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The study of wellbore vertical pipe flow is the basis of reasonable production allocation and wellbore size optimization. According to the characteristics of low water gas ratio in sandstone gas reservoir of a gas field in Ordos Basin, the bottom hole pressure of typical gas wells in this area is calculated by using various wellbore pipe flow models such as Hagedorn brown, beggs Brill, Mukherjee Brill, gray and Aziz; Based on the measured bottom hole pressure, the relative performance coefficient evaluation method is used to optimize the wellbore calculation method. The results show that for the sandstone gas reservoir with low water gas ratio in gas field a, the calculation results of Hagedorn Brown model are in good agreement with the test results, so it is appropriate to use the Hagedorn Brown model to calculate the vertical pipe flow characteristics.

Platycodon grandiflorum root (PG), a popular traditional Chinese medicine, contains considerable chemical components with broad pharmacological activities. The complexity and diversity of the chemical components of PG from different origins contribute to its broad biological activities. The quality of southern PG is superior to that of northern PG, but the mechanisms underlying these differences remain unclear.In order to study variation in the differentially accumulated metabolites (DAMs), differentially expressed genes (DEGs), as well as their interactions and signalling pathways among PG from Anhui and Liaoning.The metabolomes based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the transcriptome based on high-throughput sequencing technology were combined to comprehensively analyse PGn and PGb.A total of 6515 DEGs and 83 DAMs from the comparison of PG from Anhui and Liaoning were detected. Integrated analysis of metabolomic and transcriptomic data revealed that 215 DEGs and 57 DAMs were significantly enriched in 48 pathways according to KEGG pathway enrichment analysis, and 15 DEGs and 10 DAMs significantly enriched in the main pathway sesquiterpenoid and triterpenoid and phenylpropanoid biosynthesis might play a key role in complex response or regulatory processes.Differences in PG from southern and northern China might thus stem from differences in environmental factors, such as precipitation, light duration, and humidity. The results of our study provide new insight into geographic variation in gene expression and metabolite accumulation and will enhance the utilisation of PG resources.

PurposeSmartphone addiction has been a matter of serious concern among society and parents because of its high incidence and serious negative effects. This study aimed to determine the association between smartphone addiction and eating disorders and lifestyle changes among college students.MethodsThe present article is a descriptive, cross-sectional study involving 1,112 college students from several universities in Chengdu, China. The data were collected by using the Chinese version of the Mobile Phone Addiction Index (MPAI) and the Eating Attitudes Test-26 (EAT-26). In addition, the information on sociodemographic, lifestyle, and smartphone use were obtained through a self-administered questionnaire.ResultsThe prevalence of smartphone addiction among the students involved in the study was 22.6%, of which 10.4% were at risk for eating disorders. Female students had higher MPAI scores and EAT-26 scores than male students (p < 0.001). The proportion of male students with a risk of eating disorders was significantly higher than that of female students (p < 0.05). The total EAT-26 scores of students with smartphone addiction were higher than that of others (p < 0.001). The correlation analysis indicated that the MPAI scores were significantly positively correlated with the EAT-26 scores, depression and anxiety, difficulty in falling asleep at night, the frequency of eating fast food and drinking carbonated soft drink (p < 0.01). In addition, the MPAI scores were significantly negatively correlated with skipping breakfast and the frequency of physical activity (p < 0.05).ConclusionSmartphone addiction is significantly associated with eating disorders, eating habits, and lifestyle. The influence of dietary habits and lifestyle needs to be considered for the prevention and development of an intervention for smartphone addiction among college students.

(1)Objectives: To explore the vertical changes in the maxillary central incisor and the maxillary first molar and to investigate the changes in the mandibular plane angle during process space closure by miniscrew sliding mechanics. (2) Methods: A total of 20 adult patients were enrolled from the Department of Orthodontics of Peking University Hospital of Stomatology from 2008 to 2013. A digital dental model and craniofacial cone-beam computed tomography (CBCT) scan were taken at the beginning of the treatment(T0) and immediately after space closure(T1). Stable miniscrews were used to superimpose the maxillary digital dental models (T0 and T1), and the vertical changes in the maxillary first molar and the maxillary central incisor were measured. The changes in the mandibular plane were measured by CBCT superimposition in three dimensions. (3) Results: The average extrusion of the maxillary central incisor was 2.56±0.18 mm; the average intrusion of the maxillary first molar was 1.25±1.11 mm, with a distal movement of 0.97±0.99 mm; and the average mandibular plane angle decreased by 0.83±1.65°. The differences in the three indexes were statistically significant. (4) Conclusion: In the process of space closure with the miniscrew sliding method, the upper dentition changed significantly in both the sagittal and vertical directions. The maxillary central incisors were extruded, and the maxillary first molars were intruded. The mandibular plane was rotated slightly counterclockwise.

BACKGROUND Mechanical thrombectomy (MT) has been proved to be a highly effective therapy to treat acute ischemic stroke due to large vessel occlusion. Often, the ischemic core extent on baseline imaging is an important determinant for endovascular treatment eligibility. However, computed tomography (CT) perfusion (CTP) or diffusion-weighted imaging may overestimate the infarct core on admission and, consequently, smaller infarct lesions called “ghost infarct cores.” OBSERVATIONS A 4-year-old, previously healthy boy presented with acute-onset, right-sided weakness and aphasia. Fourteen hours after the onset of symptoms, the patient presented with a National Institutes of Health Stroke Scale (NIHSS) score of 22, and magnetic resonance angiography demonstrated a left middle cerebral artery occlusion. MT was not considered because of a large infarct core (infarct core volume: 52 mL; mismatch ratio 1.6 on CTP). However, multiphase CT angiography indicated good collateral circulation, which encouraged MT. Complete recanalization was achieved via MT at 16 hours after the onset of symptoms. The child’s hemiparesis improved. Follow-up magnetic resonance imaging was nearly normal and showed that the baseline infarct lesion was reversible, in agreement with neurological improvement (NIHSS score 1). LESSONS The selection of pediatric stroke with a delayed time window guided by good collateral circulation at baseline seems safe and efficacious, which suggests a promising value of vascular window.

