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Abstract N 6-methyladenosine (m6A) is involved in most biological processes and actively participates in the regulation of reproduction. According to recent research, long non-coding RNAs (lncRNAs) and their m6A modifications are involved in reproductive diseases. In the present study, using m6A-modified RNA immunoprecipitation sequencing (m6A-seq), we established the m6A methylation transcription profiles in patients with recurrent implantation failure (RIF) for the first time. There were 1443 significantly upregulated m6A peaks and 425 significantly downregulated m6A peaks in RIF. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that genes associated with differentially methylated lncRNAs are involved in the p53 signalling pathway and amino acid metabolism. The competing endogenous RNA network revealed a regulatory relationship between lncRNAs, microRNAs and messenger RNAs. We verified the m6A methylation abundances of lncRNAs by using m6A-RNA immunoprecipitation (MeRIP)–real-time polymerase chain reaction. This study lays a foundation for further exploration of the potential role of m6A modification in the pathogenesis of RIF.

In this study, a novel composite was engineered by integrating Zr-MOF (NH2-UIO-66) with MXene layers through electrostatic self-assembly. Under simulated sunlight and at 80 °C, this composite material achieved nearly complete conversion of low-concentration atmospheric CO2 to CO and CH4 without additional sacrificial agents or alkaline absorption liquids, marking one of the few reports demonstrating near-complete reduction of low-concentration CO2 directly from the air. For high-concentration CO2 in industrial flue gas, the composite utilized residual heat at 80 °C without additional energy input, exhibiting excellent CO2 reduction efficiency with CO and CH4 production rates of 127 μmol·g-1·h-1 and 330 μmol·g-1·h-1, respectively, resulting in a total production rate 4.76 times higher than that in the air. Compared to most reports on thermocatalytic CO2 reduction (>300 °C), this material shows significant advantages below 100 °C. The performance improvement is attributed to the introduction of Zr-MOF, which provides additional active sites and reduces activation energy. Additionally, the localized surface plasmon resonance (LSPR) effect of MXene facilitates the migration of thermal charge carriers to Zr4+ sites within the MOF. Density Functional Theory (DFT) calculations validate these findings. Overall, Zr-MOF/MXene composite holds potential for reducing CO2 in air and industrial settings, advancing energy conversion and environmental management.

Abstract Introduction The rapid development of artificial intelligence (AI) in healthcare has exposed the unmet need for growing a multidisciplinary workforce that can collaborate effectively in the learning health systems. Maximizing the synergy among multiple teams is critical for Collaborative AI in Healthcare. Methods We have developed a series of data, tools, and educational resources for cultivating the next generation of multidisciplinary workforce for Collaborative AI in Healthcare. We built bulk‐natural language processing pipelines to extract structured information from clinical notes and stored them in common data models. We developed multimodal AI/machine learning (ML) tools and tutorials to enrich the toolbox of the multidisciplinary workforce to analyze multimodal healthcare data. We have created a fertile ground to cross‐pollinate clinicians and AI scientists and train the next generation of AI health workforce to collaborate effectively. Results Our work has democratized access to unstructured health information, AI/ML tools and resources for healthcare, and collaborative education resources. From 2017 to 2022, this has enabled studies in multiple clinical specialties resulting in 68 peer‐reviewed publications. In 2022, our cross‐discipline efforts converged and institutionalized into the Center for Collaborative AI in Healthcare. Conclusions Our Collaborative AI in Healthcare initiatives has created valuable educational and practical resources. They have enabled more clinicians, scientists, and hospital administrators to successfully apply AI methods in their daily research and practice, develop closer collaborations, and advanced the institution‐level learning health system.

Abstract Background The key to the prevention and treatment of Alzheimer’s disease (AD) is to be able to predict and diagnose AD at the preclinical or early stage, but the lack of a preclinical model of AD is the critical factor that causes this problem to remain unresolved. Methods We assessed 18 monkeys in vivo evaluation of pro-inflammatory cytokines and AD pathological biomarkers (n = 9 / type 2 diabetic mellitus (T2DM) group, age 20, fasting plasma glucose (FPG) ≥ 100 mg/dL, and n = 9 / negative control (NC) group, age 17, FPG

Abstract Recent studies have identified a previously uncharacterized protein C11orf53 (now named POU2AF2/OCA-T1), which functions as a robust co-activator of POU2F3, the master transcription factor which is critical for both normal and neoplastic tuft cell identity and viability. Here, we demonstrate that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements. Loss of POU2AF2 leads to an inhibition of active enhancer nearby genes, such as tuft cell identity genes, and a derepression of Polycomb-dependent poised enhancer nearby genes, which are critical for cell viability and differentiation. Mechanistically, depletion of POU2AF2 results in a global redistribution of the chromatin occupancy of the SWI/SNF complex, leading to a significant 3D genome structure change and a subsequent transcriptional reprogramming. Our genome-wide CRISPR screen further demonstrates that POU2AF2 depletion or SWI/SNF inhibition leads to a PTEN-dependent cell growth defect, highlighting a potential role of POU2AF2-SWI/SNF axis in small cell lung cancer (SCLC) pathogenesis. Additionally, pharmacological inhibition of SWI/SNF phenocopies POU2AF2 depletion in terms of gene expression alteration and cell viability decrease in SCLC-P subtype cells. Therefore, impeding POU2AF2-mediated transcriptional regulation represents a potential therapeutic approach for human SCLC therapy.

