ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer.

Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies.

Phase-separated ParB enforces diverse DNA compaction modes and stabilizes the parS-centered partition complex.

The tripartite ParABS system mediates chromosome segregation in the majority of bacterial species. Typically, DNA-bound ParB proteins around the parS sites condense the chromosomal DNA into a higher-order multimeric nucleoprotein complex for the ParA-driven partition. Despite extensive studies, the molecular mechanism underlying the dynamic assembly of the partition complex remains unclear. Herein, we demonstrate that Bacillus subtilis ParB (Spo0J), through the multimerization of its N-terminal domain, forms phase-separated condensates along a single DNA molecule, leading to the concurrent organization of DNA into a compact structure. Specifically, in addition to the co-condensation of ParB dimers with DNA, the engagement of well-established ParB condensates with DNA allows for the compression of adjacent DNA and the looping of distant DNA. Notably, the presence of CTP promotes the formation of condensates by a low amount of ParB at parS sites, triggering two-step DNA condensation. Remarkably, parS-centered ParB-DNA co-condensate constitutes a robust nucleoprotein architecture capable of withstanding disruptive forces of tens of piconewton. Overall, our findings unveil diverse modes of DNA compaction enabled by phase-separated ParB and offer new insights into the dynamic assembly and maintenance of the bacterial partition complex.

Promote electroreduction of CO2 via catalyst valence state manipulation by surface-capping ligand.

Electrochemical CO2 reduction provides a potential means for synthesizing value-added chemicals over the near equilibrium potential regime, i.e., formate production on Pd-based catalysts. However, the activity of Pd catalysts has been largely plagued by the potential-depended deactivation pathways (e.g., [Formula: see text]-PdH to [Formula: see text]-PdH phase transition, CO poisoning), limiting the formate production to a narrow potential window of 0 V to -0.25 V vs. reversible hydrogen electrode (RHE). Herein, we discovered that the Pd surface capped with polyvinylpyrrolidone (PVP) ligand exhibits effective resistance to the potential-depended deactivations and can catalyze formate production at a much extended potential window (beyond -0.7 V vs. RHE) with significantly improved activity (~14-times enhancement at -0.4 V vs. RHE) compared to that of the pristine Pd surface. Combined results from physical and electrochemical characterizations, kinetic analysis, and first-principle simulations suggest that the PVP capping ligand can effectively stabilize the high-valence-state Pd species (Pdδ+) resulted from the catalyst synthesis and pretreatments, and these Pdδ+ species are responsible for the inhibited phase transition from [Formula: see text]-PdH to [Formula: see text]-PdH, and the suppression of CO and H2 formation. The present study confers a desired catalyst design principle, introducing positive charges into Pd-based electrocatalyst to enable efficient and stable CO2 to formate conversion.

CircAKT3 alleviates postoperative cognitive dysfunction by stabilizing the feedback cycle of miR-106a-5p/HDAC4/MEF2C axis in hippocampi of aged mice.

Circular RNAs (circRNAs) have garnered significant attention in the field of neurodegenerative diseases including Alzheimer's diseases due to their covalently closed loop structure. However, the involvement of circRNAs in postoperative cognitive dysfunction (POCD) is still largely unexplored. To identify the genes differentially expressed between non-POCD (NPOCD) and POCD mice, we conducted the whole transcriptome sequencing initially in this study. According to the expression profiles, we observed that circAKT3 was associated with hippocampal neuronal apoptosis in POCD mice. Moreover, we found that circAKT3 overexpression reduced apoptosis of hippocampal neurons and alleviated POCD. Subsequently, through bioinformatics analysis, our data showed that circAKT3 overexpression in vitro and in vivo elevated the abundance of miR-106a-5p significantly, resulting in a decrease of HDAC4 protein and an increase of MEF2C protein. Additionally, this effect of circAKT3 was blocked by miR-106a-5p inhibitor. Interestingly, MEF2C could activate the transcription of miR-106a-5p promoter and form a positive feedback loop. Therefore, our findings revealed more potential modulation ways between circRNA-miRNA and miRNA-mRNA, providing different directions and targets for preclinical studies of POCD.

