Identification of cuproptosis-related miRNAs in triple-negative breast cancer and analysis of the miRNA-mRNA regulatory network.

Introduction: The close association between cuproptosis and tumor immunity in triple-negative breast cancer (TNBC) allows its monitoring for predicting the prognosis of patients with TNBC. Nevertheless, the biological function and prognostic value of cuproptosis-related miRNAs and their target genes have not been reported. Purpose: To construct the miRNA and mRNA-based risk models associated with cuproptosis for patients with TNBC. Methods: Comparison of expression levels for genes associated with cuproptosis was executed between patients in the normal individuals and the TCGA-TNBC cohort. Conducting differential analysis resulted in the identification of differentially expressed miRNA (DE-miRNAs) and differentially expressed genes (DEGs) between the TNBC and Control samples. Screening for prognostic miRNAs and biomarkers involved employing univariate Cox analysis and least absolute shrinkage and selection operator regression analyses. These methods were utilized to construct risk models aimed at predicting the survival of patients with TNBC. Based on the median value of risk scores, patients were then stratified into low- and high-risk groups. Functional enrichment analysis was employed to explore the potential function and pathways of prognostic genes. Additionally, independent prognostic analysis was performed through univariate and multivariate Cox regression. Immune infiltration analysis was performed to examine disparities in the infiltration of immune cells between the two risk groups. Finally, the prognostic gene expression was mined in key cell types of TNBC. Results: We obtained 5213 DEGs and 204 DE-miRNAs related to cuproptosis between TNBC and Control samples. Five prognostic miRNAs (miR-203a-3p, miR-1277-3p, miR-135b-5p, miR-200c-3p, and miR-592) and three biomarkers (DENND5B, IGF1R, and MEF2C) were closely associated with TNBC. Significant differences in the functions of prognostic genes between the two risk groups were observed, encompassing adipogenesis, inflammatory response, and hormone metabolic process. The prognostic gene regulatory network revealed that miR200C-3p regulated ZFPM2 and CFL2, and miR-1277-3p regulated BMP2 and RORA. A nomogram was created based on riskScore, cancer status, and pathologic stage to predict 1/3/5-year survival of patients with TNBC. Immune infiltration analysis indicated that the immune microenvironment may be associated with the progression of TNBC. Interestingly, prognostic genes exhibited higher expression levels in T cells, fibroblasts, endothelial cells, and monocytes compared to other cells. Conclusions: Five prognostic miRNA (miR-203a-3p, miR-1277-3p, miR-135b-5p, miR-200c-3p, and miR-592) and three biomarkers (DENND5B, IGF1R, and MEF2C) were significantly associated with TNBC, it provides new therapeutic targets for the treatment and prognosis of TNBC.

Abrasive Wear Properties of Wear-Resistant Coating on Bucket Teeth Assessed Using a Dry Sand Rubber Wheel Tester.

Ni60-WC coatings with different WC contents on the bucket tooth substrates were pre- pared using laser cladding technology. Their abrasive wear properties were assessed using the dry sand rubber wheel test system. The substrate and the hard-facing layer were tested for comparison. The results showed that the hardness of the Ni60-WC coatings increased with the increase in WC content. The wear resistance of the bucket tooth substrate was greatly improved by hard-facing and laser cladding Ni60-WC coatings. The wear rate of the hard-facing layer was reduced to 1/6 of that of the tooth substrate. The wear rate of the laser cladding coatings with 20-40 wt.% WC was similar to that of the hard-facing layer. It is worth mentioning that the wear rate of the coatings with 60-80 wt.% WC was only 1/4 of that of the hard-facing layer. Micro-cutting with surface plastic deformation was the main wear mechanism of the substrate to form narrow and deep furrows. The wear mechanism of the hard-facing layer was mainly plastic deformation with a wide groove, and the surface cracks promoted the removal of the material. The removal of the binder phase caused by micro-cutting was the main wear mechanism of the laser cladding Ni60-WC coatings. However, the hard phase of WC hinders micro-cutting and plastic deformation, which improves the wear resistance of the coating.

Data-driven evaluation of electric vehicle energy consumption for generalizing standard testing to real-world driving.

