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OBJECTIVE: Stigma can create divisions within societies, hindering social cohesion and cooperation. Notably, it has significant public health implications, especially during infectious disease outbreaks like COVID-19. However, little is known about the neural and molecular basis of disease-related stigma and their association with individual differences. METHODS: To address this gap, we performed a double-blind, placebo-controlled, within-subject design study with 70 males, to investigate the effect of intranasal oxytocin (OT) administration on the explicit and implicit processing of disease-related stigma (i.e., COVID-19 stigma). After self-administrated 24 IU of OT or placebo, participants completed a stigma evaluation task and an Implicit Association Test (IAT) to assess the explicit and implicit processes of stigma evaluation, respectively. RESULTS: The results showed that oxytocin amplified the differences between participants with high and low social anxiety in explicit COVID-19 stigma, with a higher inclination to attribute the stigmatized status of the stigmatized targets (i.e., COVID-19 related group) to personal causes in high social anxiety individuals, but reduced blame towards the stigmatized targets in low social anxiety individuals under oxytocin compared to placebo treatment. Furthermore, oxytocin strengthened the connections between responsibility attribution and the other processes (i.e., emotional, approach motivation, social deviance). While no modulation of oxytocin on implicit stigma emerged, oxytocin did modulate the associations between specific dimensions of explicit stigma (i.e., social deviance and approach motivation) and implicit stigma. CONCLUSION: In conclusion, these findings demonstrated that intranasal oxytocin administration could temporally impact the explicit cognitive judgment in disease-related stigma but not the implicit aspect; furthermore, it modulated in distinct ways in individuals with different levels of social anxiety. These findings highlight the trait-dependent oxytocin modulation on disease-related stigma, implying that oxytocin is partly involved in the endocrine system of disease-related stigma. By unraveling the molecular basis of stigma and its association with individual traits, such as social anxiety, we can tailor interventions to meet specific needs of different individuals in the future.

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The discovery of new targets and lead compounds is the key to developing new pesticides. The herbicidal target of drupacine has been identified as shikimate dehydrogenase (SkDH). However, the mechanism of interaction between them remains unclear. This study found that drupacine specifically binds to SkDH with a dissociation equilibrium constant (KD) of 8.88 µM and a Kd value of 2.15 µM, as confirmed by surface plasmon resonance and microscale thermophoresis. Site-directed mutagenesis coupled with fluorescence quenching analysis indicated that residue THR431 was the key amino acid site for drupacine binding to SkDH. Nine compounds with the best binding ability to SkDH were identified by virtual screening from about 120,000 compounds. Among them, compound 8 showed the highest inhibition rate with values of 41.95% against SkDH, also exhibiting the strongest herbicidal activity. This research identifies a novel potential target SkDH and a candidate lead compound with high herbicidal activity for developing new herbicides.

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Background: The choroid is the most vascularized structure in the human eye, associated with numerous retinal and choroidal diseases. However, the vessel distribution of choroidal sublayers has yet to be effectively explored due to the lack of suitable tools for visualization and analysis. Methods: In this paper, we present a novel choroidal angiography strategy to more effectively evaluate vessels within choroidal sublayers in the clinic. Our approach utilizes a segmentation model to extract choroidal vessels from OCT B-scans layer by layer. Furthermore, we ensure that the model, trained on B-scans with high choroidal quality, can proficiently handle the low-quality B-scans commonly collected in clinical practice for reconstruction vessel distributions. By treating this process as a cross-domain segmentation task, we propose an ensemble discriminative mean teacher structure to address the specificities inherent in this cross-domain segmentation process. The proposed structure can select representative samples with minimal label noise for self-training and enhance the adaptation strength of adversarial training. Results: Experiments demonstrate the effectiveness of the proposed structure, achieving a dice score of 77.28 for choroidal vessel segmentation. This validates our strategy to provide satisfactory choroidal angiography noninvasively, supportting the analysis of choroidal vessel distribution for paitients with choroidal diseases. We observed that patients with central serous chorioretinopathy have evidently (P < 0.05) lower vascular indexes at all choroidal sublayers than healthy individuals, especially in the region beyond central fovea of macula (larger than 6 mm). Conclusions: We release the code and training set of the proposed method as the first noninvasive mechnism to assist clinical application for the analysis of choroidal vessels.

