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Abstract Advanced pancreatic ductal adenocarcinomas (PDACs) respond poorly to all therapies, including the first-line treatment, chemotherapy, the latest immunotherapies, and KRAS-targeting therapies. Despite an enormous effort to improve therapeutic efficacy in late-stage PDAC patients, effective treatment modalities remain an unmet medical challenge. To change the status quo, we explored the key signaling networks underlying the universally poor response of PDAC to therapy. Here, we report a previously unknown chemo-induced symbiotic signaling circuit that adaptively confers chemoresistance in patients and mice with advanced PDAC. By integrating single-cell transcriptomic data from PDAC mouse models and clinical pathological information from PDAC patients, we identified Yap1 in cancer cells and Cox2 in stromal fibroblasts as two key nodes in this signaling circuit. Co-targeting Yap1 in cancer cells and Cox2 in stroma sensitized PDAC to Gemcitabine treatment and dramatically prolonged survival of mice bearing late-stage PDAC, whereas simultaneously inhibiting Yap1 and Cox2 only in cancer cells was ineffective. Mechanistically, chemotherapy triggers non-canonical Yap1 activation by nemo-like kinase in 14-3-3ζ-overexpressing PDAC cells and increases secretion of CXCL2/5, which bind to CXCR2 on fibroblasts to induce Cox2 and PGE2 expression, which reciprocally facilitate PDAC cell survival. Finally, analyses of PDAC patient data revealed that patients who received Statins, which inhibit Yap1 signaling, and Cox2 inhibitors (including Aspirin) while receiving Gemcitabine displayed markedly prolonged survival compared to others. The robust anti-tumor efficacy of Statins and Aspirin, which co-target the chemo-induced adaptive circuit in the tumor cells and stroma, signifies a unique therapeutic strategy for PDAC.

Abstract Background Cancer patients are more susceptible to an aggressive course of COVID-19. Developing biomarkers identifying cancer patients at high risk of COVID-19-related death could help determine who needs early clinical intervention. The miRNAs hosted in the genomic regions associated with the risk of aggressive COVID-19 could represent potential biomarkers for clinical outcomes. Patients and methods Plasma samples were collected at The University of Texas MD Anderson Cancer Center from cancer patients (N = 128) affected by COVID-19. Serum samples were collected from vaccinated healthy individuals (n = 23) at the Municipal Clinical Emergency Teaching Hospital in Timisoara, Romania. An in silico positional cloning approach was used to identify the presence of miRNAs at COVID-19 risk-associated genomic regions: CORSAIRs (COvid-19 RiSk AssocIated genomic Regions). The miRNA levels were measured by RT-qPCR. Results We found that miRNAs were enriched in CORSAIR. Low plasma levels of hsa-miR-150-5p and hsa-miR-93-5p were associated with higher COVID-19-related death. The levels of hsa-miR-92b-3p were associated with SARS-CoV-2 test positivity. Peripheral blood mononuclear cells (PBMC) increased secretion of hsa-miR-150-5p, hsa-miR-93-5p, and hsa-miR-92b-3p after in vitro TLR7/8- and T cell receptor (TCR)-mediated activation. Increased levels of these three miRNAs were measured in the serum samples of healthy individuals between one and nine months after the second dose of the Pfizer-BioNTech COVID-19 vaccine. SARS-CoV-2 infection of human airway epithelial cells influenced the miRNA levels inside their secreted extracellular vesicles. Conclusions MiRNAs are enriched at CORSAIR. Plasma miRNA levels can represent a potential blood biomarker for predicting COVID-19-related death in cancer patients.

Abstract Single-cell RNA sequencing is a powerful tool to investigate the cellular makeup of tumor samples. However, due to the sparse data and the complex tumor microenvironment, it can be challenging to identify neoplastic cells that play important roles in tumor growth and disease progression. This is especially relevant for blood cancers, where neoplastic cells may be highly similar to normal cells. To address this challenge, we have developed partCNV and partCNVH, two methods for rapid and accurate detection of aneuploid cells with local copy number deletion or amplification. PartCNV uses an expectation-maximization (EM) algorithm with mixtures of Poisson distributions and incorporates cytogenetic information to guide the classification. PartCNVH further improves partCNV by integrating a hidden Markov model for feature selection. We have thoroughly evaluated the performance of partCNV and partCNVH through simulation studies and real data analysis using three scRNA-seq datasets from blood cancer patients. Our results show that partCNV and partCNVH have favorable accuracy and provide more interpretable results compared to existing methods. In the real data analysis, we have identified multiple biological processes involved in the oncogenesis of myelodysplastic syndromes and acute myeloid leukemia.

At room temperature, the conversion of greenhouse gases into valuable chemicals using metal-free catalysts for dry reforming of methane (DRM) is quite promising and challenging. Herein, we developed a novel covalent organic porous polymer (TPE-COP) with rapid charge separation of the electron–hole pairs for DRM driven by visible light at room temperature, which can efficiently generate syngas (CO and H2). Both electron donor (tris(4-aminophenyl)amine, TAPA) and acceptor (4,4′,4″,4‴-((1 E,1′E,1″E, 1‴E)-(ethene-1,1,2,2-tetrayltetrakis (benzene-4,1-diyl))tetrakis (ethene-2,1-diyl))tetrakis (1-(4-formylbenzyl)quinolin-1-ium), TPE-CHO) were existed in TPE-COP, in which the push–pull effect between them promoted the separation of photogenerated electron–hole, thus greatly improving the photocatalytic activity. Density functional theory (DFT) simulation results show that TPE-COP can form charge-separating species under light irradiation, leading to electrons accumulation in TPE-CHO unit and holes in TAPA, and thus efficiently initiating DRM. After 20 h illumination, the photocatalytic results show that the yields reach 1123.6 and 30.8 μmol g−1 for CO and H2, respectively, which are significantly higher than those of TPE-CHO small molecules. This excellent result is mainly due to the increase of specific surface area, the enhancement of light absorption capacity, and the improvement of photoelectron-generating efficiency after the formation of COP. Overall, this work contributes to understanding the advantages of COP materials for photocatalysis and fundamentally pushes metal-free catalysts into the door of DRM field.