Standard energy-consumption testing, providing the only publicly available quantifiable measure of battery electric vehicle (BEV) energy consumption, is crucial for promoting transparency and accountability in the electrified automotive industry; however, significant discrepancies between standard testing and real-world driving have hindered energy and environmental assessments of BEVs and their broader adoption. In this study, we propose a data-driven evaluation method for standard testing to characterize BEV energy consumption. By decoupling the impact of the driving profile, our evaluation approach is generalizable to various driving conditions. In experiments with our approach for estimating energy consumption, we achieve a 3.84% estimation error for 13 different multiregional standardized test cycles and a 7.12% estimation error for 106 diverse real-world trips. Our results highlight the great potential of the proposed approach for promoting public awareness of BEV energy consumption through standard testing while also providing a reliable fundamental model of BEVs.

Ureteropelvic Junction Obstruction Caused by Crossing Vessels in Infants and Young Children.

BACKGROUND: To analyze the clinical characteristics of ureteropelvic junction obstruction (UPJO) caused by crossing vessels (CV) in infants and young children. METHODS: A retrospective analysis was performed on children with UPJO who underwent primary surgery. Patients were classified into laparoscopic pyeloplasty (LP) and open pyeloplasty (OP) groups and classified as ≤3 or >3 (years old) groups. Children with CV-caused UPJO were identified. RESULTS: A total of 747 patients were included. Ninety cases of CV were identified. The CV discovery rate was higher in the LP group (78/457, 17.1%) than in the OP group (12/290, 4.1%) (P < 0.001). In the ≤3 group, the CV discovery rate in the LP group (27/144, 18.8%) was higher than that in the OP group (11/274, 4.0%) (P < 0.001). In the LP group, there was no significant difference between ≤3 (27/144, 18.8%) and >3 (51/313, 16.3%) groups in the CV discovery rate. The rate in children with UPJO was not significantly different at any age (P > 0.05). Progressive aggravation of hydronephrosis (21/27, 77.8%) and symptomatic hydronephrosis (44/51, 86.3%) were the main surgical indications in the ≤3 and > 3 groups, respectively. There were no preoperatively confirmed cases of CV in the ≤3 group. In the OP group, five patients underwent reoperation, three of whom were due to failure to detect CV during the initial operation. CONCLUSIONS: The CV distribution is similar in children with UPJO across all ages; CV in infants and young children are not rare. LP should be considered as CV are prone to being missed during OP. LEVELS OF EVIDENCE: III.

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease.

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (MPro), a highly conserved protease among various CoVs, is essential for viral replication and pathogenesis, making it a prime target for antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 MPro. Among them, MPD2 was demonstrated to effectively reduce MPro protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing MPro protein levels in SARS-CoV-2-infected A549-ACE2 cells. MPD2 also displayed potent antiviral activity against various SARS-CoV-2 strains and exhibited enhanced potency against nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights the potential of targeted protein degradation of MPro as an innovative approach for developing antivirals that could fight against drug-resistant viral variants.

Effect of overweight/obesity on relationship between fractional exhaled nitric oxide and airway hyperresponsiveness in Chinese elderly patients with asthma.

Purpose: This retrospective study investigates the influence of overweight and obesity status on pulmonary function, airway inflammatory markers, and airway responsiveness in elderly asthma patients. Methods: Patients with asthma older than 65 years old who completed a bronchial provocation test (BPT) or bronchial dilation test (BDT) and a fractional exhaled nitric oxide (FeNO) test between December 2015 and June 2020 were identified retrospectively for this study. All of the patients were categorized into overweight/obesity and non-obesity groups based on their BMI. Pulmonary function test (PFT) and FeNO measurements were accomplished according to the 2014 recommendations of the Chinese National Guidelines of Pulmonary Function Test and American Thoracic Society/European Respiratory Society recommendations, respectively. Results: A total of 136 patients with an average age of 71.2 ± 5.40 years were identified. The average BMI was 23.8 ± 3.63, while the value of FeNO was 42.3 ± 38.4 parts per billion (ppb). In contrast to the non-obesity group, which had a value of 48.8 ± 43.1 ppb for FeNO, the overweight/obesity group had a significant lower value of 35.4 ± 31.4 ppb. There was no significant difference in the proportion of individuals with high airway hyperresponsiveness between the overweight/obesity and non-obesity groups (96 patients in total). Multiple linear regression analysis established an inverse correlation between FeNO and Provocation concentration causing a 20% fall in FEV1(PC20) but excluded significant relationships with age and BMI. The model's R is 0.289, and its p value is 0.045. Conclusion: The elderly Chinese Han asthmatics with overweight/obesity had lower FeNO levels than those with non-obese according to our findings. In addition, the FeNO level was inversely correlated between FeNO levels and PC20 in elderly asthmatics.