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To explore the relationship between serum folic acid (FA) or Vitamin B12 (VB12) and elevated BP in children and adolescents. Both a nested case control and a cohort study were designed to explore the relationship between serum folic acid (FA) or Vitamin B12 (VB12) and elevated blood pressure (BP). All the included participants were from primary school. A total of 326 subjects (116:210) in nested case control were from an established cohort. And 270 participants without hypertension at baseline and followed in 2019 in cohort. FA and VB12 levels were lower in the elevated BP group than in the control group, and homocysteine level was higher than that in the control group. In the elevated BP group, overweight/obese children had lower FA than overweight/obese children in the normal BP group. FA was positively correlated with high-density lipoprotein (HDL) and Apo lipoprotein A (APOA), but negatively correlated with triglyceride (TG). FA was significantly correlated with elevated BP in children and adolescents (ß = -0.353, P = 0.032), after adjusting VB12, and homocysteine (HCY), and the interaction effect of FA*HCY was significant. Both systolic and diastolic BP levels were statistically lower in the FA high exposure group than in the FA low exposure group in the cohort study. This study found that FA and vitamin B12 deficiency in childhood was correlated with elevated BP levels, which may affect BP by regulating lipid levels, and confirmed the importance of maintaining high levels of FA and vitamin B12 in childhood either by diet or supplementation.

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Despite China's building into a leading sporting nation and sport-tourism integration high-quality development strategy in the 20th National Congress of the Communist Party of China, existing tourism studies seldom concern sport-tourism integration, especially their spatial hot spots and evolutional trend based on geospatial big data. This study aims to probe into the spatiality and the underlying mechanism of sport tourism through internet attention data in 2015, 2018, and 2021 by social network analysis, with a specific focus on aero-sports tourism. Shaanxi Province is chosen as the study site given its advantages of rich aero-sports tourism resources and various aero-sports modes (e.g., sky diving, paragliding, etc.). The results are concluded: (1) At the provincial scale, the aero-sports tourism internet attention shows a pattern of "strong in the middle and weak in the north and south". (2) At the regional scale, the sub-group clusters within the three specific regions (Shanbei, Guanzhong, and Shannan) of Shaanxi Province turn to be inter-regional clusters. Guanzhong region, especially with Xi'an as the core, is dominant in connecting its peripheral area. Since 2016, the radiation effects of the Guanzhong Region have shown a homogeneous trend of yearly growth and effect strengthening, yet become loosely connected with a heterogeneous trend in 2021 due to the COVID-19 epidemic. (3) At the city scale, the core area of aero-sports tourism internet attention expanded from Xi'an and Xianyang to Yulin and Baoji from 2015 to 2021, resulting from urban economic strength and aviation flight camp club development. (4) The number of general aviation manufacturers, tourist attendance, and tourism revenue significantly affect aero-sports tourism internet attention.

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Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

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The 2022 eruption of the Hunga submarine volcano injected an unprecedented volume of water vapor into the stratosphere, presenting a unique, natural experiment for ascertaining the influence of stratospheric water vapor within the global radiation budget. This study examines the radiative forcings of the Hunga stratospheric water vapor enhancement, comparing stratosphere-adjusted radiative forcing derived from offline methods to an effective radiative forcing derived from Earth System Model simulations. Assuming a uniform 2 parts per million mass mixing ratio increase of water vapor in the Southern Hemisphere stratosphere, we estimated the instantaneous, stratosphere-adjusted, and overall effective radiative forcing to be -0.04, 0.08, and 0.05 W m-2, respectively. The lower magnitude of the positive volcanic stratospheric water vapor effective radiative forcing is due to compensating effects from atmospheric adjustments. Ensemble simulations of a coupled atmosphere-ocean model suggest a surface warming of 0.05 K, affirming a limited influence on global mean surface temperature from the volcanic stratospheric water vapor injection.

