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Genome mining and gene deletion experiments in Penicillium crustosumproved the involvement of the PKS-NRPS PemA and the trans-enoyl reductase PemB in the formation of three enantiomeric clavatol-containing tetramate pairs. Overexpression of a transcription factor significantly improved the product yields. Feeding experiments provided evidence for their formation via 1,4-Michael addition of hydroxyclavatol to two tetramates from the Pem pathway. This study provides another example of the involvement of reactive intermediates in multiple biosynthetic pathways.

Deficits in impulse control are observed in several neurocognitive disorders, including attention deficit hyperactivity (ADHD), substance use disorders (SUDs), and those following traumatic brain injury (TBI). Understanding brain circuits and mechanisms contributing to impulsive behavior may aid in identifying therapeutic interventions. We previously reported that intact lateral habenula (LHb) function is necessary to limit impulsivity defined by impaired response inhibition in rats. Here, we examine the involvement of a synaptic input to the LHb on response inhibition using cellular, circuit, and behavioral approaches. Retrograde fluorogold tracing identified basal forebrain (BF) inputs to LHb, primarily arising from ventral pallidum and nucleus accumbens shell (VP/NAcs). Glutamic acid decarboxylase and cannabinoid CB1 receptor (CB1R) mRNAs colocalized with fluorogold, suggesting a cannabinoid modulated GABAergic pathway. Optogenetic activation of these axons strongly inhibited LHb neuron action potentials and GABA release was tonically suppressed by an endogenous cannabinoid in vitro. Behavioral experiments showed that response inhibition during signaled reward omission was impaired when VP/NAcs inputs to LHb were optogenetically stimulated, whereas inhibition of this pathway did not alter LHb control of impulsivity. Systemic injection with the psychotropic phytocannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), also increased impulsivity in male, and not female rats, and this was blocked by LHb CB1R antagonism. However, as optogenetic VP/NAcs pathway inhibition did not alter impulse control, we conclude that the pro-impulsive effects of Δ9-THC likely do not occur via inhibition of this afferent. These results identify an inhibitory LHb afferent that is controlled by CB1Rs that can regulate impulsive behavior.

Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-β-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

Targeted delivery systems combined with the stimuli-responsive release of drug molecules hold noteworthy promise for precision medicine, enabling treatments with enhanced effectiveness and reduced adverse effects. An ideal drug delivery platform with versatile targeting moieties, the capability of combinational payloads, and simple preparation is highly desirable. Herein, we developed pH-sensitive fluorescent self-assembled complexes (SACs) of a galactose-functionalized G-quadruplex (G4) and a coumarin carboxamidine derivative as a targeted delivery platform through the nanoprecipitation method. These SACs selectively targeted hepatocellular carcinoma (HepG2) cells in fluorescence imaging after a short incubation and exerted specific anticancer effects in an appropriate dose range. Co-delivery of 1 μM prodrug floxuridine oligomers and 16 μg/mL SACs (minimal hemolytic effect) significantly reduced the cytotoxicity of the nucleoside anticancer drug on normal cells (NIH/3T3), kept up to 70% alive after 72-h incubation, and improved anticancer efficacy compared to SACs alone. This strategy can be extended to ratiometric multidrug delivery through self-assembly for targeted combinational therapy.

Parabens are frequently used preservatives in food and personal care products. These are also termed endocrine disruptors which have the potential to damage the endocrine system Therefore, an easy and facile extraction and detection of parabens are critically important. This work evaluates different magnetic sorbents such as Fe3O4@MIL‐101(Cr), Fe3O4@MIL‐101(Cr)@NH2, and Fe3O4@MIL‐101(Cr)@SO3H for magnetic solid phase extraction (MSPE) and further selected Fe3O4@MIL‐101(Cr)@NH2to determine paraben content in chili powder and facial toner samples. Fe3O4@MIL‐101(Cr)@NH2is an efficient sorbent material specially designed for MSPE, which profoundly extracted nine parabens within a short span of just 6 min, driven by π–π interaction and hydrogen bonding. And a detailed optimization and LC–MS/MS analysis was carried out. Fe3O4@MIL‐101(Cr)@NH2exhibited superior extraction efficiency, enabling subsequent quantification via LC–MS/MS. The limit of detection ranged from 0.063 to 0.622 ng mL−1and limit of quantification of 0.211 to 2.073 ng mL−1were a good recovery in the range of 76.2%–108%. An effective detection of eight parabens in chili powder and four parabens in facial toner samples was determined indicating that Fe3O4@MIL‐101(Cr)‐NH2sorbents are suitable for MSPE.

In 2008, sorafenib became the first approved systemic therapeutic agent for advanced HCC. Although its pharmacological efficacy has been established, reimbursement for such a new, high‐cost drug, as well as physicians' awareness and prescription practice, likewise contribute to its clinical effectiveness. We therefore conducted a retrospective study using 38 sorafenib‐eligible, advanced HCC patients when sorafenib was approved but not yet reimbursed as a control and 216 patients during the reimbursed era. Study group showed longer survival at 8.2 months versus the control's 4.9 months (p= 0.0063 hazard ratio: 0.612 [0.431 ~ 0.868], p= 0.0059). Among the 42 (19.4%) patients who survived more than 2 years, 50% had tumor rupture, and all 32 patients with portal vein tumor thrombus and/or extrahepatic metastasis received sorafenib (p= 0.003). Furthermore, during their first 2 years of HCC management, sorafenib had been given in 29.1% of the treatment courses among survivors between 2 and 5 years while it was prescribed in 55.8% among the more than 5 years survivor group (p< 0.001). In conclusion, survival of sorafenib‐eligible HCC patients significantly improved after reimbursement. Patients who underwent longer sorafenib treatment had a survival advantage, except for those with tumor rupture. Reimbursement and awareness of prescriptions for a newly introduced medication therefore improve clinical effectiveness.