Influence of para-substituted benzaldehyde derivatives with different push/pull electron strength groups on the conformation of human serum albumin and toxicological effects in zebrafish.

Excessive intake of benzaldehyde and its derivatives can cause irreversible damage to living organisms. Hence, benzaldehyde derivatives with different para-substitutions of push/pull electronic groups were chosen to investigate the effect of different substituent properties on the structure of human serum albumin (HSA). The binding constants, number of binding sites, major interaction forces, protein structural changes, and binding sites of benzaldehyde (BzH) and its derivatives (4-BzHD) with HSA in serum proteins were obtained based on multispectral and molecular docking techniques. The mechanism of BzH/4-BzHD interaction on HSA is mainly static quenching and is accompanied by the formation of a ground state complex. BzH/4-BzHD is bound to HSA in a 1:1 stoichiometric ratio. The interaction forces for the binding of BzH/4-BzHD to HSA are mainly hydrogen bonding and hydrophobic interaction, which are also accompanied by a small amount of electrostatic interactions. The effect of BzH/4-BzHD on HSA conformation follows: 4-Diethylaminobenzaldehyde (4-DBzH) > 4-Nitrobenzaldehyde (4-NBzH) > 4-Hydroxybenzaldehyde (4-HBzH) > 4-Acetaminobenzaldehyde (4-ABzH) > BzH, which means that the stronger push/pull electronic strength of the para-substituted benzaldehyde derivatives has a greater effect on HSA conformation. Furthermore, the concentration-lethality curves of different concentrations for BzH/4-BzHD on zebrafish verified above conclusion. This work provides a scientific basis for the risk assessment of benzaldehyde and its derivatives to the ecological environment and human health and for the environmental toxicological studies of benzaldehyde derivatives with different strengths of push/pull electron substitution.

Spatial and temporal distribution characteristics and risk assessment of heavy metals in groundwater of Pingshuo mining area.

Groundwater pollution in the Pingshuo mining area is strongly associated with mining activities, with heavy metals (HMs) representing predominant pollutants. To obtain accurate information about the pollution status and health risks of groundwater, 189 groups of samples were collected from four types of groundwater, during three periods of the year, and analyzed for HMs. The results showed that the concentration of HMs in groundwater was higher near the open pit, waste slag pile, riverfront area, and human settlements. Except for Ordovician groundwater, excessive HMs were found in all investigated groundwater of the mining area, as compared with the standard thresholds. Fe exceeded the threshold in 13-75% of the groundwater samples. Three sources of HMs were identified and quantified by Pearson's correlation analysis and the PMF model, including coal mining activities (68.22%), industrial, agricultural, and residential chemicals residue and leakage (16.91%), and natural sources (14.87%). The Nemerow pollution index revealed that 7.58% and 100% of Quaternary groundwater and mine water samples were polluted. The health risk index for HMs in groundwater showed that the non-carcinogenic health risk ranged from 0.18 to 0.42 for adults, indicating an acceptable level. Additionally, high carcinogenic risks were identified in Quaternary groundwater (95.45%), coal series groundwater (91.67%), and Ordovician groundwater (26.67%). Both carcinogenic and non-carcinogenic risks were greater for children than adults, highlighting their increased vulnerability to HMs in groundwater. This study provides a scientific foundation for managing groundwater quality and ensuring drinking water safety in mining areas.

XQZ3, a Chlorella pyrenoidosa polysaccharide suppresses cancer progression by restraining mitochondrial bioenergetics via HSP90/AKT signaling pathway.