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BACKGROUND: Metabolic syndrome (MetS) is highly prevalent in individuals with schizophrenia (SZ), leading to negative consequences like premature mortality. Gut dysbiosis, which refers to an imbalance of the microbiota, and chronic inflammation are associated with both SZ and MetS. However, the relationship between gut dysbiosis, host immunological dysfunction, and SZ comorbid with MetS (SZ-MetS) remains unclear. This study aims to explore alterations in gut microbiota and their correlation with immune dysfunction in SZ-MetS, offering new insights into its pathogenesis. METHODS AND RESULTS: We enrolled 114 Chinese patients with SZ-MetS and 111 age-matched healthy controls from Zhejiang, China, to investigate fecal microbiota using Illumina MiSeq sequencing targeting 16 S rRNA gene V3-V4 hypervariable regions. Host immune responses were assessed using the Bio-Plex Pro Human Cytokine 27-Plex Assay to examine cytokine profiles. In SZ-MetS, we observed decreased bacterial α-diversity and significant differences in ß-diversity. LEfSe analysis identified enriched acetate-producing genera (Megamonas and Lactobacillus), and decreased butyrate-producing bacteria (Subdoligranulum, and Faecalibacterium) in SZ-MetS. These altered genera correlated with body mass index, the severity of symptoms (as measured by the Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms), and triglyceride levels. Altered bacterial metabolic pathways related to lipopolysaccharide biosynthesis, lipid metabolism, and various amino acid metabolism were also found. Additionally, SZ-MetS exhibited immunological dysfunction with increased pro-inflammatory cytokines, which correlated with the differential genera. CONCLUSION: These findings suggested that gut microbiota dysbiosis and immune dysfunction play a vital role in SZ-MetS development, highlighting potential therapeutic approaches targeting the gut microbiota. While these therapies show promise, further mechanistic studies are needed to fully understand their efficacy and safety before clinical implementation.

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As a promising direct measurement method of atmospheric hydroperoxyl radicals (HO2), bromide chemical ionization mass spectrometry (Br-CIMS) has been first demonstrated by Sanchez et al. (Atmos. Meas. Tech. 2016, 9, 3851-3861). However, field application of this method is currently still sparse, and there is still a gap between measured HO2 concentrations and calculated ones derived from the atmospheric equilibrium between HO2 and peroxynitric acid (HO2NO2). In this work, we constructed an improved Br-CIMS with optimizations of custom-built front-end devices, chamber pressures, and instrumental voltages to achieve a 3σ detection limit of 0.5 ppt at an integration time of 60 s and a sensitivity of 1-3 cps ppt-1 under a total reagent ion signal of 0.2 MHz for HO2 detection. HO2NO2, a product from atmospheric reactions between HO2 and NO2, can also be detected by Br-CIMS, whose interference on the HO2 measurement was found but nearly eliminated by regulating key CIMS voltages to minimize the decomposition of (BrHO2NO2)- ions in the MS. In addition, a 2 week field campaign was carried out in urban Shanghai, demonstrating that the interference of HO2 from ambient HO2NO2 was less than 10% of the true HO2 signal under our optimized CIMS voltage setting. Our study suggests that Br-CIMS is a reliable technique for atmospheric HO2 measurements.