Abstract Background To systematically analyze differences in atherosclerotic cardiovascular disease (ASCVD) burden between young and older adults. Methods We estimated the prevalence, mortality, and disability-adjusted life years (DALYs) of ASCVD, including ischemic heart disease (IHD), ischemic stroke (IS), and peripheral artery disease (PAD), in individuals aged 20–54 and > 55 years from 1990–2019, utilizing data from the 2019 Global Burden of Disease Study. The annual percentage changes (EAPCs) for age-specific prevalence, mortality, or DALY rates were calculated to quantify the temporal trends of ASCVD burden. We also analyzed population attribution fractions (PAF) of premature ASCVD mortality and DALYs for different risk factors and compared the burden of extremely premature, premature, and non-premature ASCVD cases based on clinical classifications. Results From 1990–2019, the global prevalence rates of IHD, IS, and PAD in the 20–54 years age group increased by 20.55% (from 694.74 to 837.49 per 100,000 population), 11.50% (from 439.48 to 490.03 per 100,000 population), and 7.38% (from 384.24 to 412.59 per 100,000 population), respectively. Conversely, the ASCVD prevalence in > 55years age group decreased. Adverse outcome burdens, including mortality and DALYs, varied among ASCVD subtypes. The decrease in the mortality/DALY burden of IHD and IS was lower in the 20–54 years group than in the > 55 years group. For PAD, DALYs among those aged 20–54 increased but decreased among those aged > 55 years. When grouped according to socio-demographic index (SDI) values, lower SDI regions exhibited a higher proportion of young ASCVD burden. The prevalence of young IHD, IS, and PAD in low SDI regions reached 20.70%, 40.05%, and 19.31% in 2019, respectively, compared with 12.14%, 16.32%, and 9.54%, respectively, in high SDI regions. Metabolic risks were the primary contributors to the ASCVD burden in both age groups. Increased susceptibility to ambient particulate matter pollution and inadequate control of high body-mass index and high fasting plasma glucose in young individuals may partially explain the differing temporal trends between young and older individuals. Conclusions The ASCVD burden in young individuals may become a growing global health concern, especially in areas with lower socioeconomic development levels that require more effective primary prevention strategies.

Average leaf inclination angle (θ¯L) is an important canopy structure variable that influences light regime, photosynthesis, and evapotranspiration of plants. θ¯L can be measured through direct methods (e.g., protractor), which are labor-intensive and time-consuming, or through indirect optical instruments, which are more efficient than the direct methods. However, uncertainties of different indirect optical instruments for quantifying θ¯L remain largely unquantified. In this study, we evaluated and compared the performances of three major indirect optical instruments: (1) LAI-2200, (2) 30°-tilted camera, and (3) digital hemispherical photography (DHP), in different crop fields over a growing season, benchmarked with direct measurements. LAI-2200 and 30°-tilted camera showed higher agreement with direct θ¯ measurements (R2 = 0.54, RMSE = 7.37°; R2 = 0.58, RMSE = 8.08°) than DHP (R2 = 0.14, RMSE = 13.96°). Different performances of indirect optical instruments could be attributed to the accuracy of gap fraction measurement and the performance of the θ¯L quantification algorithms. When using the LAI-2200 algorithm, larger gap fraction gradients over view zenith angles led to larger θ¯L values, and smaller gap fraction gradients led to smaller θ¯L values. Such error propagation was larger in sparse canopy than in dense canopy. The Wilson G function of the LAI-2200 algorithm performed better in estimating θ¯L than the G function based on the ellipsoidal LAD function used by the CAN_EYE algorithm. We also proposed a modification of the LAI-2200 algorithm, which further improved the performance of LAI-2200 and 30°-tilted cameras in estimating θ¯L. We envision that the low-cost 30°-tilted cameras provide a promising sensor solution to continuously monitor canopy structure for various ecosystems.

Summary: Background: Dementia among younger people is rapidly emerging as a global health concern; however, comprehensive research on its shifting burden trends remains insufficient. Methods: Data on the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) associated with dementia occurring in individuals

Abstract Stealth address protocol (SAP) is widely used in blockchain to achieve anonymity. In this paper, we formalize a key derivable signature scheme (KDS) to capture the functionality and security requirements of SAP. We then propose a framework to construct key separation KDS, which follows the key separation principle as all existing SAP solutions to avoid the reuse of the master keys in the derivation and signature component. We also study the joint security in KDS and construct a key reusing KDS framework, which implies the first compact stealth address protocol using a single key pair. Finally, we provide instantiations based on the elliptic curve (widely used in cryptocurrencies) and on the lattice (with quantum resistance), respectively.

Abstract We study spinning particle/defect geometries in the context of AdS3/CFT2. These solutions lie below the BTZ threshold, and can be obtained from identifications of AdS3. We construct the Feynman propagator by solving the bulk equation of motion in the spinning particle geometry, summing over the modes of the fields and passing to the boundary. The quantization of the scalar fields becomes challenging when confined to the regions that are causally well-behaved. If the region containing closed timelike curves (CTCs) is included, the normalization of the scalar fields enjoys an analytical simplification and the propagator can be expressed as an infinite sum over image geodesics. In the dual CFT2, the propagator can be recast as the HHLL four-point function, where by taking into account the PSL(2, ℤ) modular images, we recover the bulk computation. We comment on the casual behavior of bulk geometries associated with single-trace operators of spin scaling with the central charge below the BTZ threshold.

Abstract Single-cell RNA sequencing (scRNA-seq) technology has been widely used to study the differences in gene expression at the single cell level, providing insights into the research of cell development, differentiation, and functional heterogeneity. Various pipelines and workflows of scRNA-seq analysis have been developed but few considered multi-timepoint data specifically. In this study, we develop CASi, a comprehensive framework for analyzing multiple timepoints’ scRNA-seq data, which provides users with: (1) cross-timepoint cell annotation, (2) detection of potentially novel cell types emerged over time, (3) visualization of cell population evolution, and (4) identification of temporal differentially expressed genes (tDEGs). Through comprehensive simulation studies and applications to a real multi-timepoint single cell dataset, we demonstrate the robust and favorable performance of the proposal versus existing methods serving similar purposes.

Abstract Background Protein cysteine oxidation is substantially involved in various biological and pathogenic processes, but its implications in pancreatic cancer development remains poorly understood. Methods and results In this study, we performed a global characterization of protein oxidation targets in PDAC cells through iodoTMT-based quantitative proteomics, which identified over 4300 oxidized cysteine sites in more than 2100 proteins in HPDE6c7 and PANC-1 cells. Among them, 1715 cysteine residues were shown to be differentially oxidized between HPDE6c7 and PANC-1 cells. Also, charged amino acids including aspartate, glutamate and lysine were significantly overrepresented in flanking sequences of oxidized cysteines. Differentially oxidized proteins in PANC-1 cells were enriched in multiple cancer-related biological processes and signaling pathways. Specifically, the HIF-1 signaling proteins exhibited significant oxidation alterations in PANC-1 cells, and the reduced PHD2 oxidation in human PDAC tissues was correlated with lower survival time in pancreatic cancer patients. Conclusion These investigations provided new insights into protein oxidation-regulated signaling and biological processes during PDAC pathogenesis, which might be further explored for pancreatic cancer diagnosis and treatment.