Study design Single centre, cross-sectional study.Objectives The objective is to report the prevalence of spondylolisthesis and retrolisthesis, analyse both conditions in terms of the affected levels and severity, as well as identify their risk factors.Methods A review of clinical data and radiographic images of consecutive spine patients seen in outpatient clinics over a 1-month period is performed. Images are obtained using the EOS® technology under standardised protocol, and radiographic measurements were performed by 2 independent, blinded spine surgeons. The prevalence of both conditions were shown and categorised based on the spinal level involvement and severity. Associated risk factors were identified.Results A total of 256 subjects (46.1% males) with 2304 discs from T9/10 to L5/S1 were studied. Their mean age was 52.2(± 18.7) years. The overall prevalence of spondylolisthesis and retrolisthesis was 25.9% and 17.1% respectively. Spondylolisthesis occurs frequently at L4/5(16.3%), and retrolisthesis at L3/4(6.8%). Majority of the patients with spondylolisthesis had a Grade I slip (84.3%), while those with retrolisthesis had a Grade I slip. The presence of spondylolisthesis was found associated with increased age (P< .001), female gender (OR: 2.310; P= .005), predominantly sitting occupations (OR:2.421; P= .008), higher American Society of Anaesthesiology grades (P= .001), and lower limb radiculopathy (OR: 2.175; P= .007). Patients with spondylolisthesis had larger Pelvic Incidence (P< .001), Pelvic Tilt (P< .001) and Knee alignment angle (P= .011), but smaller Thoracolumbar junctional angle (P= .008), Spinocoxa angle (P= .007). Retrolisthesis was associated with a larger Thoracolumbar junctional angle (P=.039).Conclusion This is the first study that details the prevalence of spondylolisthesis and retrolisthesis simultaneously, using the EOS technology and updated sagittal radiographic parameters. It allows better understanding of both conditions, their mutual relationship, and associated clinical and radiographic risk factors.

Century eggs (also known as pídàn) are a widely used preserved food product in Taiwanese cuisine. Due to their peculiar appearance, pungent odor, and unusual texture, several consumers have raised concerns. Actually, some metallic additives are employed to control the quality of gelation of protein during the production of century eggs. Therefore, a method involving microwave plasma‐atomic emission spectrometer and microwave‐assisted digestion was proposed in this study. In addition, to clarify distribution information of metallic additives in century eggs, detailed analyses based on the egg structure were adopted. The linearities for Fe and Zn were obtained in the range of 0.1–5, and 0.02–1 mg L−1for Cu and Pb. The method detection limits for test metals were 0.06–0.036 mg L−1. The measured values for the RM EGGS‐1 sample agreed reasonably well with the reference values, demonstrating that the developed method is practical for routine analysis with lower instrument procurement/running cost. The analytical results for century eggs collected from local markets revealed diverse distributions of metal ions in different parts. Remarkably, this method can readily identify the metallic additives used during the production processes even in the presence of complicated matrices. Because metallic additives are widely employed to control protein gelation during the production of century eggs, quantitative information regarding these additives is crucial for ensuring the safe consumption of century eggs. The developed methodology can not only identify such additives during the production processes but also clearly indicate the distribution of metal ions in century eggs.

Productivity of tropical and subtropical grasslands is often limited by inadequate nitrogen (N) supply. Aeschynomene (Aeschynomene americanaL.) is a warm‐season legume that may contribute as N input in grazing systems, but there is limited information about aeschynomene litter decomposition and N dynamics on pastures. The objective of this study was to quantify the effect of overseeding aeschynomene or applying N fertilizer to existing bahiagrass (Paspalum notatumFlüggé) on litter disappearance and decomposition rates. The study was conducted in Ona, FL, from October 2019 to May 2020 and October 2020 to May 2021. Treatments were the split‐plot arrangement of bahiagrass‐aeschynomene or bahiagrass monoculture (main plot) and N fertilization level, (0 [control] or 60 kg N ha−1) as subplot, distributed in a randomized complete block design with four replicates. The nylon bag technique was used to estimate organic matter (OM), N and carbon (C) disappearance, and lignin concentration for 184 days of incubation. Bahiagrass‐aeschynomene had greater OM disappearance (from 330 to 356 g kg−1OM) and was driven by C disappearance. Nitrogen fertilization did not impact litter decomposition responses, except for C:N ratio. Overseeding aeschynomene is an effective management practice to increase OM decomposition and optimize nutrient cycling in warm‐season pastures. Overseeding aeschynomene into bahiagrass increased organic matter and N disappearance litter decomposition.Nitrogen fertilization did not affect bahiagrass‐aeschynomene litter decomposition.Bahiagrass‐aeschynomene litter supported soil N mineralization.

Human amniotic membranes (hAMs) are widely used as wound management biomaterials, especially as grafts for corneal reconstruction due to the structure of the extracellular matrix and excellent biological properties. However, their fragile nature and rapid degradation rate hinder widespread clinical use. In this work, we engineered a novel self-powered electronic dress (E-dress), combining the beneficial properties of an amniotic membrane and a flexible electrical electrode to enhance wound healing. The E-dress displayed a sustained discharge capacity, leading to increased epidermal growth factor (EGF) release from amniotic mesenchymal interstitial stem cells. Live/dead staining, CCK-8, and scratch-wound-closure assays were performed in vitro. Compared with amniotic membrane treatment alone, the E-dress promoted cell proliferation and migration of mouse fibroblast cells and lower cytotoxicity. In a mouse full-skin defect model, the E-dress achieved significantly accelerated wound closure. Histological analysis revealed that E-dress treatment promoted epithelialization and neovascularization in mouse skin. The E-dress exhibited a desirable flexibility that aligned with tissue organization and displayed maximum bioactivity within a short period to overcome rapid degradation, implying great potential for clinical applications.

The first direct catalytic asymmetric Mannich reaction of 2-alkylazaarenes and ketimines was realized with a chiral Cu–bis(oxazoline) complex as the catalyst. The asymmetric addition of 2-alkylpyridines to isatin-derived ketimines proceeded smoothly to afford α,β-functionalized 2-substituted pyridines bearing 3-amino-3,3-disubstituted oxindole motifs with excellent results (≤99% yield, 99:1 dr, and 98% ee). The catalytic system was also extended to 2-alkylbenzothiazoles as nucleophiles for the asymmetric Mannich reaction of ketimines.

School practitioners’ receptivity to reform influences the success of policy implementation. In Taiwan, the Ministry of Education launched a curriculum reform in 2019. To determine how to enhance school agency for the policy, we explored the individual and contextual factors affecting receptivity to the new curriculum. With a survey design, this study recruited secondary school teachers and principals throughout Taiwan as samples. Hierarchical regression models were conducted to examine the effects of individual factors (conceptions of distributed leadership and collective learning) and organizational culture (power distance, uncertainty avoidance, and academic emphasis) on practitioners’ receptivity to curriculum reform. Both the main and interactive effects were investigated. The results indicate that respondents who positively conceived distributed leadership and collective learning were more receptive to change. Regarding the three indicators of organizational culture, we found no significant effect of power distance, while the main effect of uncertainty avoidance and the moderation effect of academic emphasis existed. Those who perceived their schools with high uncertainty avoidance levels were more resistant to reform efforts. Besides, a positive linkage between teacher conception of collective learning and affection for change was more evident in schools with less academic emphasis. Our study suggests that school reforms must be understood within the individual and school contexts. The finding about the moderation effect of academic emphasis furthermore signifies the cultural implication in Asian societies.

