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Abstract Background The purpose of this in vitro study was to compare and evaluate the stress distribution of maxillary first premolar residual crowns restored with post-core crowns, endocrowns and inlay crowns after deep margin elevation, to explore the fitting restoration for residual crowns using finite element analysis. Methods A healthy complete right maxillary first premolar from a male adult was scanned by cone beam computed tomography (CBCT). The finite element model of the tooth was established by reverse engineering software such as Mimics, Geomagic and Hypermesh. On this basis, the residual crown model after deep margin elevation was made, and the experimental group models were divided into three groups, those restored with post core crowns, endocrowns and inlay crowns. Vertical and oblique static loads were applied to the experimental models to simulate the force on the tooth during mastication (the loading position was located in the central fossa of the occipital surface, and the load was 100 N) using Abaqus software. Results The peak value and distribution of von Mises stress in each part of the experimental model were observed. After deep margin elevation, the peak dentin von Mises stresses were lower than the tensile strength of normal dentin in the post-core crown, endocrown, and inlay crown groups; the lowest stress results were found in the post-core crown group for the dentin, restoration, enamel, and deep margin elevation (DME) layers under vertical and oblique loading. In terms of stress distribution clouds, the peak stresses in the dentin tissue were located in the apical 1/3 of the root after postcore crown restorations for both loads, while stress concentrations were evident in the cervical and root areas after endocrown and inlay crown restorations; regardless of the load and restoration method, the corresponding stress concentration areas appeared at the junction of the DME and dentin tissue at the loading site of the restorations; Conclusions Post-core crowns, endocrowns and inlay crowns can be used to restore residual crowns after deep margin elevation, and post-core crowns can better protect the residual tooth tissue.

Purpose The influence of pregnancy on tuberculosis (TB) has not been well studied. This study aimed to investigate the demographics, clinical characteristics and outcomes of pregnant-related TB compared with the general population with TB.Methods We retrospectively analysed medical records of women during pregnancy or within six months postpartum with active TB who were admitted to the West China Hospital between 2011 and 2022. According to age, gender and admission time, the general population with active TB was matched at a ratio of 1:2, and the demographics, clinical characteristics and outcomes were compared.Results All the participants in both the pregnant and non-pregnant groups were females, averaging 26 years old, with a majority of Han nationality (72.4% vs. 69.5%, respectively). The two groups were comparable (p

The study aims to provide an up-to-date review at the advancements of the investigations on the ethnopharmacology, phytochemistry, pharmacological effect and exploitation and utilizations of Zanthoxylum L. Besides, the possible tendency and perspective for future research of this plant are discussed, as well. This article uses “Zanthoxylum L.” “Zanthorylum bungeanum” as the keywords and collects relevant information on Zanthoxylum L. plants through electronic searches (Elsevier, PubMed, ACS, Web of Science, Science Direct, CNKI, Google Scholar), relevant books, and classic literature about Chinese herb. The plants of this genus are rich in volatile oils, alkaloids, amides, lignans, coumarins and organic acids, and has a wide range of pharmacological activities, including but not limited to anti-inflammatory, analgesic, anti-tumor, hypoglycemic, hypolipidemic, antioxidant and anti-infectious. This article reviewed both Chinese and international research progress on the active ingredients and pharmacological activities of Zanthoxylum L. as well as the applications of this genus in the fields of food, medicinal and daily chemicals, and clarified the material basis of its pharmacological activities. Based on traditional usage, phytochemicals, and pharmacological properties, of Zanthoxylum L. species, which indicate that they possess diverse bioactive metabolites with interesting bioactivities. Zanthoxylum L. is a potential medicinal and edible plant with diverse pharmacological effects. Due to its various advantages, it may have vast application potential in the food and medicinal industries and daily chemicals. Nonetheless, the currently available data has several gaps in understanding the herbal utilization of Zanthoxylum L. Thus, further research into their toxicity, mechanisms of actions of the isolated bioactive metabolites, as well as scientific connotations between the traditional medicinal uses and pharmacological properties is required to unravel their efficacy in therapeutic potential for safe clinical application.

Reducing the impact of electromagnetic interference (EMI) on switching inverters is an essential part of improving the performance of motor drives. This paper proposed a charge pump circuit with a hybrid modulation method to reduce the EMI of motor drive chips. This innovative method uses a combination of coarse modulation and fine modulation. The periodic modulation technique is used as coarse modulation to alter the spread spectrum range, while the random modulation technique is used as fine modulation to slow down switching transitions by adjusting the delay of the oscillating signal edges. Additionally, a buffer circuit is proposed to restrict the charge and discharge current of the charge pump, thus reducing the EMI due to the rapid variation of the current peak. Theoretical analysis and MATLAB simulation have confirmed that the hybrid modulation method has a pronounced effect on reducing the EMI of the circuit. The proposed motor drive system has been designed and verified by a 0.18 $\mu {\mathrm{ m}}$ BCD process, and the test results show that the proposed circuit can reduce the EMI by up to 22.27 dB compared to the non-modulated circuit. The motor drive chip area is $0.173~mm^{2}$ , and the power consumption is 5.677 mW.