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BACKGROUND: Spontaneous thought is a universal, complex, and heterogeneous cognitive activity that significantly impacts mental activity and strongly correlates with mental disorders. METHODS: Utilizing the think-aloud method, we captured spontaneous thoughts during rest from 38 diagnosed with depression, alongside 36 healthy controls and 137 healthy individuals. Through a comprehensive assessment of various dimensions of thought content, we compared thought content between individuals with depression and healthy controls, and between healthy women and men. Finally, we employed natural language processing (NLP) to develop regression models for multidimensional content assessment and a classification model to differentiate between individuals with and without depression. RESULTS: Compared to healthy controls, individuals with depression had more internally oriented and less externally oriented spontaneous thoughts. They focused more on themselves and negative things, and less on positive things, experiencing higher levels of negative emotions and lower levels of positive emotions. Besides, we found that compared to healthy men, healthy women's spontaneous thoughts focus more on interoception, the self, past events, and negative events, and they experience higher levels of negative emotions. Meanwhile, we identified the potential application of the think-aloud method to collect spontaneous thoughts and integrate NLP in the field of depression. CONCLUSIONS: This study offers direct insights into the stream of thought during individuals' resting state, revealing differences between individuals with depression and healthy controls, as well as sex differences in the content of spontaneous thoughts. It enhances our understanding of spontaneous thought and offers a new perspective for preventing, diagnosing, and treating depression.

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The inhibitory properties and underlying mechanism of chlorine dioxide (ClO2) fumigation on the pathogen Ceratocystis fimbriata (C. fimbriata) and resultant sweetpotato black rot were investigated in vitro and in vivo. Results revealed that the ClO2 fumigation effectively inhibited fungal growth and induced obvious morphological variation of C. fimbriata mycelia. Furthermore, the mycelial membrane suffered damage, as evidenced by a significant increase in malondialdehyde content and the leakage of protein and nucleic acid from mycelia cells, accompanied by a marked decrease in ergosterol content. Additionally, ClO2 fumigation caused spores cell membrane damage, a notable decrease in spore viability, and induced cell apoptosis as indicated by reductions in spore germination rate, two fluorescence staining observations, and flow cytometry analysis. Moreover, the decay diameter of sweetpotato black rot lesions decreased significantly after ClO2 fumigation, and the growth of C. fimbriata was also inhibited. These findings present a novel and effective technology for inhibiting the progression of sweetpotato black rot.

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BACKGROUND: Housing has been associated with dementia risk and disability, but associations of housing with differential patterns of neuropsychiatric symptoms (NPS) among dementia-free older adults remain to be explored. The present study sought to explore the contribution of housing status on NPS and subsyndromes associated with cognitive dysfunction in community-dwelling dementia-free elderly in Singapore. METHODS: A total of 839 dementia-free elderly from the Epidemiology of Dementia in Singapore (EDIS) study aged ≥ 60 were enrolled in the current study. All participants underwent clinical, cognitive, and neuropsychiatric inventory (NPI) assessments. The housing status was divided into three categories according to housing type. Cognitive function was measured by a comprehensive neuropsychological battery. The NPS were assessed using 12-term NPI and were grouped into four clinical subsyndromes: psychosis, hyperactivity, affective, and apathy. Associations of housing with composite and domain-specific Z-scores, as well as NPI scores, were assessed using generalized linear models (GLM). Binary logistic regression models analysed the association of housing with the presence of NPS and significant NPS (NPI total scores ≥ 4). RESULTS: Better housing status (5-room executive apartments, condominium, or private housing) was associated with better NPS (OR = 0.49, 95%CI = 0.24 to 0.98, P < 0.05) and significant NPS profile (OR = 0.20, 95%CI = 0.08 to 0.46, P < 0.01), after controlling for demographics, risk factors, and cognitive performance. Compared with those living in 1-2 room apartments, older adults in better housing had lower total NPI scores (ß=-0.50, 95%CI=-0.95 to -0.04, P = 0.032) and lower psychosis scores (ß=-0.36, 95%CI=-0.66 to -0.05, P = 0.025), after controlling for socioeconomic status (SES) indexes. Subgroup analysis indicated a significant correlation between housing type and NPS in females, those of Malay ethnicity, the more educated, those with lower income, and those diagnosed with cognitive impairment, no dementia (CIND). CONCLUSIONS: Our study showed a protective effect of better housing arrangements on NPS, especially psychosis in a multi-ethnic Asian geriatric population without dementia. The protective effect of housing on NPS was independent of SES and might have other pathogenic mechanisms. Improving housing could be an effective way to prevent neuropsychiatric disturbance among the elderly.

