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Background: The study explored the differences in nightmare, insomnia, depression, anxiety, and cognitive deficits among adolescents and the chain mediating effects of insomnia, depression, and anxiety on the relationship between nightmares and cognitive deficits in adolescents., Methods: An online survey was used to collect demographic data of 6014 adolescents and assess nightmare, insomnia, depression, anxiety, and cognitive deficits using the Chinese Version of Nightmare Distress Questionnaire, Insomnia Severity Index, Patient Health Questionnaire 9, Generalized Anxiety Disorder 7, and Perceived Deficits Questionnaire-Depression. Spearman correlation analysis and the SPSS function "PROCESS macro" were used for correlation and mediation analyses, respectively., Results: Female adolescents, senior high school, and poor academic performance had higher nightmare, insomnia, and cognitive deficit scores; those living in the city had higher depression and anxiety scores. Cognitive deficits were positively correlated with nightmares, insomnia, depression, and anxiety. Further, insomnia, depression, and anxiety had a chain mediating effect between nightmares and cognitive deficits in adolescents. Nightmares indirectly affect cognition deficits by affecting insomnia and then depression and anxiety symptoms., Limitations: As this was a cross-sectional study, the causal relationship between the variables could not be determined. Moreover, reporting bias and volunteer bias might be present., Conclusions: These findings suggest that clinicians should identify adolescents with frequent nightmares early and provide timely treatment to minimize negative outcomes and possibly limit the chronicity of nightmare disorder. It is significant to maintain the physical and mental health development of adolescents to reduce the risk of insomnia, depression, anxiety, and cognitive deficits., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: We aimed to evaluate the effect of the ABCC2 1249G>A (rs2273697) and -24C>T (rs717620) polymorphisms on lacosamide (LCM) plasma concentrations and the efficacy of LCM in Uygur pediatric patients with epilepsy., Methods: We analyzed 231 pediatric patients with epilepsy, among which 166 were considered to be LCM responsive. For drug assays, 2-3 mL of venous blood was collected from each patient just before the morning LCM dose was administered (approximately 12 hours after the evening dose, steady-state LCM concentrations). The remaining samples after routine therapeutic drug monitoring were used for genotyping analysis. The χ 2 test and Fisher exact test were utilized for comparative analysis of the allelic and genotypic distribution of ABCC2 polymorphisms between the LCM-resistant and LCM-responsive groups. The Student t test or Mann-Whitney U test was conducted to analyze differences in plasma LCM concentration among pediatric patients with epilepsy with different genotypes., Results: Patients with the ABCC2 1249G>A GA genotype (0.7 ± 0.3 mcg/mL per kg/mg) and AA genotype (0.5 ± 0.3 mcg/mL per kg/mg) showed significantly ( P < 0.001) lower LCM concentration-to-dose (CD) ratios than patients with the GG genotype (1.0 ± 0.4 mcg/mL per kg/mg). Moreover, patients with the ABCC2 -24C>T CT genotype (0.6 ± 0.2 mcg/mL per kg/mg) and TT genotype (0.6 ± 0.3 mcg/mL per kg/mg) presented a significantly ( P < 0.001) lower LCM CD ratio than patients with the CC genotype (1.1 ± 0.4 mcg/mL per kg/mg)., Conclusions: The ABCC2 1249G>A (rs2273697) and ABCC2 -24C>T (rs717620) polymorphisms can affect plasma LCM concentrations and treatment efficacy among a population of Uygur pediatric patients with epilepsy, causing these patients to become resistant to LCM. In clinical practice, ABCC2 polymorphisms should be identified before LCM treatment, and then, the dosage should be adjusted for pediatric patients with epilepsy accordingly., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Background:  Monocyte-platelet aggregates (MPAs) represent the crossroads between thrombosis and inflammation, and targeting this axis may suppress thromboinflammation. While antiplatelet therapy (APT) reduces platelet-platelet aggregation and thrombosis, its effects on MPA and platelet effector properties on monocytes are uncertain., Objectives:  To analyze the effect of platelets on monocyte activation and APT on MPA and platelet-induced monocyte activation., Methods:  Agonist-stimulated whole blood was incubated in the presence of P-selectin, PSGL1, PAR1, P2Y 12 , GP IIb/IIIa, and COX-1 inhibitors and assessed for platelet and monocyte activity via flow cytometry. RNA-Seq of monocytes incubated with platelets was used to identify platelet-induced monocyte transcripts and was validated by RT-qPCR in monocyte-PR co-incubation ± APT., Results:  Consistent with a proinflammatory platelet effector role, MPAs were increased in patients with COVID-19. RNA-Seq revealed a thromboinflammatory monocyte transcriptome upon incubation with platelets. Monocytes aggregated to platelets expressed higher CD40 and tissue factor than monocytes without platelets ( p  < 0.05 for each). Inhibition with P-selectin (85% reduction) and PSGL1 (87% reduction) led to a robust decrease in MPA. P2Y 12 and PAR1 inhibition lowered MPA formation (30 and 21% reduction, p  < 0.05, respectively) and decreased monocyte CD40 and TF expression, while GP IIb/IIIa and COX1 inhibition had no effect. Pretreatment of platelets with P2Y 12 inhibitors reduced the expression of platelet-mediated monocyte transcription of proinflammatory SOCS3 and OSM. CONCLUSIONS:  Platelets skew monocytes toward a proinflammatory phenotype. Among traditional APTs, P2Y 12 inhibition attenuates platelet-induced monocyte activation., Competing Interests: Dr. J.B. is PI for the NIH-funded ACTIV4a trial investigating P2Y12 inhibitors in patients hospitalized with COVID-19. C.C.R., M.A.S., T.T.W., M.C., K.M., T.S., H.B., and T.J.B. declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: Interfacility hospital transfer for isolated midfacial fractures is common but rarely clinically necessary. The purpose of this study was to generate nationally representative estimates regarding the incidence, risk factors, and cost of transfer for isolated midface fractures., Methods: This was a retrospective cohort study using the Nationwide Emergency Department Sample 2018 to identify patients with isolated midface fractures. The primary predictor variable was hospital trauma center designation (Level I, Level II, Level III, and nontrauma center). The primary outcome variable was hospital transfer. Total emergency department (ED) charges were also assessed. Covariates were demographic, medical, injury-related, and hospital characteristics. Descriptive, bivariate, and multiple logistic regression statistics were used to evaluate the incidence and predictors of interfacility transfer., Results: During the study period, there were 161,022 ED encounters with a midface fracture as primary diagnosis, of which 5,680 were transferred (3.53%). In an unadjusted analysis, evaluation at a nontrauma center, level III trauma center, nonteaching hospital, and numerous demographic, medical, and injury-related variables were associated with transfer (P ≤ .001). In the adjusted model, the strongest independent predictors for hospital transfer were evaluation at a nontrauma center (odds ratio [OR] = 16.2, 95% confidence interval [CI] = 13.6-19.4), level III trauma center (OR = 13.4, 95% CI = 11.1-16.1) or level II trauma center (OR = 3.25, 95% CI = 2.66-3.98), any Le Fort fracture (OR = 12.0, 95% CI = 10.4-14.0), orbital floor fracture (OR = 3.73, 95% CI = 3.48-4.00), history of cerebrovascular event (OR = 2.74, 95% CI = 2.18-3.45), and cervical spine injury (OR = 5.87, 95% CI = 4.79-7.20) (P ≤ .001). The average ED charge per encounter was $7,206 ± 9,294 for a total nationwide charge of approximately 1.16 billion dollars. Transferred subjects had total ED charges of $97 million, not including additional charges at the recipient hospital., Conclusion: Isolated midface fractures are transferred infrequently, but given the high incidence have substantial healthcare costs. Predictors of transfer were mixed rather than clustered within one variable type, although it is likely that transfers are driven in part by lack of access to maxillofacial specialists given the predominance of hospital covariates. Programs evaluating necessity of transfer and facilitating specialist evaluation in the outpatient setting may reduce healthcare expenditures for these injuries., (Copyright © 2022 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