Abstract Introduction Recent cross-sectional research has demonstrated a substantial link between tuberculosis (TB) and gut microbiota. Nevertheless, the causal impact of the gut microbiota on TB susceptibility in humans remains unknown. Methods The Mendelian randomization (MR) method was utilized for investigating the causality between them. The main method used for MR analysis was the inverse variance weighted (IVW) test, with the MR-Egger, weighted median, weighted mode, and simple median methods serving as supplements. And several sensitivity tests were carried out to validate the MR findings. Results The IVW outcomes suggested that three bacterial traits exhibited associations with susceptibility to respiratory TB after Bonferroni correction, namely Lachnospiraceae UCG010 (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.17–2.55, P = 0.005), Eubacterium (brachy group) (OR 1.33, 95% CI 1.07–1.65, P = 0.009), and Ruminococcaceae UCG005 (OR 0.71, 95% CI 0.52–0.98, P = 0.034). Sensitivity analyses demonstrated that horizontal pleiotropy and heterogeneity were absent, thereby guaranteeing the reliability of the results. Conclusion This research sheds light on the causal impact of gut microbiota on respiratory tuberculosis susceptibility, improving our knowledge of therapeutic strategies for managing TB.

In this study, different concentrations of 17-β estradiol silk fibroin (SF)porous scaffolds (SFPS) were prepared using freeze-drying technique, with a hope for optimal concentration and apply it locally to the bone defect area. In this study, the porous scaffold morphology structure was characterized by SEM, FTIR and universal capacity testing machines, and the in vitro cytocompatibility and biological activity of scaffold materials were studied by cell adhesion, viability and proliferation experiments. The results showed that SFPS boasts better physicochemical properties, while 17-β estradiol SF scaffolds with low concentrations of 10−10 mol/L and 10−12 mol/L had more growth and proliferation of SF scaffolds with higher concentrations, and 10−10 mol/L was the optimal concentration of 17-β estradiol SFPS, which was more conducive to cell adhesion and proliferation. On the other hand, after osteogenesis induction of BMSCs inoculated on 17-β estradiol SFPS at different concentrations, it was found that the expression of alkaline phosphatase in BMSCs on different concentrations of 17-β estradiol porous scaffolds was not large. No conflict of interest exits in the submission of this manuscript.

Summary: A key regulatory mechanism involves circular RNA (circRNA) acting as a sponge to modulate microRNA (miRNA), and thus, studying their interaction has significant medical implications. In this field, there are currently two pressing issues that remain unresolved. Firstly, due to the scarcity of verified interactions, we require a minimal amount of samples for training. Secondly, the current models lack interpretability. Therefore, we propose SPBCMI, a method that combines sequence features extracted using the Bidirectional Encoder Representations from Transformer (BERT) model and structural features of biological molecule networks extracted through graph embedding to train a GBDT (Gradient-boosted decision trees) classifier for prediction. Our method yielded an AUC of 0.9143, which is currently the best for this problem. Furthermore, in the case study, SPBCMI accurately predicted 7 out of 10 circRNA-miRNA interactions. These results show that our method provides an innovative and high-performing approach to understanding the interaction between circRNA and miRNA.

Objective: To identify host factors associated with false-negative results of interferon-γ release tests in adults with active tuberculosis. Methods: The clinical data of 943 patients with active tuberculosis diagnosed by acid-fast smear staining, Mycobacterium tuberculosis culture, Mycobacterium tuberculosis PCR and pathological examination at West China Hospital of Sichuan University were retrospectively analysed. According to the results of the interferon γ release test (IGRA), the patients were divided into the IGRA− group and IGRA+ group. Logistic regression was used to analyze the sociodemographic data and clinical characteristics of participants in the IGRA− group and IGRA+ group. Results: Among 943 patients with active tuberculosis, 174 (18.5 %) were IGRA negative (false negative), and 769 (81.5 %) were IGRA positive. Multivariate logistic regression analysis identified the following characteristics independently associated with IGRA negativity: age (OR: 1.02; 95 % CI: 1.01 1.03; p = 0.006), anti-tuberculosis treatment >1 month (OR: 1.68; 95 % CI: 1.12 2.52; p = 0.013), HIV infection (OR: 9.48; 95 % CI: 3.23 27.85; p = 0.000), combined with connective tissue diseases (OR: 2.78; 95 % CI: 1.30 5.94; p = 0.008) and low hemoglobin (OR: 0.99; 95 % CI: 0.98 1.00; p = 0.044) was associated with an increased false-negative probability of IGRA. Conclusion: Age, anti-tuberculosis therapy >1 month, coinfection with HIV, coassociated connective tissue disease and decreased hemoglobin were identified as risk factors for false-negative results of IGRA. Our results suggest a careful interpretation of IGRA in adults with these characteristics.

MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however, sustained mTORC1 activation prevents generation of long-lived memory CD8+ T cells. Here we show that manipulating TSC2 at Ser1365 potently regulated activated but not basal mTORC1 signaling in CD8+ T cells. Unlike nonstimulated TSC2-KO cells, CD8+ T cells expressing a phosphosilencing mutant TSC2-S1365A (TSC2-SA) retained normal basal mTORC1 activity. PKC and T cell receptor (TCR) stimulation induced TSC2 S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and T cell effector function. Consequently, SA CD8+ T cells displayed greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8+ T cells also displayed enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, SA CD8+ T cells used as adoptive cell therapy displayed greater antitumor immunity than WT CD8+ T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhanced both T cell effector function and long-term persistence/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.

Although the biological utilities of endogenous RNAi (endo-RNAi) have been largely elusive, recent studies reveal its critical role in the non-model fruitfly Drosophila simulans to suppress selfish genes, whose unchecked activities can severely impair spermatogenesis. In particular, hairpin RNA (hpRNA) loci generate endo-siRNAs that suppress evolutionary novel, X-linked, meiotic drive loci. The consequences of deleting even a single hpRNA (Nmy) in males are profound, as such individuals are nearly incapable of siring male progeny. Here, comparative genomic analyses of D. simulans and D. melanogaster mutants of the core RNAi factor dcr-2 reveal a substantially expanded network of recently-emerged hpRNA-target interactions in the former species. The de novo hpRNA regulatory network in D. simulans provides insight into molecular strategies that underlie hpRNA emergence and their potential roles in sex chromosome conflict. In particular, our data support the existence of ongoing rapid evolution of Nmy/Dox-related networks, and recurrent targeting of testis HMG-box loci by hpRNAs. Importantly, the impact of the endo-RNAi network on gene expression flips the convention for regulatory networks, since we observe strong derepression of targets of the youngest hpRNAs, but only mild effects on the targets of the oldest hpRNAs. These data suggest that endo-RNAi are especially critical during incipient stages of intrinsic sex chromosome conflicts, and that continual cycles of distortion and resolution may contribute to speciation.

Tiltrotor aircrafts have both fixed-wing control surfaces and helicopter rotors for attitude control. The redundancy of control surfaces provides the possibility for the control system to reconfigure the control law when actuator faults occur during flight. Possible actuator faults have been classified into two categories: predictable and unpredictable faults, and a different strategy has been adopted to deal with each kind of fault. Firstly, the predictable faults are handled by a multiple-model switching adaptive scheme. These kinds of faults are modeled, and their corresponding controllers are derived offline. Secondly, since the degree of drop in aerodynamic effectiveness cannot be predicted a priori, unpredictable faults are handled by a simple adaptive control scheme, to force the plant with faults to track the prescribed reference model. The presented methodology has been verified by nonlinear full-envelope flight simulation for both categories of actuator faults. The predictable fault is represented by the elevator floating. Elevator damage causing an aerodynamic effectiveness drop by 80% is chosen as the example of unpredictable fault. Both faults are simulated at the late stage of the tiltrotor conversion mode. Results show that the presented strategy of reconfiguration is able to detect the fault rapidly and stabilize the aircraft when a fault occurs, while the aircraft motion diverges without the reconfiguration scheme. The aircraft also presents a relatively good performance under controller reconfiguration with a well-tracked conversion path.

Neural networks have been widely used as compensational models for aircraft control designs and as surrogate models for other optimizations. In the case of tiltrotor aircraft, the total number of aircraft states and controls is much greater than that of both traditional fixed-wings and helicopters. This requires, in general, a huge amount of training data for the network to reach a satisfactory approximation precision and makes the network size rise considerably. To solve the practical problem of reducing the size of the approximating network, efforts have to be made in the efficient utilization of the limited amount of training data. This work presents the methodology of optimizing the sample pattern of the training data set by adopting the metaheuristic algorithm of the particle swarm optimizer improved by the fourth-order Runge–Kutta algorithm. A 6-degree-of-freedom nonlinear flight dynamics model of the tiltrotor aircraft is derived, along with its approximation radial basis function neural network. An example case of approximating a highly nonlinear function is studied to illustrate the principle and main parameters of the optimizer, and the approximation performance of the time-domain response of the unstable nonlinear system is revealed by the study of a Van der Pol oscillator. Then, the presented method is applied to the modeled tiltrotor aircraft for its early and late conversion modes. The optimization scheme shows great improvement in both cases, as the function approximation error is reduced significantly.