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The origin of life on Earth is believed to be from the ocean, which offers abundant resources in its depths. However, deep-sea operations are limited due to the lack of underwater robots and rigid grippers with sensitive force sensors. Therefore, it is crucial for deep-sea pressure sensors to be integrated with mechanical hands for manipulation. Here, a flexible stress sensor is presented that can function effectively under high water pressure in the deep ocean. Inspired by biological structures found in the abyssal zone, our sensor is designed with an internal and external pressure balance structure (hollow interlocking spherical structure). The digital light processing (DLP) three-dimensional (3D) printing technology is utilized to construct this complex structure after obtaining optimized structural parameters using finite element simulation. The sensor exhibits linear sensitivity of 0.114 kPa-1 within the range of 0-15 kPa and has an extremely short response time of 32 ms, good dynamic-static load response capability, and excellent resistance cycling stability. It shows high sensitivity of 1.74 kPa-1 even under 30 MPa static water pressures and the theoretical working pressure can exceed 110 MPa, which provides a new solution for deep-sea robots.

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Milk alternative attracts more attention due to nutrition benefits, but the low solubility and the calcium deficiency of plant protein hinder the development of milk alternatives. Therefore, pH shifting was optimized to improve chickpea protein solubility and calcium fortification while ensuring good digestibility. The results showed that pH shifting reduced the particle size from 2197.67 ± 178.2 nm to 80.2 ± 2 nm, and increased the net ζ potential from -0.48 ± 0.24 to -21.27 ± 0.65 due to the unfolding of secondary protein structure, by which chickpea protein bring better solution stability. Additionally, the whiteness of the solution with chickpea protein increased. The calcium addition kept the solution stable with small particle size despite a slight increase. The microstructure of chickpea protein during digestion was well disrupted even with fortifying calcium. This study provides proof of the positive effect of pH shifting on chickpea protein stability and calcium fortification.

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Background: Capecitabine has been reported to be associated with severe gastrointestinal (GI) adverse drug reactions (gastrointestinal ulceration, haemorrhage, and obstruction). However, statistical correlations have not been demonstrated, and specific GI adverse drug reactions, such as GI obstruction, are not listed on its label. Aim: We aimed to determine the associations between capecitabine and GI ulceration, haemorrhage, or obstruction among patients with breast cancer by examining data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: We performed disproportionality analysis of GI ulceration, haemorrhage, and obstruction by evaluating the reporting odds ratio (ROR) and the information component (IC) with their 95% confidence intervals (CIs). Results: We identified 279 patients with capecitabine-associated GI ulceration, haemorrhage, or obstruction reported between 1 January 2004 and 31 December 2020. One-fourth of the cases of GI ulceration, haemorrhage, or obstruction resulted in death. Capecitabine as a drug class had disproportionately high reporting rates for GI ulceration [ROR 1.94 (1.71-2.21); IC 0.80 (0.60-0.99)], haemorrhage [ROR 2.27 (1.86-2.76); IC 0.99 (0.69-1.28)], and obstruction [ROR 2.19 (1.63-2.95); IC 0.96 (0.51-1.40)]. Conclusion: Pharmacovigilance research on the FAERS has revealed a slight increase in reports of GI ulceration, haemorrhage, and obstruction in capecitabine users, which may cause serious or deadly consequences. In addition to the adverse reactions described in the package insert, close attention should be paid to GI obstruction to avoid discontinuation or life-threatening outcomes.

