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In the present study, the influence of training on the microstructural evolution, martensitic transformation behavior and mechanical/functional properties of Ti–V–Al–Zr shape memory alloy was investigated systematically. With the increasing of training cycling number, the degree of martensite reorientation became larger and larger. Moreover, higher density of dislocations appeared in the interior of martensite variants, upon the excessive training cycling number was applied. The international stress can be brought into the matrix, which not only promoted to the ω→αˊˊ transition, but also made the martensite phase stabilizer and even suppressed the αˊˊ→β martensitic transformation during training process. The superior mechanical properties including maximum fracture stress of 906 MPa and the higher fracture strain of 33.6% can be obtained in Ti–V–Al–Zr shape memory alloy subjected with the training cycles number of 5th, which can be attributed to the matrix strengthening stemmed from work hardening and suppression of ω precipitation. Meanwhile, the lower critical stress for the martensite variant reorientation and enhanced matrix strength synergistically contributed to the superior strain recovery characteristics with total completely recoverable strain of 6% in Ti–V–Al–Zr shape memory alloy by controlling training cycles number of 5th. Meanwhile, the higher micro-hardness can be obtained by training.

Abstract Vertical field effect transistor (VFET), in which the semiconductor is sandwiched between source/drain electrodes and the channel length is simply determined by the semiconductor thickness, has demonstrated promising potential for short channel devices. However, despite extensive efforts over the past decade, scalable methods to fabricate ultra-short channel VFETs remain challenging. Here, we demonstrate a layer-by-layer transfer process of large-scale indium gallium zinc oxide (IGZO) semiconductor arrays and metal electrodes, and realize large-scale VFETs with ultra-short channel length and high device performance. Within this process, the oxide semiconductor could be pre-deposited on a sacrificial wafer, and then physically released and sandwiched between metals, maintaining the intrinsic properties of ultra-scaled vertical channel. Based on this lamination process, we realize 2 inch-scale VFETs with channel length down to 4 nm, on-current over 800 A/cm2, and highest on-off ratio up to 2 × 105, which is over two orders of magnitude higher compared to control samples without laminating process. Our study not only represents the optimization of VFETs performance and scalability at the same time, but also offers a method of transfer large-scale oxide arrays, providing interesting implication for ultra-thin vertical devices.

Abstract Astragali radix (AR, namded Huangqi in Chinese) is the dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. As a widely used ethnomedicine, the biological activities of AR include immunomodulatory, anti-hyperglycemic, anti-oxidant, anti-aging, anti-inflammatory, anti-viral, anti-tumor, cardioprotective, and anti-diabetic effects, with minimum side effects. Currently, it is known that polysaccharides, saponins, and flavonoids are the indispensable components of AR. In this review, we will elaborate the research advancements of AR on ethnobotany, ethnopharmacological practices, phytochemicals, pharmacological activities, clinical uses, quality control, production developments, and toxicology. The information is expected to assist clinicians and scientists in developing useful therapeutic medicines with minimal systemic side effects.

Abstract Background Occult Macular Dystrophy (OMD), primarily caused by retinitis pigmentosa 1-like 1 (RP1L1) variants, is a complex retinal disease characterised by progressive vision loss and a normal fundus appearance. This study aims to investigate the diverse phenotypic expressions and genotypic correlations of OMD in Chinese patients, including a rare case of Vitelliform Macular Dystrophy (VMD) associated with RP1L1. Methods We analysed seven OMD patients and one VMD patient, all with heterozygous pathogenic RP1L1 variants. Clinical assessments included Best Corrected Visual Acuity (BCVA), visual field testing, Spectral Domain Optical Coherence Tomography (SD-OCT), multifocal Electroretinograms (mfERGs), and microperimetry. Next-generation sequencing was utilised for genetic analysis. Results The OMD patients displayed a range of phenotypic variability. Most (5 out of 7) had the RP1L1 variant c.133 C > T; p.R45W, associated with central vision loss and specific patterns in SD-OCT and mfERG. Two patients exhibited different RP1L1 variants (c.3599G > T; p.G1200V and c.2880G > C; p.W960C), presenting milder phenotypes. SD-OCT revealed photoreceptor layer changes, with most patients showing decreased mfERG responses in the central rings. Interestingly, a unique case of VMD linked to the RP1L1 variant was observed, distinct from traditional OMD presentations. Conclusions This study highlights the phenotypic diversity within OMD and the broader spectrum of RP1L1-associated macular dystrophies, including a novel association with VMD. The findings emphasise the complexity of RP1L1 variants in determining clinical manifestations, underscoring the need for comprehensive genetic and clinical evaluations in macular dystrophies.

Abstract The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation.

To explore the influence of raw materials from different cultivars on the quality of Sichuan dark tea, the raw materials of 4 tea cultivars were used in this study. The main chemicals and aroma components were analyzed by sensory evaluation, chemical analysis and gas chromato graphy-mass spectrometry (GC-MS) . The main components of Sichuan dark teas made from different tea cultivars were significantly different. The contents of water extract, tea polyphenols, catechins and caffeine of Sichuan dark teas from 'Zijuan' were the highest, which were 49.45%, 18.54%, 4.77%, and 4.21%, respectively, followed by Sichuan dark tea processed with 'Huangjinya' cultivar, all of them were significantly (P

Dexamethasone (DEX) is used to treat ocular surface diseases. However, regulating DEX duration in tears while preventing its absorption into the anterior chamber is critical for balancing its therapy effects and the side effects. In this study, a novel magnetic nanoparticle (MNP)-micelle (MC) co-delivery system (MMDS) was developed. The MC moiety in the MMDS served as the carrier for DEX and the MNP part endowed the MMDS with magnetic-responsive properties. To extend its residency, the MMDS was magnetically attracted by an external magnet after instilling, which acted as a precorneal drug-depot enabling a sustainable release of DEX in tears. With combination of magnet treatment, the topical instillation of MMDS@DEX significantly prolonged the DEX-retention in tears and increased the DEX-concentration in the cornea and conjunctiva, as well as concurrently reduced the DEX-level in the aqueous humor, when compared with the commercial DEX eye drop treatment. The combination of MMDS@DEX and magnet treatment exerted significantly better therapeutic effects against DED with smaller side effects than conventional treatments including DEX suspension, commercial DEX eye drops, as well as the MMDS@DEX treatment alone. The present work provided a new method for the effective delivery of DEX to ocular surface tissues while reducing its side effects, which will be beneficial to the treatments of a wide range of ocular surface diseases.

Abstract Background The accuracy of traditional knee MR imaging in diagnosing anterior cruciate ligament tears, especially partial tears, is relatively low, which may lead to misdiagnosis and missed diagnosis. This study aimed to assess the diagnostic performance of a novel imaging method, high-resolution oblique coronal MRI at an optimal flexed-knee Angle, for ACL tears. Methods 50 healthy volunteers were scanned with a scan-assisted device for the optimal flexion angle of ACL. For 92 knee trauma patients selected strictly according to inclusion and exclusion criteria, conventional extended-knee scans (control group) and high-resolution oblique coronal scans based on the optimal flexed-knee angle (experimental group) were conducted. Two observers rated ACL visibility blindly on a 5-point scale. Arthroscopy-defined outcomes determined diagnostic metrics for each method and sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated. Results The average optimal flexion angle for healthy volunteers was approximately 30° (30.3° ± 5.0°). Imaging demonstrated complete visualization of the ACL in 96.7% of images in the experimental group versus 12.0% in the control group. The diagnostic indicators of the experimental group surpassed those of the control group: sensitivity (94.9% vs. 76.3%), specificity (97.0% vs. 81.8%), positive predictive value (98.2% vs. 88.2%), negative predictive value(91.4% vs. 65.9%), and accuracy (95.7% vs. 78.3%). ROC analysis indicated superior diagnostic performance in the experimental group, with an AUC of 0.945 compared with 0.776 for the control group (p