Recent large datasets measuring the gene expression of millions of possible gene promoter sequences provide a resource to design and train optimized deep neural network architectures to predict expression from sequences. High predictive performance due to the modeling of dependencies within and between regulatory sequences is an enabler for biological discoveries in gene regulation through model interpretation techniques. To understand the regulatory code that delineates gene expression, we have designed a novel deep-learning model (CRMnet) to predict gene expression in Saccharomyces cerevisiae. Our model outperforms the current benchmark models and achieves a Pearson correlation coefficient of 0.971 and a mean squared error of 3.200. Interpretation of informative genomic regions determined from model saliency maps, and overlapping the saliency maps with known yeast motifs, supports that our model can successfully locate the binding sites of transcription factors that actively modulate gene expression. We compare our model's training times on a large compute cluster with GPUs and Google TPUs to indicate practical training times on similar datasets.

Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis.

Summary: Canonical microRNA (miRNA) hairpins are processed by the RNase III enzymes Drosha and Dicer into ∼22 nt RNAs loaded into an Argonaute (Ago) effector. In addition, splicing generates numerous intronic hairpins that bypass Drosha (mirtrons) to yield mature miRNAs. Here, we identify hundreds of previously unannotated, splicing-derived hairpins in intermediate-length (∼50–100 nt) but not small (20–30 nt) RNA data. Since we originally defined mirtrons from small RNA duplexes, we term this larger set as structured splicing-derived RNAs (ssdRNAs). These associate with Dicer and/or Ago complexes, but generally accumulate modestly and are poorly conserved. We propose they contaminate the canonical miRNA pathway, which consequently requires defense against the siege of splicing-derived substrates. Accordingly, ssdRNAs/mirtrons comprise dominant hairpin substrates for 3′ tailing by multiple terminal nucleotidyltransferases, notably TUT4/7 and TENT2. Overall, the rampant proliferation of young mammalian mirtrons/ssdRNAs, coupled with an inhibitory molecular defense, comprises a Red Queen’s race of intragenomic conflict.

Summary: T cell activation, proliferation, function, and differentiation are tightly linked to proper metabolic reprogramming and regulation. By using [U-13C]glucose tracing, we reveal a critical role for GOT1 in promoting CD8+ T cell effector differentiation and function. Mechanistically, GOT1 enhances proliferation by maintaining intracellular redox balance and serine-mediated purine nucleotide biosynthesis. Further, GOT1 promotes the glycolytic programming and cytotoxic function of cytotoxic T lymphocytes via posttranslational regulation of HIF protein, potentially by regulating the levels of α-ketoglutarate. Conversely, genetic deletion of GOT1 promotes the generation of memory CD8+ T cells.

ObjectiveTo analyze the effects and mechanisms of berberine in the treatment of aging-related cognitive dysfunction based on network pharmacology methods, molecular docking techniques, and animal experiments.MethodsA mouse model of cognitive dysfunction was constructed by subcutaneous injection of D-galactose (D-gal) for 10 weeks, and the neuroprotective effects of berberine on aging-related cognitive dysfunction mice were evaluated by the Morris water maze (MWM) and immunofluorescence staining. The targets of berberine were obtained by SwissTargetPrediction, GeneCards, and PharmMapper. Putative targets of cognitive dysfunction were obtained by GeneCards, TTD, and DrugBank database. The STRING database and Cytoscape software were applied for protein-protein interaction (PPI) analysis and further screening of core targets. The DAVID database was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis to clarify the biological processes and pathways involved in the intersection targets, and AutoDockTools was adopted for molecular docking verification of core targets. Finally, the core genes were validated using real-time quantitative PCR.ResultsThe MWM results showed that treatment with berberine significantly improved spatial learning and memory in mice with cognitive decline induced by D-gal. Immunofluorescence staining indicated that berberine modified the levels of aging-related markers in the brain. A total of 386 berberine putative targets associated with cognitive dysfunction were identified based on the public database. The core targets of berberine for improving cognitive function, include Mapk1, Src, Ctnnb1, Akt1, Pik3ca, Tp53, Jun, and Hsp90aa1. GO enrichment and KEGG pathway enrichment analyses indicated that the mechanism of berberine in the treatment of aging-related cognitive dysfunction is attributed to pathways such as PI3K-AKT and MAPK pathways. In vivo experiments further confirmed that Akt1, Ctnnb1, Tp53, and Jun were involved in the neuroprotective actions of berberine.ConclusionThis study reveals the multi-target and multi-pathway effects of berberine on regulating aging-related cognitive dysfunction, which provides preclinical evidence and may promote new drug development in mitigating cognitive dysfunction.

