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Vinca alkaloids, a class of tubulin-binding agent, are widely used in treating cancer, yet the emerging resistance compromises their efficacy. Hepatoma up-regulated protein (HURP), a microtubule-associated protein displaying heightened expression across various cancer types, reduces cancer cells' sensitivity to vinca-alkaloid drugs upon overexpression. However, the molecular basis behind this drug resistance remains unknown. Here we discover a tubulin-binding domain within HURP, and establish its role in regulating microtubule growth. Cryo-EM analysis reveals interactions between HURP's tubulin-binding domain and the vinca domain on β-tubulin -- the site targeted by vinca alkaloid drugs. Importantly, HURP competes directly with vinorelbine, a vinca alkaloid-based chemotherapeutic agent, countering microtubule growth defects caused by vinorelbine both in vitro and in vivo. Our findings elucidate a mechanism driving drug resistance in HURP-overexpressing cancer cells and emphasize HURP tubulin-binding domain's role in mitotic spindle assembly. This underscores its potential as a therapeutic target to improve cancer treatment. Vinca alkaloids, tubulin-binding agents that impair microtubule growth, are widely used in cancer treatment. Here, the authors show that resistance to these drugs is due to Hepatoma up-regulated protein (HURP) competitively binding to the same site on tubulin, countering the drug's effects. [ABSTRACT FROM AUTHOR]

ABSTRACT A novel Wiener‐type dynamic neural network (Wiener‐type DNN) method for large signal modeling of power amplifiers (PAs) is proposed in this paper. In this method, the proposed model structure for the PA contains two Wiener‐type DNNs to describe the input impedance and the amplification efficiency, respectively. The Wiener‐type DNN includes a simplified linear dynamic equation module and a nonlinear static equation module. For the simplification process of the linear dynamic equation, it is proposed to process fundamental frequency components of the large signal harmonic data of the PA by vector fitting. The neural network is used to implement the static equation in the Wiener‐type DNN. The formulas for training the proposed Wiener‐type DNN model of the PA using large signal data are derived. The training algorithm of the PA model is proposed to improve the training efficiency. A Motorola MOSFET PA example and a Freescale lateral double‐diffused MOSFET PA example are present to validate the proposed Wiener‐type DNN method. For the Motorola MOSFET PA, a dynamic neural network (DNN) model and a time‐delay deep neural network (TDDNN) are established for comparison. For the Freescale PA, the DNN model is used for comparison experiment. The comparison figures show that the Wiener‐type DNN model has better convergence properties than the DNN model in the nonlinear region of the PA. The established accurate PA model is conducive to the design of subsequent communication circuits. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 (PSEN1) E280A carriers for autosomal dominant Alzheimer's disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers. Methods: We analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer's Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups. Results: Analyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18–75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers' estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group. Conclusions: APOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE-modifying drugs with the potential to help in the treatment and prevention of ADAD. [ABSTRACT FROM AUTHOR]

It has been reported for decades that preschool children (age 4-7) tend to assign non-adult-like interpretations for sentences with pre-subject exclusive only. This study reports findings from two experiments investigating (1) the effects of (in)congruent implicit questions in discourse contexts and (2) word order transformation on children's interpretations of Mandarin pre-subject zhiyou 'only'. Experiment 1 showed that children performed non-adult-like in the incongruent discourse condition, similar to the patterns found in previous studies, but adult-like in the congruent discourse condition. Experiment 2 showed that using sentences similar to English 'Those who ate apples was only the boy' where the VP precedes the subject NP with zhiyou 'only' was not sufficient to overcome the processing difficulty caused by the incongruent discourse for preschool children. The results demonstrate that a congruent context taking the VP as the background (i.e., given and salient information) in Experiment 1, but not the syntactic manipulation in Experiment 2, is sufficient for children to interpret sentences with pre-subject zhiyou 'only' at an adult-like level of accuracy. The findings demonstrate that children have the syntactic knowledge for sentences with exclusive zhiyou 'only', but the discourse incongruence hinders them from correctly interpreting sentences with exclusive zhiyou 'only' when it is in pre-subject position.It has been reported for decades that preschool children (age 4-7) tend to assign non-adult-like interpretations for sentences with pre-subject exclusive only. This study reports findings from two experiments investigating (1) the effects of (in)congruent implicit questions in discourse contexts and (2) word order transformation on children's interpretations of Mandarin pre-subject zhiyou 'only'. Experiment 1 showed that children performed non-adult-like in the incongruent discourse condition, similar to the patterns found in previous studies, but adult-like in the congruent discourse condition. Experiment 2 showed that using sentences similar to English 'Those who ate apples was only the boy' where the VP precedes the subject NP with zhiyou 'only' was not sufficient to overcome the processing difficulty caused by the incongruent discourse for preschool children. The results demonstrate that a congruent context taking the VP as the background (i.e., given and salient information) in Experiment 1, but not the syntactic manipulation in Experiment 2, is sufficient for children to interpret sentences with pre-subject zhiyou 'only' at an adult-like level of accuracy. The findings demonstrate that children have the syntactic knowledge for sentences with exclusive zhiyou 'only', but the discourse incongruence hinders them from correctly interpreting sentences with exclusive zhiyou 'only' when it is in pre-subject position. [ABSTRACT FROM AUTHOR]

