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Abstract The three major anatomic regions of the human kidney include the cortex, medulla and papilla, with different functions and vulnerabilities to kidney diseases. Epigenetic mechanisms underlying these anatomic structures are incompletely understood. Here, we performed chromatin conformation capture with Hi-C and histone modification H3K4me3/H3K27me3 Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing on the kidney cortex, medulla and papilla dissected from one individual donor. Nuclear suspensions were generated from each region and split subjected to paired Hi-C and CUT&RUN sequencing. We evaluated the quality of next-generation sequencing data, Hi-C chromatin contact matrices and CUT&RUN peak calling. H3K4me3 and H3K27me3 histone modifications represent active and repressive gene transcription, respectively, and differences in chromatin conformation between kidney regions can be analyzed with this dataset. All raw and processed data files are publicly available, allowing researchers to survey the epigenetic landscape across regional human kidney anatomy.

Abstract Background The potential involvement of circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m6A-modified circMARK2 and its role in WT progression. Methods We identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining. Results CircMARK2, upregulated in WT tissues, was found to be m6A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates. Conclusions Our study provides the first comprehensive evidence that m6A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m6A modification in pediatric renal cancer.

ObjectiveThis study explores design methods for explosion-resistant energy-absorbing core elements in cabin subject to the joint effects of blast-induced shockwave and quasi-static barometric pressure. MethodsFinite element numerical calculations are used to analyze the characteristics of flexing-type and yielding-type energy-absorbing elements in the above conditions in terms of load weakening factor, energy absorption, deformation damage mode and maximum displacement at the center point of the lower panel, and the protective performance characteristics are obtained. On this basis, a dual-stiffness energy-absorbing element is proposed to resist the combined action of blast-induced shockwave and quasi-static barometric pressure and its performance is then compared with that of the two energy-absorbing elements. ResultsUnder the action of blast-induced shockwave, the load dissipation and energy absorption ability of the yielding-type energy-absorbing element is better than that of the flexing-type energy-absorbing element; under the action of quasi-static barometric pressure, the deformation of the yielding-type energy-absorbing element is greatly affected by the time of action of the load, while the deformation of the flexing-type energy-absorbing element is almost unaffected by the time of action; under the combined action of blast-induced shockwave and quasi-static barometric pressure, the protection ability of the dual-stiffness energy-absorbing element is better than that of the single-stiffness flexing-type and yielding-type energy-absorbing elements. ConclusionThe results of this study can provide a new approach to the design of explosion-resistant configurations in cabins.

As urbanization progresses and the impacts of climate change become more pronounced, urban flooding has emerged as a critical challenge for resilient cities, particularly concerning urban underground spaces where flooding can lead to significant loss of life and property. Drawing upon a comprehensive review of global research on underground space flood simulation and evacuation, this paper undertakes the modelling of inundation in a substantial underground area during the extraordinary rainfall event on 7 September 2023, in Shenzhen, China. Specifically, it introduces a two-step method to simulate the coupled surface-underground inundation process with high accuracy. The study simulates the inflow processes in three types of underground spaces: parking lots, metro stations, and underpasses. Utilizing the specific force per unit width evaluation, the research examines how varying flood barrier heights influence evacuation time and inundation risk. Subsequently, the paper proposes corresponding evacuation strategies based on the obtained findings. By highlighting the vulnerability of urban underground spaces to flooding, the study underscores the urgent need for further research in this domain. HIGHLIGHTS This study conducts a systematic review of existing research findings on urban underground space inundation, categorizing them into four types.; This article employs an authentic case to simulate the water ingress process and utilizes specific force per unit width evaluation to assess the associated risks.; Tailored strategies for addressing diverse underground spaces are proposed in this paper.;