Abstract Background Reactive astrocytes participate in various pathophysiology after subarachnoid hemorrhage (SAH), including neuroinflammation, glymphatic–lymphatic system dysfunction, brain edema, BBB disruption, and cell death. Astrocytes transform into two new reactive phenotypes with changed morphology, altered gene expression, and secretion profiles, termed detrimental A1 and beneficial A2. This study investigates the effect of 67LR activation by PEDF-34, a PEDF peptide, on neuroinflammation and astrocyte polarization after the experimental SAH. Methods A total of 318 male adult Sprague-Dawley rats were used in experiments in vivo, of which 272 rats were subjected to the endovascular perforation model of SAH and 46 rats underwent sham surgery. 67LR agonist (PEDF-34) was administrated intranasally 1 h after SAH. 67LR-specific inhibitor (NSC-47924) and STAT1 transcriptional activator (2-NP) were injected intracerebroventricularly 48 h before SAH. Short- and long-term neurological tests, brain water content, immunostaining, Nissl staining, western blot, and ELISA assay were performed. In experiments in vitro, primary astrocyte culture with hemoglobin (Hb) stimulation was used to mimic SAH. The expression of the PEDF-34/67LR signaling pathway and neuro-inflammatory cytokines were assessed using Western blot, ELISA, and immunohistochemistry assays both in vivo and in vitro. Results Endogenous PEDF and 67LR expressions were significantly reduced at 6 h after SAH. 67LR was expressed in astrocytes and neurons. Intranasal administration of PEDF-34 significantly reduced brain water content, pro-inflammatory cytokines, and short-term and long-term neurological deficits after SAH. The ratio of p-JNK/JNK and p-STAT1/STAT1 and the expression of CFB and C3 (A1 astrocytes marker), significantly decreased after PEDF-34 treatment, along with fewer expression of TNF-α and IL-1β at 24 h after SAH. However, 2-NP (STAT1 transcriptional activator) and NSC-47924 (67LR inhibitor) reversed the protective effects of PEDF-34 in vivo and in vitro by promoting A1 astrocyte polarization with increased inflammatory cytokines. Conclusion PEDF-34 activated 67LR, attenuating neuroinflammation and inhibiting astrocyte A1 polarization partly via the JNK/STAT1 pathway, suggesting that PEDF-34 might be a potential treatment for SAH patients. Graphical Abstract

Abstract Vertical transistors, in which the source and drain are aligned vertically and the current flow is normal to the wafer surface, have attracted considerable attention recently. However, the realization of high-density vertical transistors is challenging, and could be largely attributed to the incompatibility between vertical structures and conventional lateral fabrication processes. Here we report a T-shape lamination approach for realizing high-density vertical sidewall transistors, where lateral transistors could be pre-fabricated on planar substrates first and then laminated onto vertical substrates using T-shape stamps, hence overcoming the incompatibility between planar processes and vertical structures. Based on this technique, we vertically stacked 60 MoS2 transistors within a small vertical footprint, corresponding to a device density over 108 cm−2. Furthermore, we demonstrate two approaches for scalable fabrication of vertical sidewall transistor arrays, including simultaneous lamination onto multiple vertical substrates, as well as on the same vertical substrate using multi-cycle layer-by-layer laminations.

Abstract Background Renal interstitial fibrosis (RIF) is a progressive, irreversible terminal kidney disease with a poor prognosis and high mortality. Angiopoietin-like 4 (ANGPTL4) is known to be associated with fibrosis in various organs, but its impact on the RIF process remains unclear. This study aimed to elucidate the role and underlying mechanisms of ANGPTL4 in the progression of RIF. Methods In vivo, a chronic kidney disease (CKD) rat model of renal interstitial fibrosis was established via intragastric administration of adenine at different time points (4 and 6 weeks). Blood and urine samples were collected to assess renal function and 24-h urinary protein levels. Kidney tissues were subjected to HE and Masson staining for pathological observation. Immunohistochemistry and real-time quantitative PCR (qRT‒PCR) were performed to evaluate the expression of ANGPTL4 and hypoxia-inducible factor-1α (HIF-1α), followed by Pearson correlation analysis. Subsequently, kidney biopsy tissues from 11 CKD patients (6 with RIF and 5 without RIF) were subjected to immunohistochemical staining to validate the expression of ANGPTL4. In vitro, a fibrosis model of human renal tubular epithelial cells (HK2) was established through hypoxic stimulation. Subsequently, an HIF-1α inhibitor (2-MeOE2) was used, and ANGPTL4 was manipulated using siRNA or plasmid overexpression. Changes in ANGPTL4 and fibrosis markers were analyzed through Western blotting, qRT‒PCR, and immunofluorescence. Results ANGPTL4 was significantly upregulated in the CKD rat model and was significantly positively correlated with renal injury markers, the fibrotic area, and HIF-1α. These results were confirmed by clinical samples, which showed a significant increase in the expression level of ANGPTL4 in CKD patients with RIF, which was positively correlated with HIF-1α. Further in vitro studies indicated that the expression of ANGPTL4 is regulated by HIF-1α, which in turn is subject to negative feedback regulation by ANGPTL4. Moreover, modulation of ANGPTL4 expression influences the progression of fibrosis in HK2 cells. Conclusion Our findings indicate that ANGPTL4 is a key regulatory factor in renal fibrosis, forming a loop with HIF-1α, potentially serving as a novel therapeutic target for RIF.

AZ31 Mg alloy thin walls are prepared using wire arc additive manufacturing (WAAM) and interlayer ultrasonic impact (UI) techniques with cold metal transition (CMT) serving as the heat source. The microstructure, mechanical and corrosion properties of thin walls prepared by WAAM and WAAM + UI are studied. Results showed that the recrystallization area fraction along traveling direction (TD) increased by 68.6% after UI treatment, and many fine equiaxed crystals were formed, resulting in grain refinement, anisotropy reduction, mechanical and corrosion properties improvement. The average grain size along TD decreased from 66.6 ± 3.5 μm to 32.7 ± 1.6 μm. Through UI treatment, the ultimate tensile strength (UTS) and elongation (EL) along TD increased from 205 MPa to 230 MPa and 13.5%–17%, respectively. The anisotropic percentage of UTS and EL were decreased from 10.8% to 4.5%, and 42.1%–9.7%, respectively. Electrochemical experimental results showed that the average corrosion rate along TD decreased from 1.93 mm year−1 to 1.53 mm year−1. Grain refinement, dislocation density variation and texture strength reduction were the main reasons for these results.

Background: Bulbus Fritillariae Pallidiflorae (BFP) is a traditional Chinese medicine that has long been used to treat lung diseases, but the active components and mechanism are still unclear. Objective: This study aimed to investigate the effect and mechanism of the total alkaloid extract from BFP (BFP-TA) on cigarette smoke extract (CSE)-induced Beas-2B cells injury. Design: The Beas-2B cells injury model was induced by 2% CSE, then the effect of BFP-TA on the levels of total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and malondialdehyde (MDA) was detected according to the instructions of the T-AOC assay kit, the SOD detection kit and the MDA detection kit, and the production of ROS was detected by fluorescence microscopy. The effect of BFP-TA on Beas-2B cells apoptosis was detected by flow cytometry, and the effect of BFP-TA on related protein expression was detected by western blot. Subsequently, the effect of BFP-TA on differentially expressed genes (DEGs) in CSE-induced Beas-2B cells was studied by transcriptomic sequencing, and the expression of DEGs was verified by quantitative real-time polymerase chain reaction (qPCR). Results: The results showed that BFP-TA could attenuate CSE-induced oxidative damage in Beas-2B cells by elevating T-AOC and SOD levels while inhibiting ROS and MDA levels, and the mechanism was potentially related to the SIRT1/Nrf2/Keap1 signaling pathway. Furthermore, BFP-TA could inhibit CSE-induced apoptosis by inhibiting the protein expression of Bax, MST1 and FOXO3a, and exert anti-inflammatory effect by inhibiting the activation of MAPK signaling pathway. Subsequently, transcriptome analysis and qPCR validation showed that BFP-TA could alleviate inflammation, oxidative stress, apoptosis and lipid metabolism disorders by regulating the expression of DEGs in PPAR and PI3K-Akt signaling pathways, thereby exerting a protective effect against CSE-induced Beas-2B cell injury. Conclusion: This study is the first to demonstrate that BFP-TA could exert a protective effect on CSE-induced Beas-2B cell injury by exerting anti-inflammatory, antioxidant, anti-apoptotic and regulate lipid metabolism disorders.