The mitochondria are known to exert significant influence on various aspects of cancer cell physiology. The suppression of mitochondrial function represents a novel avenue for the advancement of anti-cancer pharmaceuticals. The heat shock protein HSP90 functions as a versatile regulator of mitochondrial metabolism in cancer cells, rendering as a promising target for anticancer interventions. In this work, a novel acid polysaccharide named as XQZ3 was extracted from Chlorella pyrenoidosa and purified by DEAE-cellulose and gel-filtration chromatography. The structural characteristic of XQZ3 was evaluated by monosaccharides composition, methylation analysis, TEM, FT-IR, and 2D-NMR. It was found that XQZ3 with a molecular weight of 29.13 kDa was a complex branched polysaccharide with a backbone mainly composed of galactose and mannose. It exhibited good antitumor activity in vitro and in vivo by patient-derived 3D organoid models and patient-derived xenografts models. The mechanistic investigations revealed that XQZ3 specifically interacted with HSP90, impeding the activation of the HSP90/AKT/mTOR signaling cascade. This, in turn, led to the induction of mitochondrial dysfunction, autophagy, and apoptosis, ultimately resulting in the demise of cancer cells due to nutrient deprivation. This study offers a comprehensive theoretical foundation for the advancement of XQZ3, a novel polysaccharide inhibitor targeting HSP90, with potential as an effective therapeutic agent against cancer.

Prevalence and associated factors of abortion among women with severe mental disorders.

BACKGROUND: Abortion behaviors among individuals with mental disorders presented major obstacles to women's health. However, few studies reported the prevalence and associated factors of abortion among women with severe mental disorders in China. Consequently, this study aims to investigate the prevalence of abortion among female patients in rural communities and identify potential health risks. METHOD: This was a cross-sectional study of 276 women aged 18 years and older with severe mental disorders in rural areas of Shandong Province, China. The pregnancy history, abortion history and socio-demographic characteristics of women were investigated by questionnaire. Logistic regression analysis was employed to examine the associated factors for different abortion behaviors. RESULT: The study showed that 82.61 % (228/276) of patients had a pregnancy history. Among the patients with a pregnancy history, 43.42 % (99/228) reported having had at least one abortion, and 15.79 % (36/228) had more than one. In the other side, 31.58 % (72/228) of them experienced spontaneous abortion, while 12.72 % (29/228) experienced induced abortion. Age at first gestation (aOR 0.80, 95 % CI 0.70-0.90) and age at last gestation (aOR 1.17, 95 % CI 1.07-1.27) were both associated with abortion. Anxiety was related to spontaneous (aOR 1.08, 95 % CI 1.02-1.15) and repeat abortions (aOR 1.10, 95 % CI 1.01-1.19). In addition, religion (aOR 10.47, 95 % CI 2.81-39.01), number of children≥2 (aOR 0.18, 95 % CI 0.04-0.77), and family functioning (aOR 1.31, 95 % CI 1.06-1.63) were associated with induced abortion. CONCLUSION: Women with severe mental disorders in rural regions have notably higher rates of abortion compared to the general female population, particularly for spontaneous abortions. Gestational age and anxiety of pregnant patients deserve attention and preventive measures to avoid the outcomes of abortion.

Effects of sleep deprivation and hazard types on the hazard perception of young novice drivers: An ERP study.

OBJECTIVE: The present study aimed to explore the effects of sleep deprivation on young novice drivers' cognitive neural processing of different hazard types. METHOD: A 2 (sleep deprivation group, control group) × 3 (no hazard, covert hazard, overt hazard) mixed experimental design was used. Twenty-eight young drivers were sleep-deprived (no sleep within the past 24 h), while 28 drivers were in the control group (maintaining a normal schedule throughout the week). Eighty pictures containing a covert hazard (20 pictures), overt hazard (20 pictures) and no hazard (40 pictures) were presented. Participants were asked to press the keyboard quickly if they detected a hazard situation. The reaction time, accuracy, and changes in the N1 (100-150 ms) and N2 (250-350 ms) components of event-related potentials (ERP) measured using electroencephalography (EEG) were obtained. RESULTS: Compared to the control group, the response accuracy of sleep-deprived drivers was higher in the cover-hazard situation and their N1 latency was longer in the no-hazard situation. Compared to the no-hazard and overt-hazard situations, the participants' reaction times and N2 amplitudes were significantly greater, and the response accuracy was significantly lower in the covert-hazard situation. CONCLUSION: Hazard perception is compromised when drivers are sleep-deprived, especially when they are confronted with covert hazard situations. The findings help understand the negative effects of sleep deprivation in the early stage of young novice drivers' hazard perception.