Escherichia coli has robust regulatory mechanisms against elevated peptidoglycan cleavage by lytic transglycosylases.

Peptidoglycan (PG) is an essential and conserved exoskeletal component in all bacteria that protects cells from lysis. Gram-negative bacteria such as Escherichia coli encode multiple redundant lytic transglycosylases (LTs) that engage in PG cleavage, a potentially lethal activity requiring proper regulation to prevent autolysis. To elucidate the potential effects and cellular regulatory mechanisms of elevated LT activity, we individually cloned the periplasmic domains of two membrane-bound LTs, MltA and MltB, under the control of the arabinose-inducible system for overexpression in the periplasmic space in E. coli. Interestingly, upon induction, the culture undergoes an initial period of cell lysis followed by robust growth restoration. The LT-overexpressing E. coli exhibits altered morphology with larger spherical cells, which is in line with the weakening of the PG layer due to aberrant LT activity. On the other hand, the restored cells display a similar rod shape and PG profile that is indistinguishable from the uninduced control. Quantitative proteomics analysis of the restored cells identified significant protein enrichment in the regulator of capsule synthesis (Rcs) regulon, a two-component stress response known to be specifically activated by PG damage. We showed that LT-overexpressing E. coli with an inactivated Rcs system partially impairs the growth restoration process, supporting the involvement of the Rcs system in countering aberrant PG cleavage. Furthermore, we demonstrated that the elevated LT activity specifically potentiates ß-lactam antibiotics against E. coli with a defective Rcs regulon, suggesting the dual effects of augmented PG cleavage and blocked PG synthesis as a potential antimicrobial strategy.

TMEM100 acts as a TAK1 receptor that prevents pathological cardiac hypertrophy progression.

Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53-75 and 85-107) directly interacts with the C-terminal region of TAK1 (amino acids 1-300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.

CircNSD1 promotes cardiac fibrosis through targeting the miR-429-3p/SULF1/Wnt/ß-catenin signaling pathway.

Cardiac fibrosis is a detrimental pathological process, which constitutes the key factor for adverse cardiac structural remodeling leading to heart failure and other critical conditions. Circular RNAs (circRNAs) have emerged as important regulators of various cardiovascular diseases. It is known that several circRNAs regulate gene expression and pathological processes by binding miRNAs. In this study we investigated whether a novel circRNA, named circNSD1, and miR-429-3p formed an axis that controls cardiac fibrosis. We established a mouse model of myocardial infarction (MI) for in vivo studies and a cellular model of cardiac fibrogenesis in primary cultured mouse cardiac fibroblasts treated with TGF-ß1. We showed that miR-429-3p was markedly downregulated in the cardiac fibrosis models. Through gain- and loss-of-function studies we confirmed miR-429-3p as a negative regulator of cardiac fibrosis. In searching for the upstream regulator of miR-429-3p, we identified circNSD1 that we subsequently demonstrated as an endogenous sponge of miR-429-3p. In MI mice, knockdown of circNSD1 alleviated cardiac fibrosis. Moreover, silence of human circNSD1 suppressed the proliferation and collagen production in human cardiac fibroblasts in vitro. We revealed that circNSD1 directly bound miR-429-3p, thereby upregulating SULF1 expression and activating the Wnt/ß-catenin pathway. Collectively, circNSD1 may be a novel target for the treatment of cardiac fibrosis and associated cardiac disease.

ModelHamiltonian: A Python-scriptable library for generating 0-, 1-, and 2-electron integrals.