ABSTRACT: The study aimed to investigate the distribution and expression of nesfatin-1 in Bactrian camels and its impact on adipocyte glucose metabolism. Polyclonal antibodies against a single antigenic epitope of NUCB2/nesfatin-1 protein were prepared. Nesfatin-1 expression was detected in various adipose tissues, including the hypothalamus, humps, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, pancreas, liver, and abdomen, using Western blot and qRT-PCR. Glucose uptake levels, pyruvic acid content, and hexokinase and phosphofructokinase activities were measured in cultured 3T3-L1 preadipocytes treated with nesfatin-1 in a high glucose state using a non-radiofluorimetric assay. The results showed that nesfatin-1 was found in all Bactrian camel tissues, with higher adipose tissue and pancreas expression. However, qRT-PCR analysis revealed higher expression of nesfatin-1 mRNA in the abdominal fat and liver. After nesfatin-1 treatment, a significant decrease (p

Megalobrama amblycephala (Wuchang bream) is a widely farmed native species with the lowest hypoxic tolerance among the major aquaculture species in China. It is often threatened by hypoxic environments in aquaculture due to high culture densities and weather changes. Identification of the key genes and elucidation of the mechanisms involved in hypoxic tolerance provide the basis for genetic breeding of hypoxia-tolerant Megalobrama amblycephala strains. Here, we report that fih is evolutionarily conserved across species. CRISPR/Cas9-generated fih heterozygotes in Megalobrama amblycephala facilitate hypoxic tolerance and exhibit increased expression of hypoxia-responsive genes, including pdh3, glut1 and vegfa. Mechanistically, coimmunoprecipitation experiments indicated that overexpressed Megalobrama amblycephala fih (Ma-fih) interacts with the transcription factor hypoxia inducible factor (Ma-hif-α). Dual-luciferase assay showed that overexpression of Ma-fih inhibited the transcriptional activity of Ma-hif-α. In addition, we found that overexpression of Ma-fih suppressed hypoxia-induced glucose uptake in EPC cells. This study not only highlights the critical function of Ma-fih in regulating the hypoxia signaling pathway, but also provides a candidate gene for breeding hypoxia-tolerant Megalobrama amblycephala strains.

Achieving carbon neutrality through increasing carbon sinks is a crucial strategy for reaching long-term climate objectives. During rapid urbanization, the degradation of vegetation structure and quantity in fragmented patches leads to the reduction of the carbon sink capacity. Establishing the well-design ecological spatial network is crucial for improving the carbon sink capacity. This study focuses on enhancing the carbon sink capacity in the Wuhan Metropolitan Area (WMA) through a four-step approach–identification, construction, assessment, and optimization–to improve the ecological spatial structure of carbon sink patches and increase carbon sink capacity. The results show that we initially built 27 carbon sink patches and 52 networks, prioritizing 15 core networks. Due to the low connectivity between the Western and other regions, we added 18 steppingstones and 12 networks to enhance overall connectivity and stability of spatial network. Verification shows that our scheme benefits the connectivity and stability of whole ecological network of WMA, and increases the total carbon sink by 11.17 Mt CO2. This research enriches methods for increasing carbon sinks in urban areas and provides theoretical support for achieving carbon neutrality.

Gentiana szechenyii Kanitz. and Gentiana veitchiorum Hemsl. are two wild medicinal plants widely used in Tibetan medicine. In recent decades, their wild populations have declined rapidly due to persistent over-harvesting of their flowers. Because their flowers are small and dense, it is difficult to rely on manual counting under wild conditions. The combination of deep learning and unmanned aerial vehicle remote sensing (UAVRS) is a new method for plant surveys. We trained 12 of the most advanced or widely used YOLO models on a custom dataset to achieve quantitative detection of both plant flowers in UAVRS images. The accuracy, precision and recall of G. szechenyii Flower (GSF) detection can reach 97.00%, 90.40% and 95.40%, respectively (based on YOLOv7). Similarly, those of G. veitchiorum Flower (GVF) detection can reach 93.40%, 91.30% and 90.60%, respectively (based on YOLOv5n), and the highest mAP can reach 94.90% (based on YOLOv5m). Based on the detection results, it is calculated that the total yield of dried GSF and GVF that can be harvested as medicinal materials in study area ranges from 1.88 to 2.10 g·m−2 and 4.42–4.62 g·m−2, respectively. The results show that deep learning and UAVRS can be used for quantitative detection of GSF and GVF, which is helpful for further research and protection of these two plants.

Abstract Background Universities have widely switched from traditional face-to-face classes to online instruction as a result of the epidemic. Self-directed learning is becoming the new norm for university students’ learning styles. The ability of health professions students to learn independently during online study directly impacts the effectiveness of online medical education. The ability to learn on their own initiative may be affected by health professions students’ professional identities, defined as their positive perceptions, evaluations, emotional experiences, and identity as professionals related to medicine. This study aimed to look into the current status and the factors that influence health professions students’ self-directed learning ability (SDLA) during online study and its relationship with professional identity. Methods This study was conducted from September to November 2022 at a medical school in East China. An online questionnaire was used to collect participants’ status of online learning, self-directed learning ability (SDLA), and professional identity. Results One thousand two hundred ninety-eight health professions students demonstrated intermediate self-directed learning ability during online study. In terms of teacher-student interaction (F = 14.778, P

Abstract Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer–immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.

Backgrounds: A contemporary public health challenge is the increase in the prevalence rates of herpes zoster (HZ) worldwide. Methods: In this work, the gE gene structure was analyzed using bioinformatics techniques, and three plasmids of varying lengths, tgE537, tgE200, and tgE350, were expressed in Chinese hamster ovary (CHO) cells. These proteins were used to immunize BALB/c mice with Al/CpG adjuvant; ELISPOT and FCM were used to evaluate cellular immunity; and ELISA, VZV microneutralization, and FAMA assays were performed to detect antibody titers. Results: Target protein concentrations of 1.8 mg/mL for tgE537, 0.15 mg/mL for tgE200 and 0.65 mg/mL for tgE350 were effectively produced. The ability of the three protein segments to stimulate CD4+ and CD8+ T cells, as well as to cause lymphocytes to secrete IFN-γ and IL-4, did not significantly differ from one another. Both tgE537 and tgE350 were capable of generating VZV-specific antibodies and neutralizing antibodies, while tgE350 had the highest neutralizing antibody titer (4388). There was no equivalent humoral immune response induced by tgE200. Conclusions: The results of this investigation provide the groundwork for the creation of HZ recombinant vaccines using truncated proteins as antigens.

Phenylalanine ammonia lyase (PAL) is a pivotal enzyme in the phenylalanine metabolic pathway in plants and has a crucial role in the plant’s response to environmental stress. Although the PAL family has been widely studied in many plant species, limited is known about its particular role in cucumbers under stress. We investigated the physicochemical properties, gene structure, gene duplication events, conserved motifs, cis-acting elements, protein interaction networks, stress-related transcriptome data, and quantitatively validated key stress-related genes. The main results indicated that 15 PAL genes were grouped into four clades: I, II, and III when arranged in a phylogenetic tree of PAL genes in angiosperms. The analysis of the promoter sequence revealed the presence of multiple cis-acting elements related to hormones and stress responses in the cucumber PAL genes (CsPALs). The analysis of protein interaction networks suggested that CsPAL1 interacts with eight other members of the PAL family through CsELI5 and CsHISNA, and directly interacts with multiple proteins in the 4CL family. Further investigation into the expression patterns of CsPAL genes in different tissues and under various stress treatments (NaCl, Cu2+, Zn2+, PEG6000, aphids) demonstrated significant differential expression of CsPALs across cucumber tissues. In summary, our characterization of the CsPAL family offers valuable insights and provides important clues regarding the molecular mechanisms of CsPALs in managing abiotic and biotic stress interactions in cucumbers.