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Purpose: to explore the anti-inflammatory effects of a nanobody (Nb) specific to ß-glucan on fungal keratitis (FK). Methods: in order to verify the therapeutic and anti-inflammatory efficacy of Nb in FK, the severity of inflammation was assessed with inflammatory scores, hematoxylin-eosin (HE) staining, and myeloperoxidase (MPO) assays. In corneas of mice of FK model and human corneal epithelial cells stimulated by fungal hyphae, real-time reverse transcriptase polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay were used to detect the expression levels of inflammatory cytokines and pattern recognition receptors (PRRs). In vivo, macrophages and neutrophils infiltration in the cornea stroma was detected by immunofluorescence (IFS) staining. Results: In murine models infected with Aspergillus fumigatus (A. fumigatus), Nb treatment could reduce the inflammatory scores. HE staining and MPO results showed Nb significantly alleviated corneal edema and reduced inflammatory cell infiltration 3 days post-infection. In addition, the expression levels of LOX-1 and Dectin-1 were significantly decreased in the Nb group in vivo. The expression of chemokines CCL2 and CXCL2 also decreased in the Nb group. Compared with the PBS group, the number of macrophages and neutrophils in the Nb group was significantly decreased, which was shown in IFS results. Moreover, Nb attenuated the expression of Dectin-1, LOX-1, and inflammatory mediators, including IL-6 and IL-8 in vitro. Conclusion: our study showed that Nb could alleviate FK by downregulating the expression of PRRs and inflammatory factors as well as reducing the infiltration of macrophages and neutrophils.

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HPK1, a well-known negative regulator of T cell receptors, can cause T cell dysfunction when abnormally activated. In this study, a PROTAC C3 was designed and synthesized by optimizing the physicochemical properties of the warhead, linker, and CRBN ligand. C3 demonstrated significant HPK1 degradation with a DC50 of 21.26 nM, excellent oral absorption with a Cmax of 10,899.92 ng/mL, and a bioavailability (F %) of 81.7%. C3 also showed degradation selectivity and potent immune activation effects. Proteomic and WB analyses revealed that immune-activating effect of C3 is attributed to the inhibition of SLP76 and NF-κB signaling pathways, as well as the enhancement of MAPK signaling pathway transduction. In vivo efficacy study demonstrated that oral administration of C3 in combination with anti-PDL1 antibody significantly inhibited tumor growth (tumor growth inhibition = 65.58%). These findings suggest that C3, a novel HPK1 PROTAC, holds promise as a therapeutic agent for tumor immunotherapy.

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BACKGROUND: Considering the high comorbidity, shared risk factors, and genetic pathways between irritable bowel syndrome (IBS) and major depressive disorder (MDD), we hypothesized that there would be both shared and disorder-specific alterations in brain function. METHODS: A total of 39 IBS patients, 39 MDD patients, and 40 healthy controls (HCs) were enrolled and matched for sex, age, and educational level. All subjects underwent resting-state functional MRI. The clinical variables of anxiety, depression, gastrointestinal symptoms and alexithymia were recorded. The 12 subregions of the striatum were employed as seeds to assess their functional connectivity (FC) with every voxel throughout the whole brain. RESULTS: Compared to HC, IBS and MDD patients exhibited aberrant frontal-striatal circuitry. We observed a common decrease in FC between the dorsal striatum and regions of the hippocampus, sensorimotor cortex, and prefrontal cortex (PFC) in both IBS and MDD patients. Patients with IBS exhibited disorder-specific decreases in FC within the striatum, along with reduced connectivity between the ventral striatum and sensorimotor cortex. In contrast, MDD patients showed disorder-specific hyperconnectivity in the medial PFC-limbic system. Receiver operating characteristic curve analysis showed that frontal-striatal FC values could serve as transdiagnostic markers of IBS and MDD. Within the IBS group, striatal connectivity was not only negatively associated with weekly abdominal pain days but also negatively correlated with the levels of anxiety and alexithymia. CONCLUSIONS: This exploratory analysis indicated that patients with IBS and MDD exhibited both shared and disorder-specific frontal-striatal circuit impairments, potentially explaining both comorbidity and distinct phenotypes.

