Evaluating the relationship between the proportion of X-chromosome deletions and clinical manifestations in children with turner syndrome.

Purpose: Analyze the relationship between changes in the proportion of X-chromosome deletions and clinical manifestations in children with Turner syndrome (TS). Methods: X-chromosome number abnormalities in 8,635 children with growth retardation were identified using fluorescence in situ hybridization (FISH). Meanwhile, the relationship between the proportion of X-chromosome deletions and the clinical manifestations of TS, such as face and body phenotype, cardiovascular, renal, and other comorbidities in children with TS was analyzed. Results: A total of 389 children had X-chromosome number abnormalities, with an average age at diagnosis of 9.2 years. There was a significant increase in diagnoses around the ages of 3 and 7 years and highest number of diagnoses at 10 years of age. 130 with XO (complete loss of an X-chromosome), 205 with XO/XX, 8 with XO/XXX, 23 with XO/XX/XXX, 19 with XO/XY, and 4 with XO/XY/XYY. Body and facial phenotypes increased with higher mosaicism proportions, with a relatively high correlation shown with Pearson correlation analysis (r = 0.26, p = 1.7e-06). The incidence of congenital heart malformations was 25.56%, mainly involving a bicuspid aortic valve, and were more common in patients who had complete loss of an X-chromosome. However, this relationship was not present for renal disease (p = 0.26), central nervous system, thyroid, or liver disease. Conclusion: The mosaicism (XO/XX) is the most common karyotype of TS in screened cases. The phenotypes in children with TS may increase with the proportion of X-chromosome deletions, but the renal disease and comorbidities did not show the same characteristics.

[Application of fluorescence in situ hybridization combined with chromosomal karyotyping analysis in children with disorders of sex development due to sex chromosome abnormalities].

OBJECTIVE: To retrospectively analyze sex chromosomal abnormalities and clinical manifestations of children with disorders of sex development (DSD). METHODS: A total of 14 857 children with clinical features of DSD including short stature, cryptorchidism, hypospadia, buried penis and developmental delay were recruited from Zhengzhou Children's Hospital from January 2013 to March 2022. Fluorescence in situ hybridization (FISH) and chromosomal karyotyping were carried out for such children. RESULTS: In total 423 children were found to harbor sex chromosome abnormalities, which has yielded a detection rate of 2.85%. There were 327 cases (77.30%) with Turner syndrome and a 45,X karyotype or its mosaicism. Among these, 325 were females with short stature as the main clinical manifestation, 2 were males with short stature, cryptorchidism and hypospadia as the main manifestations. Sixty-two children (14.66%) had a 47,XXY karyotype or its mosaicism, and showed characteristics of Klinefelter syndrome (KS) including cryptorchidism, buried penis and hypospadia. Nineteen cases (4.49%) had sex chromosome mosaicisms (XO/XY), which included 11 females with short stature, 8 males with hypospadia, and 6 cases with cryptorchidism, buried penis, testicular torsion and hypospadia. The remainder 15 cases (3.55%) included 9 children with a XYY karyotype or mosaicisms, with main clinical manifestations including cryptorchidisms and hypospadia, 4 children with a 47,XXX karyotype and clinical manifestations including short stature and labial adhesion, 1 child with a 46,XX/46,XY karyotype and clinical manifestations including micropenis, hypospadia, syndactyly and polydactyly, and 1 case with XXXX syndrome and clinical manifestations including growth retardation. CONCLUSION: Among children with DSD due to sex chromosomal abnormalities, sex chromosome characteristics consistent with Turner syndrome was most common, among which mosaicism (XO/XX) was the commonest. In terms of clinical manifestations, the females mainly featured short stature, while males mainly featured external genital abnormalities. Early diagnosis and treatment are particularly important for improving the quality of life in such children.

Integrating genetics with single-cell multiomic measurements across disease states identifies mechanisms of beta cell dysfunction in type 2 diabetes.

Dysfunctional pancreatic islet beta cells are a hallmark of type 2 diabetes (T2D), but a comprehensive understanding of the underlying mechanisms, including gene dysregulation, is lacking. Here we integrate information from measurements of chromatin accessibility, gene expression and function in single beta cells with genetic association data to nominate disease-causal gene regulatory changes in T2D. Using machine learning on chromatin accessibility data from 34 nondiabetic, pre-T2D and T2D donors, we identify two transcriptionally and functionally distinct beta cell subtypes that undergo an abundance shift during T2D progression. Subtype-defining accessible chromatin is enriched for T2D risk variants, suggesting a causal contribution of subtype identity to T2D. Both beta cell subtypes exhibit activation of a stress-response transcriptional program and functional impairment in T2D, which is probably induced by the T2D-associated metabolic environment. Our findings demonstrate the power of multimodal single-cell measurements combined with machine learning for characterizing mechanisms of complex diseases.