Abstract Motivated by hydraulic stimulation of enhanced geothermal systems, the present paper investigates the coupled thermo-hydro-mechanical response of a geothermal well imbedded in a thermoporoelastic medium, subjected to a non-isothermal fluid flux and convective cooling on the borehole surface. Our focus centers on the effect of local thermal non-equilibrium (LTNE) on the temporal-spatial evolution of temperatures, pore pressure, and stresses, where the solid and fluid phases have two distinct temperatures and local heat transfer between the two phases is addressed. We employ integral transform and load decomposition techniques to derive analytical solutions in the Laplace domain. This methodology allows us to disentangle and separate the individual contributions to changes in pore pressure and stresses from fluid injection and convective heat transfer. The results reveal that compared to the classical local thermal equilibrium model, the thermally induced pore pressure is slightly lower under LTNE conditions. The LTNE has a significant influence on the temporal evolution of thermally induced stresses, especially in the vicinity of the wellbore.

This paper is devoted to the study of a multi-criteria scheduling problem on unrelated processors with machines’ learning effect, with the goal of minimizing makespan, machine cost and maximal flow-time simultaneously, which is an NP-hard problem. An improved particle swarm optimization algorithm equipped with the overloaded operators, as well as a procedure of Levy flight, is proposed to generate the Pareto-optimal solutions. The experimental results show that the Levy flight strategy can effectively improve the performance of the algorithm, which can generate more non-dominated solutions, and slightly reduce the execution time of the process.

To mitigate the impact of singular values in voltage and current signals on regression results and achieve a more accurate delineation of harmonic responsibilities for both the system and users， this paper proposes a method for calculating system harmonic impedance based on partial least squares （PLS） equivalent weight regression. Utilizing harmonic voltage and current data from common connection points， the paper formulates a regression equation containing the sought-after parameters. The PLS is then employed to determine regression coefficients， which correspond to the harmonic impedance and harmonic voltage on the system side. These coefficients are used as initial values for iterative equivalent weight calculations. Then， the user’s harmonic emission level is deduced based on the iterative results. This approach overcomes the drawbacks of using the least squares solution as an initial value for iterative calculations， enhancing the precision of user’s harmonic emission level calculations. The accuracy of the proposed method is validated through simulation analysis in case studies.

The direct conversion of atmospheric CO2 into fuel via photocatalysis exhibits significant practical application value in advancing the carbon cycle. In this study, we established an electro-assisted photocatalytic system with dual compartments and interfaces, and coated Ag nanoparticles on the titanium nanotube arrays (TNTAs) by polydopamine modification. In the absence of sacrificial agent and alkali absorption liquid conditions, the stable, efficient and highly selective conversion of CO2 to CO at the gas-solid interface in ambient air was realized by photoelectric synergy. Specifically, with the assistance of potential, the CO formation rates reached 194.9 μmol h−1 m−2 and 103.9 μmol h−1 m−2 under ultraviolet and visible light irradiation, respectively; the corresponding CO2 conversion rates in ambient air were 30% and 16%, respectively. The excellent catalytic effect is mainly attributed to the formation of P–N heterojunction during the catalytic process and the surface plasmon resonance effect. Additionally, the introduction of solid agar electrolytes effectively inhibits the hydrogen evolution reaction and improves the electron utilization rate. This system promotes the development of photocatalytic technology for practical applications and provides new insights and support for the carbon cycle.

Abstract The degenerative process in Parkinson’s disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. Here we generated high-quality profiles for 250,173 cells from the substantia nigra (SN) and putamen (PT) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian macaques and matched controls. Our primate model of parkinsonism recapitulates important pathologic features in nature PD and provides an unbiased view of the axis of neuronal vulnerability and resistance. We identified seven molecularly defined subtypes of nigral DaNs which manifested a gradient of vulnerability and were confirmed by fluorescence-activated nuclei sorting. Neuronal resilience was associated with a FOXP2-centered regulatory pathway shared between PD-resistant DaNs and glutamatergic excitatory neurons, as well as between humans and nonhuman primates. We also discovered activation of immune response common to glial cells of SN and PT, indicating concurrently activated pathways in the nigrostriatal system. Our study provides a unique resource to understand the mechanistic connections between neuronal susceptibility and PD pathophysiology, and to facilitate future biomarker discovery and targeted cell therapy.

Abstract Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210a AKO ) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210a AKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210a iAKO ) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.

In response to a series of engineering disasters encountered during the excavation and support construction of loess tunnels, considering the issues of water enrichment in surrounding rock induced by excavation disturbance and system bolt failure, drawing on the concepts of lime pile composite foundation and composite bearing arch, and based on the principle of the New Austrian Tunneling Method (NATM) that fully mobilizes and leverages the self-supporting capacity of surrounding rock, this study comprehensively considers the wetting and stress adjustment processes of the surrounding rock after excavation disturbance in loess tunnels. By adopting the technical principle of “water absorption and densification of shallow surrounding rock, suspension and anchoring of deep surrounding rock, and composite arch bearing”, a new type of water-absorbing, densifying, and anchoring bolt was developed that can reduce the water content of surrounding rock while enhancing its resistance. To further investigate the water absorption, densification effect, and pull-out bearing characteristics of this new bolt, laboratory model tests were conducted, examining the temperature, pore water pressure, densification stress of the soil around the bolt, as well as the physical properties of the soil in the consolidation zone. The test results indicate that a cylindrical heat source forms around the water-absorbing, densifying, and anchoring bolt, significantly inducing the thermal consolidation of the surrounding soil. The variations in temperature, pore water pressure, and densification stress of the soil around the bolt truly reflect the qualitative patterns of hydro-thermal–mechanical changes during the water absorption, curing, and exothermic reaction processes. The water absorption and densification segment of the bolt effectively enhances the density of the soil in the water absorption, densification, and consolidation zone, improving soil strength parameters. Compared to traditional mortar-bonded bolts, the water-absorbing, densifying, and anchoring bolt exhibits a greater pull-out bearing capacity. The research findings provide important guidance for the theoretical design and engineering application of this new type of bolt.