In recent years, the number of people driving from plain areas to the western plateau of China has been increasing, and their safety is threatened by acute high-altitude reactions caused by hypoxia. Vehicle-mounted pressure swing adsorption oxygen supply technology can help solve this problem. For the optimization of vehicle pressure swing adsorption oxygen production, the influence of different pressure equalization methods on oxygen production efficiency was studied. The best oxygen production performance was achieved when the initial upper pressure equalization method and the simultaneous pressure equalization method were used. Using a 160 W air compressor, the product gas flow rate could reach 2.5 L/min with an oxygen concentration of 93.48%. The impact of adsorption time, equalization time, flow rate, and throttle inner diameter on oxygen concentration and recovery rate was analyzed using the response surface method. The order of the four factors affecting oxygen concentration is as follows: flow rate > adsorption time > equalization time > throttle inner diameter. After optimization, the product gas flow rate was 2.6 L/min, the oxygen concentration was 92.11%, and the oxygen recovery rate was 44.51%.

In oxygen production on plateaus, pressure swing adsorption (PSA) oxygen production is currently the most commonly used oxygen production method. In plateau regions, low pressure leads to a decrease in adsorbent nitrogen–oxygen separation performance, which affects the performance of PSA oxygen production, so it is particularly important to enhance adsorbent nitrogen–oxygen separation performance. In this paper, Li-LSX (lithium low-silicon aluminum X zeolite molecular sieve) adsorbents were modified using the liquid phase ion exchange method, and five kinds of modified adsorbents were obtained, namely AgLi-LSX, CaLi-LSX, ZnLi-LSX, CuLi-LSX, and FeLi-LSX, respectively. The influences of different metal ions and modification time lengths on the adsorbent nitrogen adsorption and nitrogen–oxygen separation coefficients were analyzed. Through theoretical calculations, the nitrogen and oxygen adsorption and separation performances of the modified adsorbents at different altitudes and low adsorption pressures were investigated. It is shown that the nitrogen adsorption capacity of the AgLi-LSX-1 adsorbent obtained from the modification experiment reaches 27.92 mL/g, which is 3.24 mL/g higher than that of Li-LSX; the nitrogen–oxygen separation coefficients of S1 and S2 are 19.24 and 7.54 higher, respectively; and the nitrogen–oxygen separation coefficients of S4 are 20.85 and 7.54 higher than those of Li-LSX, respectively. With the increase in altitude from 50 m to 5000 m, the nitrogen–oxygen separation coefficient of the AgLi-LSX-1 adsorbent increased rapidly from 20.85 to 57, and its nitrogen–oxygen separation coefficient S4 exceeded that of the Li-LSX adsorbent to reach 47.61 at an altitude of 4000 m. Therefore, the modified adsorbent AgLi-LSX-1 in this paper can enhance the performance of the PSA oxygen process for oxygen production in plateau applications.

In the current study, which focuses on the operational safety problem in intelligent three-dimensional garages, an obstacle avoidance measurement and control scheme for the AGV parking robot is proposed. Under the premise of high-precision distance detection using Kalman filtering, a mathematical model of a brushless DC (BLDC) motor with full-speed range hybrid control is established. MATLAB/Simulink (R2022a) is used to build the control model, which has dual closed-loop vector-controlled motors in the low- to medium-speed range, with photoelectric encoders for speed feedback. The simulation results show that, at lower to medium speeds, the maximum overshoot of the output response curve is 1.5%, and the response time is 0.01 s. However, at higher speeds, there is significant jitter in the speed output waveform. Therefore, the speed feedback is switched to a sliding mode observer (SMO) instead of the original speed sensor at high speeds. Experiments show that, based on the SMO, the problem of speed waveform jitter at high motor speeds can be significantly improved, and the BLDC motor system has strong robustness. The above shows that the motor speed under the full-speed range hybrid control system can meet the AGV control and safety requirements.

IFN regulatory factor 3 (IRF3) is the transcription factor crucial for the production of type I IFN in viral defence and inflammatory responses. The activity of IRF3 is strictly modulated by post-translational modifications (PTMs) to effectively protect the host from infection while avoiding excessive immunopathology. Here, we report that zebrafish myosin-regulated light chain interacting protein b (mylipb) inhibits virus-induced type I IFN production via two synergistic mechanisms: induction of autophagic degradation of irf3 and reduction of irf3 phosphorylation. In vivo, mylipb-null zebrafish exhibit reduced lethality and viral mRNA levels compared to controls. At the cellular level, overexpression of mylipb significantly reduces cellular antiviral capacity, and promotes viral proliferation. Mechanistically, mylipb associates with irf3 and targets Lys 352 to increase K6-linked polyubiquitination, dependent on its E3 ubiquitin ligase activity, leading to autophagic degradation of irf3. Meanwhile, mylipb acts as a decoy substrate for the phosphokinase tbk1 to attenuate irf3 phosphorylation and cellular antiviral responses independent of its enzymatic activity. These findings support a critical role for zebrafish mylipb in the limitation of antiviral innate immunity through two synergistic mechanisms targeting irf3.

The hypoxia-inducible factor (HIF)-mediated hypoxia signaling pathway influences oxygen homeostasis in aerobic organisms. This pathway is regulated by several other pathways. Elucidation of its regulation and the underlying mechanisms may provide insights into the strategies of adaptation and tolerance of organisms to hypoxia. In this study, we found that loss of ubiquitin-specific protease 3 (usp3) in zebrafish promotes hypoxia tolerance. Zebrafish usp3 specifically binds to hif-1αa and induces its proteasomal degradation, which is dependent on its deubiquitinase activity. This process leads to the suppression of hypoxia signaling under hypoxia. In addition, usp3 catalyzes the deubiquitination of K63-polyubiquitinated hif-1αa. Endogenous evidence indicated that mammalian USP3 behaves like zebrafish usp3 in regulating the activity of HIF-1α. These findings revealed a novel role for usp3 in influencing hypoxia signaling and showed that usp3-mediated HIF-1α degradation impairs hypoxia signaling, leading to a decrease in hypoxia tolerance.

ABSTRACT“Candidatus Liberibacter asiaticus” (CLas), the causal agent of citrus Huanglongbing (HLB), is able to multiply to a high abundance in citrus fruit pith. However, little is known about the biological processes and phytochemical substances that are vital for CLas colonization and growth in fruit pith. In this study, CLas-infected fruit pith of three citrus cultivars (“Shatangju” mandarin, “Guanxi” pomelo, and “Shatian” pomelo) exhibiting different tolerance to CLas were collected and used for dual RNA-Seq and untargeted metabolome analysis. Comparative transcriptome analysis found that the activation of the CLas noncyclic TCA pathway and pathogenic-related effectors could contribute to the colonization and growth of CLas in fruit pith. The pre-established Type 2 prophage in the CLas genome and the induction of its CRISPR/cas system could enhance the phage resistance of CLas and, in turn, facilitate CLas population growth in fruit pith. CLas infection caused the accumulation of amino acids that were correlated with tolerance to CLas. The accumulation of most sugars and organic acids in CLas-infected fruit pith, which could be due to the phloem blockage caused by CLas infection, was thought to be beneficial for CLas growth in localized phloem tissue. The higher levels of flavonoids and terpenoids in the fruit pith of CLas-tolerant cultivars, particularly those known for their antimicrobial properties, could hinder the growth of CLas. This study advances our understanding of CLas multiplication in fruit pith and offers novel insight into metabolites that could be responsible for tolerance to CLas or essential to CLas population growth.IMPORTANCECitrus Huanglongbing (HLB, also called citrus greening disease) is a highly destructive disease currently threatening citrus production worldwide. HLB is caused by an unculturable bacterial pathogen, “Candidatus Liberibacter asiaticus” (CLas). However, the mechanism of CLas colonization and growth in citrus hosts is poorly understood. In this study, we utilized the fruit pith tissue, which was able to maintain the CLas at a high abundance, as the materials for dual RNA-Seq and untargeted metabolome analysis, aiming to reveal the biological processes and phytochemical substances that are vital for CLas colonization and growth. We provided a genome-wide CLas transcriptome landscape in the fruit pith of three citrus cultivars with different tolerance and identified the important genes/pathways that contribute to CLas colonization and growth in the fruit pith. Metabolome profiling identified the key metabolites, which were mainly affected by CLas infection and influenced the population dynamic of CLas in fruit pith.

