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This article provides a general ion exchange and calcination method for sythesizing CoCeMOx, and demonstrates CoCeZnOx PNs exhibit the best electrocatalytic performance among them due to their higher content of oxygen vacancies and Co2+.

In the volatile, uncertain, complex, and ambiguous environment (VUCA), employees can better match the organization and jobs by crafting their job perceptions, work tasks, and relationships, which is valuable to maintain organizational sustainable competitiveness and promote employees’ personal growth. This study explores the influence mechanisms of job autonomy and work meaning on employees’ job-crafting behaviors and the moderating effect of perceived organizational change through a survey of 318 employees in Chinese companies. The results show that job autonomy and work meaning can promote employees’ job-crafting behaviors by increasing individuals’ harmonious work passion. The indirect effects of job autonomy and work meaning on employee job-crafting behaviors through harmonious work passion are stronger for individuals with high perceived organizational change relative to those with low perceived organizational change. Organizations should concentrate on job redesign to improve employees’ job autonomy and work meaning. A climate of change should also be created within the organization to keep employees aware of the crisis. Meanwhile, employees should actively use work resources to meet the changing needs of organizational development and promote individual career development through job-crafting behaviors.

With declining birth rates, and decreasing family sizes being witnessed around the world, helicopter parenting—characterized by high warmth, high control, and low empowerment—is becoming increasingly common among parents. Parenting styles exert long-term effects on individuals’ cognition and behavior, not only in early childhood, but also in adulthood: therefore, within this context, this study explored the underlying influence mechanism of helicopter parenting style on interpersonal conflict, through a survey of 505 Chinese college students. Using multiwave data, our analysis uncovered the mediating roles of psychological entitlement and fear of missing out, as well as the moderating role of a competitive climate. In particular, we found that helicopter parenting enhances interpersonal conflict among college students, by strengthening psychological entitlement and fear of missing out. In addition, the indirect effect of fear of missing out is stronger than that of psychological entitlement. We also found that a competitive climate positively moderates the indirect effect of helicopter parenting on interpersonal conflict among college students through psychological entitlement and fear of missing out, indicating that the negative effects of helicopter parenting are more pronounced in a high competitive climate. These results provide a novel theoretical account of how early parenting styles affect an adult’s cognition and behavior. Practically, these results suggest that parents should limit the use of helicopter parenting, and that, while loving and caring for their child, they should allow their child appropriate autonomy. On the other hand, children should strive for positive self-improvement and harmonious peer relationships, to alleviate the negative influence of helicopter parenting.

The increasing demand for compact and high-performance photonic devices drives the development of optical resonators with nanoscale sizes and ultrahigh quality factors. Fabry-Pérot (FP) resonators, the most widely employed optical resonators, can support ultrahigh quality factors in the simple structure, which is particularly attractive for applications in lasers, filters, and ultrasensitive sensors. However, the construction of FP resonators with both nanoscale sizes and high quality factors has still faced challenges. Herein we demonstrate the construction of FP nanoresonators out of single Au nanodisks (NDs) and a Au film, with a WS