Regardless of which community, incentivizing users is a necessity for well-sustainable operations. In the blockchain-backed Web3 communities, known for their transparency and security, airdrop serves as a widespread incentive mechanism for allocating capital and power. However, it remains a controversy on how to justify airdrop to incentive and empower the decentralized governance. In this paper, we use ParaSwap as an example to propose a role taxonomy methodology through a data-driven study to understand the characteristic of community members and the effectiveness of airdrop. We find that users receive more rewards tend to take positive actions towards the community. We summarize several arbitrage patterns and confirm the current detection is not sufficient in screening out airdrop hunters. In conjunction with the results, we discuss from the aspects of interaction, financialization, and system design to conclude the challenges and possible research directions for decentralized communities., 16 pages, 14 figures

Repeated administration of cisplatin causes CKD. In previous studies, we reported that the kidney-secreted survival protein renalase (RNLS) and an agonist peptide protected mice from cisplatin-induced AKI.To investigate whether kidney-targeted delivery of RNLS might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a RNLS agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of RNLS, single-cell RNA sequencing analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma RNLS in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy.In mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney RNLS; genetic deletion of RNLS was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA sequencing analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature and suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma RNLS levels trended lower at day 14 post-treatment.Kidney-targeted delivery of RNLS agonist RP81-MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.

Insect olfactory receptors (iORs) with atypical 7-transmembrane domains, unlike Chordata olfactory receptors, are not in the GPCR protein family. iORs selectively bind to volatile ligands in the environment and affect essential insect behaviors. In this study, we constructed a new platform (iORbase, https://www.iorbase.com) for the structural and functional analysis of iORs based on a combined algorithm for gene annotation and protein structure prediction. Moreover, it provides the option to calculate the binding affinities and binding residues between iORs and pheromone molecules by virtual screening of docking. Furthermore, iORbase supports the automatic structural and functional prediction of user-submitted iORs or pheromones. iORbase contains the well-analyzed results of approximately 6 000 iORs and their 3D protein structures identified from 59 insect species and 2 077 insect pheromones from the literature, as well as approximately 12 million pairs of simulated interactions between functional iORs and pheromones. We also built four online tools, iORPDB, iInteraction, iModelTM, and iOdorTool, to easily retrieve and visualize the 3D structures and interactions. iORbase can help greatly improve the experimental efficiency and success rate, identify new insecticide targets, or develop electronic nose technology. This study will shed light on the olfactory recognition mechanism and evolutionary characteristics from the perspectives of omics and macroevolution. This article is protected by copyright. All rights reserved.

The nature of electronic motion and structural information of atoms and molecules is encoded into strong field induced radiations ranging from terahertz (THz) to extreme ultraviolet wavelength. The dependence of THz yields in bichomatic laser fields on ellipticity and interpulse time delay were experimentally measured, and the trajectory-based calculations straightforwardly establish the link between the THz emission and the motion of photoelectron wave packet under the influence of the Coulomb potential. The asymmetry of the photoelectron wave packet modified by the Coulomb potential imprints itself on the polarization direction of the THz electric fields. By filtering out the rapidly-varying dynamics of the propagating wave packet while retaining the slowly-varying dynamics, the Coulomb potential of the generating medium is retrieved from the Coulomb-reshaped THz radiation. Our work opens a path towards all-optical THz detection of electronic and structural dynamics, which might also allow to resolve the photo-excited dynamics in condensed phase systems.

Electric control of magnetism has significant application prospect in magnetic storage. In this work, first-principles calculations are carried out to study the ferroelectric control of magnetism of the 3d transition metal (TM = V, Cr, Mn, Fe, Co, or Ni)-adsorbed graphene monolayers by using an organic ferroelectric poly(vinylidene-fluoride) (PVDF). Although we observe the ferroelectric control of the magnetocrystalline anisotropy energy (MAE) of all the studied 3d transition metal atoms, the flip of the easy magnetization axis is only achieved in the case of Ni adsorption. When the Ni atom is adsorbed at the bridge site on the graphene monolayer, the easy axis of magnetization would undergo a transition from out-of-plane (MAE = 0.07 meV/atom) to in-plane (MAE = −0.23 meV/atom) when the polarization turns down to up. As a result, the study of Ni is particularly highlighted, and the underlying mechanism is discussed by second-order perturbation theories. We provide a means to realize electric control of the magnetism of graphene, which will facilitate relevant experimental and theoretical research., This study is funded by Scientific Research Program Funded by Shaanxi Provincial Education Department (Program No.21JK0699) and School level fund of Xi'an Aeronautical Institute (Program No.2020KY1224).