A method for detecting the surface defects of high reflection objects using phase deflection is proposed. The abrupt change in the surface gradient at the defect leads to the change in the fringe phase. Therefore, Gray code combined with a four-step phase-shift method was employed to obtain the surface gradients to characterize the defects. Then, through the double surface illumination model, the relationship between illumination intensity and phase was established. The causes of periodic error interference were analyzed, and the method of adjusting the fringe width to eliminate it was proposed. Finally, experimental results showed the effectiveness of the proposed method., Competing Interests: The authors declare no conflict of interest.

The dynamics of innate and adaptive immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to SARS-CoV-2 infection in infants and young children in the first weeks and months of life by analyzing blood samples collected before, during, and after infection with Omicron and Non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, were stably maintained for >300 days. Antigen-specific memory B cell (MCB) responses were durable for 150 days but waned thereafter. Somatic hypermutation of V-genes in MCB accumulated progressively over 9 months. The innate response was characterized by upregulation of activation markers on blood innate cells, and a plasma cytokine profile distinct from that seen in adults, with no inflammatory cytokines, but an early and transient accumulation of chemokines (CXCL10, IL8, IL-18R1, CSF-1, CX3CL1), and type I IFN. The latter was strongly correlated with viral load, and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell transcriptomics. Consistent with this, single-cell ATAC-seq revealed enhanced accessibility of chromatic loci targeted by interferon regulatory factors (IRFs) and reduced accessibility of AP-1 targeted loci, as well as traces of epigenetic imprinting in monocytes, during convalescence. Together, these data provide the first snapshot of immunity to infection during the initial weeks and months of life., Competing Interests: Declaration of Interest Alessandro Sette is a consultant for Gritstone Bio, Flow Pharma, Moderna, AstraZeneca, Qiagen, Fortress, Gilead, Sanofi, Merck, RiverVest, MedaCorp, Turnstone, NA Vaccine Institute, Emervax, Gerson Lehrman Group and Guggenheim. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work.