Abstract Binary code similarity analysis is widely used in the field of vulnerability search where source code may not be available to detect whether two binary functions are similar or not. Based on deep learning and natural processing techniques, several approaches have been proposed to perform cross-platform binary code similarity analysis using control flow graphs. However, existing schemes suffer from the shortcomings of large differences in instruction syntaxes across different target platforms, inability to align control flow graph nodes, and less introduction of high-level semantics of stability, which pose challenges for identifying similar computations between binary functions of different platforms generated from the same source code. We argue that extracting stable, platform-independent semantics can improve model accuracy, and a cross-platform binary function similarity comparison model N_Match is proposed. The model elevates different platform instructions to the same semantic space to shield their underlying platform instruction differences, uses graph embedding technology to learn the stability semantics of neighbors, extracts high-level knowledge of naming function to alleviate the differences brought about by cross-platform and cross-optimization levels, and combines the stable graph structure as well as the stable, platform-independent API knowledge of naming function to represent the final semantics of functions. The experimental results show that the model accuracy of N_Match outperforms the baseline model in terms of cross-platform, cross-optimization level, and industrial scenarios. In the vulnerability search experiment, N_Match significantly improves hit@N, the mAP exceeds the current graph embedding model by 66%. In addition, we also give several interesting observations from the experiments. The code and model are publicly available at https://www.github.com/CSecurityZhongYuan/Binary-Name_Match .

Abstract Transcription factors (TFs) play key roles in regulating differentiation and function of stem cells, including muscle satellite cells (MuSCs), a resident stem cell population responsible for postnatal regeneration of the skeletal muscle. Sox11 belongs to the Sry-related HMG-box (SOX) family of TFs that play diverse roles in stem cell behavior and tissue specification. Analysis of single-cell RNA-sequencing (scRNA-seq) datasets identify a specific enrichment of Sox11 mRNA in differentiating but not quiescent MuSCs. Consistent with the scRNA-seq data, Sox11 levels increase during differentiation of murine primary myoblasts in vitro. scRNA-seq data comparing muscle regeneration in young and old mice further demonstrate that Sox11 expression is reduced in aged MuSCs. Age-related decline of Sox11 expression is associated with reduced chromatin contacts within the topologically associating domains. Unexpectedly, Myod1Cre-driven deletion of Sox11 in embryonic myoblasts has no effects on muscle development and growth, resulting in apparently healthy muscles that regenerate normally. Pax7CreER- or Rosa26CreER- driven (MuSC-specific or global) deletion of Sox11 in adult mice similarly has no effects on MuSC differentiation or muscle regeneration. These results identify Sox11 as a novel myogenic differentiation marker with reduced expression in quiescent and aged MuSCs, but the specific function of Sox11 in myogenesis remains to be elucidated.

Abstract Nearly 70% of Uterine fibroid (UF) tumors are driven by recurrent MED12 hotspot mutations. Unfortunately, no cellular models could be generated because the mutant cells have lower fitness in 2D culture conditions. To address this, we employ CRISPR to precisely engineer MED12 Gly44 mutations in UF-relevant myometrial smooth muscle cells. The engineered mutant cells recapitulate several UF-like cellular, transcriptional, and metabolic alterations, including altered Tryptophan/kynurenine metabolism. The aberrant gene expression program in the mutant cells is, in part, driven by a substantial 3D genome compartmentalization switch. At the cellular level, the mutant cells gain enhanced proliferation rates in 3D spheres and form larger lesions in vivo with elevated production of collagen and extracellular matrix deposition. These findings indicate that the engineered cellular model faithfully models key features of UF tumors and provides a platform for the broader scientific community to characterize genomics of recurrent MED12 mutations.