Understanding cell fate acquisition in stem-cell-derived pancreatic islets using single-cell multiome-inferred regulomes.

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-ß cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro ß cell maturation and identify sex hormones as drivers of ß cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity.

Palladium-Catalyzed Asymmetric Hydrogenolysis of Aryl Triflates for Construction of Axially Chiral Biaryls.

Here we report the first palladium-catalyzed asymmetric hydrogenolysis of readily available aryl triflates via desymmetrization and kinetic resolution for facile construction of axially chiral biaryl scaffolds with excellent enantioselectivities and s selectivity factors. The axially chiral monophosphine ligands could be prepared from these chiral biaryl compounds and were further applied to palladium-catalyzed asymmetric allylic alkylation with excellent ee values and high branched and linear ratio, which demonstrated the potential utility of this methodology.

RNA binding protein DDX5 restricts RORγt+ Treg suppressor function to promote intestine inflammation.

Retinoid-related orphan receptor (RAR) gamma (RORγt)-expressing regulatory T cells (RORγt+ Tregs) play pivotal roles in preventing T cell hyperactivation and maintaining tissue homeostasis, in part by secreting the anti-inflammation cytokine interleukin-10 (IL-10). Here, we report that hypoxia-induced factor 1α (HIF1α) is the master transcription factor for Il10 in RORγt+ Tregs. This critical anti-inflammatory pathway is negatively regulated by an RNA binding protein DEAD box helicase 5 (DDX5). As a transcriptional corepressor, DDX5 restricts the expression of HIF1α and its downstream target gene Il10 in RORγt+ Tregs. T cell-specific Ddx5 knockout (DDX5ΔT) mice have augmented RORγt+ Treg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5ΔT mice. The DDX5-HIF1α-IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.

Nutrient regulation of the islet epigenome controls adaptive insulin secretion.

Adaptation of the islet ß cell insulin-secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we have shown that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in ß cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurred at sites occupied by the chromatin-modifying enzyme lysine-specific demethylase 1 (Lsd1) in islets. ß Cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient-response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.

Polarization-multiplexed, single-cavity dual-comb fiber laser based on a birefringent crystal and a saturable absorber.

We introduce a calcium carbonate birefringent crystal into an Er-fiber laser mode-locked by a saturable absorber, where dual-comb ultrashort pulses with orthogonal polarization have been obtained. The two ultrashort pulse trains from the laser exhibit polarization contrast ratios of 30 dB and 20 dB, indicating that the dual-comb mode-locking is due to the polarization-multiplexing mechanism. The dual-comb ultrashort pulses have central wavelengths of 1564.41 nm and 1564.51 nm, and pulse durations of 825 fs and 805 fs respectively. The optical spectra and pulse durations of the asynchronous ultrashort pulses are nearly identical, so that the output of the laser could be directly used for dual-comb applications. Besides, the repetition-rate difference of the two mode-locked pulses is 673 Hz, while its drift is only 0.093 Hz within 2 hours' time. The low drift of the repetition-rate difference manifests the single-cavity dual-comb Er-fiber laser has a high stability and high common-mode noise suppression. At last, we have tested the dual-comb fiber laser in a ranging experiment, where clear interferogram signal can be observed. The experimental results prove that this single-cavity dual-comb Er-fiber laser based on the birefringent crystal and saturable absorber can be a potential source for spectroscopy, optical imaging, absolute distance measurement and other dual-comb applications.

Exosomal transfer of miR-195-5p restrains lung adenocarcinoma progression.