Objective: The aim of this study was to evaluate whether a predictive model based on a contrast enhanced ultrasound (CEUS)-based nomogram and clinical features (Clin) could differentiate Her-2-overexpressing breast cancers from other breast cancers., Methods: A total of 152 pathology-proven breast cancers including 55 Her-2-overexpressing cancers and 97 other cancers from two units that underwent preoperative CEUS examination, were included and divided into training (n = 102) and validation cohorts (n = 50). Multivariate regression analysis was utilized to identify independent indicators for developing predictive nomogram models. The area under the receiver operating characteristic (AUC) curve was also calculated to establish the diagnostic performance of different predictive models. The corresponding sensitivities and specificities of different models at the cutoff nomogram value were compared., Results: In the training cohort, 7 clinical features (menstruation, larger tumor size, higher CA153 level, BMI, diastolic pressure, heart rate and outer upper quarter (OUQ)) + enlargement in CEUS with P < 0.2 according to the univariate analysis were submitted to the multivariate analysis. By incorporating clinical information and enlargement on the CEUS pattern, independently significant indicators for Her-2-overexpression were used for further predictive modeling as follows: Model I, nomogram model based on clinical features (Clin); Model II, nomogram model combining enlargement (Clin + Enlargement); Model III, nomogram model based on typical clinical features combining enlargement (MC + BMI + diastolic pressure (DP) + outer upper quarter (OUQ) + Enlargement). Model II achieved an AUC value of 0.776 at nomogram cutoff score value of 190, which was higher than that of the other models in the training cohort without significant differences (all P >0.05). In the test cohort, the diagnostic efficiency of predictive model was poor (all AUC<0.6). In addition, the sensitivity and specificity were not significantly different between Models I and II (all P >0.05), in either the training or the test cohort. In addition, Clin exhibited an AUC similar to that of model III ( P =0.12). Moreover, model III exhibited a higher sensitivity (70.0%) than the other models with similar AUC and specificity, only in the test cohort., Conclusion: The main finding of the study was that the predictive model based on a CEUS-based nomogram and clinical features could not differentiate Her-2-overexpressing breast cancers from other breast cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Wang, Zhu, Xu, Chen and Huang.)

Background: Bovine viral diarrhea is one of the diseases that cause huge economic losses in animal husbandry. Many countries or regions have successively introduced eradication plans, but BVDV still has a high prevalence in the world. This meta-analysis aims to investigate the prevalence and risk factors of BVDV in the world in recent 10 years, and is expected to provide some reference and theoretical basis for BVDV control plans in different regions., Method: Relevant articles published from 2010 to 2021 were mainly retrieved from NCBI, ScienceDirect, Chongqing VIP, Chinese web of knowledge (CNKI), web of science and Wanfang databases., Results: 128 data were used to analyze the prevalence of BVDV from 2010 to 2021. BVDV antigen prevalence rate is 15.74% (95% CI: 11.35-20.68), antibody prevalence rate is 42.77% (95% CI: 37.01-48.63). In the two databases of antigen and antibody, regions, sampling time, samples, detection methods, species, health status, age, sex, breeding mode, and seasonal subgroups were discussed and analyzed, respectively. In the antigen database, the prevalence of dairy cows in the breed subgroup, ELISA in the detection method subgroup, ear tissue in the sample subgroup, and extensive breeding in the breeding mode were the lowest, with significant differences. In the antibody database, the prevalence rate of dairy cows in the breed subgroup and intensive farming was the highest, with a significant difference. The subgroups in the remaining two databases were not significantly different., Conclusion: This meta-analysis determined the prevalence of BVDV in global cattle herds from 2010 to 2021. The prevalence of BVDV varies from region to region, and the situation is still not optimistic. In daily feeding, we should pay attention to the rigorous and comprehensive management to minimize the spread of virus. The government should enforce BVDV prevention and control, implement control or eradication policies according to local conditions, and adjust the policies in time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Su, Wang, Liu, Li, Tian, Yin, Zheng, Ma, Wang, Li, Yang, Li, Diao, Shi and Du.)

Using multiple cell types and isolates of Delta and Omicron variants of SARS-CoV-2, we report differences in virus production, replication, and infectivity in vitro. Ancestral and Delta SARS-CoV-2 variant exhibit reduced virus production and replication at 34°C compared to 37°C while Omicron replication is balanced between temperatures., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

A kind of top with a fractional operator is discussed in this paper. The top has a periodic nonlinear pulse kick sequence in the magnetic field and constant precessing around the magnetic field. Then, a fractional quantum kicked top map based on the Caputo derivative is proposed. The numerical solutions of the fractional difference equation are obtained, and the chaotic behavior is observed numerically in three aspects. Fractional quantum dynamics behaviors take place in a finite dimensional Hilbert space where the squared angular momentum is free precession. Finally, the dynamic behaviors of the fractional quantum kicked top map are systematically analyzed by using the bifurcation diagram, the phase diagram, and the maximum Lyapunov exponent.