ModelHamiltonian is a free, open source, and cross-platform Python library designed to express model Hamiltonians, including spin-based Hamiltonians (Heisenberg and Ising models) and occupation-based Hamiltonians (Pariser-Parr-Pople, Hubbard, and Hückel models) in terms of 1- and 2-electron integrals, so that these systems can be easily treated by traditional quantum chemistry software programs. ModelHamiltonian was originally intended to facilitate the testing of new electronic structure methods using HORTON but emerged as a stand-alone research tool that we recognize has wide utility, even in an educational context. ModelHamiltonian is written in Python and adheres to modern principles of software development, including comprehensive documentation, extensive testing, continuous integration/delivery protocols, and package management. While we anticipate that most users will use ModelHamiltonian as a Python library, we include a graphical user interface so that models can be built without programming, based on connectivity/parameters inferred from, for example, a SMILES string. We also include an interface to ChatGPT so that users can specify a Hamiltonian in plain language (without learning ModelHamiltonian's vocabulary and syntax). This article marks the official release of the ModelHamiltonian library, showcasing its functionality and scope.

The DNA dioxygenase Tet1 regulates H3K27 modification and embryonic stem cell biology independent of its catalytic activity.

Tet enzymes (Tet1/2/3) oxidize 5-methylcytosine to promote DNA demethylation and partner with chromatin modifiers to regulate gene expression. Tet1 is highly expressed in embryonic stem cells (ESCs), but its enzymatic and non-enzymatic roles in gene regulation are not dissected. We have generated Tet1 catalytically inactive (Tet1m/m) and knockout (Tet1-/-) ESCs and mice to study these functions. Loss of Tet1, but not loss of its catalytic activity, caused aberrant upregulation of bivalent (H3K4me3+; H3K27me3+) developmental genes, leading to defects in differentiation. Wild-type and catalytic-mutant Tet1 occupied similar genomic loci which overlapped with H3K27 tri-methyltransferase PRC2 and the deacetylase complex Sin3a at promoters of bivalent genes and with the helicase Chd4 at active genes. Loss of Tet1, but not loss of its catalytic activity, impaired enrichment of PRC2 and Sin3a at bivalent promoters leading to reduced H3K27 trimethylation and deacetylation, respectively, in absence of any changes in DNA methylation. Tet1-/-, but not Tet1m/m, embryos expressed higher levels of Gata6 and were developmentally delayed. Thus, the critical functions of Tet1 in ESCs and early development are mediated through its non-catalytic roles in regulating H3K27 modifications to silence developmental genes, and are more important than its catalytic functions in DNA demethylation.

Stochastically multimerized ParB orchestrates DNA assembly as unveiled by single-molecule analysis.

The tripartite ParABS system mediates chromosome segregation in a wide range of bacteria. Dimeric ParB was proposed to nucleate on parS sites and spread to neighboring DNA. However, how properly distributed ParB dimers further compact chromosomal DNA into a higher-order nucleoprotein complex for partitioning remains poorly understood. Here, using a single-molecule approach, we show that tens of Bacillus subtilis ParB (Spo0J) proteins can stochastically multimerize on and stably bind to nonspecific DNA. The introduction of CTP promotes the formation and diffusion of the multimeric ParB along DNA, offering an opportunity for ParB proteins to further forgather and cluster. Intriguingly, ParB multimers can recognize parS motifs and are more inclined to remain immobile on them. Importantly, the ParB multimer features distinct capabilities of not only bridging two independent DNA molecules but also mediating their transportation, both of which are enhanced by the presence of either CTP or parS in the DNA. These findings shed new light on ParB dynamics in self-multimerization and DNA organization and help to better comprehend the assembly of the ParB-DNA partition complex.

Systematic review of the mechanism and assessment of liver fibrosis in biliary atresia.