Background Polycystic ovary syndrome (PCOS) was known as the common endocrine disease in women, featured as hyperandrogenism, ovulation disorders, etc. Fat mass and obesity-associated protein (FTO), a m6A demethylase, is abnormal in the occurrence of ovarian diseases. However, the mechanism of FTO in the pathogenesis of PCOS is still unclear.Methods The level of FTO in clinical samples, PCOS rat with hyperandrogenism and granulosa cells (GCs) lines effected by DHT were investigated by ELISA, qRT-PCR, WB, and IHC, while m6A RNA methylation level was studied by m6A Colorimetric and androgen level was tested through ELISA. Changes in steroid hormone synthetase and androgen receptor (AR)/prostate-specific antigen (PSA) levels in vitro were visualized by WB after transient transfection silenced FTO. The effect of DHT combined with FTO inhibitor meclofenamic acid (MA) on FTO, AR/PSA, and AKT phosphorylation were also demonstrated by WB. The co-localization of FTO and AR in KGN cells was analyzed by confocal microscopy, and the physiological interaction between FTO and AR was studied by Co-IP assay. The effect of FTO-specific inhibitor MA, AKT phosphorylation inhibitor LY294002, and the combined them on GCs proliferation and cell cycle were evaluated by drug combination index, EDU assay, and flow cytometry analysis.Results FTO expression was upregulated in follicular fluid and GCs in PCOS patients clinically. The high FTO expression in patients was negative with the level of m6A, but positive with the level of androgen. The upregulation of FTO was accompanied with a decrease in the level of m6A in PCOS rat with hyperandrogenism. Dihydrotestosterone (DHT) promoted the FTO expression and inhibited m6A content as a dose-dependent way in vitro. In contrast, suppression of FTO with siRNA attenuated the expression of steroid hormone synthetase such as CYP11A1, CYP17A1, HSD11B1, HSD3B2 except CYP19A1 synthetase, ultimately inducing the decrease of androgen level. Suppression of FTO also decreased the biological activity of androgen through downregulation AR/PSA. MA treatment as the specific FTO antagonist decreased cell survival in time- and dose-dependent way in GCs lines. Correspondingly, MA treatment decreased the expression of FTO, AR/PSA expression, and AKT phosphorylation in the presence of DHT stimulation. Additionally, we also speculate there is a potential relation between FTO and AR according to FTO was co-localized and interacted with AR in KGN cells. Compared with AKT phosphorylation inhibitor LY294002 or MA alone, LY294002 combined with MA synergistically inhibited cell survival and increased G2/M phase arrest in GC line.Conclusions We first evaluated the correlation of FTO and m6A in PCOS clinically, and further explored the mechanism between FTO and hyperandrogenism in PCOS animal and cell models. These findings contributed the potential therapy by targeting the FTO for hyperandrogenism in PCOS.

Summary: Development is regulated by various factors, including protein methylation status. While PRMT5 is well known for its roles in oncogenesis by mediating symmetric di-methylation of arginine, its role in normal development remains elusive. Using Myod1Cre to drive Prmt5 knockout in embryonic myoblasts (Prmt5MKO), we dissected the role of PRMT5 in myogenesis. The Prmt5MKO mice are born normally but exhibit progressive muscle atrophy and premature death. Prmt5MKO inhibits proliferation and promotes premature differentiation of embryonic myoblasts, reducing the number and regenerative function of satellite cells in postnatal mice. Mechanistically, PRMT5 methylates and destabilizes FoxO1. Prmt5MKO increases the total FoxO1 level and promotes its cytoplasmic accumulation, leading to activation of autophagy and depletion of lipid droplets (LDs). Systemic inhibition of autophagy in Prmt5MKO mice restores LDs in myoblasts and moderately improves muscle regeneration. Together, PRMT5 is essential for muscle development and regeneration at least partially through mediating FoxO1 methylation and LD turnover.

Epigenetic status–altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4. CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression of purine and pyrimidine nucleotide synthesis pathways. Consistently, we observed a shift in metabolic activity toward increased purine synthesis in MLL3/4-KO mESCs. These cells also exhibited enhanced sensitivity to the purine synthesis inhibitor lometrexol, which induced a unique gene expression signature. RNA-Seq identified the top MLL3/4 target genes coinciding with suppression of purine metabolism, and tandem mass tag proteomic profiling further confirmed upregulation of purine synthesis in MLL3/4-KO cells. Mechanistically, we demonstrated that compensation by MLL1/COMPASS was underlying these effects. Finally, we demonstrated that tumors with MLL3 and/or MLL4 mutations were highly sensitive to lometrexol in vitro and in vivo, both in culture and in animal models of cancer. Our results depicted a targetable metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy for cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction.

Abstract The latest view suggests the inactive core, surface pulverization, and polysulfide shuttling effect of metal sulfides are responsible for their low capacity and poor cycling performance in sodium-ion batteries (SIBs). Whereas overcoming the above problems based on conventional nanoengineering is not efficient enough. In this work, erythrocyte-like CuS microspheres with an elastic buffering layer of ultrathin polyaniline (PANI) were synthesized through one-step self-assembly growth, followed by in situ polymerization of aniline. When CuS@PANI is used as anode electrode in SIBs, it delivers high capacity, ultrahigh rate capability (500 mAh g−1 at 0.1 A g−1, and 214.5 mAh g−1 at 40 A g−1), and superior cycling life of over 7500 cycles at 20 A g−1. A series of in/ex situ characterization techniques were applied to investigate the structural evolution and sodium-ion storage mechanism. The PANI swollen with electrolyte can stabilize solid electrolyte interface layer, benefit the ion transport/charge transfer at the PANI/electrolyte interface, and restrain the size growth of Cu particles in confined space. Moreover, finite element analyses and density functional simulations confirm that the PANI film effectively buffers the volume expansion, suppresses the surface pulverization, and traps the polysulfide.