Astrocyte-derived IL-3 activates the corresponding receptor IL-3Rα in microglia. This cross-talk between astrocytes and microglia ameliorates the pathology of Alzheimer’s disease in mice. In this study we investigated the role of IL-3/IL-3Rα cross-talk and its regulatory mechanisms in ischemic stroke. Ischemic stroke was induced in mice by intraluminal occlusion of the right middle cerebral artery (MCA) for 60 min followed by reperfusion (I/R). Human astrocytes or microglia subjected to oxygen-glucose deprivation and reoxygenation (OGD/Re) were used as in vitro models of brain ischemia. We showed that both I/R and OGD/Re significantly induced decreases in astrocytic IL-3 and microglial IL-3Rα protein levels, accompanied by pro-inflammatory activation of A1-type astrocytes and M1-type microglia. Importantly, astrocyte-derived VEGFD acting on VEGFR3 of astrocytes and microglia contributed to the cross-talk dysfunction and pro-inflammatory activation of the two glial cells, thereby mediating neuronal cell damage. By using metabolomics and multiple biochemical approaches, we demonstrated that IL-3 supplementation to microglia reversed OGD/Re-induced lipid metabolic reprogramming evidenced by upregulated expression of CPT1A, a rate-limiting enzyme for the mitochondrial β-oxidation, and increased levels of glycerophospholipids, the major components of cellular membranes, causing reduced accumulation of lipid droplets, thus reduced pro-inflammatory activation and necrosis, as well as increased phagocytosis of microglia. Notably, exogenous IL-3 and the VEGFR antagonist axitinib reestablished the cross-talk of IL-3/IL-3Rα, improving microglial lipid metabolic levels via upregulation of CPT1A, restoring microglial phagocytotic function and attenuating microglial pro-inflammatory activation, ultimately contributing to brain recovery from I/R insult. Our results demonstrate that VEGFD/VEGFR3 signaling contributes to the dysfunction of the astrocyte IL-3/microglia IL-3Rα cross-talk and drives pro-inflammatory activation, causing lipid metabolic reprogramming of microglia. These insights suggest VEGFR3 antagonism or restoring IL-3 levels as a potential therapeutic strategy for ischemic stroke.

Graphical Abstract: Graphical Abstract: Flexible surface acoustic wave technology for enhancing transdermal drug delivery

In this paper, we propose an alternating proximal gradient algorithm for solving nonsmooth nonconvex-linear minimax problems with coupled linear constraints, which have attracted wide attention in machine learning, signal processing and many other fields in recent years. The iteration complexity of the proposed algorithm is proved to be Oε-3to reach an ε-stationary point. To our knowledge, this is the first algorithm with iteration complexity guarantee for solving nonsmooth nonconvex-linear minimax problems with coupled linear constraints.

The corrosion behavior of an Al0.75CoFeCr1.25Ni high-entropy alloy (HEA) in 0.5 mol/L NaOH solution was investigated using a series of electrochemical and analytical techniques, including X-ray photoelectron spectroscopy, X-ray diffraction, scanning electron microscopy, potentiodynamic polarization measurement and electrochemical impedance spectroscopy. The results showed that the Al0.75CoFeCr1.25Ni HEA exhibited a typical columnar dendritic structure, which is composed of face-centered cubic, body-centered cubic (BCC), and ordered BCC phases (B2 phase). The corrosion resistance of this HEA in 0.5 mol/L NaOH solution is comparable to that of 304 SS, attributed to the change in the composition of the passive film formed on the surface. Although the passive film formed was generally rich in Al, the proportion of Cr2O3inside it increased with the increasing immersion time, enhancing the stability of the passive film and thus improving the corrosion performance of this HEA in 0.5 mol/L NaOH solution.

4-Tertiary-octylphenol (4-t-OP), a frequently utilized alkylphenol, is extensively utilized in a wide range of consumer goods. While experimental research has demonstrated that 4-t-OP exposure leads to increased oxidative stress, it remains unclear if this also occurs in human beings. To investigate this issue, we enrolled 886 Taiwanese adolescents and young adults (aged 12–30 years) and examined the associations among serum 4-t-OP levels, urine oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG) (a biomarker of DNA damage), and 8-iso prostaglandin F2α (8-isoPGF2α) (a biomarker of lipid peroxidation). In linear regression analyses, a 1-unit increase in natural log serum 4-t-OP levels was positively associated with urine levels of the 8-OHdG and 8-isoPGF2α (β= 0.083, SE= 0.037, P= 0.025, and β= 0.418, SE= 0.068, P< 0.001) after controlling for covariates. Furthermore, we observed an interaction between age and 4-t-OP, as well as between low-density lipoprotein cholesterol and 4-t-OP, in the association between 4-t-OP and 8-isoPGF2α. In conclusion, our study showed that serum concentrations of 4-t-OP exhibit positive connections with biomarkers of oxidative stress on DNA and lipids. Additional investigation is crucial to determine the presence of a causal link between 4-t-OP exposure and oxidative stress in human subjects.

As the protective component, steel plate had attracted extensive attention because of frequently threats of explosive loads. In this paper, the evolution of microstructure and the mechanism of damage in the quasi-cracking area of steel plate subjected to explosive load were discussed and the relationships between micro defects and dynamic mechanical response were revealed. After the explosion experiment, five observation points were selected equidistant from the quasi-cracking area of the section of the steel plate along the thickness direction, and the characteristics of micro defects at the observation points were analyzed by optical microscope (OM), scanning electron microscope (SEM) and electron back-scattered diffraction (EBSD). The observation result shows that many slip bands (SBs) appeared, and the grain orientation changed obviously in the steel plate, the two were the main damage types of micro defects. In addition, cracks, peeling pits, grooves and other lager micro defects were appeared in the lower area of the plate. The stress parameters of the observation points were obtained through an effective numerical model. The mechanism of damage generation and crack propagation in the quasi-cracking area were clarified by comparing the specific impulse of each observation point with the corresponding micro defects. The result shows that the generation and expansion of micro defects are related to the stress area (i.e. the upper compression area, the neutral plane area, and the lower tension area). The micro defects gather and expand at the grain boundary, and will become macroscopic damage under the continuous action of tensile stress. Besides, the micro defects at the midpoint of the section of the steel plate in the direction away from the explosion center (i.e. the horizontal direction) were also studied. It was found that the specific impulse at these positions were much smaller than that in the thickness direction, the micro defects were only SBs and a few micro cracks, and the those decreased with the increase of the distance from the explosion center.