Background and Objective: The impact of individual patient variables on drug metabolism is particularly important for antiseizure medication, and lacosamide has not been studied in Chinese pediatric patients with epilepsy. This study evaluated the effects of dose, age, sex, medication time, seizure type, and concomitant enzyme-inducing antiseizure medications (EIASMs) on the plasma concentration of lacosamide., Methods: A total of 500 pediatric patients from two hospitals in China were enrolled in this study. Lacosamide plasma concentration was processed using an ultra-performance liquid chromatography assay. Efficacy was evaluated based on the four-grade therapeutic effect criteria developed by the first National Epilepsy Academic Conference of the Chinese Medical Association., Results: The responder rate to lacosamide therapy was 72.2% (361/500). There was a weaker relationship between the lacosamide daily dose and lacosamide plasma concentration (r = 0.238). Lacosamide plasma concentrations of patients ranged from 1.5 to 19.7 µg/mL, with a mean of 6.9 ± 3.2 µg/mL. The study results showed a significant contribution of age, body mass index, epilepsy duration, medication time, and EIASMs to the lacosamide plasma concentration (p < 0.05). Patients taking concomitant EIASMs with lacosamide had a significantly lower mean lacosamide plasma concentration (5.9 ± 2.6 µg/mL) than patients taking concomitant non-EIASMs (7.5 ± 3.5 µg/mL, p < 0.001)., Conclusion: To ensure the clinical efficacy and safety of lacosamide therapy in pediatric patients, it is necessary to monitor the plasma concentration., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The mechanistic interplay between SARS-CoV-2 infection, inflammation, and oxygen homeostasis is not well defined. Here, we show that the hypoxia-inducible factor (HIF-1α) transcriptional pathway is activated, perhaps due to a lack of oxygen or an accumulation of mitochondrial reactive oxygen species (ROS) in the lungs of adult Syrian hamsters infected with SARS-CoV-2. Prominent nuclear localization of HIF-1α and increased expression of HIF-1α target proteins, including glucose transporter 1 (Glut1), lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase-1 (PDK1), were observed in areas of lung consolidation filled with infiltrating monocytes/macrophages. Upregulation of these HIF-1α target proteins was accompanied by a rise in glycolysis as measured by extracellular acidification rate (ECAR) in lung homogenates. A concomitant reduction in mitochondrial respiration was also observed as indicated by a partial loss of oxygen consumption rates (OCR) in isolated mitochondrial fractions of SARS-CoV-2-infected hamster lungs. Proteomic analysis further revealed specific deficits in the mitochondrial ATP synthase (Atp5a1) within complex V and in the ATP/ADP translocase (Slc25a4). The activation of HIF-1α in inflammatory macrophages may also drive proinflammatory cytokine production and complement activation and oxidative stress in infected lungs. Together, these findings support a role for HIF-1α as a central mediator of the metabolic reprogramming, inflammation, and bioenergetic dysfunction associated with SARS-CoV-2 infection.

Background: Community-based exercise is a continuation and complement to inpatient rehabilitation for Parkinson's disease and does not require a professional physical therapist or equipment. The effects, parameters, and forms of each exercise are diverse, and the effect is affected by many factors. A meta-analysis was conducted to determine the effect and the best parameters for improving motor symptoms and to explore the possible factors affecting the effect of community-based exercise.  METHODS: We conducted a comprehensive search of six databases: PEDro, PubMed/Medline, CENTRAL, Scopus, Embase, and WOS. Studies that compared community-based exercise with usual care were included. The intervention mainly included dance, Chinese martial arts, Nordic walking, and home-based exercise. The primary outcome measure was the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score. The mean difference (95% CI) was used to calculate the treatment outcomes of continuous outcome variables, and the I 2 statistic was used to estimate the heterogeneity of the statistical analysis. We conducted subgroup analysis and meta-regression analysis to determine the optimal parameters and the most important influencing factors of the exercise effect.  RESULTS: Twenty-two studies that enrolled a total of 809 subjects were included in the analysis. Exercise had a positive effect on the UPDRS-III (MD = -5.83; 95% CI, -8.29 to -3.37), Timed Up and Go test (MD = -2.22; 95% CI -3.02 to -1.42), UPDRS ((MD = -7.80; 95% CI -10.98 to -6.42), 6-Minute Walk Test (MD = 68.81; 95% CI, 32.14 to 105.48), and Berg Balance Scale (MD = 4.52; 95% CI, 2.72 to 5.78) scores. However, the heterogeneity of each included study was obvious. Weekly frequency, age, and duration of treatment were all factors that potentially influenced the effect., Conclusions: This meta-analysis suggests that community-based exercise may benefit motor function in patients with PD. The most commonly used modalities of exercise were tango and tai chi, and the most common prescription was 60 min twice a week. Future studies should consider the influence of age, duration of treatment, and weekly frequency on the effect of exercise., Prospero Trial Registration Number: CRD42022327162., (© 2022. The Author(s).)