Abstract Paroxysmal kinesigenic dyskinesia (PKD) is associated with a disturbance of neural circuit and network activities, while its neurophysiological characteristics have not been fully elucidated. This study utilized the high‐density electroencephalogram (hd‐EEG) signals to detect abnormal brain activity of PKD and provide a neural biomarker for its clinical diagnosis and PKD progression monitoring. The resting hd‐EEGs are recorded from two independent datasets and then source‐localized for measuring the oscillatory activities and function connectivity (FC) patterns of cortical and subcortical regions. The abnormal elevation of theta oscillation in wildly brain regions represents the most remarkable physiological feature for PKD and these changes returned to healthy control level in remission patients. Another remarkable feature of PKD is the decreased high‐gamma FCs in non‐remission patients. Subtype analyses report that increased theta oscillations may be related to the emotional factors of PKD, while the decreased high‐gamma FCs are related to the motor symptoms. Finally, the authors established connectome‐based predictive modelling and successfully identified the remission state in PKD patients in dataset 1 and dataset 2. The findings establish a clinically relevant electroencephalography profile of PKD and indicate that hd‐EEG can provide robust neural biomarkers to evaluate the prognosis of PKD.

Abstract Background The occurrence of somatic mutations in patients with no evidence of hematological disorders is called clonal hematopoiesis (CH). CH, whose subtypes include CH of indeterminate potential and clonal cytopenia of undetermined significance, has been associated with both hematologic cancers and systemic comorbidities. However, CH's effect on patients, especially those with concomitant malignancies, is not fully understood. Methods We performed a retrospective evaluation of all patients with CH at a tertiary cancer center. Patient characteristics, mutational data, and outcomes were collected and analyzed. Results Of 78 individuals included, 59 (76%) had a history of cancer and 60 (77%) had moderate to severe comorbidity burdens. DNMT3A, TET2, TP53, and ASXL1 were the most common mutations. For the entire cohort, the 2‐year overall survival rate was 79% (95% CI: 70, 90), while the median survival was not reached. Of 20 observed deaths, most were related to primary malignancies (n = 7, 35%), comorbidities (n = 4, 20%), or myeloid neoplasms (n = 4, 20%). Twelve patients (15%) experienced transformation to a myeloid neoplasm. According to the clonal hematopoiesis risk score, the 3‐year transformation rate was 0% in low‐risk, 15% in intermediate‐risk (p = 0.098), and 28% in high‐risk (p = 0.05) patients. By multivariate analysis, transformation was associated with variant allele frequency ≥0.2 and hemoglobin

The epidermal barrier is vital for protecting the skin from environmental stressors and ultraviolet (UV) radiation. Filaggrin-2 (FLG2), a critical protein in the stratum corneum, plays a significant role in maintaining skin barrier homeostasis. However, the precise role of FLG2 in mitigating the adverse effects of UV-induced barrier disruption and photoaging remains poorly understood. In this study, we revealed that UVB exposure resulted in a decreased expression of FLG2 in HaCaT keratinocytes, which correlated with a compromised barrier function. The administration of recombinant filaggrin-2 (rFLG2) enhanced keratinocyte differentiation, bolstered barrier integrity, and offered protection against apoptosis and oxidative stress induced by UVB irradiation. Furthermore, in a UV-induced photodamage murine model, the dermal injection of rFLG2 facilitated the enhanced restoration of the epidermal barrier, decreased oxidative stress and inflammation, and mitigated the collagen degradation that is typical of photoaging. Collectively, our findings suggested that targeting FLG2 could be a strategic approach to prevent and treat skin barrier dysfunction and combat the aging effects associated with photoaging. rFLG2 emerges as a potentially viable therapy for maintaining skin health and preventing skin aging processes amplified by photodamage.

To obtain high-quality bovine oocytes, the effects of vitamin C (VC) on the IVM of bovine oocytes and early embryo development were investigated. The results showed the following. (1) The IVM medium containing 50 µg/mL VC improved the oocyte maturation rate but did not affect the parthenogenetic embryo development. (2) The IVC medium containing 20 µg/mL VC improved the cleavage rate of the IVF embryos and enhanced the mRNA transcriptions of pluripotency gene Oct4, Sox2, Cdx2, and Nanog in the blastocysts but had no effects on the blastocyst rate. (3) Combining supplementation of 50 µg/mL VC in IVM medium + 20 µg/mL VC in IVC medium (named as VC 50/20, similar hereinafter) elevated the cleavage rate of IVF embryos and enhanced the mRNA expressions of Oct4, Sox2, Cdx2, and Nanog in the blastocysts. (4) Combination of VC 0/20 and VC 50/20 enhanced the transcription of anti-apoptotic gene Bcl-2 and VC 50/0 weakened the transcription of pro-apoptotic gene Bax, while VC 0/40 and VC 0/60 increased Bax expression and diminished the Bcl-2/Bax ratio in blastocysts. Together, employing 50 µg/mL VC improves the IVM of bovine oocytes and combination of VC 50/20 potentially changes bovine embryo quality by enhancing the expressions of the pluripotency genes and regulating the expressions of apoptosis-related genes.

In this study, RM (red mud) was acidified with sulfuric acid, and the acidified ARM (acidified red mud) was utilized as an innovative adsorption material for treating antibiotic-containing wastewater. The adsorption conditions, kinetics, isotherms, thermodynamics, and mechanism of ARM for CIP (ciprofloxacin) were investigated. The characterization of the ARM involved techniques such as scanning electron microscopy (SEM), transmission electron microscopy (TEM), Brunauer–Emmett–Teller (BET), X-ray diffraction (XRD), X-ray fluorescence (XRF), thermogravimetric analysis (TGA), and NH3-TPD analysis. Adsorption studies employed a response surface methodology (RSM) for the experimental design. The results showed that ARM can absorb CIP effectively. The RSM optimal experiment indicated that the most significant model terms influencing adsorption capacity were solution pH, CIP initial concentration, and ARM dosage, under which the predicted maximum adsorption capacity achieved 7.30 mg/g. The adsorption kinetics adhered to a pseudo-second-order model, while equilibrium data fitted the Langmuir–Freundlich isotherm, yielding maximum capacity values of 7.35 mg/g. The adsorption process occurred spontaneously and absorbed heat, evidenced by ΔGθ values between −83.05 and −91.50 kJ/mol, ΔSθ at 281.6 J/mol/K, and ΔHθ at 0.86 kJ/mol. Analysis using attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) indicated a complex reaction between the Al–O in the ARM and the ester group –COO in CIP. The C=O bond in CIP was likely to undergo a slight electrostatic interaction or be bound to the internal spherical surface of the ARM. The findings indicate that ARM is a promising and efficient adsorbent for CIP removal from wastewater.