To evaluate the diagnostic efficacy of contrast‐enhanced ultrasonography (CEUS) for detecting catheter‐related right brachiocephalic vein (RBV) and superior vena cava (SVC) obstructions in patients undergoing hemodialysis (HD). From June 1, 2021 to December 31, 2022, we enrolled 80 patients undergoing HD who had used or were using a central venous catheter as vascular access. We evaluated the diagnostic efficacy of conventional ultrasonography and CEUS for identifying RBV and SVC obstructions and compared them with that of digital subtraction angiography (DSA). In the stratified analysis, the SVC was divided into the upper and lower segments. In total, we analyzed 240 central venous segments, including the RBV. Among the RBV and SVC visualized by DSA, conventional ultrasonography and CEUS could visualize 67.92 and 100% of the vein segments, respectively; however, the lengths and diameters of the RBV and SVC were smaller than those recorded with DSA (P< .001). The diagnostic efficacy of CEUS for detecting catheter‐related central venous obstruction was better than that of conventional ultrasonography, with a higher sensitivity (83.95 vs 41.98%), specificity (89.94 vs 53.46%), accuracy (87.92 vs 49.58%), and F1 score (82.42 vs 49.64%). CEUS showed good agreement (κ= 0.732) with DSA. In the stratified analyses, CEUS also showed higher sensitivity (83.93, 83.33, and 84.62%, respectively) and better agreement with DSA (κ =0.635, 0.655, and 0.673, respectively) than conventional ultrasonography for detecting the RBV and the upper and lower segments of the SVC. CEUS had high sensitivity and specificity in diagnosing catheter‐related RBV and SVC obstructions.

A photocatalytic three-component reaction of a nitroarene, a thiophenol, and a ketone for the synthesis of multifunctional diaryl sulfides was reported using a nitro group as the nitrogen source and thiophenol as the sulfur source. Thiophenol also serves as a proton donor to reduce nitroarene to arylamine as a key intermediate for the formation of C–N and C–S bonds. Good functional group tolerance and mild reaction conditions make this method have practical synthetic value for diversified multifunctional diaryl sulfides.

In recent years, researches on improving high-voltage performance of lithium-ion batteries incorporating LiNi0.5Co0.2Mn0.3O2(NCM523) and artificial graphite (AG) have been widely reported. However, limited attentions have been paid to understand the effects and influence mechanisms of charge and discharge rates and charge limit currents on cyclability of NCM523/AG cells. Herein, a ∼1.9 Ah NCM523/AG pouch cell is employed, whose electrochemical and structural evolutions after 800 cycles at various rates are comprehensively investigated. We find that cycling performances are strongly influenced by charge rate, followed by limit current and discharge rate. The cell charged at a high rate and cell charged until reaching a low limit current both exhibit low capacity retentions compared to the cell discharged at a high rate. Possible failure reasons are analyzed by advanced characterizations. Results reveal that NCM523 cathodes of the cells deteriorated early experience severe transition metal dissolution, lattice distortion, and partial phase transformation. Meanwhile, the deposited transition metals on AG anodes catalyze the electrolyte consumption, lithium plating and active area loss. Finally, these side reactions notably increase cell impedance and electrochemical polarization. Undoubtedly, these findings clearly outline the challenges and optimization direction for high-rate NCM523/AG cells.

This study aimed to investigate the prevalence characteristics of human papillomavirus (HPV) infections in 29,508 female cases in Jinshan District, Shanghai.

In this study, a vinylene‐linked covalent organic framework (V‐COF‐1) was integrated with multi‐walled carbon nanotubes (MWCNTs) to create a modified electrode (V‐COF‐1/MWCNTs/SPCE) for electrochemical sensing applications. This research focus to investigate the application of the modified electrode for the simultaneous determination of tryptophan (Trp), uric acid (UA), and 8‐hydroxy‐2'‐deoxyguanosine (8‐OHdG) in human urine samples and the mechanism between V‐COF‐1 and the analytes (Trp, UA, and 8‐OHdG) by studying tryptophan metabolites, dopamine, and L‐3,4‐dihydroxyphenylalanine (L‐DOPA). The electrochemical performance of V‐COF‐1/MWCNTs/SPCE was evaluated using differential pulse voltammetry (DPV) and use cyclic voltammetry (CV) to detect the modified electrode to explore its electrochemical properties. Under optimized conditions, V‐COF‐1/MWCNTs/SPCE exhibited efficient electron transfer for Trp, UA, and 8‐OHdG, with low detection limits (S/N = 3) of 0.03 μM, 0.06 μM, and 0.006 μM, respectively. The modified electrode demonstrated high selectivity for the target analytes in the presence of interfering species, as well as excellent repeatability and stability. The recoveries of Trp, UA, and 8‐OHdG in human urine samples ranged from 90.6% to 104.8%, which shows that this method has been successfully applied for the simultaneous detection of Trp, UA and 8‐OHdG in biological sample analysis. The integration of V‐COF‐1 and MWCNTs onto the modified electrode showed promising results for the simultaneous detection of Trp, UA, and 8‐OHdG. The developed sensor exhibited excellent sensitivity, selectivity, repeatability, and stability. These findings contribute to the advancement of electrochemical sensor technology for biomedical applications and highlight the potential of V‐COF‐1/MWCNTs/SPCE in analytical chemistry. A vinylene‐linked covalent organic framework (V‐COF‐1) was incorporated with multi‐walled carbon nanotubes (MWCNTs) as a modified electrode (V‐COF‐1/MWCNTs/SPCE), and it was successfully applied to the simultaneous determination of tryptophan (Trp), uric acid (UA), and 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) in human urine samples.