PURPOSE: This study systematically reviewed our team's research on the mechanism and assessment of liver fibrosis in BA, summarized our experience, and discussed the future development direction. METHODS: In this study, Pubmed and Wanfang databases were searched to collect the literature published by our team on the mechanisms of liver fibrosis in BA and the assessment of liver fibrosis in BA, and the above research results were systematically reviewed. RESULTS: A total of 58 articles were retrieved. Among the included articles, 25 articles related to the mechanism of liver fibrosis in BA, and five articles evaluated liver fibrosis in BA. This article introduces the key pathways and molecules of liver fibrosis in BA and proposes a new grading system for liver fibrosis in BA. CONCLUSIONS: The new BA liver fibrosis grading method is expected to assess children's conditions, guide treatment, and improve prognosis more accurately. In addition, we believe that the TGF-ß1 signaling pathway is the most important in the study of liver fibrosis in BA, and at the same time, the study of EMT occurrence in BA should also be deepened to resolve the controversy on this issue.

High-Sensitivity and Wide-Range Flexible Ionic Piezocapacitive Pressure Sensors with Porous Hemisphere Array Electrodes.

The development of high-performance flexible pressure sensors with porous hierarchical microstructures is limited by the complex and time-consuming preparation processes of porous hierarchical microstructures. In this study, a simple modified heat curing process was first proposed to achieve one-step preparation of porous hemispherical microstructures on a polydimethylsiloxane (PDMS) substrate. In this process, a laser-prepared template was used to form surface microstructures on PDMS film. Meanwhile, the thermal decomposition of glucose monohydrate additive during heat curing of PDMS led to the formation of porous structures within PDMS film. Further, based on the obtained PDMS/CNTs electrodes with porous hemisphere array and ionic polymer dielectric layers, high-performance ionic piezocapacitive sensors were realized. Under the synergistic effect of the low-stiffness porous hemisphere microstructure and the electric double layer of the ionic polymer film, the sensor based on an ionic polymer film with a 1:0.75 ratio of P(VDF-HFP):[EMIM][TFSI] not only achieves a sensitivity of up to 106.27 kPa-1 below 3 kPa, but also has a wide measurement range of over 400 kPa, which has obvious advantages in existing flexible piezocapacitive sensors. The rapid response time of 110 s and the good stability of 2300 cycles of the sensor further elucidate its practicality. The application of the sensor in pulse monitoring, speech recognition, and detection of multiple dynamic loads verifies its excellent sensing performance. In short, the proposed heat curing process can simultaneously form porous structures and surface microstructures on PDMS films, greatly simplifying the preparation process of porous hierarchical microstructures and providing a simple and feasible way to obtain high-performance flexible pressure sensors.

Chiral Jahn-Teller Distortion in Quasi-Planar Boron Clusters.

In this work, we have observed that some chiral boron clusters (B16-, B20-, B24-, and B28-) can simultaneously have helical molecular orbitals and helical spin densities; these seem to be the first compounds discovered to have this intriguing property. We show that chiral Jahn-Teller distortion of quasi-planar boron clusters drives the formation of the helical molecular spin densities in these clusters and show that elongation/enhancement in helical molecular orbitals can be achieved by simply adding more building blocks via a linker. Aromaticity of these boron clusters is discussed. Chiral boron clusters may find potential applications in spintronics, such as molecular magnets.

Hyperuricemia May Increase Risk of Achilles Tendon Rupture: A Case Control Study.

It has been demonstrated in a number of studies that high levels of uric acid can cause crystal deposition in the tendons of the lower extremities, which in turn can impair the Achilles tendon. This study aimed to interpret whether hyperuricemia is relevant with Achilles tendon rupture. Patients diagnosed with Achilles tendon rupture at the same institution between 2013 and 2022 were included in the case group. Healthy subjects who had physical examinations during the same period were included in the control group. Propensity score matching was used to match in a 1:1 ratio. Demographic and clinical characteristics of patients in both groups were compared. Five hundred and fourteen patients were included in the study (ATR=257; Control group=257). The proportion of individuals with hyperuricemia varied significantly between the 2 groups (Achilles tendon rupture group=43.6%; control group=27.6%; p<0.001). The Achilles tendon rupture and hyperuricemia were linked by conditional logistic regression (p<0.001; OR=2.036; 95CI%=1.400-2.961). Compared with healthy subjects, patients with hyperuricemia have a higher risk of Achilles tendon rupture. Further studies are required to verify the effects of hyperuricemia and monosodium urate crystals on Achilles tendon structure.