Abstract Cryptophytes are ancestral photosynthetic organisms evolved from red algae through secondary endosymbiosis. They have developed alloxanthin-chlorophyll a/c2-binding proteins (ACPs) as light-harvesting complexes (LHCs). The distinctive properties of cryptophytes contribute to efficient oxygenic photosynthesis and underscore the evolutionary relationships of red-lineage plastids. Here we present the cryo-electron microscopy structure of the Photosystem II (PSII)–ACPII supercomplex from the cryptophyte Chroomonas placoidea. The structure includes a PSII dimer and twelve ACPII monomers forming four linear trimers. These trimers structurally resemble red algae LHCs and cryptophyte ACPI trimers that associate with Photosystem I (PSI), suggesting their close evolutionary links. We also determine a Chl a-binding subunit, Psb-γ, essential for stabilizing PSII–ACPII association. Furthermore, computational calculation provides insights into the excitation energy transfer pathways. Our study lays a solid structural foundation for understanding the light-energy capture and transfer in cryptophyte PSII–ACPII, evolutionary variations in PSII–LHCII, and the origin of red-lineage LHCIIs.

Abstract Radio‐echo sounding (RES) shows large‐scale englacial stratigraphic folds are ubiquitous in Greenland's ice sheet. However, there is no consensus yet on how these folds form. Here, we use the full‐Stokes code Underworld2 to simulate ice movements in three‐dimensional convergent flow, mainly considering ice anisotropy due to a crystallographic preferred orientation, vertical viscosity and density gradients in ice layers, and bedrock topography. Our simulated folds show complex patterns and are classified into: large‐scale folds (>100 m amplitude), small‐scale folds (<

Abstract Renal proximal tubule epithelial cells have considerable intrinsic repair capacity following injury. However, a fraction of injured proximal tubule cells fails to undergo normal repair and assumes a proinflammatory and profibrotic phenotype that may promote fibrosis and chronic kidney disease. The healthy to failed repair change is marked by cell state-specific transcriptomic and epigenomic changes. Single nucleus joint RNA- and ATAC-seq sequencing offers an opportunity to study the gene regulatory networks underpinning these changes in order to identify key regulatory drivers. We develop a regularized regression approach to construct genome-wide parametric gene regulatory networks using multiomic datasets. We generate a single nucleus multiomic dataset from seven adult human kidney samples and apply our method to study drivers of a failed injury response associated with kidney disease. We demonstrate that our approach is a highly effective tool for predicting key cis- and trans-regulatory elements underpinning the healthy to failed repair transition and use it to identify NFAT5 as a driver of the maladaptive proximal tubule state.

BackgroundHead and neck cancer acts as the sixth most common malignant tumor worldwide with an increasing incidence. The needs and methods of its rehabilitation are diverse and constantly evolving.ObjectiveThis study aims to provide an in-depth depiction and visualization of the knowledge structure, hotspots, and emerging trends within the domain in the past 30 years through utilizing bibliometric analysis.MethodsThe literature about rehabilitation for head and neck cancer in Web of Science was collected. CiteSpace and VOSviewer were used to analyze main countries, institutions, authors, journals, subject hotspots, trends, frontiers, etc.ResultsA total of 1869 papers have been published since 1994. These publications were written by 874 authors from 514 institutions in 74 countries. The United States published 397 papers in this field and ranked first. Head & Neck is the most widely published journal, with Finizia, Caterina as the core author. The main keyword clustering includes terms such as #0 mandibular reconstruction (2009); #1 functional impairment (2014); #2 device lifetime (2006); #3 head and neck cancer (2003); #4 maxillofacial prosthetics (2004); #5 squamous cell carcinoma (2002); #6 readiness for return to work (2009); #7 total laryngopharyngectomy (2004). The current research frontier that has been sustained is “survivors”, “reliability”, and “meta analysis”.ConclusionWe reveal the current status, hotspots, and trends in the field of rehabilitation for head and neck cancer. And we provided new academic insights into the characteristics and limitations of the field’s development.