Abstract We present a calculation of the bosonic contribution to the two-loop mixed QCD-electroweak scattering amplitudes for Z-boson production in association with one hard jet at hadron colliders. We employ a method to calculate amplitudes in the ’t Hooft-Veltman scheme that reduces the amount of spurious non-physical information needed at intermediate stages of the computation, to keep the complexity of the calculation under control. We compute all the relevant Feynman integrals numerically using the Auxiliary Mass Flow method. We evaluate the two-loop scattering amplitudes on a two-dimensional grid in the rapidity and transverse momentum of the Z boson, which has been designed to yield a reliable numerical sampling of the boosted-Z region. This result provides an important building block for improving the theoretical modelling of a key background for monojet searches at the LHC.

Abstract Type 1 polyketides are a major class of natural products used as antiviral, antibiotic, antifungal, antiparasitic, immunosuppressive, and antitumor drugs. Analysis of public microbial genomes leads to the discovery of over sixty thousand type 1 polyketide gene clusters. However, the molecular products of only about a hundred of these clusters are characterized, leaving most metabolites unknown. Characterizing polyketides relies on bioactivity-guided purification, which is expensive and time-consuming. To address this, we present Seq2PKS, a machine learning algorithm that predicts chemical structures derived from Type 1 polyketide synthases. Seq2PKS predicts numerous putative structures for each gene cluster to enhance accuracy. The correct structure is identified using a variable mass spectral database search. Benchmarks show that Seq2PKS outperforms existing methods. Applying Seq2PKS to Actinobacteria datasets, we discover biosynthetic gene clusters for monazomycin, oasomycin A, and 2-aminobenzamide-actiphenol.

ABSTRACT Introduction Lysinuric protein intolerance (LPI) is a rare genetic disorder caused by mutations in the solute carrier family 7A member 7 (SLC7A7) gene. Case presentation We presented two siblings with LPI, carrying novel mutations of c.776delT (p.L259Rfs*18) and c.155G>T (p.G52V) in SLC7A7. The younger sibling, preferring protein‐rich foods, showed severe symptoms, including alveolar proteinosis, macrophage activation syndrome, severe diarrhea, and disturbance of consciousness with involuntary movements. In contrast, the elder sibling only had mild symptoms, likely due to aversion to protein‐rich food since toddler age. Conclusion LPI is a congenital genetic metabolic disease with multi‐system involvement. Initiating appropriate protein‐restricted diet therapy as soon as possible could help prevent the progression of LPI.

Abstract Objective This study aimed to develop and validate the Salt Reduction Behavior Scale (SRBS) to measure the behavior of hypertensive Chinese individuals in adhering to salt reduction practices. Methods The SRBS was constructed based on the Health Belief Model, consisting of five constructs: knowledge, perceived severity, perceived benefits, perceived barriers, and cues to action. Data were collected from 2,082 hypertensive patients in Beijing, China, who completed a questionnaire administered through an online platform. Kaiser-Meyer-Olkin (KMO) test was used to assess the adequacy of the sample and the Bartlett’s test of sphericity to examine the factorability of the dataset. Confirmatory Factor Analysis (CFA) was used to assess the structural validity and reliability of the SRBS. Results The KMO analysis yielded a notably elevated value of 0.95, indicating that the data was highly suitable for Exploratory Factor Analysis (EFA). Bartlett’s test of sphericity yielded a statistically significant test statistic (P

Abstract Various factors affect translation effort. This research aims to explore the impact of source text type on Chinese-English translation effort with reference to translation entropy. An eye-tracking and key-logging experiment was conducted. Thirty-one student translators translated four text types, namely legal, advertising, news, and poetic texts. Data analyses show that there is a significant difference in participants’ effort of translating the four texts, which can be seen in such indicators as subjective ratings, fixation, pause, translation time, and edits. We further studied participants’ translations and calculated the translation entropy for each text type, which is a measure of uncertainty in translation. Analysis shows that there is a significant difference in translation entropy among the four text types, which provides evidence that source text features affect translation uncertainty and, hence, translation effort to search for appropriate options. The discussions are intended to provide further insight into the impact of text type on the translation process, and the result confirms the reliability of translation entropy as a predictor of translation effort.

Abstract Ebola virus (EBOV) matrix protein VP40 can assemble and bud as virus-like particles (VLPs) when expressed alone in mammalian cells. Nucleoprotein (NP) could be recruited to VLPs as inclusion body (IB) when co-expressed, and increase VLP production. However, the mechanism behind it remains unclear. Here, we use a computational approach to study NP-VP40 interactions. Our simulations indicate that NP may enhance VLP production through stabilizing VP40 filaments and accelerating the VLP budding step. Further, both the relative timing and amount of NP expression compared to VP40 are important for the effective production of IB-containing VLPs. We predict that relative NP/VP40 expression ratio and time are important for efficient production of IB-containing VLPs. We conclude that disrupting the expression timing and amount of NP and VP40 could provide new avenues to treat EBOV infection. This work provides quantitative insights into EBOV proteins interactions and how virion generation and drug efficacy could be influenced.

Abstract Objective Mild therapeutic hypothermia (MTH) is an important method for perioperative prevention and treatment of myocardial ischemia–reperfusion injury (MIRI). Modifying mitochondrial proteins after protein translation to regulate mitochondrial function is one of the mechanisms for improving myocardial ischemia–reperfusion injury. This study investigated the relationship between shallow hypothermia treatment improving myocardial ischemia–reperfusion injury and the O-GlcNAcylation level of COX10. Methods We used in vivo Langendorff model and in vitro hypoxia/reoxygenation (H/R) cell model to investigate the effects of MTH on myocardial ischemia–reperfusion injury. Histological changes, myocardial enzymes, oxidative stress, and mitochondrial structure/function were assessed. Mechanistic studies involved various molecular biology methods such as ELISA, immunoprecipitation (IP), WB, and immunofluorescence. Results Our research results indicate that MTH upregulates the O-GlcNACylation level of COX10, improves mitochondrial function, and inhibits the expression of ROS to improve myocardial ischemia–reperfusion injury. In vivo, MTH effectively alleviates ischemia–reperfusion induced cardiac dysfunction, myocardial injury, mitochondrial damage, and redox imbalance. In vitro, the OGT inhibitor ALX inhibits the OGT mediated O-GlcNA acylation signaling pathway, downregulates the O-Glc acylation level of COX10, promotes ROS release, and counteracts the protective effect of MTH. On the contrary, the OGA inhibitor ThG showed opposite effects to ALX, further confirming that MTH activated the OGT mediated O-GlcNAcylation signaling pathway to exert cardioprotective effects. Conclusions In summary, MTH activates OGT mediated O-glycosylation modified COX10 to regulate mitochondrial function and improve myocardial ischemia–reperfusion injury, which provides important theoretical basis for the clinical application of MTH.