Artificial sweeteners have been frequently detected in the feedstocks of anaerobic digestion. As these sweeteners can lead to the shift of anaerobic microbiota in the gut similar to that caused by antibiotics, we hypothesize that they may have an antibiotic-like impact on antibiotic resistance genes (ARGs) in anaerobic digestion. However, current understanding on this topic is scarce. This investigation aimed to examine the potential impact of acesulfame, a typical artificial sweetener, on ARGs in anaerobic digestion by using metagenomics sequencing and qPCR. It was found that acesulfame increased the number of detected ARG classes and the abundance of ARGs during anaerobic digestion. The abundance of typical mobile genetic elements (MGEs) and the number of potential hosts of ARGs also increased under acesulfame exposure, suggesting the enhanced potential of horizontal gene transfer of ARGs, which was further confirmed by the correlation analysis between absolute abundances of the targeted ARGs and MGEs. The increased horizontal dissemination of ARGs may be associated with the SOS response induced by the increased ROS production, and the increased cellular membrane permeability. These findings indicate that artificial sweeteners may accelerate ARG spread through digestate disposal, thus corresponding strategies should be considered to prevent potential risks in practice.

Purpose: Learning power is crucial in today's rapidly changing world, yet its application to teachers is under-explored. This study delved into the investigation of teacher learning power and examined how it matters in the relationship between teachers' experiences in lesson study and the adoption of constructivist pedagogy. Design/methodology/approach: A cross-sectional survey of 226 elementary, junior high, and senior high school teachers in Taiwan was conducted, and the results were analyzed using structural equation modeling. Findings: The findings suggest that both participation in lesson study and teacher learning power were positively associated with the practice of constructivist pedagogy. Moreover, teacher learning power partially mediated the relationship between lesson study and constructivist pedagogy. Originality/value: By incorporating the concept of teacher learning power and performing a mediation analysis to understand how it matters, this study has added to the expanding collection of works on lesson study explored from different perspectives and in various contexts.

Aeschynomene (Aeschynomene americanaL.) is a warm‐season annual legume forage used in tropical and subtropical regions; however, there is limited information on agronomic and environmental benefits of aeschynomene when overseeded into bahiagrass (Paspalum notatumFlüggé) swards. The objective of this study was to evaluate the effects of overseeding aeschynomene or applying N fertilizer to existing bahiagrass on forage characteristics, atmospheric N fixation, and N2O‐N emissions. The study was conducted in Ona, FL, from April 2019 to March 2021. Treatments were the split‐plot arrangement of bahiagrass‐aeschynomene or bahiagrass monoculture (main plot) and N fertilization level (0 or 60 kg N ha−1; subplot), distributed in a randomized complete block design with four replicates. Nitrogen fixation was estimated in plots receiving no N fertilization. The static chamber technique was used to estimate N2O‐N emissions. Overseeding aeschynomene did not increase forage accumulation (mean = 1300 kg dry matter [DM] ha−1harvest−1) or N2O emissions (mean = 15 g N2O‐N ha−1per day), but increased forage crude protein (CP) concentration (from 98 to 108 g kg−1) when compared to bahiagrass monoculture. Nitrogen fertilization increased forage accumulation (from 1200 to 1400 kg DM ha−1per harvest) but it did not affect aeschynomene N fixation (84% N derived from atmospheric fixation [Ndfa]). Nitrous oxide emissions had significant temporal variability across all treatments; however, there were no differences in accumulated N2O‐N emissions among treatments (mean = 2.4 kg N2O‐N ha−1per year). Overseeding aeschynomene is an effective management practice to increase forage CP concentration in pastures without increasing N2O‐N emissions. Overseeding aeschynomene into bahiagrass increased sward bahiagrass‐aeschynomene forage nutritive value.Nitrogen fertilization increased 18% forage accumulation of bahiagrass.Forage accumulation was the main factor affecting legume atmospheric N fixation.Overseeding aeschynomene into bahiagrass pastures had no impact on soil N2O‐N emissions.

Dietary patterns related to inflammation have become a focus of disease prevention but the patterns may vary among populations.

The synthesis of a series of ruthenium 1,5‐disubstituted 1,2,3‐triazolato complexes, 1,5‐disubstituted 1,2,3‐triazoles, and a triazolium salt is reported. Treatment of the ruthenium azido complex [Ru]‐N3(1, [Ru] = (η5‐C5H5)(dppe)Ru, dppe = Ph2PCH2CH2PPh2) with an excess of ethyl propiolate results in the formation of a mixture of the Z‐ and E‐forms of zwitterionic N(1)‐bound N(3)‐ethyl acryl‐4‐carboxylate triazolato complexes [Ru]N3(CH=CHCO2Et)C2H(CO2) (Z‐2) and (E‐2). The arylation of 2with aromatic bromides gives a series of cationic N(1)‐bound N(3)‐ethyl acryl‐4‐alkoxycarbonyl triazolato complexes {[Ru]N3(CH=CHCO2Et)C2H(CO2CH2R)}[Br] (3a, R = Ph; 3b, R = C6F5; 3c, R = 4‐C6H4CN, 3d, R = 2,6‐C6H3F2) and the subsequent cleavage of the Ru‐N bond of 3a–dgives 1,5‐disubstituted 1,2,3‐triazoles N3(CH=CHCO2Et)C2H(CO2CH2R) (4a, R = Ph; 4b, R = C6F5; 4c, R = 4‐C6H4CN; 4d, R = 2,6‐C6H3F2) and [Ru]‐Br. A 1,2,3‐triazolium salt [N3(CH=CHCO2Et)(CH2C6F5)C2H2][Br] (5) was formed by transformation of 4bin BrCH2C6F5/chloroform mixture. The structures of Z‐3aand Z‐5were confirmed by single‐crystal x‐ray diffraction analysis and both complexes participate in non‐covalent aromatic interactions in the solid‐state structures which can be favorable in the binding of DNA/biomolecular targets and have shown great potential in the application of biologically active anticancer drugs. The arylation of zwitterionic ruthenium triazolato complexes gives a series of aryl‐functionalized 1,5‐disubstituted 1,2,3‐triazoles.