Background. The clinical outcomes of low-grade glioma (LGG) are associated with T cell infiltration, but the specific contribution of heterogeneous T cell types remains unclear. Method. To study the different functions of T cells in LGG, we mapped the single-cell RNA sequencing results of 10 LGG samples to obtain T cell marker genes. In addition, bulk RNA data of 975 LGG samples were collected for model construction. Algorithms such as TIMER, CIBERSORT, QUANTISEQ, MCPCOUTER, XCELL, and EPIC were used to depict the tumor microenvironment landscape. Subsequently, three immunotherapy cohorts, PRJEB23709, GSE78820, and IMvigor210, were used to explore the efficacy of immunotherapy. Results. The Human Primary Cell Atlas was used as a reference dataset to identify each cell cluster; a total of 15 cell clusters were defined and cells in cluster 12 were defined as T cells. According to the distribution of T cell subsets (CD4+ T cell, CD8+ T cell, Naïve T cell, and Treg cell), we selected the differentially expressed genes. Among the CD4+ T cell subsets, we screened 3 T cell-related genes, and the rest were 28, 4, and 13, respectively. Subsequently, according to the T cell marker genes, we screened six genes for constructing the model, namely, RTN1, HERPUD1, MX1, SEC61G, HOPX, and CHI3L1. The ROC curve showed that the predictive ability of the prognostic model for 1, 3, and 5 years was 0.881, 0.817, and 0.749 in the TCGA cohort, respectively. In addition, we found that risk scores were positively correlated with immune infiltration and immune checkpoints. To this end, we obtained three immunotherapy cohorts to verify their predictive ability of immunotherapy effects and found that high-risk patients had better clinical effects of immunotherapy. Conclusion. This single-cell RNA sequencing combined with bulk RNA sequencing may elucidate the composition of the tumor microenvironment and pave the way for the treatment of low-grade gliomas.

IntroductionThe second most prevalent cause of dementia is vascular dementia (VaD). Furthermore, acupuncture is a relatively safe and effective traditional therapy for individuals with VaD. We performed a network meta-analysis to assess the effectiveness and safety of various acupuncture therapies for VaD based on existing research.MethodsWe searched six electronic databases to screen for randomized controlled trials (RCTs) comparing different acupuncture treatments in VaD patients. The Cochrne tool (Review Manager 5.3) was used to evaluate the risk of bias of the included RCTs. Based on the Grading of Recommendations Assessment, Development and Evaluation framework, we assessed the confidence in the evidence using the Confidence In the results from Network Meta-Analysis approach. We used the frequency approach to perform the network meta-analysis. Data were analyzed using R 4.1.1.ResultsIn total, we included 46 eligible studies. The results of the network analysis showed that the combined interventions of moxibustion (MB) with body acupuncture (BA) (MB + BA) and electroacupuncture (EA) with scalp acupuncture (SA) with BA (EA + SA + BA) were more effective in improving cognitive functions and activities of daily living compared with SA or BA alone. However, in the subgroup analysis, EA + SA + BA showed better efficacy in short- and mid-term acupuncture compared with other acupuncture therapies.ConclusionCombined acupuncture therapy may be a safe and effective intervention for individuals with VaD, and MB + BA and EA + SA + BA appear to be the most effective interventions. However, because the analysis of this study was based on low-to-moderate evidence, there remains no strong supporting evidence. Thus, high-quality, large-scale, and long-term studies should be conducted in the future to assess the effectiveness and safety of acupuncture in VaD.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42022354573.

Synaptic dysfunction is closely related to Alzheimer’s disease (AD) which is also recognized as synaptic disorder. β-amyloid (Aβ) is one of the main pathogenic factors in AD, which disrupts synaptic plasticity and mediates the synaptic toxicity through different mechanisms. Aβ disrupts glutamate receptors, such as NMDA and AMPA receptors, which mediates calcium dyshomeostasis and damages synapse plasticity characterized by long-term potentiation (LTP) suppression and long-term depression (LTD) enhancement. As Aβ stimulates and Ca2+ influx, microglial cells and astrocyte can be activated and release cytokines, which reduces glutamate uptake and further impair synapse function. Besides, extracellular glutamate accumulation induced by Aβ mediates synapse toxicity resulting from reduced glutamate receptors and glutamate spillovers. Aβ also mediates synaptic dysfunction by acting on various signaling pathways and molecular targets, disrupting mitochondria and energy metabolism. In addition, Aβ overdeposition aggravates the toxic damage of hyperphosphorylated tau to synapses. Synaptic dysfunction plays a critical role in cognitive impairment of AD. The review addresses the possible mechanisms by which Aβ mediates AD-related synaptic impairment from distant perspectives.