The orientation and ellipticity of terahertz (THz) polarization generated by a two-color strong field not only casts light on underlying mechanisms of laser–matter interaction, but also plays an important role for various applications. We develop the Coulomb-corrected classical trajectory Monte Carlo (CTMC) method to well reproduce the joint measurements, that the THz polarization generated by the linearly polarized 800 nm and circularly polarized 400 nm fields is independent on two-color phase delay. The trajectory analysis shows that the Coulomb potential twists the THz polarization by deflecting the orientation of asymptotic momentum of electron trajectories. Further, the CTMC calculations predict that, the two-color mid-infrared field can effectively accelerate the electron rapidly away from the parent core to relieve the disturbance of Coulomb potential, and simultaneously create large transverse acceleration of trajectories, leading to the circularly polarized THz radiation.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer.METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed.RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; PCONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

The Holliday junction (HJ) is a universal DNA intermediate of homologous recombination that is involved in many fundamental physiological processes. In bacteria, RuvB, a motor protein of the AAA+ ATPase superfamily, drives branch migration of the Holliday junction with a mechanism that had yet to be elucidated. Here, we report two cryo-EM structures of RuvB in complex with DNA and nucleotides, providing a comprehecomplex, which was further purified nsive understanding of HJ branch migration. Six RuvB protomers assemble into a spiral staircase, in the shape of a ring, with DNA in the central pore. Four protomers of RuvB hexamer interact with the backbone of the DNA substrate, suggesting a pulling-and-revolving mechanism of DNA translocation with a basic step size of 2 nucleotides. Moreover, the variation of nucleotide-binding states in our RuvB hexamer supports a sequential model for ATP hydrolysis, ADP release, and ATP reloading, which occur at specific positions on the RuvB hexamer. Furthermore, the asymmetric assembly of RuvB also explains the 6:4 stoichiometry between RuvB and RuvA, which assembles into a complex to coordinate HJ migration in cells. Taken together, we provide a comprehensive framework for the mechanistic understanding of HJ branch migration facilitated by RuvB motor protein, which may be universally shared in both prokaryotic and eukaryotic organisms.

Blockchain games introduce unique gameplay and incentive mechanisms by allowing players to be rewarded with in-game assets or tokens through financial activities. However, most blockchain games are not comparable to traditional games in terms of lifespan and player engagement. In this paper, we try to see the big picture in a small way to explore and determine the impact of gameplay and financial factors on player behavior in blockchain games. Taking Aavegotchi as an example, we collect one year of operation data to build player profiles. We perform an in-depth analysis of player behavior from the macroscopic data and apply an unsupervised clustering method to distinguish the attraction of the gameplay and incentives. Our results reveal that the whole game is held up by a small number of players with high-frequent interaction or vast amounts of funds invested. Financial incentives are indispensable for blockchain games for they provide attraction and optional ways for players to engage with the game. However, financial services are tightly linked to the free market. The game will face an irreversible loss of players when the market experiences depression. For blockchain games, well-designed gameplay should be the fundamental basis for the long-lasting retention of players.

The basic leucine zipper (bZIP) is a transcription factor family that plays critical roles in abiotic and biotic stress responses as well as plant development and growth. A comprehensive genome-wide study in

To create a functional neural circuit, neurons develop a molecular identity to discriminate self from non-self. The invertebrate Dscams and vertebrate Pcdhs are implicated in determining synaptic specificity. Recently identified in Chelicerata, a shortened Dscam (sDscam) has been shown to resemble the isoform-generating characters of both Dscam and Pcdh and represent an evolutionary transition. Here we presented the molecular details of sDscam self-recognition via both trans and cis interactions using X-ray crystallographic data, functional assays and mathematical analysis. Based on our results, we proposed a molecular zipper model for the assemblies of sDscam to mediate cell-cell recognition. In this model, sDscam utilized FNIII domain to form side-by-side interactions with neighboring molecules in the same cell while established hand-in-hand interactions via Ig1 domain with molecules from another cell around. Together, our study provided a framework for understanding the assembly, recognition, and evolution of sDscam.

The two-color strong-field mixing in gas medium is a widely used approach to generate bright broadband terahertz (THz) radiation. Here, we present a new, to the best of our knowledge, and counterintuitive method to promote THz performance in the two-color scheme. Beyond our knowledge that the maximum THz generation occurs with two-color foci overlapped, we found that, when the foci of two-color beams are noticeably separated along the propagation axis resulting in cascading plasmas, the THz conversion efficiency is surged by one order of magnitude and the bandwidth is stretched by more than two times, achieving 10−3 conversion efficiency and >100 THz bandwidth under the condition of 800/400 nm, ∼35 fs driving lasers. With the help of the pulse propagation equation and photocurrent model, the observations can be partially understood by the compromise between THz generation and absorption due to the spatial redistribution of laser energy in cascading plasmas. The present method can be extended to a mid-infrared driving laser, and new records of THz peak power and conversion efficiency are expected.

Objectives to evaluate three-dimensional postsurgical stability of surgery-first approach with 2-jaw surgery and maxillary premolar extraction in skeletal class III patients and excavate factors influencing the relapse. Material and methods 24 patients were enrolled in this prospective cohort study. Serial cone-beam computer tomography images were superimposed and measured the surgical stability at the presurgical examination, 1 week, 3 month, 6 month and 12 month postoperatively. Patients were grouped by the amount of mandible sagittal relapse(stable group, n = 8; highly unstable group, n = 7). Skeletal and dental morphological variables, the amount of surgical changes, and orthodontic-related variables were compared between groups and analyzed for correlations with postsurgical stability. Results Considerable amount of pronation relapse on mandible were within three month postoperatively. The maxilla remained clinically stable. The coronoid process height, posterior maxillary height, the mandibular setback, distal segment intraoperative rotation and the amount maxillary second molar orthodontic intrusion showed significant difference between groups. The above variables, mandibular height, occlusal vertical dimension, and the mandibular and anterior maxillary intraoperative descent were significantly correlated with postoperative instability. Conclusions Mandibular pronation relapse mainly in the first three months after surgery.The maxilla postsurgical position is clinically stable. The factors for instability in the surgery-first approach include a longer coronoid process, longer facial height, a wider occlusal vertical dimension, greater surgical setback and descent, and more maxillary second molar intrusion. Clinical relevance Results can provide reference for patient selection, surgical planning and preoperative dental alignment stimulation for surgery-first approach. Trial Registration ChiCTR2200055787