BackgroundMolecular glues, which reshape E3 ligase receptors to promote targeted protein degradation, are emerging as a promising therapeutic strategy, particularly in oncology, driven by rapidly advancing insights into their mechanisms and structural properties.ObjectiveThis study aims to offer an insightful depiction and visualization of the knowledge structure, prevalent themes, and emerging trends within the domain since the year 2000, employing bibliometric analysis to achieve this goal.MethodsTo conduct this research, a comprehensive collection of literature on molecular glues was sourced from the Web of Science database. Subsequently, the data underwent analysis utilizing CiteSpace and VOSviewer tools, enabling the identification of pivotal countries, institutions, authors, and journals, as well as the delineation of subject hotspots, trends, and the forefront of research in this evolving field.ResultSince 2000, 388 papers on molecular glues have been published, with a notable increase to an annual average of 43 articles post-2018. This research, contributed by 506 authors across 329 institutions, highlights the United States and China as leading nations in output, with 122 and 104 articles respectively. Takuzo Aida, Luc Brunsveld, and Christian Ottmann are identified as key authors. Nature emerges as the foremost publication venue, while the Chinese Academy of Sciences is the top contributing institution, underscoring the global engagement and interdisciplinary nature of molecular glue research. This study identified 19 distinct research clusters within the molecular glues domain.ConclusionWe reveal the current status, hotspots, and trends of molecular glue research since 2000, offering insights and novel scholarly perspectives on the field’s prevailing limitations.

Among the known planar pentacoordinate atoms, chlorine is missing due to its large radius and high electronegativity. Herein, we report the first star-like superhalogen anion D5h Cl©Li5Cl5− (1), which contains a planar pentacoordinate chlorine (ppCl) at the center. Computer structural searches and high-level calculations reveal that 1 is a true global minimum (GM) on the potential energy surfaces. Molecular dynamics simulations indicate it is kinetically stable against isomerization or decomposition. Although detailed chemical bonding analyses reveal one delocalized 6c-2e σ bond over the Cl©Li5 central unit and five delocalized 3c-2e σ bonds along the periphery, while aromaticity has very little beneficial effect on stability, instead, ionic interaction dominates the stability of the system. More encouragingly, with the large HOMO–LUMO energy gap of 7.66 eV and vertical detachment energy of 7.87 eV, the highly chemically inert 1 can be viewed as a typical superhalogen anion and is possible to be synthesized and characterized in future experiments.

The flowering period of rice significantly impacts variety adaptability and yield formation. Properly shortening the reproductive period of rice varieties can expand their ecological range without significant yield reduction. Targeted genome editing, like CRISPR/Cas9, is an ideal tool to fine-tune rice growth stages and boost yield synergistically. In this study, we developed a CRISPR/Cas9-mediated multiplex genome-editing vector containing five genes related to three traits, Hd2, Ghd7, and DTH8 (flowering-stage genes), along with the recessive rice blast resistance gene Pi21 and the aromatic gene BADH2. This vector was introduced into the high-quality japonica rice variety in Zhejiang province, Jiahe212 (JH212), resulting in 34 T0 plants with various effective mutations. Among the 17 mutant T1 lines, several displayed diverse flowering dates, but most exhibited undesirable agronomic traits. Notably, three homozygous mutant lines (JH-C15, JH-C18, and JH-C31) showed slightly earlier flowering dates without significant differences in yield-related traits compared to JH212. Through special Hyg and Cas marker selection of T2 plants, we identified seven, six, and two fragrant glutinous plants devoid of transgenic components. These single plants will serve as sib lines of JH212 and potential resources for breeding applications, including maintenance lines for indica–japonica interspecific three-line hybrid rice. In summary, our research lays the foundation for the creation of short-growth-period CMS (cytoplasmic male sterility, CMS) lines, and also provides materials and a theoretical basis for indica–japonica interspecific hybrid rice breeding with wider adaptability.