Single-cell or low-input multi-omics techniques have revolutionized the study of pre-implantation embryo development. However, the single-cell or low-input proteomic research in this field is relatively underdeveloped because of the higher threshold of the starting material for mammalian embryo samples and the lack of hypersensitive proteome technology. In this study, a comprehensive solution of ultrasensitive proteome technology (CS-UPT) was developed for single-cell or low-input mouse oocyte/embryo samples. The deep coverage and high-throughput routes significantly reduced the starting material and were selected by investigators based on their demands. Using the deep coverage route, we provided the first large-scale snapshot of the very early stage of mouse maternal-to-zygotic transition, including almost 5,500 protein groups from 20 mouse oocytes or zygotes for each sample. Moreover, significant protein regulatory networks centered on transcription factors and kinases between the MII oocyte and 1-cell embryo provided rich insights into minor zygotic genome activation.

Abstract Flexible covalent organic frameworks (COFs) have been studied for applications containing sorption, selective separation, and catalysis. How to correlate the microscopic structure with flexibility in COFs is a great challenge. Herein, we visually track the flexible deformation behaviors of single COF-300 and COF-300-AR particles in response to solvent vapour guests with dark-field microscopy (DFM) in an in operando manner. COF-300-AR with freely-rotating C-N single bonds are synthesized by the reduction of imine-based COF-300 consisting of rigid C=N double bonds without changing topological structure and crystallinity. Unexpectedly, we observe that the flexible deformation of COF-300 is extremely higher than that of COF-300-AR despite it bears many C-N single bonds, clearly illustrating the apparent flexibility decrease of COF-300 after reduction. The high spatiotemporal resolution of DFM enables the finding of inter-particle variations of the flexibility among COF-300 crystals. Experimental characterizations by variable-temperature X-ray diffraction and infrared spectroscopy as well as theoretical calculations demonstrate that the flexible deformation of COF-300 is ascribed to the pedal motion around rigid C=N double bonds. These observations provide new insights into COF flexibility.

Abstract We propose a statistical framework ISLET to infer individual-specific and cell-type-specific transcriptome reference panels. ISLET models the repeatedly measured bulk gene expression data, to optimize the usage of shared information within each subject. ISLET is the first available method to achieve individual-specific reference estimation in repeated samples. Using simulation studies, we show outstanding performance of ISLET in the reference estimation and downstream cell-type-specific differentially expressed genes testing. We apply ISLET to longitudinal transcriptomes profiled from blood samples in a large observational study of young children and confirm the cell-type-specific gene signatures for pancreatic islet autoantibody. ISLET is available at https://bioconductor.org/packages/ISLET .

Previous studies have uncovered the key role of circular RNAs (circRNAs) in various diseases, including cancer. However, the growth‐inhibitory effects of circRNAs on esophageal squamous cell carcinoma (ESCC) have not been completely elucidated. This study characterized a newly identified circRNA derived from exons 9–13 of TNRC6B (named circ‐TNRC6B). The expression of circ‐TNRC6B in ESCC tissues was markedly downregulated when compared to that in non‐tumor tissues. In 53 ESCC cases, circ‐TNRC6B expression was negatively correlated with the T stage. Multivariate Cox regression analysis showed that circ‐TNRC6B upregulation was an independent protective factor for ESCC patients' prognosis. Overexpression and knockdown functional experiments demonstrated that circ‐TNRC6B inhibited ESCC cell proliferation, migration, and invasion. RNA immunoprecipitation and dual‐luciferase reporter assays demonstrated that circ‐TNRC6B sponges oncogenic miR‐452‐5p to upregulate the expression and activity of DAG1. Treatment with miR‐452‐5p inhibitor partially reversed the circ‐TNRC6B‐induced changes in the biological behavior of ESCC cells. These findings demonstrated that circ‐TNRC6B exerts a tumor‐suppressing effect in ESCC through the miR‐452‐5p/DAG1 axis. Thus, circ‐TNRC6B is a potential prognostic biomarker for the clinical management of ESCC.

BackgroundCoronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) are closely related. The function of immunocytes in the pathogenesis of CAD and T2DM has not been extensively studied. The quantitative bioinformatics analysis of the public RNA sequencing database was applied to study the key genes that mediate both CAD and T2DM. The biological characteristics of associated key genes and mechanism of CD8+ T and NK cells in CAD and T2DM are our research focus.MethodsWith expression profiles of GSE66360 and GSE78721 from the Gene Expression Omnibus (GEO) database, we identified core modules associated with gene co-expression relationships and up-regulated genes in CAD and T2DM using Weighted Gene Co-expression Network Analysis (WGCNA) and the ‘limma’ software package. The enriched pathways of the candidate hub genes were then explored using GO, KEGG and GSEA in conjunction with the immune gene set (from the MSigDB database). A diagnostic model was constructed using logistic regression analysis composed of candidate hub genes in CAD and T2DM. Univariate Cox regression analysis revealed hazard ratios (HRs), 95% confidence intervals (CIs), and p-values for candidate hub genes in diagnostic model, while CIBERSORT and immune infiltration were used to assess the immune microenvironment. Finally, monocytes from peripheral blood samples and their immune cell ratios were analyzed by flow cytometry to validate our findings.ResultsSixteen candidate hub genes were identified as being correlated with immune infiltration. Univariate Cox regression analysis revealed that NPEPPS and ABHD17A were highly correlated with the diagnosis of CAD and T2DM. The results indicate that CD8+ T cells (p = 0.04) and NKbright cells (p = 3.7e-3) are significantly higher in healthy controls than in individuals with CAD or CAD combined with T2DM. The bioinformatics results on immune infiltration were well validated by flow cytometry.ConclusionsA series of bioinformatics studies have shown ABHD17A and NPEPPS as key genes for the co-occurrence of CAD and T2DM. Our study highlights the important effect of CD8+ T and NK cells in the pathogenesis of both diseases, indicating that they may serve as viable targets for diagnosis and therapeutic intervention.

IntroductionAs the rapid expanding of internet technology, it is necessary to pay attention to the factors that predict Internet addiction. This study aimed to investigate the longitudinal impact of reinforcement sensitivity on internet addiction among college students and the mediating role of self-control.MethodsThe study involves two follow-up assessments with a 5-month interval. 383 college students’ reinforcement sensitivity, self-control, and internet addiction were measured at two-time points.Results①The revised Behavioral Approach System (r-BAS) at Time Point 1 (T1) could predict both T1 and Time Point 2 (T2) internet addiction through the complete mediation of T1 self-control. ②The revised Behavioral Inhibition System (r-BIS) at T1, along with the Fight/Flight/Freeze System (FFFS), can predict T1 and T2 internet addiction through the partial mediation of T1 self-control.ConclusionReinforcement sensitivity can predict current and future internet addiction, with self-control playing a mediating role. This study provides longitudinal experimental evidence for the revised Reinforcement Sensitivity Theory (r-RST), further revealing the underlying mechanisms through which reinforcement sensitivity influences internet addiction. Additionally, it has implications for clinical intervention.