Background: Assessing how clinical resistance to PARP inhibitors develops has been challenging, due to the lack of coverage of potential resistance genes in sequencing panels and biopsies being subject to spatial heterogeneity. We studied the development of PARPi and/or platinum resistant disease using both tissue and a novel liquid biopsy assay, in patients treated for BRCA1/2-mutated metastatic breast cancer (BRCA1/2m mBC). Approach: A cohort of 35 mBC patients with germline or somatic BRCA1/2 mutations were identified as having developed PARPi or platinum resistant disease. Tumour biopsies were analysed by exome and transcriptome sequencing whereas ctDNA isolated from plasma sampled across the pre-treatment, response and eventual progression journey were analysed using the Guardant INFINITY platform equipped to detect mutations in >800 genes, and genome wide methylation, including promoter methylation in 398 cancer-related genes. Somatic mutations or regions of methylation that were associated with resistance were identified, including BRCA1/2 reversion mutations. Somatic mutations with the potential to cause PARPi resistance were annotated using CRISPR screen data and other functional analyses describing genes that alter PARPi synthetic lethality. Results: The most common resistance mechanism was BRCA1/2 reversion mutation (51%; n=8 BRCA1m patients, n=10 BRCA2m patients). Most reversions (77%) occurred via deletions (BRCA1, 70%; BRCA2, 79%) and exhibited microhomology use at junctions (> 80% for both BRCA1 and BRCA2). In 14 patients, multiple concurrent reversion mutations were detected with VAFs ranging from 0.1-40% for BRCA1 and 0.05-18% for BRCA2. Changes in VAF over time indicated that different reversions in the same patient may impart different fitness advantages in the face of treatment. Loss-of-function mutations in the 53BP1-Shieldin pathway were identified in two BRCA1m patients, and VUS mutations in the pathway were seen in two further patients. In some patients, reversion mutations co-occurred with either 53BP1-Shieldin pathway mutations or with replication fork stability mutations (PAXIP1 in BRCA2m patients) - indicating concurrent but mechanistically distinct forms of resistance develop in the same patient. We isolated a PDX model from one patient that exhibits resistance via both BRCA1 reversion and loss of 53BP1, allowing this phenomenon to be modelled in more detail. We also detected BRCA1 methylation in ctDNA in a patient with a somatic rearrangement in BRCA1. Conclusions: Liquid biopsy profiling of PARPi-resistance breast cancer patients indicates that many patients develop multiple reversion mutations, and that alterations in the 53BP1-Shieldin pathway are present but less frequent. The co-occurrence of 53BP1-Shieldin pathway mutations and reversion mutations suggests parallel mechanisms of resistance can operate in the same patient. Citation Format: Elizabeth Harvey-Jones, Maya Raghunandan, Luisa Robbez-Masson, Alaguthurai Thanussuyah, Roberta Liccardo, Arielle Yablonovitch, Mingyang Cai, Leylah Drusbosky, Michael Dorschner, Lorena Magraner Pardo, Rebecca Marlow, Asha Konde, Jennifer Trendell, John Alexander, Syed Haider, Chris Starling, Ioannis Roxanis, Jennifer Yen, Stephen J. Pettitt, Christopher J. Lord, Andrew N. Tutt. Longitudinal analysis of PARP inhibitor and platinum resistance in BRCA1/2m breast cancer using liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6094.

Glioblastoma multiforme (GBM) heterogeneity causes a greater number of deaths than any other brain tumor, despite the availability of alkylating chemotherapy. GBM stem-like cells (GSCs) contribute to GBM complexity and chemoresistance, but it remains challenging to identify and target GSCs or factors that control their activity. Here, we identified a specific GSC subset and show that activity of these cells is positively regulated by stabilization of methyl CpG binding domain 3 (MBD3) protein. MBD3 binds to CK1A and to BTRCP E3 ubiquitin ligase, triggering MBD3 degradation, suggesting that modulating this circuit could antagonize GBM recurrence. Accordingly, xenograft mice treated with the CK1A activator pyrvinium pamoate (Pyr-Pam) showed enhanced MBD3 degradation in cells expressing high levels of O(6)-methylguanine-DNA methyltransferase (MGMT) and in GSCs, overcoming temozolomide chemoresistance. Pyr-Pam blocked recruitment of MBD3 and the repressive nucleosome remodeling and deacetylase (NuRD) complex to neurogenesis-associated gene loci and increased acetyl–histone H3 activity and GSC differentiation. We conclude that CK1A/BTRCP/MBD3/NuRD signaling modulates GSC activation and malignancy, and that targeting this signaling could suppress GSC proliferation and GBM recurrence.

Summary Both 3D chromatin architecture and long non-coding RNAs (lncRNAs) play essential roles in pluripotency maintenance. However, whether lncRNAs are involved in organizing 3D chromatin structure remains largely unexplored. We identified 39 lncRNAs bound by Klf4, among which we further revealed the 5430416N02Rik promoter is a chromatin interaction hub. Knockout of the 5430416N02Rik locus reduces the proliferation rate of embryonic stem cells (ESCs). Moreover, deleting both the promoter and the gene body of 5430416N02Rik causes a more severe proliferation defect and has a more profound impact on the transcriptome than deleting the gene body alone. The reduced proliferation of the 5430416N02Rik locus knockout ESCs is mainly due to the downregulation of Mid1, the expression of which requires the inter-chromosomal interaction between Mid1 and 5430416N02Rik loci. In summary, our data demonstrated that the lncRNA 5430416N02Rik gene locus maintains the fast proliferation of ESCs by activating the expression of Mid1 through chromatin interaction., Highlights • lncRNA 5430416N02Rik participates in organizing 3D chromatin architecture • lncRNA gene 5430416N02Rik promoter is a chromatin interaction hub • Knockout of 5430416N02Rik locus reduces the proliferation rate of ESCs • Interaction between 5430416N02Rik and Mid1 loci activates Mid1 transcription, In this article, Chen and Lu and colleagues show that 5430416N02Rik, a long non-coding RNA (lncRNA) gene, is involved in organizing 3D chromatin structure in embryonic stem cells (ESCs). It is revealed that 5430416N02Rik gene serves as the chromatin interaction hub. In addition, 5430416N02Rik gene locus maintains the fast proliferation of ESCs by activating the expression of Mid1 through chromatin interaction.