Background. Chronic obstructive pulmonary disease (COPD) is a common respiratory disease. Currently, no specific treatment strategy has been established; therefore, finding new treatment methods is essential. Clinically, Shenqi Huatan Decoction (SQHT) is a traditional Chinese medicinal formula for COPD treatment; however, its mechanism of action in treatment needs to be clarified. Methods. The COPD rat model was replicated by cigarette smoking and tracheal injection using the LPS method. The control group and the SQHT groups were treated with dexamethasone and SQHT by gavage, respectively. After treatment, superoxide dismutase (SOD) serum levels, total antioxidant capacity (TAOC), lipid peroxidation, and malondialdehyde (MDA) were detected by enzyme-linked immunosorbent assay (ELISA). Activated protein kinase alpha (AMPK-α), forkhead transcription factor O3a (FOXO3a), manganese SOD (MnSOD), and peroxisome proliferator-activated receptor gamma (PPARγ) were detected using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot. Microribonucleic acid and protein expression levels were measured, and pathological changes in lung tissue were observed using hematoxylin and eosin staining. Results. The pathological findings suggested that SQHT substantially affects COPD treatment by enhancing alveolar fusion and reducing emphysema. ELISA results showed that SQHT could lower the blood levels of MDA and lipid peroxide and raise SOD and TAOC levels, suggesting that it could lessen oxidative stress. In the lung tissue of rats with COPD, large doses of SQHT intervention dramatically increased AMPK protein expression, AMPK-α, FOXO3a, MnSOD, and PPARγ, indicating that SQHT may reduce oxidative stress by activating the PPARγ-mediated AMPK/FOXO3a signaling pathway. Similar results were obtained using RT-qPCR. Conclusion. SQHT is effective for COPD treatment. The mechanism of action may be related to the activation of the PPARγ-mediated AMPK/FOXO3a signaling pathway to improve oxidative stress in lung tissue.

Background & Aims: Current antiviral drugs, including nucleoside analogs and interferon, fail to eliminate the HBV covalently closed circular DNA (cccDNA), which serves as a transcript template in infected hepatocytes. Silencing the HBV X protein, which plays a crucial role in cccDNA transcription, is a promising approach to inhibit HBV replication. Therefore, the identification of novel compounds that can inhibit HBx-mediated cccDNA transcription is critical. Methods: Initially, a compound library consisting of 715 monomers derived from traditional Chinese medicines known for their liver-protecting properties was established. Then, MTT assays were used to determine the cytotoxicity of each compound. The effect of candidates on Flag-HBx expression was examined by real-time PCR and western blotting in Flag-HBx transfected HepG2-NTCP cells. Ultimately, the antiviral effect of gambogic acid (GA) on HBV was observed in HBV-infected HepG2-NTCP cells. Mechanistically, the functional role of DTX1 in GA-induced HBV inhibition was examined using RNA-seq. Finally, the antiviral effect of GA was estimated in vivo. Results: Gambogic acid (GA), a natural bioactive compound with a myriad of biological activities, markedly reduced Flag-HBx expression. Potent and dose-dependent reductions in extracellular HBV RNAs, HBV DNA, HBsAg, HBeAg and HBc protein were discovered three days after GA treatment in HBV-infected cells, accompanied by the absence of significant cytotoxicity. Furthermore, our research revealed that GA exhibited a dose-dependent inhibition of HBx expression, which is a pleiotropic protein required for HBV infection in vivo. We explored the mechanisms underlying GA-mediated inhibition of HBV and confirmed that this inhibition is accomplished by upregulating the expression of the DTX1 gene and boosting the Notch signaling pathway. Finally, the inhibitory effect of GA on HBV replication was tested in vivo using a mouse model of hepatitis B virus recombinant cccDNA. Conclusions: Herein, we discovered GA, which is a natural bioactive compound that targets HBx to inhibit hepatitis B virus replication by activating the DTX1-Notch signaling pathway.