Purpose: To determine whether the rate of progression of scoliosis is higher following thoracotomies and sternotomies in children. Methods: We undertook a retrospective review of 1744 patients from a tertiary paediatric referral unit who had sternotomies or thoracotomies from 2005 to 2010 to identify those with scoliosis and to determine where possible, the pre- and post-operative rate of scoliosis progression. A secondary objective was to assess the risk factors for progression after surgery through Chi-square analysis. Results: 1419/1744 (81.4%) patients (55% M, 45% F) had post-op chest X-rays. 25% had a thoracotomy, and 75% had a sternotomy. 5.8% had scoliosis at their most recent chest X-ray (mean Cobb angle 20° (range 11–63°)). There was no significant difference for rates of scoliosis for those who had sternotomies vs thoracotomies (6.3% vs. 4.6% P= 0.258) but a significant difference for those who had primary vs revision sternotomies (5.1% vs. 9.9% P= 0.008). Pre- and post-op progression calculations were possible in 30 patients. The mean time from surgery to the start of the progression was 12 months (range 0–93 months). There was no significant difference between the rates of progression pre-op vs post-op: 1.0 vs. 0.5 deg/month, P= 0.228. There was no significant difference between the rates of post-op progression for those who had a sternotomy versus a thoracotomy (0.5 vs. 0.5 deg/month P= 0.503). Conclusion: Thoracotomies and sternotomies do not appear to increase the rate of progression of scoliosis in these patients. Level of evidence: III. Graphical Abstract: Radiographs illustrating scoliosis progression

Herein, a series of face-capped (Tr2M3)4L4(Tr = cycloheptatrienyl cationic ring; M = metal; L = organosulfur ligand) tetrahedral cages 1–3functionalized with 12 appended crown ether moieties were designed and synthesized. The reversible binding of ammonium cations with peripheral crown ether moieties to adjust internal guest-binding was realized. Combination of a bisammonium linker and cage 3led to the formation of a supramolecular gel SPN1via host–guest interactions between the crown ether moieties and ammonium salts. The obtained supramolecular gel exhibited multiple-stimuli responsiveness, injectability, and excellent self-healing properties and could be further developed to a SPN1-based drug delivery system. In addition, the storage modulus of SPN1was 20 times higher than that of the model gel without Pd–Pd bonded blocks, and SPN1had better self-healing properties compared with the latter, demonstrating the importance of such cages in improving mechanical strength without losing the dynamic properties of the material. The cytotoxicity in vitro of the drug-loaded (doxorubicin or methotrexate) SPN1was significantly improved compared to that of free drugs.

Wearable non-invasive sensors facilitate the continuous measurement of glucose in sweat for the treatment and management of diabetes. However, the catalysis of glucose and sweat sampling are challenges in the development of efficient wearable glucose sensors. Herein, we report a flexible wearable non-enzymatic electrochemical sensor for continuous glucose detection in sweat. We synthesized a catalyst (Pt/MXene) by the hybridization of Pt nanoparticles onto MXene (Ti3C2Tx) nanosheets with a broad linear range of glucose detection (0–8 mmol/L) under neutral conditions. Furthermore, we optimized the structure of the sensor by immobilizing Pt/MXene with a conductive hydrogel to enhance the stability of the sensor. Based on Pt/MXene and the optimized structure, we fabricated a flexible wearable glucose sensor by integrating a microfluidic patch for sweat collection onto a flexible sensor. We evaluated the utility of the sensor for the detection of glucose in sweat, and the sensor could detect the glucose change with the replenishment and consumption of energy by the body, and a similar trend was observed in the blood. An in vivo glucose test in sweat indicated that the fabricated sensor is promising for the continuous measurement of glucose, which is essential for the treatment and management of diabetes.

InP quantum dots (QDs) attract growing interest in recent years, owing to their environmental advantages upon applications in display and lighting. However, compared to Cd-based QDs and Pb-based perovskites, the synthesis of InP QDs with high optical quality is relatively more difficult. Here, we established a mid-synthetic modification approach to improve the optical properties of InP-based QDs. Tris(dimethylamino)phosphine ((DMA)3P) and indium iodide were used to prepare InP QDs with a green emission (∼527 nm). By introducing zinc halides (ZnX2) during the mid-synthetic process, the photoluminescence quantum yield (PLQY) of the resulting InP/ZnSeS/ZnS core/shell/shell QDs was increased to >70%, and the full-width-at-half-maximum (FWHM) could be narrowed to ∼40 nm. Transmission electron microscopy clearly showed the improvement of the QDs particle size distribution after introducing ZnX2. It was speculated that ZnX2was bound to the surface of QDs as a Z-type ligand, which not only passivated surface defects and suppressed the emission of defect states but also prevented Ostwald ripening. The InP cores were also activated by ZnX2, which made the growth of the ZnSeS shell more favorable. The photoluminescence properties started to be improved significantly only when the amount of ZnX2exceeded 0.5 mmol. As the amount increased, more ZnX2was distributed around the QDs to form a ligand layer, which prevented the shell precursor from crossing the ligand layer to the surface of the InP core, thus reducing the size of the InP/ZnSeS/ZnS QDs. This work revealed a new role of ZnX2and found a method for InP QDs with high brightness and low FWHM by the mid-synthetic modification, which would inspire the synthesis of even better InP QDs.

Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.

A calliandra-like ligand-free CsPbBr3nanostructure is constructed by a seed-assisted growth method, which exhibits significantly enhanced photocatalytic activity for artificial photosynthesis compared with traditional CsPbBr3nanocrystals.

ABSTRACTThis research examines three strategies that a multi-product firm can adopt when facing a single-product entrant under Bertrand competition: (i) staying in the duopoly market, (ii) abandoning the duopoly market, and (iii) bundling the two goods. When the competing good is homogenous, bundling is the most profitable strategy if the product differentiation of the two goods produced by the multi-product firm is not too high. When the competing good is heterogeneous, the preferred strategy of the multi-product firm and the welfare ranking depend on the substitutability of the competing good and the degree of product differentiation between the two goods.

ABSTRACTThe concept and connotation of critical thinking are formed based on human activities and social development in Europe and America, while relevant studies in East Asia are lacking. How to deconstruct the characteristics, formation and deep reasons of critical thinking in the East based on its continuous and dynamic human activities is still a challenge. Taking China as the research object, we reveal that the East also produces logic-based and intense critical thinking, and gradually integrates the characteristics of inclusiveness, euphemism, and result-oriented noun in the evolution, which can be attributed to the influence of war, religion, and nomadic and agricultural conflicts. This study is of great significance to the in-depth fundamental understanding of oriental critical thinking. It also holds promise to promote critical thinking education in East Asian countries and the cultural exchanges between the East and the West.