Ozone‐depleting substances (ODSs) are well known as primary emission from the production and consumption of traditional industrial sectors. Here, we reported the unintentional emission of ODSs from iron and steel plants as a new source, basing on real‐world measurements of flue gases emitted from their major processes. The sintering was found to be the major emission process of ODSs, including chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs), halons, methyl halide (CH3Cl), methyl chloroform, carbon tetrachloride, methyl bromide and halogenated very short‐lived substances. The median emission factors of CFC‐113, CFC‐115, HCFC‐22, and CH3Cl for typical sintering processes are 1.7, 0.7, 44.5 and 237.0 mg/t, respectively. Quantum chemical calculation figures out that the ODS species are mainly formed in the low efficiency combustion process of halogenated materials. Annual amounts of ODS and CFC‐11‐equivalent emissions were estimated to be 1,785 tons and 78 tons in 2019 over mainland China, respectively. Given these findings, this study provides a new prospective on searching for ODS emission sources, especially unintentional sources such as iron and steel industry and other combustion related activities. Plain Language Summary: Ozone‐depletion substances (ODSs) are halocarbons that can damage the ozone layer. Although the tropospheric chlorine has been continuously declined, some halogenated organic gaseous species are still found to be increasingly emitted. This study firstly reports the unintentional emission of ODSs from iron and steel plants via real‐world measurements. ODS emission from the sintering process shows larger ozone depleting effect than that from ironmaking and steelmaking processes. The halogen‐containing iron ore, coke and fluxing agent provide mineral halogens for the generation of halogenated compounds, while the high temperature of combustion atmosphere in the sinter machine benefits for the chemical combination of halogens and hydrocarbons. Current air pollution control devices cannot effectively remove ODSs. This study aims at attracting attention to the identification and control of unintentional ODS emission sources in the future. Key Points: CFCs, HCFCs and halons were observed to be unintendedly emitted from iron and steel industryThe total CFC‐11‐eq emission from iron and steel industry was 78 tons over mainland China in 2019Homogenous gas‐phase formation routes of ODS species in flue gas were proposed and calculated [ABSTRACT FROM AUTHOR]

Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In this regard, lipid nanoparticles have been successfully utilized to improve mRNA delivery and protect the cargo from extracellular degradation. Encapsulation in lipid nanoparticles was an essential factor in the successful clinical application of mRNA vaccines, which conclusively demonstrated the technology's potential to yield approved medicines. In this review, we begin by describing current advances in mRNA modifications, design of novel lipids and development of lipid nanoparticle components for mRNA-based drugs. Then, we summarize key points pertaining to preclinical and clinical development of mRNA therapeutics. Finally, we cover topics related to targeted delivery systems, including endosomal escape and targeting of immune cells, tumors and organs for use with mRNA vaccines and new treatment modalities for human diseases. [ABSTRACT FROM AUTHOR]

Individuals with severe burn injuries may develop depression, yet knowledge about psychological risk factors for depression following trauma is limited. This study investigated the prospective impact and interplay of prior depression and trauma-related cognitive processes (posttraumatic negative appraisals and trauma-related rumination) to depressive symptoms between 6 and 24 months after burn injury. Taiwanese adult survivors of burn (N = 118) participated in surveys immediately post-burn and at 6-, 12-, and 24-months follow-up. Participants were 7 5% men, with an average age of 41.8 years and an average of TBSA of 18.3%. A total of 8.5%, 5.9%, and 4.2% met criteria for probable major depression at 6, 12, and 24 months post-burn, respectively. The prevalence increased to 23.7%, 11.0%, and 5.9% using the cutoff on the PHQ-9. Prior depression and trauma-related cognitive processes immediately post-burn explained 13.5%, 20.5%, and 18.6% of the variance in depressive symptoms at 6, 12, and 24 months post-burn, respectively. Posttraumatic negative appraisals strongly predicted depressive symptoms post-burn across follow-ups. Moreover, posttraumatic negative appraisals significantly mediated the effect of prior depression on subsequent depressive symptoms across follow-ups. Prior depression significantly moderated the effect of trauma-related rumination on depressive symptoms at 6 months post-burn. Our results are the first to demonstrate the role and interplay of prior depression and trauma-related cognitive processes in post-burn depression. Findings highlight that pre-and post-trauma psychological factors jointly affect depression following trauma, broadening the applicability of cognitive theories of PTSD. • This study examined the contribution effect of early psychological risk factors to post-burn depressive symptoms. • Depression is relatively common at 6 months post-burn and then gradually decreased. • Posttraumatic negative appraisals strongly predicted depressive symptoms between 6 and 24 months post-burn. • Posttraumatic negative appraisals mediated the effect of prior depression on long-term depressive symptoms after burn. [ABSTRACT FROM AUTHOR]