Abstract Post-translational modifications (PTMs) couple feed-fast cycles to diurnal rhythms. However, it remains largely uncharacterized whether and how meal timing organizes diurnal rhythms beyond the transcriptome. Here, we systematically profile the daily rhythms of the proteome, four PTMs (phosphorylation, ubiquitylation, succinylation and N-glycosylation) and the lipidome in the liver from young female mice subjected to either day/sleep time-restricted feeding (DRF) or night/wake time-restricted feeding (NRF). We detect robust daily rhythms among different layers of omics with phosphorylation the most nutrient-responsive and succinylation the least. Integrative analyses reveal that clock regulation of fatty acid metabolism represents a key diurnal feature that is reset by meal timing, as indicated by the rhythmic phosphorylation of the circadian repressor PERIOD2 at Ser971 (PER2-pSer971). We confirm that PER2-pSer971 is activated by nutrient availability in vivo. Together, this dataset represents a comprehensive resource detailing the proteomic and lipidomic responses by the liver to alterations in meal timing.

Here, the single-target parameterization of alternatives to leading-edge noise is carried out using analytical models based on the Wiener–Hopf technique. Four leading-edge serration profiles with different frequencies, amplitudes, and phases are implemented to aid the understanding of sound suppression mechanisms. The effects of the serrated shape factor, wavelength, and amplitude are analyzed at tip-to-root ratios of 0.5, 1, and 2, respectively. An effective double-wavelength sinusoidal serration design can substantially reduce the noise emissions of 5.2 dB at h¯ = 2. Additionally, compared to single-wavelength serrations, an additional 1.47 dB noise reduction effect can be obtained by double-wavelength serrations under the appropriate design parameters. The surface pressure and phase distribution of different spanwise-varying leading edges indicate that the phase interference effect affected by source-radiated noise reduction is enhanced by this serration at the hills for serrations with a small curvature, and noise emission in the low-frequency band is more effectively suppressed. The sharper the serration is, the more conducive it is to a reduction in high-frequency noise. Nevertheless, the effectiveness of serrations is usually partially limited by the non-negligible trailing-edge self-noise. The sound source intensity of the root is decreased by the ogee-shaped serrations with a large curvature transition. A secondary noise reduction mechanism with a local source cut-off effect caused by nonlinearity is demonstrated.

Abstract Cytokine monitoring has attracted great attention due to its significance in the diagnosis and treatment of many diseases, such as tumors, microbial infections, and immunological diseases. Enzyme‐linked immunosorbent assay (ELISA) is one of the most popular methods in cytokine detection, ascribing to the lavish signal amplification methods in the ELISA platform. In addition to classical enzymes, other signal amplifiers such as fluorescent probes, artificial nano‐enzymes, and photothermal reagents have been applied to reduce the detection limit and produce more sensitive ELISA kits. Due to the accumulative effect of heat, photothermal reagents are promising materials in the signal amplification of ELISA. However, the lack of efficient photothermal generation material at an aggregate scale may delay the further development of this area. In this contribution, based on an efficient organic photothermal aggregate material, an enzyme‐free photothermally amplified fluorescent immunosorbent assay system consisting of an assay microfluidic chip and detecting platform was developed. The photothermal nanoparticles with highly efficient photothermal conversion by harvesting energy via excited‐state intramolecular motions and enlarging molar absorptivity were successfully prepared. The detection concentration at 50 pg/mL of interleukin‐2 was achieved, realizing a signal improvement of detection limits by 20‐fold compared to that of previously reported photothermal ELISA. The microscopic imaging integrated with plane sweeping technology provided high spatial resolution and precision, indicating the potential of achieving high throughput profiling at the microscale. Moreover, as an alternative excitation source, light‐emitting diode not only provided a more affordable and miniaturized detection system but also revealed the great feasibility of intramolecular motion‐induced photothermy nanoparticles for biological analyses.