Background: Neutralising antibodies against SARS-CoV-2 are a vital component in the fight against COVID-19 pandemic, having the potential of both therapeutic and prophylactic applications. Bispecific antibodies (BsAbs) against SARS-CoV-2 are particularly promising, given their ability to bind simultaneously to two distinct sites of the receptor-binding domain (RBD) of the viral spike protein. Such antibodies are complex molecules associated with multi-faceted mechanisms of action that require appropriate bioassays to ensure product quality and manufacturing consistency., Methods: We developed procedures for biolayer interferometry (BLI) and a cell-based virus neutralisation assay, the focus reduction neutralisation test (FRNT). Using both assays, we tested a panel of five BsAbs against different spike variants (Ancestral, Delta and Omicron) to evaluate the use of these analytical methods in assessing binding and neutralisation activities of anti-SARS-CoV-2 therapeutics., Results: We found comparable trends between BLI-derived binding affinity and FRNT-based virus neutralisation activity. Antibodies that displayed high binding affinity against a variant were often followed by potent neutralisation at lower concentrations, whereas those with low binding affinity also demonstrated reduced neutralisation activity., Conclusion: The results support the utility of BLI and FRNT assays in measuring variant-specific binding and virus neutralisation activity of anti-SARS-CoV-2 antibodies., (© The Author(s) 2022. Published by Oxford University Press on behalf of Antibody Therapeutics. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The present study aimed to compare the differences in positive screening rates of attention deficit hyperactivity disorder (ADHD) symptoms between parents and teachers in the same sample of primary school students. Concurrently, parental awareness and information sources of ADHD were investigated, and possible relevant factors affecting parental awareness and their influence on positive screening rate of ADHD were analyzed., Methods: A cross-sectional study was conducted in Changchun, China, between September 2020 and January 2021. Parents of 1,118 primary school students and 24 head teachers were recruited in the survey. Data were collected through a structured self-administered questionnaire. It consisted of socio-demographic characteristics, ADHD symptom screening questionnaire, parental awareness, and information sources of ADHD., Results: Among the 1,118 primary school students, 30 (2.7%) and 60 (5.4%) students were positive for Swanson, Nolan, and Pelham Rating Scale (SNAP-IV) screening in the parent version and teacher version, respectively. Parents had lower positive screening rates for ADHD symptoms than teachers. Relationship with children (mother, OR = 1.552, 95% CI = 1.104-2.180), bachelor degree or above of parents (OR = 1.526, 95% CI = 1.054-2.210), children's sex (girl, OR = 1.442, 95% CI = 1.093-1.904), and age (OR = 1.344, 95% CI = 1.030-1.754), children's grade (grade 2, OR = 0.522, 95% CI = 0.310-0.878; grade 3, OR = 0.388, 95% CI = 0.185-0.782), information sources of ADHD (medical staff, OR = 1.494, 95% CI = 1.108-2.015; family/relative/friend, OR = 1.547, 95% CI = 1.148-2.083; TV/Internet, OR = 3.200, 95% CI = 2.270-4.510) were the factors related to the parental awareness of ADHD., Conclusion: Parents and teachers of primary school students recognize ADHD symptoms differently. The positive screening rate of ADHD among teachers was significantly higher than that of parents. Relationship with children, educational level of parents, children's sex, age, and grade, and information sources of ADHD are the relevant factors affecting parental awareness of ADHD. More efforts should be made to disseminate ADHD knowledge through mass media, and medical staff. Fathers, parents with low educational level, and parents of grade 2 and 3 pupils should be encouraged to acquire more knowledge on ADHD to improve the early recognition rate of ADHD symptoms., Clinical Trial Registration: [http://www.chictr.org.cn/showproj.aspx?proj=54 072], identifier [ChiCTR2000033388]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Wang, Dong, Liu and Jia.)

A series of di- and tetranuclear lanthanide complexes with the formulas [Dy 2 bmzch(tmhd) 5 (CH 3 OH)]·CH 3 OH ( 1 ), [Dy 2 bmzch(dbm) 4 (CH 3 O)(CH 3 OH)]·0.5CH 3 OH·0.5H 2 O ( 2 ), and Dy 4 bmzch(btfa) 10 ( 3 ), where tmhd = 2,2,6,6-tetramethyl-3,5-heptanedionate, dbm = dibenzoylmethane, btfa = benzoyltrifluoroacetone, and bmzch = ( Z )- N -[( E )-pyrimidin-2-ylmethylene]pyrimidine-2-carbohydrazonate, were structurally and magnetically characterized. More strikingly, although the nitrogen-enriched bridged ligand 3,6-di(pyrimidin-2-yl)-1,2,4,5-tetrazine (bmtz) was initially adopted, the structures of the complexes obtained indicated that bmtz underwent unprecedented asymmetric ring opening and generated a new ligand bmzch. Combined with different β-diketonates, di- and tetranuclear dysprosium complexes were constructed in which the structural patterns are very sensitive to the selected β-diketonates. In view of this, the bilateral and unilateral dinuclear Dy2 complexes 1 and 2 and tetranuclear Dy4 complex 3 were obtained by choosing different β-diketonates. Magnetic test results reveal that both complexes 1 and 3 showcase typical slow magnetic relaxation behavior without an external direct-current field and the effective energy barrier of the latter is almost twice that of the former, while complex 2 only displays in-field single-molecule-magnetic behavior. Also of note is that these are the first tetrazine-type dysprosium-based single-molecule-magnets undergoing in situ asymmetric ring-opening reaction of this ligand that are formed.