Youth entrepreneurship is regarded as an important part of rural revitalization. Against the backdrop of the rural revitalization strategy, the Chinese government has introduced many policies to encourage return-home entrepreneurship among young people. However, highly educated youth have a lower willingness to return home for entrepreneurship, and prefer urban entrepreneurship or getting a job in a city. Therefore, this study used a two-stage approach to explore the factors that influence young people’s contribution to the development of their homeland, the barriers they face, and the support mechanisms they need. The study found that many barriers affect young people’s intention to return home for entrepreneurship. In rural areas, young people consider lagging environmental development to be the biggest barrier. In urban areas, infrastructure, lack of entrepreneurial experience, and funding are the factors that concern young people the most. As they have limited entrepreneurial experience, young people in both rural and urban areas have a high demand for shared entrepreneurial experience, as well as entrepreneurship courses and mentoring. The government and universities should remove the barriers faced by young people, provide more assistance, improve the environment for young people engaging in return-home entrepreneurship, and form a good entrepreneurial ecology.

This work presents a systematic approach to analyzing the aerodynamic characteristics of tandem rotor forward autorotation considering rotor-to-rotor interference. The single-rotor computational model trimmed from a generic helicopter flight dynamics analysis program was used as the baseline model. The effectiveness of the baseline model is demonstrated by a comparison with data from wind tunnel tests performed in this work. The rotor disk angle of attack and driven moment distribution obtained by the modified model indicate the fact that the rotor acceleration is primarily caused by the higher angle of attack region of the disk. This is of great significance in the rotor blade design, in terms of the drag-to-lift ratio characteristics of the airfoil under different angle-of-attack ranges. The influence of wind speed, rotor shaft angle, and collective pitch on the steady-state rotor speed was then studied. The results show a nonlinear nature of the variation of steady rotor speed with collective pitch, which can cause a thrust control reverse problem during flight operations. To reveal the flow field details of rotor-to-rotor interference, the flow field Navier–Stokes equations of tandem rotor autorotation were solved. Computational results of both rotors’ inflow velocities were considered when deriving the empirical model of interference. The refined interference model was compared to the wind tunnel test data of the tandem rotor autorotation and showed good performance. This synthetical methodology, which combines mechanism analysis with CFD-aided refinement and experiment verification, achieves a balance between computational costs and accuracy and thus can be readily applied to engineering practices.

The BEN-solo proteins—including Insensitive (Insv), Elba1 and Elba2—function in both transcriptional repression and chromatin insulation. Here, the authors investigate the role of these proteins in Drosophila embryos, finding that ELBA and Insv function as general insulators and partition active chromatin to ensure proper gene activation in Drosophila.

ELAV/Hu factors are conserved RNA binding proteins (RBPs) that play diverse roles in mRNA processing and regulation. The founding member, Drosophila Elav, was recognized as a vital neural factor 35 years ago. Nevertheless, little was known about its impacts on the transcriptome, and potential functional overlap with its paralogs. Building on our recent findings that neural-specific lengthened 3' UTR isoforms are co-determined by ELAV/Hu factors, we address their impacts on splicing. While only a few splicing targets of Drosophila are known, ectopic expression of each of the three family members (Elav, Fne and Rbp9) alters hundreds of cassette exon and alternative last exon (ALE) splicing choices. Reciprocally, double mutants of elav/fne, but not elav alone, exhibit opposite effects on both classes of regulated mRNA processing events in larval CNS. While manipulation of Drosophila ELAV/Hu RBPs induces both exon skipping and inclusion, characteristic ELAV/Hu motifs are enriched only within introns flanking exons that are suppressed by ELAV/Hu factors. Moreover, the roles of ELAV/Hu factors in global promotion of distal ALE splicing are mechanistically linked to terminal 3' UTR extensions in neurons, since both processes involve bypass of proximal polyadenylation signals linked to ELAV/Hu motifs downstream of cleavage sites. We corroborate the direct action of Elav in diverse modes of mRNA processing using RRM-dependent Elav-CLIP data from S2 cells. Finally, we provide evidence for conservation in mammalian neurons, which undergo broad programs of distal ALE and APA lengthening, linked to ELAV/Hu motifs downstream of regulated polyadenylation sites. Overall, ELAV/Hu RBPs orchestrate multiple broad programs of neuronal mRNA processing and isoform diversification in Drosophila and mammalian neurons.