Objective: This was a large-scale multicenter study with two objectives. One was to study the factors influencing pedestrian smartphone use while crossing roads, and the other was to study the effect of combined visual and auditory intervention on smartphone zombies (smombies) at crossroads.Methods: This study was conducted in four different Chinese cities. By observing pedestrians crossing intersections, the weather, time, and characteristics of the pedestrians were recorded by four researchers. Then, its influencing factors and the effects of the intervention were studied in two consecutive periods.Results: A total of 25,860 pedestrians (13,086 without intervention and 12,774 with visual and auditory intervention) were observed in this study. Logistic regressions showed that gender, age of the pedestrians, weather, and time were the factors influencing smombies crossing roads. The number of smartphone users decreased from 4,289 to 3,579 (28.1%) (χ2 = 69.120, p < 0.001) when the intervention was conducted.Conclusion: Based on large-sample, multicenter research, this study revealed the factors influencing pedestrian smartphone use while crossing roads, contributing to our understanding of the current situation of smombies in China. Furthermore, the effect of visual and auditory intervention was demonstrated, providing a new paradigm for global prevention of smombie behavior.

INTRODUCTION The nuclear pore complex (NPC) is the molecular conduit in the nuclear membrane of eukaryotic cells that regulates import and export of biomolecules between the nucleus and the cytosol, with vertebrate NPCs ~110 to 125 MDa in molecular mass and ~120 nm in diameter. NPCs are organized into four main rings: the cytoplasmic ring (CR) at the cytosolic side, the inner ring and the luminal ring on the plane of the nuclear membrane, and the nuclear ring facing the nucleus. Each ring possesses an approximate eightfold symmetry and is composed of multiple copies of different nucleoporins. NPCs have been implicated in numerous biological processes, and their dysfunctions are associated with a growing number of serious human diseases. However, despite pioneering studies from many groups over the past two decades, we still lack a full understanding of NPCs’ organization, dynamics, and complexity. RATIONALE We used the Xenopus laevis oocyte as a model system for the structural characterization because each oocyte possesses a large number of NPC particles that can be visualized on native nuclear membranes without the aid of detergent extraction. We used single-particle cryo–electron microscopy (cryo-EM) analysis on data collected at different stage tilt angles for three-dimensional reconstruction and structure prediction with AlphaFold for model building. RESULTS We reconstructed the CR map of X. laevis NPC at 6.9 and 6.7 Å resolutions for the full CR protomer and a core region, respectively, and predicted the structures of the individual nucleoporins using AlphaFold because no high-resolution models of X. laevis Nups were available. For any ambiguous subunit interactions, we also predicted complex structures, which further guided model fitting of the CR protomer. We placed the nucleoporin or complex structures into the CR density to obtain an almost full CR atomic model, composed of the inner and outer Y-complexes, two copies of Nup205, two copies of the Nup214-Nup88-Nup62 complex, one Nup155, and five copies of Nup358. In particular, we predicted the largest protein in the NPC, Nup358, as having an S-shaped globular domain, a coiled-coil domain, and a largely disordered C-terminal region containing phenylalanine-glycine (FG) repeats previously shown to form a gel-like condensate phase for selective cargo passage. Four of the Nup358 copies clamp around the inner and outer Y-complexes to stabilize the CR, and the fifth Nup358 situates in the center of the cluster of clamps. AlphaFold also predicted a homo-oligomeric, likely specifically pentameric, coiled-coil structure of Nup358 that may provide the avidity for Nup358 recruitment to the NPC and for lowering the threshold for Nup358 condensation in NPC biogenesis. CONCLUSION Our studies offer an example of integrative cryo-EM and structure prediction as a general approach for attaining more precise models of megadalton protein complexes from medium-resolution density maps. The more accurate and almost complete model of the CR presented here expands our understanding of the molecular interactions in the NPC and represents a substantial step forward toward the molecular architecture of a full NPC, with implications for NPC function, biogenesis, and regulation. Cryo-EM structure of the cytoplasmatic ring of the nuclear pore complex from X. leavis . The 6.9 Å map was generated with single-particle cryo-EM, and the model was built with AlphaFold structure prediction. The secondary structural elements guided EM map fitting, resulting in an almost complete model of the complex. The approach allowed the identification of five copies of Nup358 and a second copy of the trimeric Nup214-Nup88-Nup62 complex.

BackgroundVascular dementia (VaD) is the accumulation of vascular lesions in the subcortical white matter of the brain. These lesions progress and there is no direct medical therapy.AimsTo determine the specific cellular responses in VaD so as to provide molecular targets for therapeutic development.Materials and methodsSingle-nucleus transcriptome analysis was performed in human periventricular white matter (PVWM) samples of VaD and normal control (NC) subjects.ResultsDifferential analysis shows that cell type-specific transcriptomic changes in VaD are associated with the disruption of specific biological processes, including angiogenesis, immune activation, axonal injury and myelination. Each cell type in the neurovascular unit within white matter has a specific alteration in gene expression in VaD. In a central cell type for this disease, subcluster analysis of endothelial cells (EC) indicates that VaD contains a disease-associated EC subcluster that expresses genes associated with programmed cell death and a response to protein folding. Two other subpopulations of EC in VaD express molecular systems associated with regenerative processes in angiogenesis, and in axonal sprouting and oligodendrocyte progenitor cell maturation.ConclusionThis comprehensive molecular profiling of brain samples from patients with VaD reveals previously unknown molecular changes in cells of the neurovascular niche, and an attempt at regeneration in injured white matter.