Polyploidization leads to novel phenotypes and is a major force in evolution. However, the relationship between the evolution of new traits and variations in the post-translational modifications (PTM) of proteins during polyploidization has not been studied. Acetylation of lysine residues is a common protein PTM that plays a critical regulatory role in central metabolism. To test whether changes in metabolism in citrus fruit is associated with the reprogramming of lysine acetylation (Kac) in non-histone proteins during allotetraploidization, we performed a global acetylome analysis of fruits from a synthetic allotetraploid citrus and its diploid parents. A total of 4,175 Kac sites were identified on 1,640 proteins involved in a wide range of fruit traits. In the allotetraploid, parental dominance (i.e. resemblance to one of the two parents) in specific fruit traits, such as fruit acidity and flavonol metabolism, was highly associated with parental Kac level dominance in pertinent enzymes. This association is due to Kac-mediated regulation of enzyme activity. Moreover, protein Kac probably contributes to the discordance between the transcriptomic and proteomic variations during allotetraploidization. The acetylome reprogramming can be partially explained by the expression pattern of several lysine deacetylases (KDACs). Overexpression of silent information regulator 2 (CgSRT2) and histone deacetylase 8 (CgHDA8) diverted metabolic flux from primary metabolism to secondary metabolism and partially restored a metabolic status to the allotetraploid, which expressed attenuated levels of CgSRT2 and CgHDA8. Additionally, KDAC inhibitor treatment greatly altered metabolism in citrus fruit. Collectively, these findings reveal the important role of acetylome reprogramming in trait evolution during polyploidization., (© American Society of Plant Biologists 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Few live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are in pre-clinical or clinical development. We seek to attenuate SARS-CoV-2 (isolate WA1/2020) by removing the polybasic insert within the spike protein and the open reading frames (ORFs) 6-8, and by introducing mutations that abolish non-structural protein 1 (Nsp1)-mediated toxicity. The derived virus (WA1-ΔPRRA-ΔORF6-8-Nsp1 K164A/H165A ) replicates to 100- to 1000-fold-lower titers than the ancestral virus and induces little lung pathology in both K18-human ACE2 (hACE2) transgenic mice and Syrian hamsters. Immunofluorescence and transcriptomic analyses of infected hamsters confirm that three-pronged genetic modifications attenuate the proinflammatory pathways more than the removal of the polybasic cleavage site alone. Finally, intranasal administration of just 100 PFU of the WA1-ΔPRRA-ΔORF6-8-Nsp1 K164A/H165A elicits robust antibody responses in Syrian hamsters and protects against SARS-CoV-2-induced weight loss and pneumonia. As a proof-of-concept study, we demonstrate that live but sufficiently attenuated SARS-CoV-2 vaccines may be attainable by rational design., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Multiple myeloma is a plasma cell neoplasm characterized by clonal immunoglobulin V(D)J signatures and oncogenic immunoglobulin gene translocations. Additional subclonal genomic changes are acquired with myeloma progression and therapeutic selection. PCR-based methods to detect V(D)J rearrangements can have biases introduced by highly multiplexed reactions and primers undermined by somatic hypermutation, and are not readily extended to include mutation detection. Here, we report a hybrid-capture approach (CapIG-seq) targeting the 3' and 5' ends of the V and J segments of all immunoglobulin loci that enable the efficient detection of V(D)J rearrangements. We also included baits for oncogenic translocations and mutation detection. We demonstrate complete concordance with matched whole-genome sequencing and/or PCR clonotyping of 24 cell lines and report the clonal sequences for 41 uncharacterized cell lines. We also demonstrate the application to patient specimens, including 29 bone marrow and 39 cell-free DNA samples. CapIG-seq shows concordance between bone marrow and cfDNA blood samples (both contemporaneous and follow-up) with regard to the somatic variant, V(D)J, and translocation detection. CapIG-seq is a novel, efficient approach to examining genomic alterations in myeloma., (© 2022 Chow et al.)