As Internet applications and services become more and more extensive, the endless network attacks lead to great risks and challenges to the security of information systems.As a model-based network security risk analysis technology, attack graph is helpful to find the vulnerability between network nodes and the harm of being attacked.It has been proved to be an effective method to find and prevent network security risks.Attack graph is mainly divided into state-based attack graph and attribute-based attack graph.Due to the problem of state explosion in state-based attack graph, most researchers prefer the attribute-based attack graph for network risk assessment.In view of the existing researches on attribute-based attack graph, they excessively rely on the vulnerability of network nodes and the essential attributes of atomic attack.However, they ignore that rational attackers usually choose specific attack paths by maximizing attack benefits.Then, a network risk assessment framework and a quantification method of attack benefits-rate based on expected benefits-rate attack graph were proposed.The network risk assessment framework took the open vulnerability resource database, the new vulnerabilities found by the vulnerability mining system and the big data related to network attack and defense as the basic data source.The network risk assessment framework also took the open source big data platform as the analysis tool to mine and calculate the elements related to attack cost and attack benefit.Using the concepts of cost, benefit and benefit-rate in economics, the calculation model of expected benefit-rate of atomic attack was constructed.By constructing the attribute-based attack graph of the target network, the expected benefit-rate of atomic attack on the attack path was calculated, and the expected benefit-rate list of all possible attack paths was generated.Furthermore, taking the expected goal as the starting point, the search was carried out according to the specific optimization strategy (backtracking method, greedy algorithm, dynamic programming).And the complete attack path with the maximum benefit-rate was obtained, which provided the basis for network risk assessment.The simulation results show the effectiveness and rationality of the proposed expected benefit-rate attack graph network risk assessment method, which can provide support for discovering and preventing network security problems.

Summary: Suppressor of cytokine signaling-1 (SOCS1) exerts control over inflammation by targeting p65 nuclear factor-κB (NF-κB) for degradation in addition to its canonical role regulating cytokine signaling. We report here that SOCS1 does not operate on all p65 targets equally, instead localizing to a select subset of pro-inflammatory genes. Promoter-specific interactions of SOCS1 and p65 determine the subset of genes activated by NF-κB during systemic inflammation, with profound consequences for cytokine responses, immune cell mobilization, and tissue injury. Nitric oxide synthase-1 (NOS1)-derived nitric oxide (NO) is required and sufficient for the displacement of SOCS1 from chromatin, permitting full inflammatory transcription. Single-cell transcriptomic analysis of NOS1-deficient animals led to detection of a regulatory macrophage subset that exerts potent suppression on inflammatory cytokine responses and tissue remodeling. These results provide the first example of a redox-sensitive, gene-specific mechanism for converting macrophages from regulating inflammation to cells licensed to promote aggressive and potentially injurious inflammation.

An unsupervised change-detection problem is formulated as a binary classification problem corresponding to the change and no change areas. This paper proposes a novel unsupervised object-oriented change detection method based on neighborhood correlation images (NCIs) and k-means clustering for high-resolution remote sensing images. We tested our proposed method in two study areas of Beijing with RapidEye images and compared it with three other popular change detection methods based on different images: change vector analysis (CVA), principal component analysis (PCA), and multivariate alteration detection (MAD). The results indicate that our method has the highest overall accuracy (90.80% in Shunyi District, Beijing and 90.40% in Daxing District, Beijing) and Kappa coefficient (0.7922 in Shunyi District, Beijing and 0.7796 in Daxing District, Beijing). In addition, the McNemar test indicates that our method is robust and stable across different study areas. We concluded that the object-oriented NCIs method outperforms traditional difference images (CVA, PCA, and MAD) in unsupervised change detection. The experimental results demonstrate the effectiveness of the proposed approach in solving the problem of unsupervised change detection for high-resolution images.

Abstract In the field of network security, although there has been related work on software vulnerability detection based on classic machine learning, detection ability is directly proportional to the scale of training data. A quantum neural network has been proven to solve the memory bottleneck problem of classical machine learning, so it has far-reaching prospects in the field of vulnerability detection. To fill the gap in this field, we propose a quantum neural network structure named QDENN for software vulnerability detection. This work is the first attempt to implement word embedding of vulnerability codes based on a quantum neural network, which proves the feasibility of a quantum neural network in the field of vulnerability detection. Experiments demonstrate that our proposed QDENN can effectively solve the inconsistent input length problem of quantum neural networks and the problem of batch processing with long sentences. Furthermore, it can give full play to the advantages of quantum computing and realize a vulnerability detection model at the cost of a small amount of measurement. Compared to other quantum neural networks, our proposed QDENN can achieve higher vulnerability detection accuracy. On the sub dataset with a small-scale interval, the model accuracy rate reaches 99%. On each subinterval data, the best average vulnerability detection accuracy of the model reaches 86.3%.

Abstract The Chchd10 gene encodes a coiled-coil-helix-coiled-coil-helix-domain containing protein predicted to function in the mitochondrion and nucleus. Mutations of Chchd10 are associated with ALS, dementia and myopathy in humans and animal models, but how knockout of Chchd10 (Chchd10 KO ) affects various tissues especially skeletal muscle and adipose tissues remains unclear. Here we show that Chchd10 expression increases as myoblasts and preadipocytes differentiate. During myogenesis, CHCHD10 interacts with TAR DNA binding protein 43 (TDP-43) in regenerating myofibers in vivo and in newly differentiated myotubes ex vivo. Surprisingly, Chchd10 KO mice had normal skeletal muscle development, growth and regeneration, with moderate defects in grip strength and motor performance. Chchd10 KO similarly had no effects on development of brown and white adipose tissues (WAT). However, Chchd10 KO mice had blunted response to acute cold and attenuated cold-induced browning of WAT, with markedly reduced UCP1 levels. Together, these results demonstrate that Chchd10 is dispensable for normal myogenesis and adipogenesis but is required for normal motility and cold-induced, mitochondrion-dependent browning of adipocytes. The data also suggest that human CHCHD10 mutations cause myopathy through a gain-of-function mechanism.