Downregulated mitochondrial transcription factor A enhances mycoplasma infection to promote the metastasis of hepatocellular carcinoma.

Mycoplasma is widespread in various hosts and may cause various diseases in animals. Interestingly, the occurrence of mycoplasma infection was observed in many tumor types. However, the mechanism regulating its infection is far from clear. We unexpectedly found that the knockdown of mitochondrial transcription factor A (TFAM) remarkably enhanced mycoplasma infection in hepatocellular carcinoma (HCC) cells. More importantly, we found that mycoplasma infection facilitated by TFAM knockdown significantly promoted HCC cell metastasis. Mycoplasma infection was further found to be positively correlated with poor prognosis in patients with HCC. Mechanistically, the decreased TFAM expression upregulated the transcription factor Sp1 to increase the expression level of Annexin A2 (ANXA2), which was reported to interact with membrane protein of mycoplasma. Moreover, we found that mycoplasma infection enhanced by the TFAM downregulation promoted HCC migration and invasion by activating the nuclear factor-κB signaling pathway. The downregulation of TFAM enhanced mycoplasma infection in HCC cells and promoted HCC cell metastasis. Our study contributes to the understanding of the pathological role of mycoplasma infection and provides supporting evidence that targeting TFAM could be a potential strategy for the treatment of HCC with mycoplasma infection.

ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis.

Strengthened glycolysis is crucial for the macrophage pro-inflammatory response during sepsis. Activating transcription factor 4 (ATF4) plays an important role in regulating glucose and lipid metabolic homeostasis in hepatocytes and adipocytes. However, its immunometabolic role in macrophage during sepsis remains largely unknown. In the present study, we found that the expression of ATF4 in peripheral blood mononuclear cells (PBMCs) was increased and associated with glucose metabolism in septic patients. Atf4 knockdown specifically decreased LPS-induced spleen macrophages and serum pro-inflammatory cytokines levels in mice. Moreover, Atf4 knockdown partially blocked LPS-induced pro-inflammatory cytokines, lactate accumulation and glycolytic capacity in RAW264.7. Mechanically, ATF4 binds to the promoter region of hexokinase II (HK2), and interacts with hypoxia inducible factor-1α (HIF-1α) and stabilizes HIF-1α through ubiquitination modification in response to LPS. Furthermore, ATF4-HIF-1α-HK2-glycolysis axis launches pro-inflammatory response in macrophage depending on the activation of mammalian target of rapamycin (mTOR). Importantly, Atf4 overexpression improves the decreased level of pro-inflammatory cytokines and lactate secretion and HK2 expression in LPS-induced tolerant macrophages. In conclusion, we propose a novel function of ATF4 as a crucial glycolytic activator contributing to pro-inflammatory response and improving immune tolerant in macrophage involved in sepsis. So, ATF4 could be a potential new target for immunotherapy of sepsis.

Mate-pair genome sequencing reveals structural variants for idiopathic male infertility.