This study proposed a model for deterministic and probabilistic wind power generation forecasting and its corresponding procedures. The main contents include numerical weather prediction (NWP) systems, data preprocessing techniques, and forecasting models that use artificial intelligence methods. NWP wind speeds generated by the Central Weather Bureau (CWB) of Taiwan based on three atmospheric models, namely deterministic weather research and forecasting (WRFD), radar weather research and forecasting (RWRF), and WRF-based ensemble prediction system (WEPS), were used as model inputs. In terms of data preprocessing, the NWP wind speeds were corrected based on the height of the wind turbines, and principal components analysis (PCA) and empirical mode decomposition (EMD) were also evaluated for their feature extraction performance. Artificial neural network (ANN), long short-term memory (LSTM), gated recurrent unit (GRU), and eXtreme gradient boosting (XGBoost) were the forecast models used to predict wind power generation. The forecast results demonstrated that the use of the XGBoost model in conjunction with both PCA and EMD data preprocessing achieved the most accurate forecasting. The average forecasting errors (i.e., normalized root mean square error (NRMSE) and mean absolute percentage error (MAPE)) were 5.43% and 3.30% for one-hour-ahead and 9.78% and 6.83% for one-day-ahead, respectively. The empirical data collected at a wind farm in Taiwan verified the accuracy of the proposed method. Thus, the importance of model selection, NWP, and data preprocessing is ultimately self-evident.

Sunn hemp (Crotalaria junceaL.) is a warm‐season legume often used as a cover crop; however, there is limited information about nutrient cycling of sunn hemp residue. The objective of this study was to evaluate the effect of sunn hemp genotype and residue management on plant characteristics, decomposition, and suppression of Fusarium, Pythium, Sclerotinia, and Sclerotiummicrobe species. Two field experiments were conducted in Ona, FL. In Experiment 1, treatments were the split‐plot arrangement of three sunn hemp genotypes (Ubon, Blue Leaf, and ‘Tropic Sun’; main plot) and two biomass managements (removal or leaving the biomass on the field; subplot), distributed in a randomized complete block design. There was a greater biomass accumulation in 2019, but with no differences among genotypes (mean = 4,431 kg DM ha−1). Blue Leaf had greater N concentration than Ubon (23 vs. 19 g kg−1) and greater suppression of the Phytiumpopulations than Ubon and Tropic sun in 2019 (0.9 vs. 2.0 colony forming unit g soil−1). In Experiment 2, the litter bag technique was used to estimate biomass and N decomposition. Treatments were the factorial arrangement of three genotypes and two residue management strategies (incorporated into the soil or placed on the soil surface). Sunn hemp biomass incorporation enhanced organic matter disappearance and N mineralization rate but leaving sunn hemp on the soil surface may result in a steadier N supply for the subsequent crop. Sunn hemp genotypes differed in chemical composition.The genotype Blue Leaf most effectively suppressed Pythium populations in the soil.Sunn hemp residue management (surface vs. incorporated) affected decomposition.Genotypes did not differ in residue organic matter and N decomposition.

Ultraviolet (UV) detectors based on surface acoustic wave (SAW) technology offer unique advantages of remote or wireless operation capability with a potential of zero power consumption. Frequency shift of SAW devices induced by UV irradiation is mainly caused by acoustoelectric and thermal effects, although mass-loading and photo-capacitive effects might also have minor influences. Currently, the individual contribution from either acoustoelectric effect or thermal effect for UV sensing has not been thoroughly studied. In this work, we systematically investigated the contribution of acoustoelectric and thermal effects at different UV light intensities based on a LiNbO3 SAW device with its wavelength of $20 \mu \text{m}$ , and decoupled their individual contributions to the overall UV responses for acoustic wave sensing. We found that for the LiNbO3 SAW device without any surface treatment, the frequency shift was mainly caused by the thermal accumulation induced by UV radiation. Whereas for the LiNbO3 SAW devices coated with zinc oxide nanowires (ZnO NWs), the frequency shift is caused by the combined acoustoelectric and thermal effects. We found that the frequency shift caused by acoustic electric effect is dominant at a low UV intensity (< 30 mW/cm $^{{2}}{)}$ . Whereas with the UV light intensity larger than 90 mW/cm2, the photogenerated carriers generated by ZnO NWs became saturated, and then the thermal effect became dominant. This study clarifies the nature of individual influences of these two factors on the dominant mechanisms of the SAW-based UV sensing under different conditions.

This paper reviews the recent literature on solving the Boolean satisfiability problem (SAT), an archetypal NP-complete problem, with the aid of machine learning (ML) techniques. Over the last decade, the machine learning society advances rapidly and surpasses human performance on several tasks. This trend also inspires a number of works that apply machine learning methods for SAT solving. In this survey, we examine the evolving ML SAT solvers from naive classifiers with handcrafted features to emerging end-to-end SAT solvers, as well as recent progress on combinations of existing conflict-driven clause learning (CDCL) and local search solvers with machine learning methods. Overall, solving SAT with machine learning is a promising yet challenging research topic. We conclude the limitations of current works and suggest possible future directions. The collected paper list is available at https://github.com/Thinklab-SJTU/awesome-ml4co.

Receptor-interacting protein kinase 1 (RIPK1) contributes to necroptosis. Our previous study showed that pharmacological or genetic inhibition of RIPK1 protects against ischemic stroke-induced astrocyte injury. In this study, we investigated the molecular mechanisms underlying RIPK1-mediated astrocyte injury in vitro and in vivo. Primary cultured astrocytes were transfected with lentiviruses and then subjected to oxygen and glucose deprivation (OGD). In a rat model of permanent middle cerebral artery occlusion (pMCAO), lentiviruses carrying shRNA targeting RIPK1 or shRNA targeting heat shock protein 70.1B (Hsp70.1B) were injected into the lateral ventricles 5 days before pMCAO was established. We showed that RIPK1knockdown protected against OGD-induced astrocyte damage, blocked the OGD-mediated increase in lysosomal membrane permeability in astrocytes, and inhibited the pMCAO-induced increase in astrocyte lysosome numbers in the ischemic cerebral cortex; these results suggested that RIPK1 contributed to the lysosomal injury in ischemic astrocytes. We revealed that RIPK1knockdown upregulated the protein levels of Hsp70.1B and increased the colocalization of Lamp1 and Hsp70.1B in ischemic astrocytes. Hsp70.1Bknockdown exacerbated pMCAO-induced brain injury, decreased lysosomal membrane integrity and blocked the protective effects of the RIPK1-specific inhibitor necrostatin-1 on lysosomal membranes. On the other hand, RIPK1knockdown further exacerbated the pMCAO- or OGD-induced decreases in the levels of Hsp90 and the binding of Hsp90 to heat shock transcription factor-1 (Hsf1) in the cytoplasm, and RIPK1knockdown promoted the nuclear translocation of Hsf1 in ischemic astrocytes, resulting in increased Hsp70.1B mRNA expression. These results suggest that inhibition of RIPK1 protects ischemic astrocytes by stabilizing lysosomal membranes via the upregulation of lysosomal Hsp70.1B; the mechanism underlying these effects involves decreased Hsp90 protein levels, increased Hsf1 nuclear translocation and increased Hsp70.1B mRNA expression.