ObjectiveTo explore the effect of Erythronium sibiricum bulb polysaccharides on asthma and its mechanism based on oxidative stress.MethodsFifty female BALB/c mice were randomly divided into the negative control group， asthma model group， dexamethasone group， low and high-dose Erythronium sibiricum bulb polysaccharides groups. Except the negative control group， the asthma model was established by sensitizing with chicken egg albumin （OVA）. The number and classification of inflammatory cells in bronchoalveolar lavage fluid （BALF） were determined by a whole blood analyzer. Hematoxylin-eosin （HE）， Periodate acid-Schiff （PAS） and Masson staining were used to observe the lung pathology of asthmatic mice. The contents of malondialdehyde （MDA） and the activity of superoxide dismutase （SOD） in serum were detected by colorimetry. Determination of protein expression and mRNA abundance of nuclear factor erythroid2-related factor 2（Nrf2）， HemeoxygenasE1 （HO-1） and Vascular endothelial growth factor （VEGF） in the lung were detected by immunohistochemistry and real-time fluorescence determination polymerase chain reaction （RT-PCR）.ResultsCompared with the negative control group， the numbers of total inflammatory cells， neutrophils， monocytes and eosinophils in the BALF of the model group were significantly increased （P

The effects of hydrophilic and hydrophobic SiO2 composite organic resin on the properties of FeSiCr magnetic powder cores and the effects of annealing treatment on magnetic properties were studied. After phosphating, the FeSiCr alloy powders were coated by two types of SiO2 composite resin, which are hydrophobic and hydrophilic, respectively. The FeSiCr magnetic powder cores were prepared by compaction and curing. The results show that the coating effect of coupling modified hydrophilic SiO2 composite organic resin is better than that of hydrophobic SiO2 composite organic resin. With the increase of SiO2 addition, the specific resistance and coercivity of the magnetic powder cores are increased, while the density, saturation magnetization and effective permeability are decreased. The FeSiCr magnetic powder cores coated with 0.5% hydrophobic SiO2 composite organic resin have excellent comprehensive performance after annealing. Under the condition of 20 mT, 100 kHz, the magnetic core loss is 49.84 kW/m3, which is 16.9% lower than that of the magnetic powder cores coated with pure resin. Annealing can effectively promote magnetic properties of FeSiCr magnetic powder cores.

ObjectivesAssisted reproductive technology (ART) is an important part of reproductive medicine, whose possible effects on offspring’s health have drawn widespread attention in recent years. However, relevant studies are limited to postnatal short-term follow-up and lack of diverse sample sources analysis other than blood.MethodsIn this study, a mouse model was used to explore the effects of ART on fetal development and gene expression in the organs of offspring in the adulthood using next-generation sequencing. The sequencing results were then analyzed.ResultsThe results showed that it caused abnormal expression in 1060 genes and 179 genes in the heart and spleen, respectively. Differentially expressed genes (DEGs) in the heart are mainly enriched in RNA synthesis and processing, and the cardiovascular system development also shows enrichment. STRING analysis identified Ccl2, Ptgs2, Rock1, Mapk14, Agt, and Wnt5a as the core interacting factors. DEGs in the spleen are significantly enriched in anti-infection and immune responses, which include the core factors Fos, Jun and Il1r2. Further exploration revealed the abnormal expression of 42 and 5 epigenetic modifiers in the heart and spleen, respectively. The expression of the imprinted genes Dhcr7, Igf2, Mest and Smoc1 decreased in the hearts of ART offspring, and the DNA methylation levels of Igf2- and Mest-imprinting control regions (ICRs) increased abnormally.ConclusionIn the mouse model, ART can interfere with the gene expression pattern in the heart and spleen of the adult offspring and that these changes are related to the aberrant expression of epigenetic regulators.

Audio steganography is to hide secret information into the audio carrier and has become a research hotspot in the field of information hiding.Most of the existing studies focus on minimizing distortion at the expense of steganography capacity, and it is often difficult for them to extract secret information correctly after some common signal processing attacks.Therefore, based on the spread spectrum technology, firstly, the relationship between steganography parameters (i.e., segmented scaling parameters and steganography capacity) and imperceptibility as well as robustness was analyzed.Next, a multi-objective optimization model of audio steganography was presented, in which segmented scaling parameters and steganography capacity were decision variables, imperceptibility and steganography capacity were optimization objectives, and the signal-to-noise ratio was a constraint.Then, a robust audio steganography algorithm based on differential evolution was proposed, including the corresponding encoding, fitness function, crossover and mutation operators.Finally, comparative experimental results show that the proposed steganography algorithm can achieve better robustness against common signal processing attacks on the premise of ensuring imperceptibility and anti-detection.

As studies continue sequencing with deeper coverage, computational processing of these profiles has become increasingly resource consuming. Here the authors designed an efficient computational method called Chromap to align and preprocess high throughput sequencing data from chromatin profiling techniques, including ChIP-seq, Hi-C, or scATAC-seq, with a major decrease in runtime.