Abstract Ciprofol (HSK3486) is a newly developed, highly selective γ‐aminobutyric acid‐A (GABAA) receptor potentiator that is recently approved for a new indication of sedation for patients in the intensive care unit (ICU) in China. This analysis aimed to characterize the population pharmacokinetics (PopPKs) of ciprofol and evaluate the relationship of exposure with hypotension in mechanically ventilated patients in the ICU. A total of 462 subjects with 3918 concentration measurements from two clinical trials of mechanically ventilated patients in the ICU, four clinical trials of elective surgical patients, and six clinical trials of healthy subjects were used in the PopPK analysis. Exposure–safety relationship for hypotension was evaluated based on the data gathered from 112 subjects in two clinical trials of mechanically ventilated patients in the ICU. Ciprofol pharmacokinetics (PKs) was adequately described by a three‐compartment linear disposition model with first‐order elimination. Body weight, age, sex, blood sampling site (vein vs. arterial), study design (long‐term infusion vs. short‐term infusion), and patient population (ICU vs. non‐ICU) were identified as statistically significant covariates on the PKs of ciprofol. Within the exposure range of the mechanically ventilated ICU patient population, no meaningful association was observed between ciprofol exposure and the incidence of hypotension. These results support the dosing regimen currently used in mechanically ventilated patients in the ICU.

Heat treatment of Mg10Gd-4Y-xZn-0.6Zr (x = 0, 1, 2 wt%) alloys has been optimized based on thermodynamic calculations and experiments. The phase transformations during the heat treatment and their effect on the mechanical properties of the alloys were discussed. Using thermodynamic calculations, three solution treatment temperatures of 475 °C, 500 °C, and 525 °C were determined, and the phase transformation under these temperatures were calculated and characterized, the results aligned well with experimental results. The optimal solution treatment technology was determined to be 500 °C for 18 h. After solution treatment, experimental alloys were subject to isothermal aging at 225 °C, the peak aging time for the experimental alloys was established. The microstructure under peak-aged state of the alloy was characterized, revealing a co-existed β’ and β1 phases. The GWZ1041K alloy, after peak aging treatment, exhibited optimal mechanical properties, with a tensile strength, yield strength, and elongation of 392.3 MPa, 249.3 MPa, and 5.7%, respectively. The study further analyzed the reasons for the microstructure transformation during the heat treatment and their influence on mechanical properties.

Enzymatic malonylation of natural glycosides provides a promising alternative method for drug-like malonylated glycosides supply. However, the catalytic potential and structural basis of plant malonyltransferase are far from being fully elucidated. This work identified a new malonyltransferase CtMaT1 from Cistanche tubulosa. It displayed unprecedented mono- and/or di-malonylation activity toward diverse glucosides with different aglycons. A “one-pot” system by CtMaT1 and a malonyl-CoA synthetase was established to biosynthesize nine new malonylated glucosides. Structural investigations revealed that CtMaT1 possesses an adequately spacious acyl-acceptor pocket capable of accommodating diverse glucosides. Additionally, it recognizes malonyl-CoA through strong electrotactic and hydrogen interactions. QM/MM calculation revealed the H167-mediated SN2 reaction mechanism of CtMaT1, while dynamic simulations detected the formation of stable hydrogen bonds between the glucose-6-OH group and H167, resulting in its high malonylation regiospecificity. Calculated energy profiles of two isomeric glycosides highlighted lower reaction energy barriers towards glucoside substrates, emphasizing CtMaT1's preference for glucosides. Furthermore, a mutant CtMaT1H36A with notably increased di-malonylation activity was obtained. The underlying molecular mechanism was illuminated through MM/GBSA binding free energy calculation. This study significantly advances the understanding of plant acyltransferases from both functional and protein structural perspectives, while also providing a versatile tool for enzymatic malonylation applications in pharmacology.

We derive the potential energy of gravity waves (GWs) in the upper troposphere and stratosphere at 45°S–45°N from December 2019 to November 2022 by using temperature profiles retrieved from the Constellation Observing System for Meteorology, Ionosphere, and Climate-2 (COSMIC-2) satellite. Owing to the dense sampling of COSMIC-2, in addition to the strong peaks of gravity wave potential energy (GWPE) above the Andes and Tibetan Plateau, we found weak peaks above the Rocky, Atlas, Caucasus, and Tianshan Mountains. The land–sea contrast is responsible for the longitudinal variations of the GWPE in the lower and upper stratosphere. At 40°N/S, the peaks were mainly above the topographic regions during the winter. At 20°N/S, the peaks were a slight distance away from the topographic regions and might be the combined effect of nontopographic GWs and mountain waves. Near the Equator, the peaks were mainly above the regions with the lowest sea level altitude and may have resulted from convection. Our results indicate that even above the local regions with lower sea level altitudes compared with the Andes and Tibetan Plateau, the GWPE also exhibits fine structures in geographic distributions. We found that dissipation layers above the tropopause jet provide the body force to generate secondary waves in the upper stratosphere, especially during the winter months of each hemisphere and at latitudes of greater than 20°N/S.

Abstract With the increasing concerns about railway energy efficiency, two typical driving strategies have been used in actual train operation. One includes a sequence of full power traction, cruising, coasting, and full braking (CC). The other uses coasting–remotoring (CR) to replace cruising in CC. However, energy‐saving performance by CC and CR, which can be affected by route parameters of gradients and speed limits, has not been fully compared and studied. This paper analyses the energy distribution of CC and CR considering various route parameters and proposes an improved strategy for different gradients and speed limits. The detailed energy flow of CC and CR is analysed by Cauchy–Bunyakovsky–Schwarz inequality and the generalised Hölder's inequality, and then, a novel driving strategy CC_CR is designed. To verify the theoretical results and the effectiveness of the proposed strategy, three simulators with CC, CR, and CC_CR driving modes have been developed and implemented into case studies of four scenarios as well as a real‐world metro line. Simulation results demonstrate that CR can only outperform CC on routes with steep downhill and CC_CR is always the best strategy. The energy savings of CC_CR can be as much as 15% more than CR and 42% greater than CC.

Abstract Pinellia ternata (Thunb.) Briet., a valuable herb native to China, is susceptible to the “sprout tumble” phenomenon because of high temperatures, resulting in a significant yield reduction. However, the molecular regulatory mechanisms underlying the response of P. ternata to heat stress are not well understood. In this study, we integrated transcriptome and miRNAome sequencing to identify heat-response genes, microRNAs (miRNAs), and key miRNA-target pairs in P. ternata that differed between heat-stress and room-temperature conditions. Transcriptome analysis revealed extensive reprogramming of 4,960 genes across various categories, predominantly associated with cellular and metabolic processes, responses to stimuli, biological regulation, cell parts, organelles, membranes, and catalytic and binding activities. miRNAome sequencing identified 1,597 known/conserved miRNAs that were differentially expressed between the two test conditions. According to the analysis, genes and miRNAs associated with the regulation of transcription, DNA template, transcription factor activity, and sequence-specific DNA binding pathways may play a major role in the resistance to heat stress in P. ternata. Integrated analysis of the transcriptome and miRNAome expression data revealed 41 high-confidence miRNA-mRNA pairs, forming 25 modules. MYB-like proteins and calcium-responsive transcription coactivators may play an integral role in heat-stress resistance in P. ternata. Additionally, the candidate genes and miRNAs were subjected to quantitative real-time polymerase chain reaction to validate their expression patterns. These results offer a foundation for future studies exploring the mechanisms and critical genes involved in heat-stress resistance in P. ternata.