OBJECTIVE: To investigate the effect of inverse ratio ventilation (IRV) combined with positive end-expiratory pressure (PEEP) in infants undergoing thoracoscopic surgery with single lung ventilation (OLV) for lung cystadenomas. METHODS: A total of 66 infants undergoing thoracoscopic surgery with OLV for lung cystadenomas in our hospital from February, 2018 to February, 2019 were randomized into conventional ventilation groups (group N, n=33) and inverse ventilation group (group R, n=33). Hemodynamics and respiratory parameters of the infants were recorded and arterial blood gas analysis was performed at 15 min after two lung ventilation (TLV) (T(1)), OLV30 min (T(2)), OLV60 min (T(3)), and 15 min after recovery of TLV (T(4)). Bronchoalveolar lavage fluid was collected before and after surgery to detect the expression level of advanced glycation end product receptor (RAGE). RESULTS: Sixty-three infants were finally included in this study. At T(2) and T(3), Cdyn, PaO(2) and OI in group R were significantly higher (P < 0.05) and Ppeak, PaCO(2) and PA-aO(2) were significantly lower than those in group N (P < 0.05). There was no significant difference in HR or MAP between the two groups at T(2) and T(3) (P > 0.05). The level of RAGE significantly increased after the surgery in both groups (P < 0.05), and was significantly lower in R group than in N group (P < 0.05). CONCLUSION: In infants undergoing thoracoscopic surgery with OLV for pulmonary cystadenoma, appropriate IRV combined with PEEP does not affect hemodynamic stability and can increases pulmonary compliance, reduce the peak pressure, and improve oxygenation to provide pulmonary protection.

Regional specification is critical for skin development, regeneration, and evolution. The contribution of epigenetics in this process remains unknown. Here, using avian epidermis, we find two major strategies regulate β-keratin gene clusters. (1) Over the body, macro-regional specificities (scales, feathers, claws, etc.) established by typical enhancers control five subclusters located within the epidermal differentiation complex on chromosome 25; (2) within a feather, micro-regional specificities are orchestrated by temporospatial chromatin looping of the feather β-keratin gene cluster on chromosome 27. Analyses suggest a three-factor model for regional specification: competence factors (e.g., AP1) make chromatin accessible, regional specifiers (e.g., Zic1) target specific genome regions, and chromatin regulators (e.g., CTCF and SATBs) establish looping configurations. Gene perturbations disrupt morphogenesis and histo-differentiation. This chicken skin paradigm advances our understanding of how regulation of big gene clusters can set up a two-dimensional body surface map.

The rs55958994-associated enhancer regulates prostate cancer progression by long-range regulation of multiple target genes., Genome-wide association studies identified single-nucleotide polymorphism (SNP) rs55958994 as a significant variant associated with increased susceptibility to prostate cancer. However, the mechanisms by which this SNP mediates increased risk to cancer are still unknown. In this study, we show that this variant is located in an enhancer active in prostate cancer cells. Deletion of this enhancer from prostate tumor cells resulted in decreased tumor initiation, tumor growth, and invasive migration, as well as a loss of stem-like cells. Using a combination of capture chromosome conformation capture (Capture-C) and RNA sequencing, we identified genes on the same and different chromosomes as targets regulated by the enhancer. Furthermore, we show that expression of individual candidate target genes in an enhancer-deleted cell line rescued different aspects of tumorigenesis. Our data suggest that the rs55958994-associated enhancer affects prostate cancer progression by influencing expression of multiple genes via long-range chromatin interactions.