Summary: Mammalian terminal erythropoiesis involves chromatin and nuclear condensation followed by enucleation. Late-stage erythroblasts undergo caspase-mediated nuclear opening that is important for nuclear condensation through partial histone release. It remains unknown the dynamic changes of three-dimensional (3D) genomic organization during terminal erythropoiesis. Here, we used Hi-C to determine the chromatin structural change during primary mouse erythroblast terminal differentiation. We also performed RNA-sequencing and ATAC-sequencing under the same experimental setting to further reveal the genome accessibility and gene expression changes during this process. We found that late-stage terminal erythropoiesis involves global loss of topologically associating domains and establishment of inter-chromosomal interactions of the heterochromatin regions, which are associated with globally increased chromatin accessibility and upregulation of erythroid-related genes.

Summary: Lipid droplets are emerging as an important and dynamic organelle whose metabolism controls stem cell behavior. Here we present a comprehensive protocol to visualize and quantify these organelles in mouse muscle satellite cells (MuSCs). This protocol includes steps for BODIPY/LipidSpot610 staining of freshly isolated MuSCs, in vitro cultured myoblasts, and single myofibers to label lipid droplets and subsequent analysis and quantification of fluorescence signals. This protocol can be modified to stain lipid droplets in other cell types of interest.For complete details on the use and execution of this protocol, please refer to Yue et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder that features motor and non-motor deficits. The use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine neuron degeneration has been widely practiced to produce reliable animal models of PD. However, most previous preclinical studies focused on motor dysfunction, and few non-motor symptoms were evaluated. Thus far, there is a lack of comprehensive investigations of the non-motor symptoms in animal models. Objectives: In this study, we aim to use a battery of behavioral methods to evaluate non-motor symptoms in MPTP-induced non-human primate PD models. Methods: Cognitive function, sleep, and psychiatric behaviors were evaluated in MPTP-treated cynomolgus monkeys. The tests consisted of a delayed matching-to-sample (DMTS) task, the use of a physical activity monitor (PAM), an apathy feeding task (AFT), the human intruder test (HIT), novel fruit test (NFT), and predator confrontation test (PCT). In addition, we tested whether the dopamine receptor agonist pramipexole (PPX) can improve these non-motor symptoms. Results: The present results show that the MPTP-treated monkeys exhibited cognitive deficits, abnormal sleep, and anxiety-like behaviors when compared to the control monkeys. These symptoms were relieved partially by PPX. Conclusions: These results suggest that MPTP-induced PD monkeys displayed non-motor symptoms that were similar to those found in PD patients. PPX treatment showed moderate therapeutic effects on these non-motor symptoms. This battery of behavioral tests may provide a valuable model for future preclinical research.

Abstract Background Canine distemper caused by canine distemper virus that belongs to the Morbillivirus genus of the Paramyxoviridae family is still a global epidemic significant infectious disease, especially in pet dogs in China and serious harm to the development of the dog industry. It has been known that apoptosis caused by the canine distemper virus can show in culture cells, lymphoid tissues, and the cerebellum. However, its occurrence in brain tissue cells remains unclear. To investigate the relationship among canine distemper infecting brain tissues, apoptosis in brain tissue cells, and demyelinating pathogenesis was investigated. Methods 16 naturally infected dogs that exhibited clinical signs of CD and tested positive for the anti-CDV monoclonal antibody and six healthy dogs that served as the control, were used in the research. Brain specimens were divided into the cerebrum, brain stem, and cerebellum embedded in paraffin and made the sections respectively. Approximately 5 µm-thick sections were stained by hematoxylin–eosin, methyl green pyronin, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique, and immunohistochemistry. CDV nucleocapsid protein was detected by immune streptavidin-biotinylated peroxidase complex. Results Alterations in the brain tissues of CDV-infected dogs involved both various cells and nerve fibers. CDV had varying degrees of cytotropism to all brain tissue cells; apoptosis also occurred in all brain cells, especially in the endothelia of cerebral vessels, astrocytes, oligodendrocytes, and ependymal cells, the more serious infection, the more obvious apoptosis. Serious infections also involved the pyramidal and Purkinje cells. The nervous fibers exhibited demyelinating lesions (showed small multifocal vacuole), and some axonal neuron atrophy gradually disappeared (formed large vacuole). Conclusions Apoptosis in brain tissue cells was mainly related to the propagation path and cytotropism of CDV. The apoptosis of astrocytes, oligodendrocytes, and some neurons may play a significant role in the demyelinating pathogenesis in dogs with acute canine distemper. A lot of diverse nervous signs shown in the clinic may be related to different neuron apoptosis.