Abstract Background The clinical application of immune checkpoint inhibitors (ICIs) is limited by their drug resistance, necessitating the development of ICI sensitizers to improve cancer immunotherapy outcomes. Huang Lian Jie Du Decoction (HLJD, Oren-gedoku-to in Japanese, Hwangryunhaedok-tang in Korean), a famous traditional Chinese medicinal prescription, has exhibited potential in the field of cancer treatment. This study aims to investigate the impact of HLJD on the efficacy of ICIs in melanoma and elucidate the underlying mechanisms. Methods The potential synergistic effects of HLJD and ICIs were investigated on the tumor-bearing mice model of B16F10 melanoma, and the tumor infiltration of immune cells was tested by flow cytometry. The differential gene expression in tumors between HLJD and ICIs group and ICIs alone group were analyzed by RNA-seq. The effects of HLJD on oxidative stress, TLR7/8, and type I interferons (IFN-Is) signaling were further validated by immunofluorescence, PCR array, and immunochemistry in tumor tissue. Results HLJD enhanced the anti-tumor effect of ICIs, significantly inhibited tumor growth, and prolonged the survival duration in melanoma. HLJD increased the tumor infiltration of anti-tumor immune cells, especially DCs, CD4+ T cells and CD8+T cells. Mechanically, HLJD activated the oxidative stress and TLR7/8 signaling pathway and IFN-Is-related genes in tumors. Conclusions HLJD enhanced the therapeutic benefits of ICIs in melanoma, through increasing reactive oxygen species (ROS), promoting the TLR7/8 pathway, and activating IFN-Is signaling, which in turn activated DCs and T cells.

Abstract The study aimed to determine the specific relative biological effectiveness (RBE) of various cells in the hippocampus following proton irradiation. Sixty Sprague–Dawley rats were randomly allocated to 5 groups receiving 20 or 30 Gy of proton or photon irradiation. Pathomorphological neuronal damage in the hippocampus was assessed using Hematoxylin–eosin (HE) staining. The expression level of NeuN, Nestin, Caspase-3, Olig2, CD68 and CD45 were determined by immunohistochemistry (IHC). The RBE range established by comparing the effects of proton and photon irradiation at equivalent biological outcomes. Proton20Gy induced more severe damage to neurons than photon20Gy, but showed no difference compared to photon30Gy. The RBE of neuron was determined to be 1.65. Similarly, both proton20Gy and proton30Gy resulted in more inhibition of oligodendrocytes and activation of microglia in the hippocampal regions than photon20Gy and photon30Gy. However, the expression of Olig2 was higher and CD68 was lower in the proton20Gy group than in the photon30Gy group. The RBE of oligodendrocyte and microglia was estimated to be between 1.1 to 1.65. For neural stem cells (NSCs) and immune cells, there were no significant difference in the expression of Nestin and CD45 between proton and photon irradiation (both 20 and 30 Gy). Therefore, the RBE for NSCs and immune cell was determined to be 1.1. These findings highlight the varying RBE values of different cells in the hippocampus in vivo. Moreover, the actual RBE of the hippocampus may be higher than 1.1, suggesting that using as RBE value of 1.1 in clinical practice may underestimate the toxicities induced by proton radiation.

Abstract Background One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. Methods RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients. Protein level of eIF3a was estimated by western blot and immunohistochemical. Next, DLBCL cells were transfected with lentiviral vector either eIF3a-knockdown or empty to assess the biological role of eIF3a. Then, samples were divided into 2 clusters based on eIF3a expression and differentially expressed genes (DEGs) were identified. Function enrichment and mutation analysis of DEGs were employed to detect potential biological roles. Moreover, we also applied pan-cancer and chemosensitivity analysis for deep exploration. Results eIF3a expression was found to be higher in DLBCL than healthy controls, which was associated with worse prognosis. The expression of eIF3a protein was significantly increased in DLBCL cell lines compared with peripheral blood mononuclear cells (PBMCs) from healthy donors. eIF3a knockdown inhibited the proliferation of DLBCL cells and the expression of proliferation-related proteins and increase cell apoptosis rate. Besides, 114 DEGs were identified which had a close linkage to cell cycle and tumor immune. eIF3a and DEGs mutations were found to be correlated to chemosensitivity and vital signal pathways. Pan-cancer analysis demonstrated that high eIF3a expression was associated with worse prognosis in several tumors. Moreover, eIF3a expression was found to be related to chemosensitivity of several anti-tumor drugs in DLBCL, including Vincristine and Wee1 inhibitor. Conclusions We firstly revealed the high expression and prognostic role of eIF3a in DLBCL, and eIF3a might promote the development of DLBCL through regulating cell proliferation and apoptosis. eIF3a expression was related to immune profile and chemosensitivity in DLBCL. These results suggest that eIF3a could serve as a potential prognostic biomarker and therapeutic target in DLBCL.

Abstract Background Despite being a global public health concern, there is a research gap in analyzing implementation strategies for managing off-label drug use in children. This study aims to understand professional health managers’ perspectives on implementing the Guideline in hospitals and determine the Guideline’s implementation facilitators and barriers. Methods Pediatric directors, pharmacy directors, and medical department directors from secondary and tertiary hospitals across the country were recruited for online interviews. The interviews were performed between June 27 and August 25, 2022. The Consolidated Framework for Implementation Research (CFIR) was adopted for data collection, data analysis, and findings interpretation to implement interventions across healthcare settings. Results Individual interviews were conducted with 28 healthcare professionals from all over the Chinese mainland. Key stakeholders in implementing the Guideline for the Management of Pediatric Off-Label Use of Drugs in China (2021) were interviewed to identify 57 influencing factors, including 27 facilitators, 29 barriers, and one neutral factor, based on the CFIR framework. The study revealed the complexity of the factors influencing managing children’s off-label medication use. A lack of policy incentives was the key obstacle in external settings. The communication barrier between pharmacists and physicians was the most critical internal barrier. Conclusion To our knowledge, this study significantly reduces the implementation gap in managing children’s off-label drug use. We provided a reference for the standardized management of children’s off-label use of drugs.

Abstract Senecavirus A (SVA) causes outbreaks of vesicular disease in pigs, which imposes a considerable economic burden on the pork industry. As current SVA prevention measures are ineffective, new strategies for controlling SVA are urgently needed. Circular (circ)RNA is a newly characterized class of widely expressed, endogenous regulatory RNAs, which have been implicated in viral infection; however, whether circRNAs regulate SVA infection remains unknown. To investigate the influence of circRNAs on SVA infection in porcine kidney 15 (PK-15) cells, RNA sequencing technology was used to analyze the circRNA expression profiles of SVA-infected and uninfected PK-15 cells, the interactions between circRNAs, miRNAs, and mRNAs potentially implicated in SVA infection were predicted using bioinformatics tools. The prediction accuracy was verified using quantitative real-time (qRT)-PCR, Western blotting, as well as dual-luciferase reporter and RNA pull-down assays. The results showed that 67 circRNAs were differentially expressed as a result of SVA infection. We found that circ_8521 was significantly upregulated in SVA-infected PK-15 cells and promoted SVA infection. circ_8521 interacted with miR-324. miR-324 bound to LC3A mRNA which inhibited the expression of LC3A. Knockdown of LC3A inhibited SVA infection. However, circ_8521 promoted the expression of LC3A by binding to miR-324, thereby promoting SVA infection. We demonstrated that circ_8521 functioned as an endogenous miR-324 sponge to sequester miR-324, which promoted LC3A expression and ultimately SVA infection.