Major burn injuries may have long-term mental health consequences, such as posttraumatic stress disorder (PTSD). This study extended prior work to investigate DSM-5 PTSD symptoms at 6 months, 1 year, and 2 years post-burn as well as the contribution of two sets of early psychological risk factors to DSM-5 PTSD symptoms: Established PTSD risk factors (prior adjustment problems, past trauma, perception of life threat, peritraumatic emotions and dissociation) and theory-derived cognitive factors (negative appraisals of the trauma and its sequelae, memory disorganization, trauma-related rumination, and thought suppression). The current study recruited a sample of 118 adult burn patients (75.4% men, mean age 41.8, mean TBSA 18.3%) consecutively admitted to a large regional burn center in Northern Taiwan, who were assessed at 6, 12, and 24 months following their burn injury. A total of 11.0%, 5.9%, and 7.6% met probable DSM-5 PTSD at 6 months, 1 year, and 2 years post-burn, respectively. The rates rose to 15.3%, 10.2%, and 11.0% using the cutoff method. After controlling for covariates, the regression model with theory-derived cognitive factors explained an additional significant 15.9%, 17.2%, and 17.7% of the variance in DSM-5 PTSD symptoms at 6 months, 1 year, and 2 years post-burn, respectively. In contrast, the regression model with established PTSD risk factors explained an additional significant 7.2%, 14.4%, and 10.5% of the variance in DSM-5 PTSD symptoms at 6 months, 1 year, and 2 years post-burn, respectively. Of all predictors, negative appraisals of intrusions was consistently and strongly predictive of DSM-5 PTSD symptomatology post-burn across time, followed by prior depression. The results underscore the role of early cognitive risk factors in the development and persistence of DSM-5 PTSD symptomatology following burn injury. ● This study tested the effect of early psychological risk factors on DSM-5 PTSD symptoms post-burn. ● Probable DSM-5 PTSD is relatively prevalent over one year post-burn. ● Theory-derived cognitive factors strongly predicted DSM-5 PTSD symptoms between 6 and 24 months post-burn. ● Negative appraisals and prior depression were important early psychological risk factors for DSM-5 PTSD symptoms post-burn. [ABSTRACT FROM AUTHOR]

Knowledge innovation is the driving force and guarantee of regional development. Inspired by population ecology, this article uses symbiosis theory to explore the symbiotic relationship of subjects in the regional knowledge innovation ecosystem. The nonlinear Lotka–Volterra model is constructed with the main subjects to measure the knowledge innovation ability of knowledge innovation subjects. The symbiotic relationships among the knowledge innovation subjects in each region are identified. Taking Beijing, Shanghai, and Guangzhou as examples, a sensitivity analysis of the initial value and coopetition relationship is conducted. The results show that the initial value change has no significant effect on the development of knowledge innovation subjects. The interaction relationships among subjects directly affect the symbiotic evolution trend. The study extends the application scope of the symbiosis theory and develops a theoretical framework for the development of subjects in regional knowledge innovation ecosystem. It offers regions a reference to use Lotka–Volterra model adjusting the knowledge innovation structure in various regions. [ABSTRACT FROM AUTHOR]

Amino-cured epoxy resins are widely used in the electrical and electronic industry for their excellent properties. To investigate the mechanism of the effect of O2 and H2O on the pyrolysis behavior of epoxy resin, in this paper, the cross-linked structure of bisphenol A type epoxy resin cured by adducts of diethylenetriamine and butyl glycidyl ether is modeled based on the ReaxFF force field, and the thermal decomposition processes at different temperatures and gas atmospheres were simulated and the pathways of the small molecule products were clarified. The results show that epoxy resin will produce small molecule gas products, such as H2, CO, H2O, OH, CH2O, and free radicals, in the process of pyrolysis; the presence of amino groups also generates nitrogen-containing radicals, such as CN, CH2N, and C2H4N; as the reaction temperature increases, the rate of pyrolysis reaction will be accelerated. The same temperature in oxygen and water atmospheres can accelerate the breakage of epoxy resin main chain by promoting the breakage of carbon and oxygen bonds and, at the same time, promote the generation of small molecule gases, such as H2 and CO. [ABSTRACT FROM AUTHOR]