Exosome is an important way for tumor cells to communicate with other cells and plays an important role in tumor progression. Previous studies revealed that miR-195-5p acts as a tumor suppressor in lung cancer. However, the role and molecular mechanism of exosomal transferred miR-195-5p in lung adenocarcinoma (LAC) remains unknown. Here, we found that miR-195-5p expression in circulating exosomes of LAC patients was lower than that of healthy controls. Meanwhile, the expression of exosomal miR-195-5p from normal bronchial epithelial cell line BEAS-2B cells was significantly higher than that of lung cancer cell lines. The exosome labeling assay confirmed that BEAS-2B cells-derived exosomes could be captured by lung cancer cells. Furthermore, exosomal miR-195-5p derived from BEAS-2B cells remarkably inhibited the proliferation, migration, invasion of lung cancer cells, and tumor growth in vivo. In addition, exosomal miR-195-5p from BEAS-2B cells also suppressed the tube-forming ability of vascular endothelial cells. Moreover, we verified that miR-195-5p decreased apelin (APLN) expression to inactivate the Wnt signaling pathway, thereby inhibiting tumor invasiveness and angiogenesis. In conclusion, our research shows that exosomal miR-195-5p from normal bronchial epithelial cells hinders the progression of LAC, suggesting that regulation of exosomal miR-195-5p provides a novel strategy for LAC treatment.

Integration of single-cell multiomic measurements across disease states with genetics identifies mechanisms of beta cell dysfunction in type 2 diabetes.

Altered function and gene regulation of pancreatic islet beta cells is a hallmark of type 2 diabetes (T2D), but a comprehensive understanding of mechanisms driving T2D is still missing. Here we integrate information from measurements of chromatin activity, gene expression and function in single beta cells with genetic association data to identify disease-causal gene regulatory changes in T2D. Using machine learning on chromatin accessibility data from 34 non-diabetic, pre-T2D and T2D donors, we robustly identify two transcriptionally and functionally distinct beta cell subtypes that undergo an abundance shift in T2D. Subtype-defining active chromatin is enriched for T2D risk variants, suggesting a causal contribution of subtype identity to T2D. Both subtypes exhibit activation of a stress-response transcriptional program and functional impairment in T2D, which is likely induced by the T2D-associated metabolic environment. Our findings demonstrate the power of multimodal single-cell measurements combined with machine learning for identifying mechanisms of complex diseases.

Cognitive cost of empathizing with mothers and strangers by Chinese college students.

Background: Empathy is a choice and the product of a dynamic decision process based on motivation. The value trade-off in empathy is object-specific and people are more likely to empathize with ingroup, especially empathize with whom we are particularly concerned. The mother is an integral part of the self-concept, but the status of the mother in the self-concept of the eastern and western subjects was different. Previous studies have shown that mother is integrated in self-concept and share the same motivational hierarchy with self in Chinese brain. Objectives: The study's purpose is to investigate the empathic choice for mothers in Chinese culture and its regulatory mechanism. Methods: Three experiments were conducted to investigate whether Chinese college students would choose to empathize with their mothers. Experiment 1 used the Empathy Selection Task to examine the empathic choices between mother-other and stranger-other conditions with two blocks of 50 trials, and used the NASA Task Load Index to evaluate the cognitive costs for each deck option presented; Experiment 2 induced a disagreeable emotional state and replicate the same conditions of the experiment 1; Experiment 3 induced an agreeable emotional state and replicate the same conditions of the experiment one. Results and conclusions: The results showed that: (1) participants tended to avoid empathizing with their mothers and strangers for to the cognitive cost; (2) participants were more likely to choose empathy when the target was their mother rather than when the target was a stranger-other, due to the social reward; and (3) participants were more likely to opt to empathize with their mothers when positive emotions towards their mothers were primed. The results suggested that empathy is a choice and the product of a dynamic decision process based on motivation and the value trade-off in empathy is object-specific.

Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis.

Hepatocytes have important roles in liver iron homeostasis, abnormalities in which are tightly associated with liver steatosis and fibrosis. Here, we show that non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are characterized by iron-deficient hepatocytes and iron overload in hepatic stellate cells (HSCs). Iron deficiency enhances hepatocyte lipogenesis and insulin resistance through HIF2α-ATF4 signaling. Elevated secretion of iron-containing hepatocyte extracellular vesicles (EVs), which are normally cleared by Kupffer cells, accounts for hepatocyte iron deficiency and HSC iron overload in NAFLD/NASH livers. Iron accumulation results in overproduction of reactive oxygen species that promote HSC fibrogenic activation. Conversely, blocking hepatocyte EV secretion or depleting EV iron cargo restores liver iron homeostasis, concomitant with mitigation of NAFLD/NASH-associated liver steatosis and fibrosis. Taken together, these studies show that iron distribution disorders contribute to the development of liver metabolic diseases.

Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines.

We combined functional genomics and human genetics to investigate processes that affect type 1 diabetes (T1D) risk by mediating beta cell survival in response to proinflammatory cytokines. We mapped 38,931 cytokine-responsive candidate cis-regulatory elements (cCREs) in beta cells using ATAC-seq and snATAC-seq and linked them to target genes using co-accessibility and HiChIP. Using a genome-wide CRISPR screen in EndoC-ßH1 cells, we identified 867 genes affecting cytokine-induced survival, and genes promoting survival and up-regulated in cytokines were enriched at T1D risk loci. Using SNP-SELEX, we identified 2,229 variants in cytokine-responsive cCREs altering transcription factor (TF) binding, and variants altering binding of TFs regulating stress, inflammation, and apoptosis were enriched for T1D risk. At the 16p13 locus, a fine-mapped T1D variant altering TF binding in a cytokine-induced cCRE interacted with SOCS1, which promoted survival in cytokine exposure. Our findings reveal processes and genes acting in beta cells during inflammation that modulate T1D risk.

Concurrent Disruption of the Ras/MAPK and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis.

The Ras/Erk and NF-κB pathways play critical roles in cell proliferation and are known to drive oncogenesis when overactivated. Herein we report a gatekeeper function of the two pathways by working in synergy to suppress liver tumorigenesis. Hepatocyte-specific deletion of both Shp2/Ptpn11 and Ikkß in mice, which promote Ras/Erk and NF-κB signaling, respectively, exacerbated chemical carcinogenesis and even triggered spontaneous development of hepatocellular carcinoma (HCC). We show that the unanticipated severe tumor phenotype was contributed collectively by severe cholestasis, metabolic changes, upregulated cell-cycle progression, and disruption of circadian rhythm in mutant hepatocytes. Remarkably, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/Erk and NF-κB signaling and poor prognosis. Together, these data indicate that at the ground state, the two central pathways, previously known as oncogenic, cooperate to sustain tumor-suppressive physiologic homeostasis and to prevent hepatic damage. Disruption of this intricate signaling network is carcinogenic in the liver. IMPLICATIONS: We demonstrate here that basal levels of the Ras/MAPK and NF-κB pathways, while promoting tumorigenesis if overactivated, are required to maintain physiologic homeostasis and regulate circadian rhythm in the liver, which are antitumorigenic.

Developing high voltage Zn(TFSI)2/Pyr14TFSI/AN hybrid electrolyte for a carbon-based Zn-ion hybrid capacitor.

Aqueous Zn-ion hybrid capacitors (ZIHCs), integrating the typical characteristics of Zinc ion batteries and supercapacitors, have become a promising candidate to replace or supplement lithium-ion energy storage technology. However, the narrow operating voltage window and the instability of the Zn/electrolyte interface caused by aqueous solvents have become a great challenge for practical applications. Here, we developed a new type of hybrid electrolyte (Zn(TFSI)2/[[Pyr14TFSI]3]16/[AN]4) based on the organic solvent (AN) combined with ionic liquid (Pyr14TFSI) and Zn salt (Zn(TFSI)2). This non-flammable electrolyte benefited from the synergistic advantages of Pyr14TFSI and AN, and could output a wide electrochemical window (3.32 V vs. Zn/Zn2+) and good compatibility with metallic Zn, while possessing excellent wettability. Theoretical and experimental results further reveal that such superb performance originates from the change of Zn coordination environment. Consequently, the constructed ZIHC displays a stable cycling performance (10 000 cycles at 5 A g-1 without significant capacity fade) and a high operating voltage of 2.1 V. This newly developed electrolyte, which solves the conventional interface problem and improves the voltage window, will promote the development of ZIHCs.

Distribution and diversity of myxomycetes in Tiantangzhai National Forest Park, China.

Although myxomycetes are ubiquitous in terrestrial ecosystems, studies on their distribution and diversity in subtropical humid forests are still lacking. Field collections and moist chamber cultures were conducted from May to October within a two-year period in the Tiantangzhai National Forest Park of China. A total of 1,492 records representing 73 species belonging to 26 genera were obtained, of which 243 records/37 species were from field collections, and 1,249 records/52 species were from moist chamber cultures. Among the specimens obtained by culturing, 896 records/38 species and 353 records/37 species were obtained from living bark and ground litter, respectively. ANOVA showed that the sampling months had significant impacts on collection of myxomycetes from field and those that inhabit litter. An LEfSe analysis indicated that Arcyria was significantly abundant in August, while Stemonitis and Physarum were more abundant in July when collected from field. An RDA analysis showed that temperature was the main factor that affected the litter-inhabiting myxomycetes. The ANOVA indicated that forest type was the significant factor for bark-inhabiting myxomycetes. Diderma effusum was primarily obtained from mixed forests, while Clastoderma debaryanum and Colloderma oculatum were more common in coniferous forests. The RDA analysis indicated that the vegetation, pH, water retention, and elevation were the primary factors that affected the bark-inhabiting myxomycetes.