The angle of incidence of solar irradiation on photovoltaic modules varies throughout the day. At larger angles of incidence, the modules are subject to higher reflection losses, resulting in lower light transmission and energy yield. The impact of the relative angular transmittance on the energy yield is often evaluated with a correction factor, commonly referred to as incidence angle modifier (IAM). In this article, a new method to quantify the IAM of photovoltaic devices is presented, which is different from the methods proposed in IEC 61853-2: It encompasses a spot-area irradiation, a customized angle probe holder, and a current-to-voltage converter. This first part focuses on single-cell minimodules and validates the new method on two different cell architectures—an interdigitated back-contact solar cell and a four-busbar solar cell, with an analysis of the measurement bias due to busbars. A second part will follow on the implementation of the same method to commercial-size silicon modules. The study is intended to contribute to the IEC 61853-2 standard. A detailed uncertainty analysis is presented and the method is validated versus IEC 61853-2. Our proposed method shows great potential as it is less expensive and more adaptable than existing standard methods.

Renal fibrosis, inflammation, and gut dysbiosis are all linked to chronic kidney disease (CKD). Here we show that Bacteroides ovatusprotects against renal fibrosis. Mechanistically, B. ovatusenhances intestinal hyodeoxycholic acid (HDCA) levels by upregulating a strain of intestinal bacteria, Clostridium scindens, that has the capacity for direct HDCA production in mice. HDCA significantly promoted GLP-1 secretion by upregulating the expression of TGR5 and downregulating the expression of farnesoid X receptor (FXR) in the gut. Activation of renal GLP-1R attenuates renal fibrosis while delaying the subsequent development of CKD. In addition, HDCA can also protect against renal fibrosis by directly upregulating renal TGR5. The natural product neohesperidin (NHP) was found to exert its anti-renal fibrotic effects by promoting the growth of B. ovatus. Our findings provide mechanistic insights into the therapeutic potential of B. ovatus, C. scindens, and HDCA in treating CKD.

Within the electronic design automation (EDA) domain, artificial intelligence (AI)-driven solutions have emerged as formidable tools, yet they typically augment rather than redefine existing methodologies. These solutions often repurpose deep learning models from other domains, such as vision, text, and graph analytics, applying them to circuit design without tailoring to the unique complexities of electronic circuits. Such an “AI4EDA” approach falls short of achieving a holistic design synthesis and understanding, overlooking the intricate interplay of electrical, logical, and physical facets of circuit data. This study argues for a paradigm shift from AI4EDA towards AI-rooted EDA from the ground up, integrating AI at the core of the design process. Pivotal to this vision is the development of a multimodal circuit representation learning technique, poised to provide a comprehensive understanding by harmonizing and extracting insights from varied data sources, such as functional specifications, register-transfer level (RTL) designs, circuit netlists, and physical layouts. We champion the creation of large circuit models (LCMs) that are inherently multimodal, crafted to decode and express the rich semantics and structures of circuit data, thus fostering more resilient, efficient, and inventive design methodologies. Embracing this AI-rooted philosophy, we foresee a trajectory that transcends the current innovation plateau in EDA, igniting a profound “shift-left” in electronic design methodology. The envisioned advancements herald not just an evolution of existing EDA tools but a revolution, giving rise to novel instruments of design-tools that promise to radically enhance design productivity and inaugurate a new epoch where the optimization of circuit performance, power, and area (PPA) is achieved not incrementally, but through leaps that redefine the benchmarks of electronic systems’ capabilities.

ABSTRACTThe extensive use of tetracycline antibiotics has led to the widespread presence of tetracycline-resistance genes in Gram-negative bacteria and this poses serious threats to human and animal health. In our previous study, we reported a method for rapid detection of Tet(X)-producers using MALDI-TOF MS. However, there have been multiple machineries involved in tetracycline resistance including efflux pump, and ribosomal protection protein. Our previous demonstrated the limitation in probing the non-Tet(X)-producing tetracycline-resistant strains. In this regard, we further developed a MALDI-TOF MS method to detect and differentiate Tet(X)-producers and non-Tet(X)-producing tetracycline-resistant strains. Test strains were incubated with tigecycline and oxytetracycline in separate tubes for 3 h and then analyzed spectral peaks of tigecycline, oxytetracycline, and their metabolite. Strains were distinguished using MS ratio for [metabolite/(metabolite+ tigecycline or oxytetracycline)]. Four control strains and 319 test strains were analyzed and the sensitivity was 98.90% and specificity was 98.34%. This was consistent with the results obtained from LC-MS/MS analysis. Interestingly, we also found that the reactive oxygen species (ROS) produced by tetracycline-susceptible strains were able to promote the degradation of oxytetracycline. Overall, the MALDITet(X)-plustest represents a rapid and reliable method to detect Tet(X)-producers, non-Tet(X)-producing tetracycline-resistant strains, and tetracycline-susceptible strains.

The small molecule chemical compound cinobufotalin (CB) is reported to be a potential antitumour drug that increases cisplatin (DDP) sensitivity in nasopharyngeal carcinoma. In this study, we first found that CB decreased DDP resistance, migration and invasion in lung adenocarcinoma (LUAD). Mechanistic studies showed that CB induced ENKUR expression by suppressing PI3K/AKT signalling to downregulate c-Jun, a negative transcription factor of ENKUR. Furthermore, ENKUR was shown to function as a tumour suppressor by binding to β-catenin to decrease c-Jun expression, thus suppressing MYH9 transcription. Interestingly, MYH9 is a binding protein of ENKUR. The Enkurin domain of ENKUR binds to MYH9, and the Myosin_tail of MYH9 binds to ENKUR. Downregulation of MYH9 reduced the recruitment of the deubiquitinase USP7, leading to increased c-Myc ubiquitination and degradation, decreased c-Myc nuclear translocation, and inactivation of epithelial-mesenchymal transition (EMT) signalling, thus attenuating DDP resistance. Our data demonstrated that CB is a promising antitumour drug and may be a candidate chemotherapeutic drug for LUAD patients.