ABSTRACTThe progress in optical remote sensing technology presents both a possibility and challenge for small object segmentation task. However, the gap between human vision cognition and machine behavior still poses an inherent constrains to the interpretation of small but key objects in large-scale remote sensing scenes. This paper summarizes this gap as a bias of the machine against small object segmentation task, called scale-induced bias. The scale-induced bias causes the degradation in the performance of conventional remote sensing image segmentation methods. Therefore, this paper applies a straightforward but innovative insight to mitigate the scale-induced bias. Specifically, we propose a universal impartial loss, which leverages the hierarchical approach to alleviate two sub-problems separately. The pixel-level statistical methodology is applied to remove the bias between the background and small objects, and an emendation vector is introduced to alleviate the bias between small object categories. Extensive experiments explicitly manifest that our method is fully compatible with the existing segmentation structures, armed with the hierarchical unbiased loss, these structures will achieve satisfactory improvement. The proposed method is validated on two benchmark remote sensing image datasets, where it achieved a competitive performance and could narrow the gap between the human vision cognition and machine behavior.

ABSTRACTBackground Because of the wide use of information and communication technologies (ICT) in healthcare, medical students’ knowledge and skills of modern ICT have been considered essential for their successful learning and future careers. According to Bandura’s self-efficacy, enhancing ICT self-efficacy, which might be affected by technology experience, could be a pathway to improving ICT literacy and competence, which should be one focus of medical educationalists. However, there is a lack of suitable measurements of medical students’ self-efficacy and a clear understanding of its relationship with technology experience.Materials and methods We conducted a literature review and direct consultation with an expert panel to identify potential items for the ICT self-efficacy scale. Based on the data collected in a survey of 486 first-year medical students in China, the exploratory factor analysis (EFA) was employed to confirm the structure of the final version. Furthermore, we used linear regressions to quantify the association between ICT self-efficacy and technology experience measured by the age of first access to the Internet, the age at first ownership of a personal computer (PC) or a laptop, and that of a smartphone.Results The EFA results derived 15 items of four factors, with 67.02% of the total variance explained: Privacy and Safety, Differencing, Communication, and Learning and Application. The Cronbach’s alphas for the four subscales and the overall scale ranged from 0.78 to 0.89. Regression results demonstrated a significant association of ICT self-efficacy with age at first ownership of a personal computer (PC) and the mediation role of the general self-efficacy in the ICT self-efficacy’s association with the age at first ownership of a personal smartphone.Conclusion The ICT scale developed is a reliable and valid task-specific measure to assess ICT Self-Efficacy for medical students. In addition, enhancing students’ technology experience might improve their ICT self-efficacy.

BackgroundLead and manganese are heavy metal pollutants widely existing in the environment, which can accumulate in the human body through the food chain, exert neurotoxicity, and cause neurodegenerative disorders. Especially in early childhood, the developing blood-brain barrier and nervous system are highly susceptible to environmental chemical pollutants. Most of the previous studies focused on the toxic effects of single heavy metal such as lead or manganese, while the studies on combined toxic effect are still scarce, and involved mechanisms are still unclear. c-Jun N-terminal kinase (JNK) is involved in neuronal development and regeneration, and some studies have found that JNK is involved in lead or manganese induced neurotoxicity. Its role in the toxicity of combined lead and manganese is unknown. ObjectiveTo understand the neurodevelopmental toxicity mechanism and to observe changes of JNK expression in zebrafish induced by combined lead and manganese exposure at environmentlly low concentrations. MethodsZebrafish embryos within 2 h post fertilization (hpf) were divided into four groups: control group, lead exposure group (0.1 mg·L−1 lead acetate), manganese exposure group (0.3 mg·L−1 manganous chloride), and lead-manganese combined exposure group (0.1 mg·L−1 lead acetate +0.3 mg·L−1 manganous chloride) and exposed to lead or/and manganese at designed levels for 7 d. Spontaneous movements and motor locomotion were observed, and mortality rate were calculated. The changes of JNK mRNA expression in zebrafish were evaluated. ResultsThe experimental results showed that no significant effect of lead or/and manganese on spontaneous movements and mortality rate was found in zebrafish compared with the control group (P＞0.05). The results of locomotion analysis showed that compared with the control group, the activity counts and activity distance of zebrafish in the manganese exposure group were slightly increased (P＜0.01); the activity counts and activity distance of zebrafish in the lead exposure group were reduced by 50% and those in the lead-manganese exposure group were reduced by 80% (P＜0.01). Compared with the lead exposure group, the activity counts and activity distance of zebrafish in the lead-manganese combined exposure group decreased significantly by 60% (P＜0.05). The real-time quantitative PCR results showed that the JNK mRNA expression level was significantly increased in the lead-manganese combined exposure group compared with the control group(P＜0.01). ConclusionLead exposure combined with manganese exposure at environmentlly low concentration can induce neurodevelopmental toxicity to zebrafish. JNK may be involved in neurodevelopmental toxicity induced by the combined exposure to lead and manganese.

Abstract We study the Feynman propagator of free scalar fields in AdS3 with a conical defect. In the bulk, the defect is represented by a massive particle; in the dual CFT, it is a heavy operator that creates a highly excited state. We construct the propagator by solving the bulk equation of motion in the defect geometry, summing over the modes of the field, and passing to the boundary. The result agrees with a calculation based on the method of images in AdS3/ℤ N , where it is also a sum over geodesic lengths. On the boundary, the propagator becomes a semiclassical heavy-light four-point function. We interpret the field modes as double-twist primary states formed by excitations of the scalar on top of the defect, and we check that the correlator is crossing-symmetric by matching its singular behavior to that of the semiclassical Virasoro vacuum block. We also argue that long-range correlations in conical AdS are “thermally” suppressed as the defect becomes more massive by studying the critical behavior of a continuous phase transition in the correlator at the BTZ threshold. Finally, we apply our results to holographic entanglement entropy by exploiting an analogy between free scalars and replica twist fields.

Abstract N6-methyladenosine (m6A) modification has been shown to regulate RNA metabolism. Here, we investigate m6A dynamics during maternal-to-zygotic transition (MZT) in mice through multi-omic analysis. Our results show that m6A can be maternally inherited or de novo gained after fertilization. Interestingly, m6A modification on maternal mRNAs not only correlates with mRNA degradation, but also maintains the stability of a small group of mRNAs thereby promoting their translation after fertilization. We identify Ythdc1 and Ythdf2 as key m6A readers for mouse preimplantation development. Our study reveals a key role of m6A mediated RNA metabolism during MZT in mammals.