Currently, routine genetic investigation for male infertility includes karyotyping analysis and PCR for Y chromosomal microdeletions to provide prognostic information such as sperm retrieval success rate. However, over 85% of male infertility remain idiopathic. We assessed 101 male patients with primary infertility in a retrospective cohort analysis who have previously received negative results from standard-of-care tests. Mate-pair genome sequencing (large-insert size library), an alternative long-DNA sequencing method, was performed to detect clinically significant structural variants (SVs) and copy-number neutral absence of heterozygosity (AOH). Candidate SVs were filtered against our in-house cohort of 1077 fertile men. Genes disrupted by potentially clinically significant variants were correlated with single-cell gene expression profiles of human fetal and postnatal testicular developmental lineages and adult germ cells. Follow-up studies were conducted for each patient with clinically relevant finding(s). Molecular diagnoses were made in 11.1% (7/63) of patients with non-obstructive azoospermia and 13.2% (5/38) of patients with severe oligozoospermia. Among them, 12 clinically significant SVs were identified in 12 cases, including five known syndromes, one inversion, and six SVs with direct disruption of genes by intragenic rearrangements or complex insertions. Importantly, a genetic defect related to intracytoplasmic sperm injection (ICSI) failure was identified in a patient with non-obstructive azoospermia, illustrating the additional value of an etiologic diagnosis in addition to determining sperm retrieval rate. Our study reveals a landscape of various genomic variants in 101 males with idiopathic infertility, not only advancing understanding of the underlying mechanisms of male infertility, but also impacting clinical management.

A pilot investigation of low-pass genome sequencing identifying site-specific variation in chromosomal mosaicisms by a multiple site sampling approach in first-trimester miscarriages.

STUDY QUESTION: Can multiple-site low-pass genome sequencing (GS) of products of conception (POCs) improve the detection of genetic abnormalities, especially heterogeneously distributed mosaicism and homogeneously distributed mosaicism in first-trimester miscarriage? SUMMARY ANSWER: Multiple-site sampling combined with low-pass GS significantly increased genetic diagnostic yield (77.0%, 127/165) of first-trimester miscarriages, with mosaicisms accounting for 17.0% (28/165), especially heterogeneously distributed mosaicisms (75%, 21/28) that are currently underappreciated. WHAT IS KNOWN ALREADY: Aneuploidies are well known to cause first-trimester miscarriage, which are detectable by conventional karyotyping and next-generation sequencing (NGS) on a single-site sampling basis. However, there are limited studies demonstrating the implications of mosaic genetic abnormalities in first-trimester miscarriages, especially when genetic heterogeneity is present in POCs. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional cohort study carried out at a university-affiliated public hospital. One hundred seventy-four patients diagnosed with first-trimester miscarriage from December 2018 to November 2021 were offered ultrasound-guided manual vacuum aspiration (USG-MVA) treatment. Products of conception were subjected to multiple-site low-pass GS for the detection of chromosomal imbalances. PARTICIPANTS/MATERIALS, SETTING, METHODS: For each POC, multiple sites of villi (three sites on average) were biopsied for low-pass GS. Samples with maternal cell contamination (MCC) and polyploidy were excluded based on the quantitative fluorescence polymerase chain reaction (QF-PCR) results. The spectrum of chromosomal abnormalities, including mosaicism (heterogeneously distributed and homogeneously distributed) and constitutional abnormalities was investigated. Chromosomal microarray analysis and additional DNA fingerprinting were used for validation and MCC exclusion. A cross-platform comparison between conventional karyotyping and our multiple-site approach was also performed. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred sixty-five POCs (corresponding to 490 DNA samples) were subjected to low-pass GS. Genetic abnormalities were detected in 77.0% (127/165) of POCs by our novel approach. Specifically, 17.0% (28/165) of cases had either heterogeneously distributed mosaicism (12.7%, 21/165) or homogeneously distributed mosaicism (6.1%, 10/165) (three cases had both types of mosaicism). The remaining 60.0% (99/165) of cases had constitutional abnormalities. In addition, in the 71 cases with karyotyping performed in parallel, 26.8% (19/71) of the results could be revised by our approach. LIMITATIONS, REASONS FOR CAUTION: Lack of a normal gestational week-matched cohort might hinder the establishment of a causative link between mosaicisms and first-trimester miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: Low-pass GS with multiple-site sampling increased the detection of chromosomal mosaicisms in first-trimester miscarriage POCs. This innovative multiple-site low-pass GS approach enabled the novel discovery of heterogeneously distributed mosaicism, which was prevalent in first-trimester miscarriage POCs and frequently observed in preimplantation embryos, but is currently unappreciated by conventional single-site cytogenetic investigations. STUDY FUNDING/COMPETING INTEREST(S): This work was supported partly by Research Grant Council Collaborative Research Fund (C4062-21GF to K.W.C), Science and Technology Projects in Guangzhou (202102010005 to K.W.C), Guangdong-Hong Kong Technology Cooperation Funding Scheme (TCFS), Innovation and Technology Fund (GHP/117/19GD to K.W.C), HKOG Direct Grant (2019.050 to J.P.W.C), and Hong Kong Health and Medical Research Fund (05160406 to J.P.W.C). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Potential therapeutic target of EGF on bile duct ligation model and biliary atresia children.