Differentiating the association between age of alcohol use initiation and conditional suicidal behaviors among adolescents.

INTRODUCTION: Suicide and early alcohol use initiation are public health concerns. Previous studies have explored the associations between age of alcohol use initiation and suicidal behaviors, which progresses from ideation to action. Distinguishing between the various associations can help gain a deeper understanding of suicidal behaviors and aid in developing social suicide prevention strategies. METHODS: The study utilized the Youth Risk Behavior Survey to investigate this association. A total of 17 209 students were finally included in the study. Conditional suicidal behaviors included no suicidal behavior (NS), suicidal ideation without a plan or attempt (SINPA), suicide plan without an attempt (SPNA) and suicide attempt (SA). RESULTS: Among 17 209 students, the prevalence of suicidal ideation, suicide plan, and suicide attempt were 21.4%, 17.3%, and 11.1%, respectively. Moreover, 15.2% of the students used alcohol before age 13, whereas 31.7% of students used alcohol at age 13 or older. Compared to NS, students using alcohol showed significant associations with SA (OR = 2.34, p < .001; OR = 1.29, p < .01), SPNA (OR = 1.68, p < .001; OR = 1.19, p < .05) and SINPA (OR = 1.55, p < .001; OR = 1.40, p < .001). Comparing with SINPA and SNPA, students using alcohol before age 13 were associated with SA (OR = 1.61, p < .001; OR = 1.46, p < .001), whereas those using alcohol at or after the age 13 were not associated with SA (OR = 0.98, p > .05; OR = 1.09, p > .05). DISCUSSION: This study demonstrated that early alcohol use initiation was significantly associated with suicide attempts among students with suicidal ideations or plans.

RN0D, a galactoglucan from Panax notoginseng flower induces cancer cell death via PINK1/Parkin mitophagy.

Metabolic alterations within mitochondria, encompassing processes such as autophagy and energy metabolism, play a pivotal role in facilitating the swift proliferation, invasion, and metastasis of cancer cells. Despite this, there is a scarcity of currently available medications with proven anticancer efficacy through the modulation of mitochondrial dysfunction in a clinical setting. Here, we introduce the structural characteristics of RN0D, a galactoglucan isolated and purified from Panax notoginseng flowers, mainly composed of ß-1,4-galactan and ß-1,3/1,6-glucan. RN0D demonstrates the capacity to induce mitochondrial impairment in cancer cells, leading to the accumulation of reactive oxygen species, initiation of mitophagy, and reduction in both mitochondrial number and size. This sequence of events ultimately results in the inhibition of mitochondrial and glycolytic bioenergetics, culminating in the demise of cancer cells due to adenosine triphosphate (ATP) deprivation. Notably, the observed bioactivity is attributed to RN0D's direct targeting of Galectin-3, as affirmed by surface plasmon resonance studies. Furthermore, RN0D is identified as an activator of the PTEN-induced kinase 1 (PINK1)/Parkin pathway, ultimately instigating cytotoxic mitophagy in tumor cells. This comprehensive study substantiates the rationale for advancing RN0D as a potentially efficacious anticancer therapeutic.

Experimental studies on the characteristics of chisel picks in coal cutting for bucket wheel excavators.

Chisel pick is a basic and important rock cutting tool, and the performance of chisel pick directly affects rock mining. In this paper, a rock cutting device was developed for chisel picks cutting experiments. The influence of the depth of cutting, width of chisel pick, rake angle, back clearance angle and tip fillet radius on the cutting performance such as cutting force, normal force, and specific energy has been comprehensively studied. In addition to the general conclusions, the experimental results show that the back clearance angle has an influence range on the cutting, and the ratio of the normal force to the cutting force decreases with the increase of the rake angle; the tip fillet radius greatly improve the mean cutting force and specific energy. The experimental results will provide data support for the design of chisel picks on rock excavation machinery and a more reasonable chisel pick cutting rock mechanics model.