Abstract Seesaw circuits are essential for molecular computing and biosensing. However, a notable limitation of seesaw circuits lies in the irreversible depletion of components, precluding the attainment of system recovery and rendering nucleic acid circuits non-reusable. We developed a brand-new method for creating controllable and reusable seesaw circuits. By using the nicking endonucleases Nt.BbvCI and Nt.Alwi, we removed “functional components” while keeping the “skeletal components” for recurrent usage. T-inputs were introduced, increasing the signal-to-noise ratio of AND logic from 2.68 to 11.33 and demonstrating compatibility. We identified the logic switching feature and verified that it does not impair circuit performance. We also built intricate logic circuits, such as OR-AND gate, to demonstrate the versatility of our methodology. This controllable reusability extends the applications of nanotechnology and bioengineering, enhancing the practicality and efficiency of these circuits across various domains.

Abstract 5‐Fluorouracil (5‐FU) has been used for chemotherapy for colorectal and other cancers for over 50 years. The prevailing view of its mechanism of action is inhibition of thymidine synthase leading to defects in DNA replication and repair. However, 5‐FU is also incorporated into RNA causing defects in RNA metabolism, inhibition of pseudouridine modification, and altered ribosome function. We examined the impact of 5‐FU on post‐transcriptional small RNA modifications (PTxMs) and the expression and export of RNA into small extracellular vesicles (sEVs). EVs are secreted by all cells and contain a variety of proteins and RNAs that can function in cell‐cell communication. We found that treatment of colorectal cancer (CRC) cells with 5‐FU represses sEV export of miRNA and snRNA‐derived RNAs, but promotes export of snoRNA‐derived RNAs. Strikingly, 5‐FU treatment significantly decreased the levels of pseudouridine on both cellular and sEV small RNA profiles. In contrast, 5‐FU exposure led to increased levels of cellular small RNAs containing a variety of methyl‐modified bases. These unexpected findings show that 5‐FU exposure leads to altered RNA expression, base modification, and aberrant trafficking and localization of small RNAs.

Marine Spatial Planning (MSP) is essential for optimizing marine resources allocation and resolving conflicts in sea use, but it is challenged by the complex and multi-functional nature of maritime resources. This study utilizes participatory methods, inductive reasoning, and overlay analysis to explore both theoretical and practical aspects of compatible marine utilization models. The paper begins by clarifying the logic of compatible sea use through marine functional zoning and identifying its core characteristics: quantity, spatial conflict, and impacts on natural attributes. Building on China’s national territorial spatial planning reforms and practical experiences, the paper introduces three major categories of compatible marine use models: development sequencing compatibility, spatial coexistence compatibility, and functional synergy compatibility. A compatibility discrimination matrix is developed to assess these models across different marine functional areas. Combined with the compatibility discrimination results, taking the marine and coastal spatial planning of Yantai City in China as a case study, the paper analyzes the compatibility demands and planning strategies within various marine functional areas. Finally, it evaluates the risks associated with each compatibility model and proposes targeted control strategies tailored to the specific features of each model and characteristics of sea use activities. The research findings highlight the positive role of compatible sea use models in promoting marine economic development, enhancing spatial efficiency, and mitigating sea use conflicts. However, these models also present varying potential risks, necessitating differentiated control strategies aligned with legal frameworks and specific sea use activities. The study offers valuable insights for MSP and contributes to the efficient utilization of marine resources and the advancement of marine spatial governance.

Since the onset of the COVID-19 pandemic, the SARS-CoV-2 virus has caused over 600 million confirmed infections and more than 6.8 million deaths worldwide, with ongoing implications for human health. COVID-19 has been extensively documented to have extrapulmonary manifestations due to the widespread expression of necessary ACE2 receptors in the human body. Nevertheless, the association between COVID-19 and cancer risk remains inadequately explored. This study employs Mendelian randomization (MR) methods to examine the causal relationship between genetic variations associated with COVID-19 and the risk of developing cancer. The findings indicate that COVID-19 has negligible impact on most cancer risks. Interestingly, a higher COVID-19 impact is associated with a decreased risk of thyroid cancer. In summary, our findings demonstrate a genetic correlation between COVID-19 and thyroid cancer, contributing to our understanding of the interplay between COVID-19 and cancer risk.

Abstract Background This study explores molecular features associated with better prognosis in cholangiocarcinoma (CCA). Methods and Results The transcriptomic and whole‐exome sequencing data obtained from paired tissues of 70 were analyzed, grouping them based on progression‐free survival (PFS), differentiation degree, and lymph node metastasis. Among the 70 patients, the TP53 gene mutation frequency was the highest (53%), while FLG gene mutation occurred exclusively in the long PFS group. In the comparison between long and short survival groups, the short PFS group exhibited higher monocyte infiltration levels (p = 0.0287) and upregulation of genes associated with cancer‐related transcriptional misregulation, chemokine signaling, and cytokine‐cytokine receptor interactions. Differences in immune cell infiltration and gene expression were significant across differentiation and lymph node metastasis groups. Particularly noteworthy was the marked increase in CD8 T cell and NK cell infiltration (p = 0.0291, 0.0459) in the lymph node metastasis group, significantly influences prognosis. Additionally, genes related to platinum resistance, Th17 cell differentiation, and Th1 and Th2 cell differentiation pathways were overexpressed in this group. In summary, higher monocyte infiltration levels in the short PFS group, along with elevated expression of genes associated with cancer‐related pathways, suggest a poorer prognosis. The significant increase in CD8 T cell and NK cell infiltration reflects an enhanced anti‐tumor immune response, underscoring the relevance of immune infiltration levels and gene expression in predicting outcomes for CCA patients. Conclusions In this study, we elucidated the pertinent molecular mechanisms and pathways that influence the prognosis of CCAs through comprehensive multi‐omics analysis.

The COVID-19 pandemic has deprived travelers of the right to continue their travel or leisure activities, while creating concerns about the safety of travel. In view of the great impact of the COVID-19 pandemic on travelers, we discussed the impact of virtual reality on travel anxiety during the COVID-19 pandemic, and considered the regulatory effect of blockade intensity. In order to explore the relationship between virtual reality and travel anxiety in depth, this study conducted a questionnaire survey on 299 Chinese tourists who had experienced virtual reality activities related to travel, and empirically analyzed the questionnaire data using SPSS 26 software. The results show that virtual reality has a significant negative effect on travel anxiety during the COVID-19 pandemic, i.e., virtual reality technology can provide a safer virtual travel experience for people and reduce their travel anxiety. At the same time, the relationship between virtual reality and travel anxiety varied to some extent depending on the intensity of the lockdown in each region, with the mitigating effect of virtual reality on travel anxiety being enhanced by high levels of lockdown. Therefore, we believe that although lockdown policies are necessary for some time to come, travel companies need to make further efforts to provide more convenient virtual reality services to alleviate travel anxiety caused by COVID-19 pandemic and lockdown to tourists. At the same time, virtual reality opens up new ideas for travel businesses under the impact of COVID-19 and contributes to the sustainable development of the travel industry.

BackgroundGut microbiome (GM) was observed to be associated with the incidence of Hirschsprung disease (HD). However, the effect and mechanism of GM in HD is still unclear. To investigate the relationship between GM and HD and the effect of metabolites as mediators, a bidirectional two-step Mendelian randomization (MR) study was conducted.MethodsThe study selected instrument variables (IVs) from summary-level genome-wide association studies (GWAS). The MiBioGen consortium provided the GWAS data for GM, while the GWAS data for metabolites and HD were obtained from the GWAS Catalog consortium. Two-sample MR analyses were performed to estimate bidirectional correlations between IVs associated with GM and HD. Then, genetic variants related to 1,400 metabolite traits were selected for further mediation analyses using the Product method.ResultsThis study found that seven genus bacteria had a significant causal relationship with the incidence of HD but not vice versa. 27 metabolite traits were significantly correlated with HD. After combining the significant results, three significant GM-metabolites-HD lines have been identified. In the Peptococcus-Stearoyl sphingomyelin (d18:1/18:0)-HD line, the Stearoyl sphingomyelin (d18:1/18:0) levels showed a mediation proportion of 14.5%, while in the Peptococcus-lysine-HD line, the lysine levels had a mediation proportion of 12.9%. Additionally, in the Roseburia-X-21733-HD line, the X-21733 levels played a mediation proportion of 23.5%.ConclusionOur MR study indicates a protective effect of Peptococcus on HD risk that is partially mediated through serum levels of stearoyl sphingomyelin (d18:1/18:0) and lysine, and a risk effect of Roseburia on HD that is partially mediated by X-21733 levels. These findings could serve as novel biomarkers and therapeutic targets for HD.