Purpose: Interfacility hospital transfer for isolated mandibular fractures is common but rarely clinically necessary. The purpose of this study was to generate nationally representative estimates regarding the incidence, risk factors, and cost of transfer for isolated mandibular fractures., Methods: This was a retrospective cohort study using the Nationwide Emergency Department Sample 2018 to identify patients with isolated mandibular fractures. The primary predictor variable was hospital trauma center designation (Level I, Level II, Level III, and nontrauma center). The primary outcome variable was hospital transfer. Total emergency department (ED) charges were also assessed. Covariates were demographic, medical, injury-related, and hospital characteristics. Descriptive, bivariate, and multiple logistic regression statistics were used to evaluate the incidence and predictors of interfacility transfer., Results: A total of 28,357 encounters with mandibular fracture as the primary diagnosis were included. Within this cohort there were 2,893 hospital transfers (10.2%). In unadjusted analysis, evaluation at a nontrauma center, level III trauma center, metropolitan nonteaching hospital, nonmetropolitan nonteaching hospital, micropolitan region, and history of cerebrovascular event was associated with hospital transfer (P ≤ .001). In the adjusted model, independent predictors (risk factors) for hospital transfer were evaluation at a nontrauma center (P ≤ .001, odds ratio [OR] = 12.8, 95% confidence interval [CI] = 6.43 to 25.4), level III trauma center (P ≤ .001, OR = 10.7, 95% CI = 5.25 to 21.7), nonmetropolitan nonteaching hospital (P ≤ .001, OR = 2.45, 95% CI = 1.73 to 3.46), metropolitan nonteaching hospital (P ≤ .001, OR = 1.57, 95% CI = 1.20 to 2.06), cervical spine injury (P = .002, OR = 3.53, 95% CI = 1.61 to 7.75), fractures of the mandibular body (P = .007, OR = 1.33, 95% CI = 1.08 to 1.64), and unspecified mandibular fractures (P = .006, OR = 1.49, 95% CI = 1.12 to 1.99). The average ED charge per encounter was $7,482 ± 565 for a total nationwide charge of $212,172,264. Transferred subjects had total ED charges of $25,632,974, not including additional charges incurred at the recipient hospital., Conclusion: Isolated mandibular fractures are common injuries that are frequently transferred and cost the healthcare system millions of dollars annually. Hospital characteristics rather than medical or injury-related variables were the strongest predictors of transfer, suggesting that transfers are primarily driven by need to access maxillofacial surgical services. Programs evaluating necessity of transfer and facilitating specialist evaluation in the outpatient setting may reduce healthcare expenditures for this injury., (Copyright © 2022 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Abnormal myocardial Na v 1.5 expression and function cause lethal ventricular arrhythmias during myocardial ischemia-reperfusion (I/R). Protein inhibitor of activated STAT Y (PIASy)-mediated caveolin-3 (Cav-3) SUMO modification affects Cav-3 binding to the voltage-gated sodium channel 1.5 (Na v 1.5). PIASy activity is increased after myocardial I/R, but it is unclear whether this is attributable to plasma membrane Na v 1.5 downregulation and ventricular arrhythmias., Methods: Using recombinant adeno-associated virus subtype 9 (AAV9), rat cardiac PIASy was silenced using intraventricular injection of PIASy short hairpin RNA (shRNA). After two weeks, rat hearts were subjected to I/R and electrocardiography was performed to assess malignant arrhythmias. Tissues from peri-infarct areas of the left ventricle were collected for molecular biological measurements., Results: PIASy was upregulated by I/R (P < 0.01), with increased SUMO2/3 modification of Cav-3 and reduced membrane Na v 1.5 density (P < 0.01). AAV9-PIASy shRNA intraventricular injection into the rat heart downregulated PIASy after I/R, at both mRNA and protein levels (P < 0.05 vs. Scramble-shRNA + I/R group), decreased SUMO-modified Cav-3 levels, enhanced Cav-3 binding to Na v 1.5, and prevented I/R-induced decrease of Na v 1.5 and Cav-3 co-localization in the intercalated disc and lateral membrane. PIASy silencing in rat hearts reduced I/R-induced fatal arrhythmias, which was reflected by a modest decrease in the duration of ventricular fibrillation (VF; P < 0.05 vs. Scramble-shRNA + I/R group) and a significantly reduced arrhythmia score (P < 0.01 vs. Scramble-shRNA + I/R group). The anti-arrhythmic effects of PIASy silencing were also evidenced by decreased episodes of ventricular tachycardia (VT), sustained VT and VF, especially at the time 5-10 min after ischemia (P < 0.05 vs. Scramble-shRNA + IR group). Using in vitro human embryonic kidney 293 T (HEK293T) cells and isolated adult rat cardiomyocyte models exposed to hypoxia/reoxygenation (H/R), we confirmed that increased PIASy promoted Cav-3 modification by SUMO2/3 and Na v 1.5/Cav-3 dissociation after H/R. Mutation of SUMO consensus lysine sites in Cav-3 (K38R or K144R) altered the membrane expression levels of Na v 1.5 and Cav-3 before and after H/R in HEK293T cells., Conclusions: I/R-induced cardiac PIASy activation increased Cav-3 SUMOylation by SUMO2/3 and dysregulated Na v 1.5-related ventricular arrhythmias. Cardiac-targeted PIASy silencing mediated Cav-3 deSUMOylation and partially prevented I/R-induced Na v 1.5 downregulation in the plasma membrane of cardiomyocytes, and subsequent ventricular arrhythmias in rats. PIASy was identified as a potential therapeutic target for life-threatening arrhythmias in patients with ischemic heart diseases., (© 2022. The Author(s).)

Background: The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients., Methods: Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial., Results: We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset., Conclusions: Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models., Funding: Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals., Competing Interests: ZH, Kv, SC, PA, DM, KJ, HB, JP, JA, MH, AS, CK, YM, HH, Ld, KP, MT, GT, CB, ST, BG, AB, US, BP, TW, PJ No competing interests declared, IR Reviewing editor, eLife, (© 2022, Hu et al.)

With the incidence of hypertension increasing worldwide, more and more the mechanisms of hypertension from the perspective of immunity have found. Intestinal microbiota as well as its metabolites relationship with hypertension has attracted great attention from both clinicians and investigators. However, the associations of hypertension with lesions of a large number of immune factors including IL-17, MCP-1, IL-6, TGF-β, IL-10 and others have not been fully characterized. In this review, after introducing the immune factors as the most potent anti/pro-hypertension agents known, we provide detailed descriptions of the IL-17 involved in the pathology of hypertension, pointing out the underlying mechanisms and suggesting the clinical indications., (© 2022. The Author(s).)