Background This study was designed to assess stress levels and related factors during the coronavirus disease 2019 (COVID-19) epidemic among individuals in centralized quarantine camps in Wenzhou, China. Methods The survey was conducted using a questionnaire. The questionnaire included questions on sociodemographic characteristics, life events related to the COVID-19 and stressful situations, as well as Perceived Stress Scale-14. Participants included close contacts of patients with COVID-19 or at-risk individuals in quarantine camps. Multivariate logistic regression was used to analyze different factors affecting perceived stress. Results The prevalence of high stress among quarantine camp participants was 37.45%. Of the 881 respondents, 51.99% were concerned about the difficulty of controlling the epidemic, 46.20% were concerned about the health of themselves and their family members and 39.61% were concerned about not being able to leave their homes. Multivariate logistic regression analysis revealed statistically significant differences in the prevalence of stress among different groups for certain variables, including occupation, education level and knowledge of COVID-19 (all P  < 0.05). Our study found that at-risk individuals and close contacts experienced high levels of stress in quarantine camps during the COVID-19 pandemic. Conclusions These findings suggest that centralized quarantine policies should be adapted and optimized to minimize negative psychological effects on quarantined individuals. [ABSTRACT FROM AUTHOR]

Mercury (Hg) is a toxic element which impacts on biological systems and ecosystems. Because the toxicity of Hg species is highly dependent on their concentration levels and chemical forms, the sensitive identification of the chemical forms of Hg—i.e., Hg speciation—is of major significance in providing meaningful information about the sources of Hg exposure. In this study, a microfluidic-based device made of high-clarity poly(methyl methacrylate) (PMMA) was fabricated. Then, titanium dioxide nanoparticles (nano-TiO2s) were attached to the treated channel's interior with the aid of poly(diallyldimethylammonium chloride) (PDADMAC). After coupling the nano-TiO2-coated microfluidic-based photocatalyst-assisted reduction device (the nano-TiO2-coated microfluidic-based PCARD) with high-performance liquid chromatography (HPLC) and inductively coupled plasma mass spectrometry (ICP-MS), a selective and sensitive, hyphenated system for Hg speciation was established. Validation procedures demonstrated that the method could be satisfactorily applied to the determination of mercury ions (Hg2+) and methylmercury ions (CH3Hg+) in both human urine and water samples. Remarkably, the zeta potential measured clearly indicated that the PDADMAC-capped nano-TiO2s with a predominance of positive charges indeed provided a steady force for firm attachment to the negatively charged device channel. The cause of the durability of the nano-TiO2-coated microfluidic-based PCARD was clarified thus. [ABSTRACT FROM AUTHOR]

The design optimization of a direct-drive permanent magnet synchronous generator (DDPMSG) is of great significance for wind turbines because of its unique advantages. This paper proposes a two-stage model to realize multi-objective design optimization for a 6 MW DDPMSG. In the first stage, a surrogate optimized response surface model based on an improved sparrow search algorithm (ISSA) was established for modeling the cogging torque and generator efficiency. In the second-stage model, a multi-objective optimization model is proposed to optimize the cogging torque and generator efficiency of the DDPMSG. Finally, the proposed two-stage model was used for a 6 MW DDPMSG design optimization, and the simulation results demonstrated the superiority and rationality of the proposed model. In the first-stage model, the proposed surrogate model based on the ISSA had a better modeling accuracy and lower errors. Compared with traditional response surface models and correlation analysis models, the proposed optimized surrogate model reduced errors in the cogging torque by 34.63% and 42.97%, respectively, while the errors in the efficiency models were reduced by 12.92% and 60.78%, respectively, which indicates the superiority of the first-stage model. In the second stage, compared with the single-objective optimization model, the multi-objective optimization model achieved a trade-off optimization between the cogging torque and the efficiency. Compared with the cogging torque optimization model, the proposed model optimized the efficiency by 101.41%. Compared with the efficiency optimization model, the proposed model reduced the cogging torque by 16.67%. These results verified the superiority and rationality of the second-stage model. [ABSTRACT FROM AUTHOR]

