. The results supported the indirect relationship between PAEHR portal use and cancer survivors’ psychological health via (1) PCC (bp=0.029; β=.023, 95% CI .009-.054), and (2) PCC and health self-efficacy in sequence (bp=0.006; β=.005, 95% CI .002-.014). Besides, the indirect association between PAEHR portal use and cancer survivors’ physical health (bp=0.006; β=.004, 95% CI .002-.018) via sequential mediators of PCC and health self-efficacy was also statistically acknowledged. ConclusionsThis study offers empirical evidence about the significant role of PAEHR portals in delivering PCC, improving health self-efficacy, and ultimately contributing to cancer survivors’ physical and psychological health.

Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risk of progression to acute myeloid leukemia (AML). The mechanisms of transformation of MDS to AML are poorly understood, especially in relation to the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with oversecretion of proinflammatory cytokines. Here, we found that most of the DKO mice underwent leukemic transformation at 12–14 months of age. These mice showed myeloblast replacement of fibrotic bone marrow and widespread leukemic infiltration. Strikingly, depletion of IL-6 in these mice largely rescued the leukemic transformation and markedly extended survival. Single-cell RNA sequencing analyses revealed that DKO leukemic mice had increased monocytic blasts that were reduced with IL-6 knockout. We further revealed that the levels of surface and soluble IL-6 receptor (IL-6R) in the bone marrow were significantly increased in high-risk MDS patients. Similarly, IL-6R was also highly expressed in older DKO mice. Blocking of IL-6 signaling significantly ameliorated AML progression in the DKO model and clonogenicity of CD34-positive cells from MDS patients. Our study establishes a mouse model of progression of age-related MDS to AML and indicates the clinical significance of targeting IL-6 signaling in treating high-risk MDS.

Functional constipation is a common functional gastrointestinal disease. In our previous study, we found that the gut microbiota structure was disordered and the level of phenylalanine (Phe) in serum was decreased in constipated women. We conducted the present study to elucidate the role of Phe in remodeling the composition of gut microbiota and the relationship between gut microbiota and serum metabolites. Here, we demonstrated that Phe treatment significantly enhanced intestinal motility, suppressed inflammatory responses, and prevented intestinal barrier damage in rats with loperamide (Lop)-induced constipation. By metagenomic sequencing, the disbalanced gut microbial profile was analyzed in constipated rats. Phe treatment reversed changes in the abundance of several gut bacteria at the phylum, genus, and species levels. Further, we observed distinct metabolic patterns in constipated rats through targeted metabolomics and identified constipation-related gut microbial species linked to changes in circulating neurotransmitter metabolites. The abundances of species s_Lactobacillus murinus, s_Enterococcus italicus, s_Lactobacillus animalis, s_Lactobacillus apodemi, s_Enterococcus faecalis, and s_Lactobacillus backii were positively correlated with L-asparagine, L-Glutamic acid, Putrescine, and Spermidine levels. The abundances of s_Lactobacillus johnsonii and s_Butyricimonas virosa were negatively correlated with L-asparagine, L-Glutamic acid, Putrescine, and Spermidine levels. Taken together, our findings suggest that Phe can ameliorate the development of Lop-induced constipation in rats by remodeling the gut microbial community structure and changing metabolite levels.

RNA editing introduces single nucleotide changes to RNA, thus potentially diversifying gene expression. Recent studies have reported significant changes in RNA editing profiles in disease and development. The functional consequences of these widespread alterations remain elusive because of the unknown function of most RNA editing sites. Here, we carry out a comprehensive analysis of A-to-I editomes in human populations. Surprisingly, we observe highly similar editing profiles across populations despite striking differences in the expression levels of ADAR genes. Striving to explain this discrepancy, we uncover a functional mechanism of A-to-I editing in regulating mRNA abundance. We show that A-to-I editing stabilizes RNA secondary structures and reduces the accessibility of AGO2-miRNA to target sites in mRNAs. The editing-dependent stabilization of mRNAs in turn alters the observed editing levels in the stable RNA repertoire. Our study provides valuable insights into the functional impact of RNA editing in human cells.

Ventricular chamber growth and development during perinatal circulatory transition is critical for functional adaptation of the heart. However, the chamber-specific programs of neonatal heart growth are poorly understood. We used integrated systems genomic and functional biology analyses of the perinatal chamber specific transcriptome and we identified Wnt11 as a prominent regulator of chamber-specific proliferation. Importantly, downregulation of Wnt11 expression was associated with cyanotic congenital heart defect (CHD) phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Perinatal hypoxia treatment in mice suppressed Wnt11 expression and induced myocyte proliferation more robustly in the right ventricle, modulating Rb1 protein activity. Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse hearts and reduced Rb1 protein and phosphorylation in neonatal cardiomyocytes. Finally, downregulated Wnt11 in hypoxemic TOF infantile hearts was associated with Rb1 suppression and induction of proliferation markers. This study revealed a previously uncharacterized function of Wnt11-mediated signaling as an important player in programming the chamber-specific growth of the neonatal heart. This function influences the chamber-specific development and pathogenesis in response to hypoxia and cyanotic CHDs. Defining the underlying regulatory mechanism may yield chamber-specific therapies for infants born with CHDs.