Low-phosphorus stress (LPS) and pathogen attack are two important stresses frequently experienced by plants in their natural habitats, but how plant respond to them coordinately remains under-investigated. Here, we demonstrate that CaWRKY58, a known negative regulator of the pepper (Capsicum annuum) response to attack by Ralstonia solanacearum, is upregulated by LPS. Virus-induced gene silencing (VIGS) and overexpression of CaWRKY58 in Nicotiana benthamiana plants in combination with chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays (EMSA) demonstrated that CaWRKY58 positively regulates the response of pepper to LPS by directly targeting and regulating genes related to phosphorus-deficiency tolerance, including PHOSPHATE STARVATION RESPONSE1 (PHR1). Yeast two-hybrid assays revealed that CaWRKY58 interacts with a 14-3-3 protein (Ca14-3-3); this interaction was confirmed by pull-down, bimolecular fluorescence complementation (BiFC), and microscale thermophoresis (MST) assays. The interaction between Ca14-3-3 and CaWRKY58 enhanced the activation of PHR1 expression by CaWRKY58, but did not affect the expression of the immunity-related genes CaNPR1 and CaDEF1, which are negatively regulated by CaWRKY58 in pepper upon Ralstonia solanacearum inoculation. Collectively, our data indicate that CaWRKY58 negatively regulates immunity against Ralstonia solanacearum, but positively regulates tolerance to LPS and that Ca14-3-3 transcriptionally activates CaWRKY58 in response to LPS.

Grape seeds are rich in nutrients possessing high nutritional and medicinal value. Grape seed extract (GSE) mainly contains 15 phenolic compounds, such as (+)-catechin, (−)-epicatechin, proanthocyanidin, gallate, flavonols and others. Several studies on GSE and its components indicated that it has pharmacological attributes, such as antioxidation, anti-inflammation, anticancer, neuroprotection, lowering lipid, bacteriostatic, and reduced blood pressure. This article reviewed the research progress on the bioactivity of GSE and its application in foods in order to provide a reference for future studies on the development and utilization of grape seeds.

Abstract Background Drosophila melanogaster has one of best-described transcriptomes of any multicellular organism. Nevertheless, the paucity of 3′-sequencing data in this species precludes comprehensive assessment of alternative polyadenylation (APA), which is subject to broad tissue-specific control. Results Here, we generate deep 3′-sequencing data from 23 developmental stages, tissues, and cell lines of D. melanogaster, yielding a comprehensive atlas of ~ 62,000 polyadenylated ends. These data broadly extend the annotated transcriptome, identify ~ 40,000 novel 3′ termini, and reveal that two-thirds of Drosophila genes are subject to APA. Furthermore, we dramatically expand the numbers of genes known to be subject to tissue-specific APA, such as 3′ untranslated region (UTR) lengthening in head and 3′ UTR shortening in testis, and characterize new tissue and developmental 3′ UTR patterns. Our thorough 3′ UTR annotations permit reassessment of post-transcriptional regulatory networks, via conserved miRNA and RNA binding protein sites. To evaluate the evolutionary conservation and divergence of APA patterns, we generate developmental and tissue-specific 3′-seq libraries from Drosophila yakuba and Drosophila virilis. We document broadly analogous tissue-specific APA trends in these species, but also observe significant alterations in 3′ end usage across orthologs. We exploit the population of functionally evolving poly(A) sites to gain clear evidence that evolutionary divergence in core polyadenylation signal (PAS) and downstream sequence element (DSE) motifs drive broad alterations in 3′ UTR isoform expression across the Drosophila phylogeny. Conclusions These data provide a critical resource for the Drosophila community and offer many insights into the complex control of alternative tissue-specific 3′ UTR formation and its consequences for post-transcriptional regulatory networks.