CoT: Contourlet Transformer for Hierarchical Semantic Segmentation.

The Transformer-convolutional neural network (CNN) hybrid learning approach is gaining traction for balancing deep and shallow image features for hierarchical semantic segmentation. However, they are still confronted with a contradiction between comprehensive semantic understanding and meticulous detail extraction. To solve this problem, this article proposes a novel Transformer-CNN hybrid hierarchical network, dubbed contourlet transformer (CoT). In the CoT framework, the semantic representation process of the Transformer is unavoidably peppered with sparsely distributed points that, while not desired, demand finer detail. Therefore, we design a deep detail representation (DDR) structure to investigate their fine-grained features. First, through contourlet transform (CT), we distill the high-frequency directional components from the raw image, yielding localized features that accommodate the inductive bias of CNN. Second, a CNN deep sparse learning (DSL) module takes them as input to represent the underlying detailed features. This memory-and energy-efficient learning method can keep the same sparse pattern between input and output. Finally, the decoder hierarchically fuses the detailed features with the semantic features via an image reconstruction-like fashion. Experiments demonstrate that CoT achieves competitive performance on three benchmark datasets: PASCAL Context 57.21% mean intersection over union (mIoU), ADE20K (54.16% mIoU), and Cityscapes (84.23% mIoU). Furthermore, we conducted robustness studies to validate its resistance against various sorts of corruption. Our code is available at: https://github.com/yilinshao/CoT-Contourlet-Transformer.

Effects of hazard type and confidence level on hazard perception in young male drivers: an ERP study.

Hazard perception refers to a driver's ability to identify potential hazards on the road. Although studies have shown that overconfidence affects drivers' ability to perceive hazards, the neural processing of hazard perception in overconfident drivers under different hazard types has rarely been investigated. A mixed experimental design of 2 (hazard type: hazards, no hazards) × 2 (driver group: overconfident driver, control group) was used. A total of 120 images (60 with hazards and 60 without hazards) were presented to 25 overconfident drivers and 25 drivers in the control group. Reaction time, response accuracy, P200 (200-250 ms), and N2 (280-330 ms) components were measured via event-related potential (ERP) technology. Response times of overconfident drivers are slower than those of the control group regardless of hazard types. The P200 latency of overconfident drivers was longer than that of their peers in hazard situations, while the P200 latency was similar between the two groups in no-hazard situations. Although a significant interaction was found on the N2 amplitude, no significant differences were found between the two groups in both hazard and no-hazard situations. Overconfident drivers have worse hazard perception performance in hazard situations with slower reaction times and greater P200 latencies than their peers. More importantly, P200 amplitude and N2 amplitude are sensitive to hazard types, while P200 amplitude and N2 latency can discriminate between driver groups. The findings help understand the negative impact of overconfidence on young drivers and contribute to the development and training of hazard perception tests.

Recent advances in catalytic oxidation of VOCs by two-dimensional ultra-thin nanomaterials.

Catalytic oxidation, an end-of-pipe treatment technology for effectively purifying volatile organic compounds (VOCs), has received widespread attention. The crux of catalytic oxidation lies in the development of efficient catalysts, with their optimization necessitating a comprehensive analysis of the catalytic reaction mechanism. Two-dimensional (2D) ultra-thin nanomaterials offer significant advantages in exploring the catalytic oxidation mechanism of VOCs due to their unique structure and properties. This review classifies strategies for regulating catalytic properties and typical applications of 2D materials in VOCs catalytic oxidation, in addition to their characteristics and typical characterization techniques. Furthermore, the possible reaction mechanism of 2D Co-based and Mn-based oxides in the catalytic oxidation of VOCs is analyzed, with a special focus on the synergistic effect between oxygen and metal vacancies. The objective of this review is to provide valuable references for scholars in the field.

Global, regional and national burdens of bipolar disorders in adolescents and young adults: a trend analysis from 1990 to 2019.