Electrical anisotropy has a significant impact on the observation data of the magnetotelluric (MT) method; therefore, it is necessary to develop forward and inverse methods in electrical anisotropic media. Based on the axis anisotropic electric field control equations, forming a large linear equation through staggered finite difference approximation, adding boundary conditions, and using the quasi-minimum residual method to solve the equation, this study obtained MT forward modeling results in axis anisotropic media. The correctness of the algorithm was verified by comparing it with the 2D quasi-analytic solution. By designing several sets of axis anisotropic 3D models, the characteristics of the apparent resistivity tensor and tipper were analyzed. The results indicated that the ρxya, ρyya and Tzy are sensitive to changes in resistivity in the X direction of the anomalous body, whereas the ρyxa, ρxxa and Tzx are sensitive to changes in resistivity in the Y direction. The apparent resistivity tensor and tipper are insensitive to changes in resistivity in the Z direction of the anomalous body. For exploration of anisotropic media, the apparent resistivity tensor and tipper of MT can identify the changes in resistivity in two horizontal axes directions and the boundaries of the anomalous body, which has the advantages for exploration.

Abstract Studying brain‐wide hemodynamic responses to different stimuli at high spatiotemporal resolutions can help gain new insights into the mechanisms of neuro‐ diseases and ‐disorders. Nonetheless, this task is challenging, primarily due to the complexity of neurovascular coupling, which encompasses interdependent hemodynamic parameters including cerebral blood volume (CBV), cerebral blood flow (CBF), and cerebral oxygen saturation (SO2). The current brain imaging technologies exhibit inherent limitations in resolution, sensitivity, and imaging depth, restricting their capacity to comprehensively capture the intricacies of cerebral functions. To address this, a multimodal functional ultrasound and photoacoustic (fUSPA) imaging platform is reported, which integrates ultrafast ultrasound and multispectral photoacoustic imaging methods in a compact head‐mountable device, to quantitatively map individual dynamics of CBV, CBF, and SO2 as well as contrast agent enhanced brain imaging at high spatiotemporal resolutions. Following systematic characterization, the fUSPA system is applied to study brain‐wide cerebrovascular reactivity (CVR) at single‐vessel resolution via relative changes in CBV, CBF, and SO2 in response to hypercapnia stimulation. These results show that cortical veins and arteries exhibit differences in CVR in the stimulated state and consistent anti‐correlation in CBV oscillations during the resting state, demonstrating the multiparametric fUSPA system's unique capabilities in investigating complex mechanisms of brain functions.

ABSTRACT Metabolism in host cells can be modulated after viral infection, favoring viral survival or clearance. Here, we report that lipid droplet (LD) synthesis in host cells can be modulated by yin yang 1 (YY1) after porcine reproductive and respiratory syndrome virus (PRRSV) infection, resulting in active antiviral activity. As a ubiquitously distributed transcription factor, there was increased expression of YY1 upon PRRSV infection both in vitro and in vivo. YY1 silencing promoted the replication of PRRSV, whereas YY1 overexpression inhibited PRRSV replication. PRRSV infection led to a marked increase in LDs, while YY1 knockout inhibited LD synthesis, and YY1 overexpression enhanced LD accumulation, indicating that YY1 reprograms PRRSV infection-induced intracellular LD synthesis. We also showed that the viral components do not colocalize with LDs during PRRSV infection, and the effect of exogenously induced LD synthesis on PRRSV replication is nearly lethal. Moreover, we demonstrated that YY1 affects the synthesis of LDs by regulating the expression of lipid metabolism genes. YY1 negatively regulates the expression of fatty acid synthase (FASN) to weaken the fatty acid synthesis pathway and positively regulates the expression of peroxisome proliferator-activated receptor gamma (PPARγ) to promote the synthesis of LDs, thus inhibiting PRRSV replication. These novel findings indicate that YY1 plays a crucial role in regulating PRRSV replication by reprogramming LD synthesis. Therefore, our study provides a novel mechanism of host resistance to PRRSV and suggests potential new antiviral strategies against PRRSV infection.IMPORTANCEPorcine reproductive and respiratory virus (PRRSV) has caused incalculable economic damage to the global pig industry since it was first discovered in the 1980s. However, conventional vaccines do not provide satisfactory protection. It is well known that viruses are parasitic pathogens, and the completion of their replication life cycle is highly dependent on host cells. A better understanding of host resistance to PRRSV infection is essential for developing safe and effective strategies to control PRRSV. Here, we report a crucial host antiviral molecule, yin yang 1 (YY1), which is induced to be expressed upon PRRSV infection and subsequently inhibits virus replication by reprogramming lipid droplet (LD) synthesis through transcriptional regulation. Our work provides a novel antiviral mechanism against PRRSV infection and suggests that targeting YY1 could be a new strategy for controlling PRRSV.

Organic orchard management has been widely adopted to enhance soil fertility by improving the sequestration of soil organic carbon (SOC). Microbial residue carbon plays an essential role in SOC accumulation; nevertheless, how fungal and bacterial residue carbon (FRC and BRC) changes with different orchard management practices (organic vs. conventional) and the factors influencing their accumulation remain poorly understood. In this study, we quantified the FRC and BRC in the two management practices, compiled this data with the comparisons of plant, soil and microbial properties, and the dominant factor affecting their sequestration was ascertained with a 4-year orchard experiment on the Jiaodong Peninsula. Compared with conventional management, organic management significantly enhanced SOC and the accumulation of FRC and BRC, while it did not alter the contribution of FRC or BRC to SOC. Furthermore, we identified that the primary determinant affecting FRC varied with management type: Plant (AGR, BGG)-soil (SOC, density)-microbe (Nitrospirae) collectively governed FRC in organic soil, whereas soil (pH, density) and microbial (Ascomycota) properties regulated FRC in conventional soil. Nitrospirae abundance and soil pH played pivotal roles in FRC accumulation under organic and conventional management, respectively. Meanwhile, the primary factor influencing BRC was independent of management type: Soil and microbial properties consistently served as the principal determinants of BRC in both management systems, with soil pH and clay being the pivotal factors in organic and conventional managements, respectively. These findings illustrate the divergent regulatory mechanisms of FRC and BRC in organic and conventional management, thereby enhancing our comprehension of microbial-mediated SOC sequestration in organic orchard management.

Free radicals can improve the reaction rate, but most of them are unstable due to unpaired electrons. Simultaneously maintaining their stability and activity is challenging. Herein, taking sulfur (S) radicals as an example, we propose a strategy in which solvated metal complexes constructed by Al(acetylacetonate)3 and different solvents can stabilize high concentrations of S radicals with good activity through ion–dipole interactions. Based on this strategy, it is first demonstrated that S4·− is selectively stabilized by controlling the configurations of the solvated complexes. As a result, the reaction rate of S↔Li2S is increased by 8 times, and the energy efficiency and rate capability of the Li–S batteries are significantly improved, especially the 5-fold increase in cell capacities at a low electrolyte/sulfur ratio. This work provides an important strategy in which solvated metal complexes balance the activity and stability of free radicals to accelerate reactions and their application in various fields.