Mirtrons are microRNA (miRNA) substrates that utilize the splicing machinery to bypass the necessity of Drosha cleavage for their biogenesis. Expanding our recent efforts for mammalian mirtron annotation, we use meta-analysis of aggregate datasets to identify ~500 novel mouse and human introns that confidently generate diced small RNA duplexes. These comprise nearly 1000 total loci distributed in four splicing-mediated biogenesis subclasses, with 5'-tailed mirtrons as, by far, the dominant subtype. Thus, mirtrons surprisingly comprise a substantial fraction of endogenous Dicer substrates in mammalian genomes. Although mirtron-derived small RNAs exhibit overall expression correlation with their host mRNAs, we observe a subset with substantial differences that suggest regulated processing or accumulation. We identify characteristic sequence, length, and structural features of mirtron loci that distinguish them from bulk introns, and find that mirtrons preferentially emerge from genes with larger numbers of introns. While mirtrons generate miRNA-class regulatory RNAs, we also find that mirtrons exhibit many features that distinguish them from canonical miRNAs. We observe that conventional mirtron hairpins are substantially longer than Drosha-generated pre-miRNAs, indicating that the characteristic length of canonical pre-miRNAs is not a general feature of Dicer substrate hairpins. In addition, mammalian mirtrons exhibit unique patterns of ordered 5' and 3' heterogeneity, which reveal hidden complexity in miRNA processing pathways. These include broad 3'-uridylation of mirtron hairpins, atypically heterogeneous 5' termini that may result from exonucleolytic processing, and occasionally robust decapitation of the 5' guanine (G) of mirtron-5p species defined by splicing. Altogether, this study reveals that this extensive class of non-canonical miRNA bears a multitude of characteristic properties, many of which raise general mechanistic questions regarding the processing of endogenous hairpin transcripts.

miRNAs are small regulatory RNAs that, due to their considerable potential to target a wide range of mRNAs, are implicated in essentially all biological process, including cancer. miR-10a is particularly interesting considering its conserved location in the Hox cluster of developmental regulators. A role for this microRNA has been described in developmental regulation as well as for various cancers. However, previous miR-10a studies are exclusively based on transient knockdowns of this miRNA and to extensively study miR-10a loss we have generated a miR-10a knock out mouse. Here we show that, in the Apc(min) mouse model of intestinal neoplasia, female miR-10a deficient mice develop significantly more adenomas than miR-10(+/+) and male controls. We further found that Lpo is extensively upregulated in the intestinal epithelium of mice deprived of miR-10a. Using in vitro assays, we demonstrate that the primary miR-10a target KLF4 can upregulate transcription of Lpo, whereas siRNA knockdown of KLF4 reduces LPO levels in HCT-116 cells. Furthermore, Klf4 is upregulated in the intestines of miR-10a knockout mice. Lpo has previously been shown to have the capacity to oxidize estrogens into potent depurinating mutagens, creating an instable genomic environment that can cause initiation of cancer. Therefore, we postulate that Lpo upregulation in the intestinal epithelium of miR-10a deficient mice together with the predominant abundance of estrogens in female animals mainly accounts for the sex-related cancer phenotype we observed. This suggests that miR-10a could be used as a potent diagnostic marker for discovering groups of women that are at high risk of developing colorectal carcinoma, which today is one of the leading causes of cancer-related deaths.

BackgroundMicroRNAs (miRNAs) have emerged as important gene regulators and are recognized as key players in tumorigenesis. miR-145 is reported to be down-regulated in several cancers, but knowledge of its targets in colon cancer remains limited.Methodology/principal findingsTo investigate the role of miR-145 in colon cancer, we have employed a microarray based approach to identify miR-145 targets. Based on seed site enrichment analyses and unbiased word analyses, we found a significant enrichment of miRNA binding sites in the 3'-untranslated regions (UTRs) of transcripts down-regulated upon miRNA overexpression. Gene Ontology analysis showed an overrepresentation of genes involved in cell death, cellular growth and proliferation, cell cycle, gene expression and cancer. A number of the identified miRNA targets have previously been implicated in cancer, including YES, FSCN1, ADAM17, BIRC2, VANGL1 as well as the transcription factor STAT1. Both YES and STAT1 were verified as direct miR-145 targets.Conclusions/significanceThe study identifies and validates new cancer-relevant direct targets of miR-145 in colon cancer cells and hereby adds important mechanistic understanding of the tumor-suppressive functions of miR-145.

This paper presents an on-chip integrated sensing circuit for real-time detection of phase currents in three-phase brushless direct current (BLDC) motors. The three-phase sinusoidal currents generated in the motor winding are detected by an innovative Sense FET technology, which can accurately measure the currents of high side and low side power transistors simultaneously. A dynamic matching elimination method is proposed for the detection current mismatch problem due to the large difference in aspect ratio. Using a 90 nm BCD process for design and verification, the detection circuit of the high side and low side can well follow the change of sine wave phase current of the three-phase motor. The detection accuracy is above 96%, and the best accuracy can reach 99.219%. The elimination effect of circuit current mismatch is obvious, and the error of the sensing current can be reduced by 38.9%. [ABSTRACT FROM AUTHOR]