Construction of Supercapacitor-Based Ionic Diodes with Adjustable Bias Directions by Using Poly(ionic liquid) Electrolytes.

The newly emerging supercapacitor-diode (CAPode), integrating the characteristics of a diode into an electrical-double-layer capacitor, can be employed to extend conventional supercapacitors to new technological applications and may play a crucial role in grid stabilization, signal propagation, and logic operations. However, the reported CAPodes have only been able to realize charge storage in the positive-bias direction. Here, bias-direction-adjustable CAPodes realized by using a polycation-based ionic liquid (IL) or a polyanion-based IL as electrolyte in an asymmetric carbon-based supercapacitor architecture are proposed. The resulting CAPodes exhibit charge-storage function at only the positive- or negative-bias direction with a high rectification ratio (≈80% for rectification ratio II, RRII ) and an outstanding cycling life (4500 cycles), representing a crucial breakthrough for designing high-performance capacitive ionic diodes.

ERO1α mediates endoplasmic reticulum stress-induced apoptosis via microRNA-101/EZH2 axis in colon cancer RKO and HT-29 cells.

Although colon cancer is a leading and typical gastrointestinal tumor, there is little published data on the underlying molecular mechanisms of endoplasmic reticulum (ER) stress. Here, we investigated the role of ERO1α and its impact on microRNA (miR)-101 expression and ER stress in colon cancer cells. Cell ER stress was established by treating RKO or HT-29 cells with 1 µM thapsigargin (THG). Cell biological behaviors were detected using CCK-8, bromodeoxyuridine assay, flow cytometry and western blot. We also investigated the expression of ERO1α and miR-101 after THG treatment using RT-qPCR. Moreover, effects of ERO1α and miR-101 on ER stress of colon cancer cells were detected. Additionally, miR-101 impact on EZH2 expression and relevance of this regulation was confirmed by RT-qPCR and luciferase reporter. The regulation of miR-101/EZH2 axis and Wnt/ß-catenin pathway in ER stress were investigated. Our results demonstrated that THG induced ER stress in colon cancer cells. Silencing ERO1α further promoted ER stress-induced cell apoptosis. ERO1α knockdown up-regulated miR-101 expression and promoted colon cancer cell apoptosis via regulating miR-101. Surprisingly, miR-101 negatively regulated EZH2 expression via miRNA-mRNA targeting. Moreover, ER stress promoted colon cancer cell apoptosis via regulating miR-101/EZH2 axis. Wnt/ß-catenin pathway was also involved in the regulation of ERO1α/miR-101/EZH2 in ER stress of colon cancer cells. These findings illustrated that silencing ERO1α regulated ER stress-induced apoptosis via miR-101/EZH2 axis in RKO and HT-29 cells.

A tumorigenic index for quantitative analysis of liver cancer initiation and progression.

Primary liver cancer develops from multifactorial etiologies, resulting in extensive genomic heterogeneity. To probe the common mechanism of hepatocarcinogenesis, we interrogated temporal gene expression profiles in a group of mouse models with hepatic steatosis, fibrosis, inflammation, and, consequently, tumorigenesis. Instead of anticipated progressive changes, we observed a sudden molecular switch at a critical precancer stage, by developing analytical platform that focuses on transcription factor (TF) clusters. Coarse-grained network modeling demonstrated that an abrupt transcriptomic transition occurred once changes were accumulated to reach a threshold. Based on the experimental and bioinformatic data analyses as well as mathematical modeling, we derived a tumorigenic index (TI) to quantify tumorigenic signal strengths. The TI is powerful in predicting the disease status of patients with metabolic disorders and also the tumor stages and prognosis of liver cancer patients with diverse backgrounds. This work establishes a quantitative tool for triage of liver cancer patients and also for cancer risk assessment of chronic liver disease patients.