Kruppel-like factor 4 (Klf4) is a zinc-finger-containing protein that plays a critical role in diverse cellular physiology. While most of these functions attribute to its role as a transcription factor, it is postulated that Klf4 may play a role other than transcriptional regulation. Here we demonstrate that Klf4 loss in neural progenitor cells (NPCs) leads to increased neurogenesis and reduced self-renewal in mice. In addition, Klf4 interacts with RNA-binding protein Staufen1 (Stau1) and RNA helicase Ddx5/17. They function together as a complex to maintain NPC self-renewal. We report that Klf4 promotes Stau1 recruitment to the 3′-untranslated region of neurogenesis-associated mRNAs, increasing Stau1-mediated mRNA decay (SMD) of these transcripts. Stau1 depletion abrogated SMD of target mRNAs and rescued neurogenesis defects in Klf4-overexpressing NPCs. Furthermore, Ddx5/17 knockdown significantly blocked Klf4-mediated mRNA degradation. Our results highlight a novel molecular mechanism underlying stability of neurogenesis-associated mRNAs controlled by the Klf4/Ddx5/17/Stau1 axis during mammalian corticogenesis., While being known as a transcription factor, Kruppel-like factor 4 (Klf4) may have other molecular functions. This study shows that Klf4 in neural progenitor cells regulate neurogenesis and self-renewal by interacting with RNA-binding protein Staufen1 and RNA helicase Ddx5/17 to control mRNA decay.

The receptor-like tyrosine kinase (Ryk), a Wnt receptor, is important for cell fate determination during corticogenesis. During neuronal differentiation, the Ryk intracellular domain (ICD) is cleaved. Cleavage of Ryk and nuclear translocation of Ryk-ICD are required for neuronal differentiation. However, the mechanism of translocation and how it regulates neuronal differentiation remain unclear. Here, we identified Smek1 and Smek2 as Ryk-ICD partners that regulate its nuclear localization and function together with Ryk-ICD in the nucleus through chromatin recruitment and gene transcription regulation. Smek1/2 double knockout mice displayed pronounced defects in the production of cortical neurons, especially interneurons, while the neural stem cell population increased. In addition, both Smek and Ryk-ICD bound to the Dlx1/2 intergenic regulator element and were involved in its transcriptional regulation. These findings demonstrate a mechanism of the Ryk signaling pathway in which Smek1/2 and Ryk-ICD work together to mediate neural cell fate during corticogenesis.

The fate of neural progenitor cells (NPCs) during corticogenesis is determined by a complex interplay of genetic or epigenetic components, but the underlying mechanism is incompletely understood. Here, we demonstrate that Suppressor of Mek null (Smek) interact with methyl-CpG–binding domain 3 (Mbd3) and the complex plays a critical role in self-renewal and neuronal differentiation of NPCs. We found that Smek promotes Mbd3 polyubiquitylation and degradation, blocking recruitment of the repressive Mbd3/nucleosome remodeling and deacetylase (NuRD) complex at the neurogenesis-associated gene loci, and, as a consequence, increasing acetyl histone H3 activity and cortical neurogenesis. Furthermore, overexpression of Mbd3 significantly blocked neuronal differentiation of NPCs, and Mbd3 depletion rescued neurogenesis defects seen in Smek1/2 knockout mice. These results reveal a novel molecular mechanism underlying Smek/Mbd3/NuRD axis-mediated control of NPCs’ self-renewal and neuronal differentiation during mammalian corticogenesis., Author summary Neural progenitor cells are self-renewing, multipotent cells that generate major neural cell types, including neurons and glia. Their fate during development of the cerebral cortex is determined by a complex interplay of genetic and epigenetic components. It has been shown that Suppressor of Mek null (Smek) proteins—which are evolutionarily conserved—play a role during the asymmetric cell division of neuroblasts in invertebrates. Methyl-CpG–binding domain 3 (Mbd3) protein, a core component of the repressive nucleosome remodeling and deacetylase (NuRD) complex, is an important epigenetic regulator that plays an essential role in mammalian development. In this study, we discovered that Smek interacts with Mbd3 and promotes its degradation via a posttranslational modification called polyubiquitylation. Degradation of Mb3, in turn, blocks recruitment of Mbd3/NuRD complex on target gene promoters, leading to an increase in neuronal differentiation during cortical development. This study not only elucidates a distinct mechanism for Smek-mediated neuronal differentiation but also identifies Smek as a negative regulator of the Mbd3 protein during cortical brain development.