ABSTRACTBackground: Venous thromboembolism (VTE) can occur in children with COVID-19, and the efficacy and safety of prophylactic anticoagulant therapy are uncertain. This study aimed to assess the incidence of VTE in pediatric patients with COVID-19, the association of D-dimer with thrombus formation, and the effectiveness and safety of prophylactic anticoagulation treatment.Methods: We systematically searched databases from January 2020 to February 2023. A systematic review and meta-analysis were conducted to determine the incidence of VTE in children and evaluate the efficacy and safety of prophylactic anticoagulant therapy.Results: Thirteen cohort studies and one clinical trial were included. The pooled incidence rate of VTE in affected children was 1.5% (95% CI 0.4–2.9%). Children with D-dimer levels five times higher than normal had a higher risk of VTE (OR 4.92, 95% CI 1.60–15.11). Prophylactic anticoagulant therapy did not significantly reduce the risk of VTE (OR 1.35, 95% CI 0.74–2.49). The safety of prophylactic anticoagulant therapy was relatively high, with major bleeding and all-cause mortality rates below 0.1% (95% CI 0.0–0.2%).Conclusions: The incidence of VTE in children with COVID-19 is low, and prophylaxis based on ISTH standards is reasonable. Low-molecular-weight heparin (LMWH) for VTE prevention has a high level of safety. However, more high-quality studies are needed to understand the impact of anticoagulant therapy on VTE incidence in pediatric patients with COVID-19.

Abstract Boron and boron-based nanoclusters exhibit unique structural and bonding patterns in chemistry. Extensive density functional theory calculations performed in this work predict the mononuclear walnut-like C i C50B54 (1) (C2B10@C48B44), C 1 C50B54 (2) (CB11@C49B43), and S 10 C50B54 (3) (B12@C50B42) which contain one icosahedral-C n B12-n core (n = 0, 1, 2) at the center following the Wade’s skeletal electron counting rules and the approximately electron sufficient binuclear peanut-like C s C88B78 (4) ((C2B10)2@C84B58), C s C88B78 (5) ((CB11)2@C86B56), C s C88B78 (6) ((B12)2@C88B54), C s B180 (7) ((B12)2@B156), C s B182 (8) ((B12)2@B158), and C s B184 (9) ((B12)2@B160) which encapsulate two interconnected C n B12-n icosahedrons inside. These novel core–shell borafullerene and borospherene nanoclusters appear to be the most stable species in thermodynamics in the corresponding cluster size ranges reported to date. Detailed bonding analyses indicate that the icosahedral B12 2−, CB11 −, and C2B10 cores in these core–shell structures possess the superatomic electronic configuration of 1S21P61D101F8, rendering spherical aromaticity and extra stability to the systems. Such superatomic icosahedral-C n B12-n stuffed borafullerenes and borospherenes with spherical aromaticity may serve as embryos to form bulk boron allotropes and their carbon-boron binary counterparts in bottom-up approaches.

Targeted protein degradation (TPD) has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell’s endogenous protein degradation machinery. However, the susceptibility of proteins for targeting by TPD approaches, termed “degradability”, is largely unknown. Here, we developed a machine learning model, model-free analysis of protein degradability (MAPD), to predict degradability from features intrinsic to protein targets. MAPD shows accurate performance in predicting kinases that are degradable by TPD compounds [with an area under the precision–recall curve (AUPRC) of 0.759 and an area under the receiver operating characteristic curve (AUROC) of 0.775] and is likely generalizable to independent non-kinase proteins. We found five features with statistical significance to achieve optimal prediction, with ubiquitination potential being the most predictive. By structural modeling, we found that E2-accessible ubiquitination sites, but not lysine residues in general, are particularly associated with kinase degradability. Finally, we extended MAPD predictions to the entire proteome to find 964 disease-causing proteins (including proteins encoded by 278 cancer genes) that may be tractable to TPD drug development.

The nanoscale measurement of electronic bandgaps is crucial for material characterization, but it is usually performed under cryogenic conditions. Here, the authors report a scanning probe method to determine the electronic bandgap of 2D semiconductors at the nanoscale by monitoring their quantum capacitance under ambient conditions.