A family of transformer-less single-switch dual-inductor high voltage gain boost converters is proposed in this article. The proposed configurations can realize high voltage gain with low voltage and current stresses. The voltage gain of the proposed converters is analogous to the switched inductor boost converter; therefore, the proposed boost converters are suitable for high gain applications. The proposed family of converters has low component counts and reduced voltage stress on devices compared to three typical transformer-less single-switch high voltage gain converters including switched inductor boost converter, quadratic boost converter, and quasi- Z -source boost converter. Moreover, the current stress of the front-end diode and the rear-end inductor is also relatively low. Therefore, the conversion efficiency is enhanced while keeping the cost low. The operation principles and steady-state characteristics analysis of the proposed converters under the inductor current continuous conduction mode and continuous bidirectional conduction mode are discussed in detail. A prototype of 300 V, 250 W/100 kHz is developed to verify the performance of the proposed converter. The experimental results substantiate the effectiveness and advantages. The prototype achieves a peak efficiency of 97.5 $\%$ .

Signaling pathways in innate and adaptive immunity play vital roles in pathogen recognition and the functions of immune cells. Higher-order assemblies have recently emerged as a central principle that governs immune signaling and, by extension, cellular communication in general. There are mainly two types of higher-order assemblies: 1) ordered, solid-like large supramolecular complexes formed by stable and rigid protein-protein interactions, and 2) liquid-like phase-separated condensates formed by weaker and more dynamic intermolecular interactions. This review covers key examples of both types of higher-order assemblies in major immune pathways. By placing emphasis on the molecular structures of the examples provided, we discuss how their structural organization enables elegant mechanisms of signaling regulation.

Rapidly increasing interest in low-dimensional materials is driven by the emerging requirement to develop nanoscale solid-state devices with novel functional properties that are not available in three-dimensional bulk phases. Among the well-known low-dimensional systems, complex transition metal oxide interface holds promise for broad applications in electronic and spintronics devices. Herein, intriguing metal-insulator and ferromagnetic-antiferromagnetic transitions are achieved in monolayer MnO$_2$ that is sandwiched into SrTiO$_3$-based heterointerface systems through interface engineering. By using first-principles calculations, we modeled three types of SrTiO$_3$-based heterointerface systems with different interface terminations and performed a comparative study on the spin-dependent magnetic and electronic properties that are established in the confined MnO$_2$ monolayer. First-principles study predicts that metal-insulator transition and magnetic transition in the monolayer MnO$_2$ are independent on the thickness of capping layers. Moreover, 100$\%$ spin-polarized two-dimensional electron gases accompanied by robust room temperature magnetism are uncovered in the monolayer MnO$_2$. Not only is the buried MnO$_2$ monolayer a new interface phase of fundamental physical interest, but it is also a promising candidate material for nanoscale spintronics applications. Our study suggests interface engineering at complex oxide interfaces is an alternative approach to designing high-performance two-dimensional materials., 24 pages, 7 figures

Ovarian cancer (OC) is among the most common gynecologic malignancies with a poor prognosis and a high mortality rate. Most patients are diagnosed at an advanced stage (stage III or IV), with 5-year survival rates ranging from 25% to 47% worldwide. Surgical resection and first-line chemotherapy are the main treatment modalities for OC. However, patients usually relapse within a few years of initial treatment due to resistance to chemotherapy. Cell-based therapies, particularly adoptive T-cell therapy and chimeric antigen receptor T (CAR-T) cell therapy, represent an alternative immunotherapy approach with great potential for hematologic malignancies. However, the use of CAR-T-cell therapy for the treatment of OC is still associated with several difficulties. In this review, we comprehensively discuss recent innovations in CAR-T-cell engineering to improve clinical efficacy, as well as strategies to overcome the limitations of CAR-T-cell therapy in OC.

CRISPR–Cas immune systems process and integrate short fragments of DNA from new invaders as spacers into the host CRISPR locus to establish molecular memory of prior infection, which is also known as adaptation in the field. Some CRISPR–Cas systems rely on Cas1 and Cas2 to complete the adaptation process, which has been characterized in a few systems. In contrast, many other CRISPR–Cas systems require an additional factor of Cas4 for efficient adaptation, the mechanism of which remains less understood. Here we present biochemical reconstitution of the Synechocystis sp. PCC6803 type I-D adaptation system, X-ray crystal structures of Cas1–Cas2–prespacer complexes, and negative stained electron microscopy structure of the Cas4–Cas1 complex. Cas4 and Cas2 compete with each other to interact with Cas1. In the absence of prespacer, Cas4 but not Cas2 assembles with Cas1 into a very stable complex for processing the prespacer. Strikingly, the Cas1-prespacer complex develops a higher binding affinity toward Cas2 to form the Cas1–Cas2–prespacer ternary complex for integration. Together, we show a two-step sequential assembly mechanism for the type I-D adaptation module of Synechocystis, in which Cas4–Cas1 and Cas1–Cas2 function as two exclusive complexes for prespacer processing, capture, and integration.

NLRP1 and CARD8 are related cytosolic sensors that upon activation form supramolecular signalling complexes known as canonical inflammasomes, resulting in caspase−1 activation, cytokine maturation and/or pyroptotic cell death. NLRP1 and CARD8 use their C-terminal (CT) fragments containing a caspase recruitment domain (CARD) and the UPA (conserved in UNC5, PIDD, and ankyrins) subdomain for self-oligomerization, which in turn form the platform to recruit the inflammasome adaptor ASC (apoptosis-associated speck-like protein containing a CARD) or caspase-1, respectively. Here, we report cryo-EM structures of NLRP1-CT and CARD8-CT assemblies, in which the respective CARDs form central helical filaments that are promoted by oligomerized, but flexibly linked, UPAs surrounding the filaments. Through biochemical and cellular approaches, we demonstrate that the UPA itself reduces the threshold needed for NLRP1-CT and CARD8-CT filament formation and signalling. Structural analyses provide insights on the mode of ASC recruitment by NLRP1-CT and the contrasting direct recruitment of caspase-1 by CARD8-CT. We also discover that subunits in the central NLRP1CARD filament dimerize with additional exterior CARDs, which roughly doubles its thickness and is unique among all known CARD filaments. Finally, we engineer and determine the structure of an ASCCARD–caspase-1CARD octamer, which suggests that ASC uses opposing surfaces for NLRP1, versus caspase-1, recruitment. Together these structures capture the architecture and specificity of the active NLRP1 and CARD8 inflammasomes in addition to key heteromeric CARD-CARD interactions governing inflammasome signalling., Pathogen triggered N-terminal degradation of NLRP1 and CARD8 by the proteasome releases their C-terminal UPA-CARD fragments (CT) to form the inflammasome, which in turn activates caspase-1. Here, the authors present the cryo-EM structures of the NLRP1-CT and CARD8-CT helical filaments as well as the ASC−caspase-1 octamer structure, which together with in vitro and cell based assays provide further insights into the architecture and specificity of the active NLRP1 and CARD8 inflammasomes.