Background: Bipolar disorder is identified as a cause of severe damage to the physical, psychological and social functioning of adolescents and young adults. Aims: The aim of this study is to ascertain the trends in the burden of bipolar disorder among individuals aged 10-24 years at global, regional and national levels from 1990 to 2019. Methods: The data analysed in this study were from the Global Burden of Diseases 2019. The numbers, rates per 100 000 population, average annual percentage changes (AAPCs) of incidence, prevalence and years lived with disability (YLDs) of bipolar disorder are reported at the global, regional and national levels among individuals aged 10-24 years. Global trends by age, sex and Social Development Index (SDI) were further analysed. Results: Globally, the incidence of bipolar disorder among adolescents and young adults increased from 79.21 per 100 000 population (95% uncertainty interval (UI): 58.13 to 105.15) in 1990 to 84.97 per 100 000 population (95% UI: 61.73 to 113.46) in 2019, AAPC 0.24 (95% confidence interval (CI): 0.22 to 0.26). In the past three decades, there has been an increase in incidence, prevalence and YLDs in both males and females. The largest increase in incidence between 1990 and 2019 was observed in those aged 20-24 years old (from 51.76 per 100 000 population (95% UI: 26.81 to 87.20) in 1990 to 58.37 per 100 000 population (95% UI: 30.39 to 98.55) in 2019; AAPC 0.42 (95% CI: 0.38 to 0.47)). By the SDI quintile, the largest increase in incidence was observed in the middle SDI; however, the high SDI countries had the highest incidence. Regionally, the largest increase in incidence was observed in southern Latin America. At the national level, the most pronounced increase in the incidence was in Greenland. Conclusions: The global increase in incidence among adolescents and young adults between 1990 and 2019 indicates that strategies to improve their mental health still need to be emphasised.

Integrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection.

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are currently underappreciated, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of three-dimensional chromatin organization in mediating host-viral interaction. Furthermore, we discover another anti-viral regulator KLF5, a transcriptional factor involved in sphingolipid metabolism, which is up-regulated, and harbors genetic variations linked to COVID-19 patients with severe symptoms. Anti-viral effects of three identified candidates (DAZAP2/VTA1/KLF5) are confirmed individually. Molecular characterization of DAZAP2/VTA1/KLF5-knockout cells highlights the involvement of genes related to the coagulation system in determining the severity of COVID-19. Together, our results provide further resources for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies.

Design, Preclinical Evaluation, and Clinical Translation of 68Ga-FAPI-LM3, a Heterobivalent Molecule for PET Imaging of Nasopharyngeal Carcinoma.

Extensive research has been conducted on radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH2 (LM3) peptides for imaging of FAP and somatostatin receptor 2 (SSTR2)-positive tumors. In this study, we designed and synthesized a FAPI-LM3 heterobivalent molecule radiolabeled with 68Ga and evaluated its effectiveness in both tumor xenografts and patients with nasopharyngeal carcinoma (NPC). Methods: The synthesis of FAPI-LM3 was based on the structures of FAPI-46 and LM3. After radiolabeling with 68Ga, its dual-receptor-binding affinity was evaluated in vitro and in vivo. Preclinical studies, including small-animal PET and biodistribution evaluation, were conducted on HT-1080-FAP and HT-1080-SSTR2 tumor xenografts. The feasibility of 68Ga-FAPI-LM3 PET/CT in a clinical setting was evaluated in patients with NPC, and the results were compared with those of 18F-FDG. Results: 68Ga-FAPI-LM3 showed high affinity for both FAP and SSTR2. The tumor uptake of 68Ga-FAPI-LM3 was significantly higher than that of 68Ga-FAPI-46 and 68Ga-DOTA-LM3 in HT-1080-FAP-plus-HT-1080-SSTR2 tumor xenografts. In a clinical study involving 6 NPC patients, 68Ga-FAPI-LM3 PET/CT showed significantly higher uptake than did 18F-FDG in primary and metastatic lesions, leading to enhanced lesion detectability and tumor delineation. Conclusion: 68Ga-FAPI-LM3 exhibited FAPI and SSTR2 dual-receptor-targeting properties both in vitro and in vivo, resulting in improved tumor uptake and retention compared with that observed with monomeric 68Ga-FAPI and 68Ga-DOTA-LM3. This study highlights the clinical feasibility of 68Ga-FAPI-LM3 PET/CT for NPC imaging.