Research on knowledge hiding has largely focused on its antecedents while overlooking its consequences. Drawing on moral cleansing theory, we adopt a "perpetrator-centric view" and posit that employees who engage in playing dumb and evasive hiding–two specific knowledge hiding behaviors that involve deception–will subsequently perform more organizational citizenship behavior directed toward individuals (OCB-I) because they perceive a loss of moral credits following their moral transgression. Further, we propose that the indirect effects are contingent on perpetrators' moral identity internalization. We tested our hypotheses using a time-lagged research design with a sample of 362 respondents from a large pharmaceutical group company. Consistent with our hypotheses, we found that employees who engaged in playing dumb and evasive hiding subsequently exhibited more OCB-I as they perceived a loss of moral credits, whereas employees who engaged in rationalized hiding did not. In addition, the positive relationships between playing dumb and evasive hiding with perceived loss of moral credits were stronger when perpetrators had high moral identity internalization, as were the indirect effects of playing dumb and evasive hiding on OCB-I via perceived loss of moral credits. Our research contributes to the understanding of when and how engaging in knowledge hiding affects perpetrators and their compensatory behaviors toward coworkers. [ABSTRACT FROM AUTHOR]

Accurate monitoring of small molecules and precise characterization of the secretory ability of neurons are essential for effective diagnosis of neurological diseases. However, existing technologies for monitoring small molecules only provide approximate results. Plasmonic‐based biosensors are a potential solution in this biological application. Nevertheless, optical sensing nanoparticles require precise control of interparticle distance, particle shape and morphology, which can be challenging. This article discovers that the trapping of small molecules to aptamers induces a conformational change that alters the nanostructure of irregularly shaped Au nanoclusters (NCs) and aptamers due to the strong structure‐property relationships of Au NC‐aptamers. This change can be detected via resonance Rayleigh scattering (RRS) intensity in the dark‐field. This new technology overcomes the challenges of precise control of individual nanoparticles and the difficulty of small spectral peak shifts. The Au NC‐aptamers sensing device has a detection limit of 0.112 pm for dopamine, and this work detects 0.226 pm of dopamine surrounding a single epileptic neuron in polarization, which is more than those of healthy neurons. Overall, this easy‐to‐fabricate Au NC‐aptamers‐based technology has a high potential for monitoring small molecules and determining the secretory ability of single neurons, which is not possible using traditional technologies. [ABSTRACT FROM AUTHOR]

Laminated bamboo columns with box sections are favored by designers because they overcome the disadvantage of small elastic modulus, but local buckling behavior caused by an excessive width-to-thickness ratio will lead to a non-uniform distribution of stress. The discontinuous cracks at the glued joints and waveform deformation indicate that the local buckling has a significant effect on the bearing capacity of columns with box sections. However, few studies have been reported on the evaluation of bearing capacity considering local stability due to non-uniformity and discontinuity. The experiments on 5 glued laminated bamboo columns with box sections (GLBCs) with different length-to-width ratios under axial compression were carried out. The test results showed that the waveform bulging failure occurred on the surface of GLBCs before the overall buckling, and an obvious debonding failure occurred between the bamboo plates. These failures aggravated the local buckling failure. As the length-to-width ratio increased, the number of waveforms buckling increased, the lower the bearing capacity. To evaluate the local stability of GLBCs accurately, a new anisotropic plate model considering the width correction coefficient and material anisotropy for the critical buckling load of GLBC was proposed. Furthermore, it can be found that an appropriate width-to-thickness ratio can effectively avoid local buckling failure. A formula for the critical width-to-thickness ratio of GLBCs under different slenderness ratios was proposed. In this paper, the anisotropic plate model proposed can accurately evaluate the bearing capacity considering the local stability of GLBCs under axial compression. [ABSTRACT FROM AUTHOR]

Aggregate-induced emission luminogens (AIEgens) have been widely used in biological imaging, chemical sensing, and disease treatments. The rational design and construction of AIEgens have received considerable research interests during the last few years. Herein, molecular docking-aided AIEgen design has been reasonably proposed and AIEgen TBQZY with excellent 1O2 generation ability has been synthesized. The newly developed TBQZY could efficiently kill S. epidermidis and methicillin-resistant S. epidermidis (MRSE) by tightly binding to bacteria and triggering the accumulation of 1O2 in bacteria. TBQZY specifically regulated the immune system and polarized macrophages from M1 to M2 to accelerate the elimination of biofilm in vivo. In addition, healing acceleration was observed in chronic wounds treated with TBQZY, and side effects were negligible. Meanwhile, TBQZY had extraordinary potential for combating drug-resistant bacteria in the clinical setting. This research not only provided new concepts for the design of AIEgens, but also shed some lights on the discovery of drugs against drug-resistant bacteria. [ABSTRACT FROM AUTHOR]