BACKGROUND Soil environmental reference materials are important technical tools for the quality control of soil environmental monitoring. However, there is no self-developed environmental matrix reference material with total organic carbon (TOC). In particular, a soil standard sample supporting the combustion oxidation-non-dispersive infrared method has not been developed yet. OBJECTIVES To develop a soil TOC reference material that can support standard methods for the determination of TOC in soil. METHODS Agricultural land soil with a high organic carbon content was selected as the raw material. The soil TOC reference materials were prepared after drying, grinding, mixing, bottling, and sterilization. Ten bottles of the reference materials were randomly sampled in layers, and their homogeneities were determined using combustion oxidation-non-dispersive infrared (NDIR) absorption method. The data were assessed using a single element analysis of variance. The reference material was stored at room temperature, and its stability was determined for 18 months. The test results were assessed using a linear fitting model. Eleven laboratories were organized as the cooperation to determine the TOC content of the prepared reference material using combustion oxidation-NDIR absorption method and potassium dichromate volumetric method. All measurement data were statistically analyzed to obtain the certified value and uncertainty of the reference material. RESULTS The soil TOC reference material exhibited good homogeneity and stability. After evaluation, the F value was determined to be less than the critical value of F0.05 (9, 10). Additionally, the relative uncertainty (ubb) of the uniformity between bottles was 1.5%, and the sample exhibited good uniformity. The stability uncertainty was 1.2%, which indicated good stability. The certified value of the soil TOC reference material was determined to be (25.2±1.4)mg/g, using the grand mean of the collaborative determination results from multiple laboratories. CONCLUSIONS A soil TOC reference material was developed using combustion oxidation-NDIR absorption method. This reference material can be used to support the standard determination methods of TOC in soil and meets the requirements of the studies on TOC content in soil. Moreover, it is comparable with similar foreign samples.

Abstract Objective We aimed to evaluate the role of tumor size in predicting tumor risk for localized prostate cancer (PCa) patients undergoing radical prostatectomy (RP). Methods Twenty‐five thousand, one hundred twenty‐seven men with PCa receiving RP from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results database. Kaplan–Meier plots and multivariable Cox regression analyses were used to illustrate overall survival (OS) according to the tumor size. The tumor size was confirmed by postoperative pathology after RP. Results Among overall localized PCa, 84.6% were high‐risk PCa, 9.2% were intermediate‐risk PCa, and 6.2% were low‐risk PCa. Multivariate analyses demonstrated that tumor size ≥21 mm was an independent risk predict factor of low‐risk PCa (odds ratio [OR]: 11.940; 95% CI, 9.404–15.161; p

Abstract Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown. Result We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. Conclusion In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.

At present, the patients with transfusion-dependent lower-risk myelodysplastic syndromes (MDS) have limited treatment options when erythropoiesis-stimulating agent is ineffective or relapsed. With more understanding of the pathological and molecular genetics characteristics of MDS, the development of precise medical treatment of MDS has been promoted. Small-molecule inhibitors, such as transforming growth factor β inhibiter, telomerase inhibiter and hypoxia-inducible factor prolyl hydroxylase inhibitor, provide novel therapeutic strategies for patients. This article reviews the treatment of transfusion-dependent lower-risk MDS patients and discusses the latest clinical research and development of novel targeted agents.

Abstract Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.

Traditional radiotherapy and chemotherapy often cause irreversible damage to the fertility and endocrine function of cancer patients. The current methods of fertility preservation include freezing the sperms of adult and adolescent males after puberty; freezing the embryos, oocytes, and ovarian tissue of females; and drug intervention and fertility preservation surgery. This article reviews fertility preservation in cancer patients with respect to current methods, indications, and some more recently developed methods that remain under investigation.

In vitro maturation (IVM) has been used in clinical settings for 30 years. The merits of IVM include that it needs a relatively small amount of hormones and short treatment period. However, because the effectiveness of IVM is lower than that of controlled ovarian hyperstimulation, there are few centers routinely use IVM, and it is only applicable to a few special populations. In this article, several oocyte sources related to IVM have been discussed and the effects of gonadotropin priming and triggering on IVM are described. Furthermore, we have reviewed the optimization of IVM culture conditions in recent years along with the effects of IVM on genes of oocytes and cumulus cells and the obstetric and neonatal outcomes. We aim to provide indications for future improvement of IVM technology so that the success rates of IVM technology in special populations can be improved. We hope that this mild and natural protocol can be applied to more populations, including individuals with normal ovulation.

Obesity-related diseases are always the major health problems that concern the whole world. Serial studies have reported that obesity development is closely related to the out-of-control leptin encoded by the obesity gene (ob). The latest report declaimed “Less Is More,” a model explaining that partial leptin reduction triggers leptin sensitization and contributes to obesity control. Here, we came up with a novel concept, in vivo protein interference (iPRTi), an interesting protein knock-down strategy for in vivo partial leptin reduction. First, the specific immune response against leptin induced by the oral administration of ob recombinant yeast was confirmed. Subsequentally, leptin resistance was observed in diet-induced obese mice, and oral administration with ob recombinant yeast declined the circulating leptin and reduced significantly the body weight gain. To further investigate whether the iPRTi strategy is capable of obesity management, the diet-induced obese mice were administrated with ob recombinant yeast. All the indexes examined including the circulating leptin, triglyceride, and total cholesterol, as well as food intake and weight gain, demonstrated a positive effect of the iPRTi strategy on obesity control. In short, this study provides a novel strategy for the potential application of recombinant yeast for the therapy of obese individuals with leptin resistance.

Predicting chromatin loops from genome-wide interaction matrices such as Hi-C data provides insight into gene regulation events. Here, the authors present Peakachu, a Random Forest classification framework that predicts chromatin loops from genome-wide contact maps, and apply it to systematically predict chromatin loops in 56 Hi-C datasets, with results available at the 3D Genome Browser.

ENCODE is a resource comprising thousands of functional genomic datasets. Here, the authors present custom annotation within ENCODE for cancer, highlighting a workflow that can help prioritise key elements in oncogenesis.