ObjectiveInternet Addiction Disorder (IAD) has become a social problem. Literature suggests that negative life events can cause numerous problematic behaviors and part of them will result in IAD. However, there is a lack of evidence that elucidates the association between negative life events and IAD. Thereby, we performed a comprehensive analysis to further document the relationship between negative life events and IAD among adolescents and college students in China.MethodsWe searched ten electronic databases for relevant articles. We extracted correlation coefficient (r) values from each study and calculated 95% confidence interval (95% CI) after applying Fisher’s z. A random-effect or fixed-effect model was applied to analyze the data. Heterogeneity was examined using I2 statistics and the Cochran’s Q statistics.ResultsA total of 31 studies were involved in this meta-analysis. Positive correlation was observed between negative life events and IAD. The subtype interpersonal relationship of negative life events was closely associationed with IAD.ConclusionThere were significant positive association between negative life events and IAD. The findings can be used to guide IAD interventions.Systematic Review Registration[https://www.crd.york.ac.uk/prospero/#recordDetails].

Human TMEM175, a noncanonical potassium (K + ) channel in endolysosomes, contributes to their pH stability and is implicated in the pathogenesis of Parkinson’s disease (PD). Structurally, the TMEM175 family exhibits an architecture distinct from canonical potassium channels, as it lacks the typical TVGYG selectivity filter. Here, we show that human TMEM175 not only exhibits pH-dependent structural changes that reduce K + permeation at acidic pH but also displays proton permeation. TMEM175 constitutively conducts K + at pH 7.4 but displays reduced K + permeation at lower pH. In contrast, proton current through TMEM175 increases with decreasing pH because of the increased proton gradient. Molecular dynamics simulation, structure-based mutagenesis, and electrophysiological analysis suggest that K + ions and protons share the same permeation pathway. The M393T variant of human TMEM175 associated with PD shows reduced function in both K + and proton permeation. Together, our structural and electrophysiological analysis reveals a mechanism of TMEM175 regulation by pH.

BackgroundInternet addiction (IA) has become a serious social issue, inducing troubles in interpersonal relationships, which may negatively impact the healthy development of teenagers and college students. Thus, the current research aimed to synthesize the available evidence to clarify the correlation between IA and troubles in interpersonal relationships.MethodWe searched eight electronic databases from inception to December 2020. Study quality was assessed by the Newcastle-Ottawa Scale (NOS), and Agency for Healthcare Research and Quality (AHRQ). We analyzed the data by extracting the Pearson correlation coefficients of each study and converted it into Fisher's Z. Pooled r was conducted by Fisher's Z and standard error (SE). STATA (Version 15.0) software was used for data synthesis.ResultsA total of 10,173 studies were initially identified, and 26 studies (n = 14,638 participants) were retrieved for further analysis. The results indicated that there was a significant positive correlation between IA and interpersonal relationship troubles [0.36 (95% CI 0.35–0.38)]. In addition, there was a positive correlation between IA and different dimensions of interpersonal relationship reflected by troubles with interpersonal conversation, making friends, dealing with people, and heterosexual communication, with the result of [0.26 (95% CI 0.18–0.33)], [0.29 (95% CI 0.20–0.37)], [0.27 (95% CI 0.19–0.34)], [0.22 (0.15–0.30)], respectively. The Egger test suggested that there was no publication bias (P > 0.05).ConclusionIA is positively correlated with troubles in interpersonal relationships. This research will provide new ideas and direction for further intervention, clinical therapy, and policy-making regarding IA to some extent.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42020177294.

Objective To explore the morbidity of chronic obstructive pulmonary disease (COPD) related complications and mortality of the COPD patients, and analyze the risk factors for complications. Methods 1829 COPD patients were collected from Department of Respiratory and Critical Care Medicine Center of the Second Affiliated Hospital of Army Medical University and Department of Respiratory of the People's Hospital of Fengdu County from January 2018 to December 2018. Then, the morbidity and mortality of the complication were observed, meanwhile, the risk factors were analyzed by multifactor logistic regression. Results 89.2%(1631/1829) of COPD patients complicated with other diseases, the mortality rate was 2.5%(46/1829). The complications main included respiratory and cardiovascular system diseases, the mortality rates were 68.8% and 34.4%, respectively. Then, the data indicated that the disease with the highest mortality rate was nervous system diseases, which was 9.3%, especially pulmonary encephalopathy, the mortality rate was 21.7%. Furthermore, logistic regression analysis showed that age over 80 years, smoking long than 20 years, smoking more than 700 cigarettes per year, drinking, C-reactive protein (CRP) more than 50 mg/L, hyperglycemia and hypoproteinemia were the risk factors of COPD with complications (OR=3.488, 4.085, 4.086, 2.464, 2.208, 2.066, 11.804). Conclusion The incidence of COPD complications is relatively high, and the mortality also increase obviously. Therefore, more attention should be payed to the treatment and prevention for complications of COPD. DOI: 10.11855/j.issn.0577-7402.2020.08.08