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INTRODUCTION: Patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) and concomitant multivessel coronary artery disease (CAD) are considered patients with extremely high-risk atherosclerotic cardiovascular disease (ASCVD), and current guidelines specify a lower low-density lipoprotein cholesterol (LDL-C) target for this population. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to effectively reduce LDL-C levels on a statin background. Additionally, several studies have confirmed the role of PCSK9 inhibitors in plaque regression and reducing residual cardiovascular risk in patients with ACS. However, those studies included coronary lesions with a degree of stenosis <50%. Whether the application of PCSK9 inhibitors in patients with NSTE-ACS with non-culprit artery critical lesions (stenosis degree between 50% and 75%) has a similar effect on plaque regression and improvement of cardiovascular outcomes remains unknown, with a lack of relevant research. This study aims to further investigate the safety and efficacy of evolocumab in patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%). METHODS AND ANALYSIS: In this single-centre clinical randomised controlled trial, 122 patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%) will be randomly assigned to either the evolocumab treatment group or the standard treatment group after completing culprit vessel revascularisation. The evolocumab treatment group will receive evolocumab in addition to statin therapy, while the standard treatment group will receive standard statin therapy. At baseline and week 50, patients in the evolocumab treatment group will undergo coronary angiography and OCT imaging to visualise pre-existing non-lesional vessels. The primary end point is the absolute change in average minimum fibrous cap thickness (FCT) from baseline to week 50. Secondary end points include changes in plaque lipid arc, lipid length, macrophage grading, lipid levels and major adverse cardiovascular events during the 1-year follow-up period. ETHICS AND DISSEMINATION: Ethics: this study will adhere to the principles outlined in the Helsinki Declaration and other applicable ethical guidelines. This study protocol has received approval from the Medical Research Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), with approval number 2022-ky214. DISSEMINATION: we plan to disseminate the findings of this study through various channels. This includes publication in peer-reviewed academic journals, presentation at relevant academic conferences and communication to the public, policymakers and healthcare professionals. We will also share updates on the research progress through social media and other online platforms to facilitate the exchange and application of scientific knowledge. Efforts will be made to ensure widespread dissemination of the research results and to have a positive impact on society. TRIAL REGISTRATION NUMBER: ChiCTR2200066675.

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BACKGROUND: Microtubule polymerization is usually considered as the upstream of apoptotic cell death induced by taxanes, but recently published studies provide more insights into the mechanisms responsible for the antineoplastic effect of taxanes. In this study, we figure out the role of the stress-related PERK/eIF2α axis in tumor cell death upon taxane treatment along with paclitaxel resistance. METHODS: Utilizing immunoblot assay, the activation status of PERK-eIF2α signaling was detected in a panel of cancer cell lines after the treatment of taxanes. The causal role of PERK-eIF2α signaling in the cancer cell apoptosis induced by taxanes was examined via pharmacological and genetic inhibitions of PERK. The relationship between microtubule polymerization and PERK-eIF2α activation was explored by immunofluorescent and immunoblotting assays. Eventaually, the combined therapeutic effect of paclitaxel (PTX) and CCT020312, a PERK agonist, was investigated in PTX-resistant breast cancer cells in vitro and in vivo. RESULTS: PERK-eIF2α axis was dramatically activated by taxanes in several cancer cell types. Pharmacological or genetic inhibition of PERK efficiently impaired taxane-induced apoptotic cell death, independent of the cellular microtubule polymerization status. Moreover, PTX was able to activate the PERK/eIF2α axis in a very low concentration without triggering microtubule polymerization. In PTX-resistant breast cancer cells, the PERK/eIF2α axis was attenuated in comparison with the PTX-sensitive counterparts. Reactivation of the PERK/eIF2α axis in the PTX-resistant breast cancer cells with PERK agonist sensitized them to PTX in vitro. Combination treatment of the xenografted PTX-resistant breast tumors with PERK agonist and PTX validated the synergic effect of PTX and PERK activation in vivo. CONCLUSION: Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to initiate cancer cell apoptosis, which is independent of the well-known microtubule polymerization-dependent manner. Simultaneous activation of PERK-eIF2α signaling would be a promising therapeutic strategy to overcome PTX resistance in breast cancer or other cancers.