Background: Data regarding risk factors for premature coronary artery disease (PCAD) is scarce given that few research focus on it. This study aimed to develop and validate a clinical nomogram for PCAD patients in Guangzhou. Methods: We recruited 108 PCAD patients (female ≤65 years old and male ≤55 years old) and 96 healthy controls from Sun Yat-sen Memorial Hospital of Sun Yat-sen University between 01/01/2021 and 31/12/2022. Twenty potentially relevant indicators of PCAD were extracted. Next, the least absolute shrinkage and selection operator (LASSO) regression analysis was used to optimize variable selection. The nomogram was developed based on the selected variables visually. Results: Independent risk factors, including body mass index (BMI), history of PCAD, glucose, Apolipoprotein A1(ApoA1), high density lipoprotein 2-cholesterol (HDL2-C), total cholesterol and triglyceride, were identified by LASSO and logistic regression analysis. The nomogram showed accurate discrimination (area under the receiver operator characteristic curve, ROC, 87.45 %, 95 % CI: 82.58 %-92.32 %). Decision curve analysis (DCA) suggested that the nomogram was clinical beneficial. HDL2, one risk factor, was isolated by a two-step discontinuous density-gradient ultracentrifugation method. And HDL2 from PCAD patients exhibited less 3H-cholesterol efflux (22.17 % vs 26.64 %, P

Carbon-free ammonia and hydrogen have various disadvantages when used individually, which limits their application as clean energies. These disadvantages can be effectively overcome by combining them as ammonia/hydrogen mixtures in a rational manner. In this paper, the combustion of ammonia/hydrogen in oxygen (the basic form of combustion) is experimentally investigated at various experimental conditions. The results display that the laminar burning velocities of ammonia/hydrogen/oxygen mixtures increase with increasing fuel ratios. At P0 = 0.5 atm and φ = 1.0, the laminar burning velocity proliferated from 1.91 m/s to 4.7 m/s with the increase of fuel ratio from 0.5 to 2.0. As the equivalence ratio increases, the laminar burning velocity rises first and then decreases, with the highest point appearing at φ = 0.8. The initial pressure has minimal impact on the laminar burning velocity. At x = 0.5 and φ = 1.0, the laminar burning velocity decreased slightly from 3.16 m/s to 2.96 m/s with the initial pressure increased from 0.1 atm to 1.0 atm. The empirical correlation among the laminar burning velocity versus the equivalence ratio and hydrogen ratio is given, and the laminar burning velocity of ammonia/hydrogen/oxygen under varying hydrogen ratios (0 %–100 %) and equivalence ratios (0.5–1.5) at atmospheric pressure can be well predicted by the empirical equations. NO is the most emitted NOx substance from hydrogen/ammonia combustion. The amount of NO produced decreases gradually with the growing equivalence ratio. The results of this research can be utilized to renew the basic flame data of ammonia/hydrogen mixture and are important for the development and application of ammonia/hydrogen mixtures.

BackgroundPorcine deltacoronavirus (PDCoV) is a newly discovered porcine intestinal pathogenic coronavirus with a single-stranded positive-sense RNA genome and an envelope. PDCoV infects pigs of different ages and causes acute diarrhea and vomiting in newborn piglets. In severe cases, infection leads to dehydration, exhaustion, and death in sick piglets, entailing great economic losses on pig farms. The clinical symptoms of PDCoV infection are very similar to those of other porcine enteroviruses. Although it is difficult to distinguish these viral infections without testing, monitoring PDCoV is very important because it can spread in populations. The most commonly used methods for the detection of PDCoV is qPCR, which is time-consuming and require skilled personnel and equipment. Many farms cannot meet the conditions required for detection. Therefore, it is necessary to establish a faster and more convenient method for detecting PDCoV.AimsTo establish a rapid and convenient detection method for PDCoV by combining RPA (Recombinase Polymerase Isothermal Amplification) with CRISPR/Cas13a.MethodsSpecific RPA primers and crRNA for PDCoV were designed, and the nucleic acids in the samples were amplified with RPA. Fluorescent CRISPR/Cas13a detection was performed. We evaluated the sensitivity and specificity of the RPA–CRISPR/Cas13a assay using qPCR as the control method.ResultsCRISPR/Cas13a-assisted detection was completed within 90 min. The minimum detection limit of PDCoV was 5.7 × 101 copies/μL. A specificity analysis showed that the assay did not cross-react with three other porcine enteroviruses.ConclusionThe RPA–CRISPR/Cas13a method has the advantages of high sensitivity, strong specificity, fast response, and readily accessible results, and can be used for the detection of PDCoV.

BackgroundAltitude illness has serious effects on individuals who are not adequately acclimatized to high-altitude areas and may even lead to death. However, the individualized mechanisms of onset and preventive measures are not fully elucidated at present, especially the relationship between altitude illness and elements, which requires further in-depth research.MethodsFresh serum samples were collected from individuals who underwent health examinations at the two hospitals in Xining and Sanya between November 2021 and December 2021. The blood zinc (Zn), iron (Fe), and calcium (Ca) concentrations, as well as hypoxia-inducible factor 1-alpha (HIF-1α) concentrations, were measured. This study conducted effective sample size estimation, repeated experiments, and used GraphPad Prism 9.0 and IBM SPSS version 19.0 software for comparative analysis of differences in the expression of elements and HIF-1α among different ethnic groups, altitudes, and concentration groups. Linear regression and multiple linear regression were employed to explore the relationships among elements and their correlation with HIF-1α.ResultsThis study included a total of 400 participants. The results from the repeated measurements indicated that the consistency of the laboratory test results was satisfactory. In terms of altitude differences, except for Fe (p = 0.767), which did not show significant variance between low and high altitude regions, Zn, Ca, and HIF-1α elements all exhibited notable differences between these areas (p

Abstract DNA is commonly employed as a substrate for the building of artificial logic networks due to its excellent biocompatibility and programmability. Till now, DNA logic circuits are rapidly evolving to accomplish advanced operations. Nonetheless, nowadays, most DNA circuits remain to be disposable and lack of field programmability and thereby limits their practicability. Herein, inspired by the Configurable Logic Block (CLB), the CLB‐based erasable field‐programmable DNA circuit that uses clip strands as its operation‐controlling signals is presented. It enables users to realize diverse functions with limited hardware. CLB‐based basic logic gates (OR and AND) are first constructed and demonstrated their erasability and field programmability. Furthermore, by adding the appropriate operation‐controlling strands, multiple rounds of programming are achieved among five different logic operations on a two‐layer circuit. Subsequently, a circuit is successfully built to implement two fundamental binary calculators: half‐adder and half‐subtractor, proving that the design can imitate silicon‐based binary circuits. Finally, a comprehensive CLB‐based circuit is built that enables multiple rounds of switch among seven different logic operations including half‐adding and half‐subtracting. Overall, the CLB‐based erasable field‐programmable circuit immensely enhances their practicability. It is believed that design can be widely used in DNA logic networks due to its efficiency and convenience.

Summary: Styles and stigmas are crucial components of the fertilization process that allows a pear tree to bear fruit. The information regarding the development mechanism of pear style and stigma is still unclear. Our results demonstrated that IAA, ABA, and BR are significantly increased at 1 DBF, while JA is decreased at 5 DBF. The fructose and starch contents significantly increased at 1 DBF when the style with stigma was ready for pollination. Transcriptome and DNA methylation analysis showed 8087 DEGs and 3771 DMRs were enriched in plant hormones biosynthesis, carbohydrate biosynthesis and metabolism, and TFs in 1 DBF as compared with 7 DBF. The CHH methylation type of DMRs accounts for 84.75%. Most DMRs of CHH upregulated in 1 DBF vs. 7 DBF. This study found for the first time that transcription factor ERFs and DNA methylation are involved in regulating the growth and development of fruit plant style and stigma.