Summary: Circularized Chromosome Conformation Capture followed by deep sequencing (4C-Seq) is a powerful technique to identify genome-wide partners interacting with a pre-specified genomic locus. Here, we present a computational and statistical approach to analyze 4C-Seq data generated from both enzyme digestion and sonication fragmentation-based methods. We implemented a command line software tool and a web interface called w4CSeq, which takes in the raw 4C sequencing data (FASTQ files) as input, performs automated statistical analysis and presents results in a user-friendly manner. Besides providing users with the list of candidate interacting sites/regions, w4CSeq generates figures showing genome-wide distribution of interacting regions, and sketches the enrichment of key features such as TSSs, TTSs, CpG sites and DNA replication timing around 4C sites. Availability and Implementation: Users can establish their own web server by downloading source codes at https://github.com/WGLab/w4CSeq . Additionally, a demo web server is available at http://w4cseq.wglab.org . Contact: kaiwang@usc.edu or wangelu@usc.edu Supplementary information : Supplementary data are available at Bioinformatics online.

Genome-wide association studies (GWAS) have identified >100 independent susceptibility loci for prostate cancer, including the hot spot at 8q24. However, how genetic variants at this locus confer disease risk hasn’t been fully characterized. Using circularized chromosome conformation capture (4C) coupled with next-generation sequencing and an enhancer at 8q24 as “bait”, we identified genome-wide partners interacting with this enhancer in cell lines LNCaP and C4-2B. These 4C-identified regions are distributed in open nuclear compartments, featuring active histone marks (H3K4me1, H3K4me2 and H3K27Ac). Transcription factors NKX3-1, FOXA1 and AR (androgen receptor) tend to occupy these 4C regions. We identified genes located at the interacting regions, and found them linked to positive regulation of mesenchymal cell proliferation in LNCaP and C4-2B, and several pathways (TGF beta signaling pathway in LNCaP and p53 pathway in C4-2B). Common genes (e.g. MYC and POU5F1B) were identified in both prostate cancer cell lines. However, each cell line also had exclusive genes (e.g. ELAC2 and PTEN in LNCaP and BRCA2 and ZFHX3 in C4-2B). In addition, BCL-2 identified in C4-2B might contribute to the progression of androgen-refractory prostate cancer. Overall, our work reveals key genes and pathways involved in prostate cancer onset and progression.

Roots and phonemes are two important ingredients (but not independent ones) when learning the Chinese language. In order to optimize the learning strategy, various key nodes mining algorithms are implemented both in the root network (RN) and phoneme network (PN) of modern Chinese characters. The lists of important roots and phonemes, and eventually the important characters are dug out and suggested. Rather than the commonly used frequency dictionary of characters, one would find that results from the key nodes mining are more systematic. Moreover, roots and phonemes are studied from perspective of the multi-layer network, in the interest of exploring the correlation between them, which are also very useful when learning the Chinese language.

Genome structure or nuclear organization has fascinated researchers investigating genome function. Recently, much effort has gone into defining relationships between specific genome structures and gene expression in pluripotent cells. We previously analyzed chromosomal interactions of the endogenous Oct4 distal enhancer in pluripotent cells. Here, we derive ES and iPS cells from a transgenic Oct4 distal enhancer reporter mouse. Using sonication-based Circularized Chromosome Conformation Capture (4C) coupled with next generation sequencing, we determined and compared the genome-wide interactome of the endogenous and transgenic Oct4 distal enhancers. Integrative genomic analysis indicated that the transgenic enhancer binds to a similar set of loci and shares similar key enrichment profiles with its endogenous counterpart. Both the endogenous and transgenic Oct4 enhancer interacting loci were enriched in the open nucleus compartment, which is associated with active histone marks (H3K4me1, H3K27ac, H3K4me3 and H3K9ac), active cis-regulatory sequences (DNA hypersensitivity sites (DHS)), 5-hydroxymethylcytosine (5-hmc) and early DNA replication domains. In addition, binding of some pluripotency-related transcription factors was consistently enriched in our 4C sites and genes in those sites were generally more highly expressed. Overall, our work reveals critical features that may function in gene expression regulation in mouse pluripotent cells.