Cancer stem cells (CSCs) play significant roles in tumor initiation. MicroRNA-135a (miR-135a) induced the formation of a CD133+ subpopulation from a human papillomavirus-immortalized cervical epithelial cell line. Compared with the CD133− cells, the CD133+ cells expressed higher levels of miR-135a and OCT4, exhibited significantly higher tumorsphere forming capacity and the time required for tumorsphere formation was shortened in the second generation. Serum induction suppressed the expression of CD133, OCT4 and miR-135a, but increased expression of involucrin in the miR-135a-induced CD133+ cells. The miR-135a-induced CD133+ cells were tumorigenic in a limiting dilution approach in vivo. The cells expressed significantly higher level of active β-catenin and OCT4 than the CD133− counterpart. Wnt3a enhanced the expression of OCT4 and CD133 in cervical cancer cells but failed to enhance CD133 transcription in normal cervical cells. Wnt3a stimulation also increased tumorsphere size and self-renewal of miR-135a-induced CD133+ subpopulation. Wnt/β-catenin inhibition suppressed tumorsphere formation while Wnt3a partially nullified the inhibitory effect. Taken together, miR-135a induced the formation of a subpopulation of cells with CSC properties both in vitro and in vivo and the Wnt/β-catenin signaling pathway is essential to maintain its tumorigenicity.

Background Fluid overload in patients undergoing hemodialysis contributes to cardiovascular morbidity and mortality. There is a global trend to lower dialysate sodium with the goal of reducing fluid overload. Methods To investigate whether lower dialysate sodium during hemodialysis reduces left ventricular mass, we conducted a randomized trial in which patients received either low-sodium dialysate (135 mM) or conventional dialysate (140 mM) for 12 months. We included participants who were aged >18 years old, had a predialysis serum sodium ≥135 mM, and were receiving hemodialysis at home or a self-care satellite facility. Exclusion criteria included hemodialysis frequency >3.5 times per week and use of sodium profiling or hemodiafiltration. The main outcome was left ventricular mass index by cardiac magnetic resonance imaging. Results The 99 participants had a median age of 51 years old; 67 were men, 31 had diabetes mellitus, and 59 had left ventricular hypertrophy. Over 12 months of follow-up, relative to control, a dialysate sodium concentration of 135 mmol/L did not change the left ventricular mass index, despite significant reductions at 6 and 12 months in interdialytic weight gain, in extracellular fluid volume, and in plasma B-type natriuretic peptide concentration (ratio of intervention to control). The intervention increased intradialytic hypotension (odds ratio [OR], 7.5; 95% confidence interval [95% CI], 1.1 to 49.8 at 6 months and OR, 3.6; 95% CI, 0.5 to 28.8 at 12 months). Five participants in the intervention arm could not complete the trial because of hypotension. We found no effect on health-related quality of life measures, perceived thirst or xerostomia, or dietary sodium intake. Conclusions Dialysate sodium of 135 mmol/L did not reduce left ventricular mass relative to control, despite improving fluid status. Clinical trial registry name and registration number The Australian New Zealand Clinical Trials Registry, ACTRN12611000975998.

Objective To provide a portable disposable endoscopy for preventing potential viral infection in the patients with acute upper gastrointestinal bleeding (AUGIB) or those who need emergency endoscopy and reducing the process of endoscopy cleaning and disinfection during the corona virus disease 2019 (COVID-19) epidemic. Methods The novel portable and disposable endoscopy system (YunSendo) was self-designed. Two patients with suspected AUGIB underwent emergency gastroscopy with YunSendo system by a senior endoscopist. Standard image acquisition and assessments of operation performance and image quality were fulfilled to evaluate the preliminary safety, feasibility, and operation performance of the novel endoscopy. Results Emergency endoscopy was completed safely in two AUGIB patients by the YunSendo system without alternating current (AC) power supply. The endoscopic manipulation and observation, including water absorption, air inflation, water spray, body rotation, and specimen biopsy, can be smoothly and effectively achieved. The video-recording, image acquisition, and electronic graphic report output were achieved integratedly in YunSendo. The upper GI tract can be clearly visualized, with eligible specimen biopsy without any obvious adverse events and compilations. Operation time was similar to an ordinary gastroscopy. The disposable endoscope was discarded after use according to the requirements of the hospital infection-control department. Conclusions The novel portable and disposable endoscopy system, YunSendo, is safe and feasible for upper gastrointestinal examination, with favorable operation performance and image quality. The preliminary experience provides evidence for its convenient use of epidemic prevention. DOI: 10.11855/j.issn.0577-7402.2020.03.05

Impaired immunomodulatory capacity and oxidative stress are the key factors limiting the effectiveness of mesenchymal stem cell transplantation therapy. The present study was aimed to investigate the effects of jujuboside A (JuA) on the protective effect and immunomodulatory capacity of human umbilical cord mesenchymal stem cells (hUC-MSCs). Hydrogen peroxide was used to establish an oxidative damage model of hUC-MSCs, while PBMCs isolated from rats were used to evaluate the effect of JuA pre-treatment on the immunomodulatory capacity of hUC-MSCs. Furthermore, Hoechst 33258 staining, lactate dehydrogenase test, measurement of malondialdehyde, Western blot, high-performance liquid chromatography; and flow cytometry were performed. Our results indicated that JuA (25 μmol·L

SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here, we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the stem-loop 1 (SL1) region of the SARS-CoV-2 5' untranslated region (5' UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5' UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2-induced lethality in transgenic mice expressing human ACE2. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus' own virulence mechanism against itself could force a critical trade-off between drug resistance and pathogenicity.