BACKGROUND: The pathogenesis of liver fibrosis in biliary atresia (BA) is unclear. Epidermal growth factor (EGF) plays a vital role in liver fibrosis. This study aims to investigate the expression of EGF and the mechanisms of its pro-fibrotic effects in BA. METHODS: EGF levels in serum and liver samples of BA and non-BA children were detected. Marker proteins of EGF signaling and epithelial-mesenchymal transition (EMT) in liver sections were evaluated. Effects of EGF on intrahepatic cells and the underlying mechanisms were explored in vitro. Bile duct ligation (BDL) mice with/without EGF antibody injection were used to verify the effects of EGF on liver fibrosis. RESULTS: Serum levels and liver expression of EGF elevated in BA. Phosphorylated EGF receptor (p-EGFR) and extracellular regulated kinase 1/2 (p-ERK1/2) increased. In addition, EMT and proliferation of biliary epithelial cells were present in BA liver. In vitro, EGF induced EMT and proliferation of HIBEpic cells and promoted IL-8 expression in L-02 cells by phosphorylating ERK1/2. And EGF activated LX-2 cells. Furthermore, EGF antibody injection reduced p-ERK1/2 levels and alleviated liver fibrosis in BDL mice. CONCLUSION: EGF is overexpressed in BA. It aggravates liver fibrosis through EGF/EGFR-ERK1/2 pathway, which may be a therapeutic target for BA. IMPACT: The exact pathogenesis of liver fibrosis in BA is unknown, severely limiting the advancement of BA treatment strategies. This study revealed that serum and liver tissue levels of EGF were increased in BA, and its expression in liver tissues was correlated with the degree of liver fibrosis. EGF may promote EMT and proliferation of biliary epithelial cells and induce IL-8 overexpression in hepatocytes through EGF/EGFR-ERK1/2 signaling pathway. EGF can also activate HSCs in vitro. The EGF/EGFR-ERK1/2 pathway may be a potential therapeutic target for BA.

Systematic Study on the Precursor Reduction Kinetics and Growth Pattern for Size-Tunable Palladium Nanocubes.

Unveiling the underlying chemistry during the growth of well-defined nanocrystals is a fundamental but challenging task in materials chemistry. Herein, Pd NCs with tunable sizes ranging from 4.5 to 23.5 nm have been synthesized in the presence of potassium acetate (KOAc). The Pd precursor variation trends of these preparation systems along with reaction time have been determined using a UV-vis spectrometer, and corresponding reduction kinetic parameters, including the apparent reduction rate constant (k) and activation energy (Ea), are calculated by regarding the reduction processes as quasi-first-order reactions. It is confirmed that the introduction of KOAc does not affect the value of the Ea of different reaction systems. The interrelationship of k, product size (d), and reaction temperature (T) is discussed in depth. Results indicate that the three parameters are closely related, and for given reaction systems, they are specified. With the careful investigation of six specific systems (reaction systems with 10 mM, 20 mM KOAc at 55 °C, with 5 mM, 10 mM KOAc at 65 °C, without KOAc at 75 °C, and with 5 mM KOAc at 85 °C), the growth pattern of Pd NCs is described with an empirical expression and is further confirmed as a synergistic result of k and T.