The testes serve as the primary source of androgens and the site of spermatogenesis, with their development and function governed by hormonal actions via endocrine and paracrine pathways. Male fertility hinges on the availability of testosterone, a cornerstone of spermatogenesis, while follicle-stimulating hormone (FSH) signaling is indispensable for the proliferation, differentiation, and proper functioning of Sertoli and germ cells. This review covers the research on how androgens, FSH, and other hormones support processes crucial for male fertility in the testis and reproductive tract. These hormones are regulated by the hypothalamic–pituitary–gonad (HPG) axis, which is either quiescent or activated at different stages of the life course, and the regulation of the axis is crucial for the development and normal function of the male reproductive system. Hormonal imbalances, whether due to genetic predispositions or environmental influences, leading to hypogonadism or hypergonadism, can precipitate reproductive disorders. Investigating the regulatory network and molecular mechanisms involved in testicular development and spermatogenesis is instrumental in developing new therapeutic methods, drugs, and male hormonal contraceptives.

To reduce the power consumption of a TDC in high-speed applications, a TDC architecture applied to SS ADC is proposed to reduce redundant counting. This structure can remove the identical part between two rows of pixel signals in a CMOS image sensor by adjusting the start and stop signal of the TDC, which will reduce the number of flipping of D flip-flops in the TDC. This structure requires the simultaneous readout of two rows of pixels in the high-speed CMOS image sensor. In the 110 nm CMOS process, simulation results show that the designed 5-bit TDC achieves an effective number of bits (ENOB) at 4.72 bits and a figure-of-merit (FOM) at 104.7–162.3 fJ/step, with a power consumption ranging from 60 µW to 93 µW. Compared with traditional counting methods, the proposed TDC can reduce counting power consumption by 30%.

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture–induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and Gram– sepsis models. miR-93-5p met the criteria for a therapeutic target, as it was overexpressed in baboons that died early after induction of sepsis, was downregulated in patients who survived after sepsis, and correlated with negative clinical prognosticators for sepsis. Therapeutically, inhibition of miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in older mice. Mechanistically, anti–miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially the CD4+ subset. AGO2 IP in miR-93–KO T cells identified important regulatory receptors, such as CD28, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis through the regulation of both innate and adaptive immunity, with possibly a greater benefit for elderly patients than for young patients.

Summary: Here, we present a standardized, “off-the-shelf” proteomics pipeline working in a single 96-well plate to achieve deep coverage of cellular proteomes with high throughput and scalability. This integrated pipeline streamlines a fully automated sample preparation platform, a data-independent acquisition (DIA) coupled with high-field asymmetric waveform ion mobility spectrometer (FAIMS) interface, and an optimized library-free DIA database search strategy. Our systematic evaluation of FAIMS-DIA showing single compensation voltage (CV) at −35 V not only yields the deepest proteome coverage but also best correlates with DIA without FAIMS. Our in-depth comparison of direct-DIA database search engines shows that Spectronaut outperforms others, providing the highest quantifiable proteins. Next, we apply three common DIA strategies in characterizing human induced pluripotent stem cell (iPSC)-derived neurons and show single-shot mass spectrometry (MS) using single-CV (−35 V)-FAIMS-DIA results in >9,000 quantifiable proteins with

Exposure to lead (Pb) and manganese (Mn) during early life influences neurodevelopment and increases the risk of neurodegenerative disorders. However, the level of developmental neurotoxicity due to combined exposure to the two metals remains unclear. Although the microbiota plays an essential part in the development of the nervous system via the gut–brain axis, there is a paucity of information regarding the interactions between exposure to Pb and Mn, the destruction of the microbiome, and neurodevelopmental impacts. To fill in this knowledge gap, we investigated the developmental neurotoxicity and effects on the microbiota of Pb (0.05 mg·L−1) alone and in combination with Mn (0.3 mg·L−1) in zebrafish larvae. Our results revealed that combined exposure precipitated higher malformation rates and lower locomotor activity levels than exposure to either Pb or Mn alone. Additionally, when we separated the combined exposure group from the other groups by applying unsupervised principal coordinates analysis (PCoA) and linear discriminant analysis (LEfSe) of microflora sequencing results, we observed extensive alterations in microbial abundances under combined-exposure conditions. Functional prediction analysis showed that combined exposure contributed to altered amino acid and lipid metabolism, and also that combined exposure to Pb and Mn reflected the greatest number of differentially activated biological pathways compared to the other three groups. ATP-binding cassette G (ABCG) genes and genes related to serotonin signaling and metabolism were altered following combined Pb and Mn exposure and exhibited disparate trends vis-à-vis Pb or Mn exposure alone. According to the results, the combined exposure to Pb and Mn led to more severe effects on both zebrafish locomotor activity and gut microbial composition. We suggest that the microbiota contributes to the combined neurotoxicity by increasing ABCG5 and ABCG8 gene expression.

Abstract Bulk high-throughput omics data contain signals from a mixture of cell types. Recent developments of deconvolution methods facilitate cell type-specific inferences from bulk data. Our real data exploration suggests that differential expression or methylation status is often correlated among cell types. Based on this observation, we develop a novel statistical method named CeDAR to incorporate the cell type hierarchy in cell type-specific differential analyses of bulk data. Extensive simulation and real data analyses demonstrate that this approach significantly improves the accuracy and power in detecting cell type-specific differential signals compared with existing methods, especially in low-abundance cell types.

Abstract Background A growing number of investigations have suggested a close link between cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and the tumor microenvironment (TME). However, the relationships between these physiological processes in bladder urothelial carcinoma (BLCA) remain unclear. Methods We first explored biomarkers of tumor stemness (TS) by single-cell sequencing analysis. Then, subtypes of bladder urothelial carcinoma (BLCA) were identified using clustering analysis based on TS biomarkers. The TS score was constructed using principal component analysis to quantify tumor stemness in BLCA. Then, meta-analysis was performed to measure the hazard ratio of the TS score in BLCA cohorts. Moreover, we evaluated the clinical value of the TS score for predicting the response to tumor immunotherapy using immunotherapy cohorts. Finally, we built an EMT cell model by treating T24 cells with TGF-β and validated the relationship between the TS score and the EMT process in tumors by real-time quantitative PCR, cell invasion assays, and RNA-seq. In total, 3846 BLCA cells, 6 cell lines, 1627 BLCA samples, and 9858 samples from 32 other types of tumors were included in our study. Results Three TS clusters and two TS-related gene clusters were identified with differential EMT activity status, CSC features, and TME characteristics in BLCA. Then, a TS scoring system was established with 61 TS-related genes to quantify the TS. The prognostic value of the TS score was then confirmed in multiple independent cohorts. A high TS score was associated with high EMT activity, CSC characteristics, high stromal cell content, high TP53 mutation rate, poor prognosis, and high tumor immunotherapy tolerance. The cell line experiment and RNA-seq further validated that our TS score can reflect the EMT and CSC characterization of tumor cells. Conclusion Overall, this research provides a better understanding of tumor invasion and metastasis mechanisms through an analysis of TS patterns with different EMT processes and CSC characteristics. The TS score provides an index for EMT and CSC research and helps clinicians develop treatment plans and predict outcomes for patients.