Background. Polycystic ovary syndrome (PCOS) is a complex class of endocrine disorders with insulin resistance, compensatory hyperinsulinemia, and obesity. However, the pathogenesis and therapies of PCOS have not been fully elucidated. Exosomal miRNAs have the potential to serve as biomarkers and therapies for a wide range of medical conditions. Method. We collected follicular fluid from 5 PCOS patients and 5 healthy people. High-throughput sequencing technology to identify differentially expressed miRNAs and untargeted metabolome identify differential metabolites in follicular fluid exosomal. RT-qPCR and AUC analysis were performed. Result. miRNA high-throughput sequencing identified 124 differential miRNAs. RT-qPCR analysis confirmed the sequencing results. These differential miRNA target genes are mainly involved in metabolic pathways. Metabolomics studies identified 31 differential metabolites. miRNA and lncRNA coexpression networks in metabolic pathways rigorously screened 28 differentially expressed miRNAs. This network would identify miRNA signatures associated with metabolic processes in PCOS. Meanwhile, the area under curve of receiver operating characteristic revealed that hsa-miR-196a-3p, hsa-miR-143-5p, hsa-miR-106a-3p, hsa-miR-34a-5p, and hsa-miR-20a-5p were potential biomarkers for the diagnosis of PCOS. Conclusion. Collectively, these results demonstrate the potential pathogenesis of PCOS, and follicular fluid exosomal miRNAs may be efficient targets for the diagnosis and treatment of PCOS in long-term clinical studies.

Ovarian cancer is the eighth most commonly diagnosed cancer among women worldwide. Even with the development of novel drugs, nearly one-half of the patients with ovarian cancer die within five years of diagnosis. These situations indicate the need for novel therapeutic agents for ovarian cancer. Increasing evidence has shown that hypoxia-inducible factor-1α(HIF-1α) plays an important role in promoting malignant cell chemoresistance, tumour metastasis, angiogenesis, immunosuppression and intercellular interactions. The unique microenvironment, crosstalk and/or interaction between cells and other characteristics of ovarian cancer can influence therapeutic efficiency or promote the disease progression. Inhibition of the expression or activity of HIF-1α can directly or indirectly enhance the therapeutic responsiveness of tumour cells. Therefore, it is reasonable to consider HIF-1α as a potential therapeutic target for ovarian cancer. In this paper, we summarize the latest research on the role of HIF-1α and molecules which can inhibit HIF-1α expression directly or indirectly in ovarian cancer, and drug clinical trials about the HIF-1α inhibitors in ovarian cancer or other solid malignant tumours.

Cold stress limits plant geographical distribution and influences plant growth, development, and yields. Plants as sessile organisms have evolved complex biochemical and physiological mechanisms to adapt to cold stress. These mechanisms are regulated by a series of transcription factors and proteins for efficient cold stress acclimation. It has been established that the ICE-CBF-COR signaling pathway in plants regulates how plants acclimatize to cold stress. Cold stress is perceived by receptor proteins, triggering signal transduction, and Inducer of CBF Expression (ICE) genes are activated and regulated, consequently upregulating the transcription and expression of the C-repeat Binding Factor (CBF) genes. The CBF protein binds to the C-repeat/Dehydration Responsive Element (CRT/DRE), a homeopathic element of the Cold Regulated genes (COR gene) promoter, activating their transcription. Transcriptional regulations and post-translational modifications regulate and modify these entities at different response levels by altering their expression or activities in the signaling cascade. These activities then lead to efficient cold stress tolerance. This paper contains a concise summary of the ICE-CBF-COR pathway elucidating on the cross interconnections with other repressors, inhibitors, and activators to induce cold stress acclimation in plants.

Focusing two-color laser fields in gas-phase medium produces ultrashort ultra-broadband low-order harmonics spanning from terahertz to extreme ultraviolet regime. The low-order harmonic generation can be explained by both macroscopic photocurrent model and microscopic strong field approximation theory. Here, we analytically build a bridge between the macroscopic and microscopic theories by means of the trajectory method, which manifests correspondences between macroscopic and microscopic theories. And we demonstrate the trajectory analysis to explain phase-dependent terahertz and third-harmonic generations, and contribute the phase-dependent yields and spectral shapes to the coherent superposition of electron trajectories released at distinct ionization instants, reflecting electron interfering with itself in radiation process. The trajectory method readily connects the low-order harmonics characteristics and behaviors of electron wavepacket, which has potential for reconstructing ultrafast electron dynamics by means of low-harmonics observations.

The malaria parasite relies on anaerobic glycolysis for energy supply when growing inside RBCs as its mitochondrion does not produce ATP. The ring stage lasts ∼ 22 hours and is traditionally thought to be metabolically quiescent. However, recent studies show that the ring stage is active for several energy-costly processes including gene transcription/translation, protein export, and movement inside the RBC. It has remained unclear if a low glycolytic flux can meet the energy demand of the ring stage. Here we show that the metabolic by-product, pyrophosphate, is a critical energy source for the development of the ring stage and its transition to the trophozoite stage. During early phases of the asexual development, the parasite utilizes Plasmodium falciparum vacuolar pyrophosphatase 1 (PfVP1), an ancient pyrophosphate-driven proton pump, to pump protons across the parasite plasma membrane to maintain the membrane potential and cytosolic pH. Conditional deletion of PfVP1 leads to delayed ring stage development and a complete blockage of the ring-to-trophozoite transition, which can be partially rescued by Arabidopsis thaliana vacuolar pyrophosphatase 1, but not by the soluble pyrophosphatase from Saccharomyces cerevisiae. Proton-pumping pyrophosphatases are absent in humans, which highlights the possibility of developing highly selective VP1 inhibitors against the malaria parasite.