A novel strategy for the synthesis of 2-arylethenesulfonyl fluorides from nitrones and ethenesulfonyl fluoride (ESF) by the activation of the C-H bond using an inexpensive and readily available Ru-catalyst has been developed. In this process, the directing group can be concomitantly converted to an amide group. Interestingly, changing the substituent of the nitrogen of nitrones from a tert -butyl to a methyl group resulted in the formation of cyclic isoindolinones. Detailed mechanistic studies are also presented.

With the emergence of more variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the immune evasion of these variants from existing vaccines, the development of broad-spectrum vaccines is urgently needed. In this study, we designed a novel SARS-CoV-2 receptor-binding domain (RBD) subunit (RBD5m) by integrating five important mutations from SARS-CoV-2 variants of concern (VOCs). The neutralization activities of antibodies induced by the RBD5m candidate vaccine are more balanced and effective for neutralizing different SARS-CoV-2 VOCs in comparison with those induced by the SARS-CoV-2 prototype strain RBD. Our results suggest that the RBD5m vaccine is a good broad-spectrum vaccine candidate able to prevent disease from several different SARS-CoV-2 VOCs.

Pancreatic ductal adenocarcinoma (PDAC) is currently one of the most lethal cancers worldwide. Several basic studies have confirmed that Kirsten rat sarcoma virus (KRAS) is a key driver gene for the occurrence of PDAC, and KRAS mutations have also been found in most patients in clinical studies. In this study, two pan-KRAS inhibitors, BI-2852 and BAY-293, were chosen as chemical probes to investigate their antitumor potency in PDAC. Their inhibitory effects on KRAS activation were validated in vitro and their antiproliferative potency in PDAC cell lines were profiled, with half-maximal inhibitory concentration (IC 50 ) values of approximately 1 μM, demonstrating the therapeutic potential of pan-KRAS inhibitors in the treatment of PDAC. However, feedback regulation in the KRAS pathway weakened inhibitor activity, which was observed by a 50 times difference in BAY-293 from in vitro activity. Furthermore, pan-KRAS inhibitors effectively inhibited cell proliferation in 3D organoids cultured from PDAC patient samples; however, there were some variations between individuals. These results provide a sufficient theoretical foundation for KRAS as a clinical therapeutic target and for the application of pan-KRAS inhibitors in the treatment of PDAC, with important scientific significance in translational medicine., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Clinical and preclinical studies suggested that certain mutagens occurring as a reaction of creatine, amino acids, and sugar during the high temperature of cooking meat are involved in the pathogenesis of human cancer. Here we conducted a systematic review and meta-analysis to examine whether meat mutagens [PhIP, MeIQx, DiMeIQx, total HCA, and B(a)P] present a risk factor for human cancer., Methods: We searched the following databases for relevant articles published from inception to 10 Oct 2021 with no language restrictions: Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Baidu Academic, Zhejiang Digital Library. Two independent researchers screened all titles and obtained eligible texts for further screening. Independent data extraction was conducted, and meta-analysis was carried out using random-effects models to calculate the risk ratio of the meat mutagens exposure., Results: A total of 1,786,410 participants and 70,653 cancer cases were identified. Among these, there were 12 different types of cancer at various sites, i.e., breast, bladder, colorectal, colon, rectum, prostate, lung, Non-Hodgkin lymphoma, kidney, gastric, esophagus, pancreatic, hepatocellular carcinoma. Cancer risk was significantly increased by intake of PhIP (OR = 1.13;95% CI 1.07-1.21; p < 0.001), MeIQx (OR = 1.14; 95% CI: 1.07-1.21; p < 0.001), DiMeIQx (OR = 1.07; 95% CI: 1.01-1.13; p = 0.013), total HCA (OR = 1.20; 95% CI: 1.03-1.38; p = 0.016), and cancer risk was not significantly increased by intake of B(a)P (OR = 1.04; 95% CI: 0.98-1.10; p = 0.206)., Conclusion: Meat mutagens of PhIP, MeIQx, DiMeIQx, and total HCA have a positive association with the risk of cancer., Systematic Review Registration: [www.crd.york.ac.uk/prospero], identifier [CRD42022148856]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Reng, Zhu, Feng, Li, Zhu, Wang and Jiang.)

Adenomatoid tumor is a kind of benign tumor, accounts for a low percentage of scrotal tumors. It usually locates in epididymis, less commonly, arises from the tunica albuginea, spermatic cord or tunica vaginalis of male's urogenital tract system. Here, we report a case of a 32-year-old male, which presented as a 6-month history of left scrotal swelling pain with a scrotal mass, and it had progressively enlarged over the last 1 month. The ultrasonography (US) described a giant well-defined hypoechoic mass in the left scrotum, a thick pedicle connected the mass and the left scrotal wall, and the pedicle had large blood vessels in it. Enhanced CT showed an irregular solid mass in the left scrotum, the left testicular artery was thickened to supply blood for the mass, and the radiologist mentioned it could not be excluded as a malignant lesion. The patient underwent left radical orchiectomy, the mass was diagnosed as an adenomatoid tumor of the tunica vaginalis by pathology. We review literature regarding adenomatoid tumors originating in the tunica vaginalis, summarize the ultrasonographic presentations, provide the idea of diagnosis and differential diagnosis to improve diagnostic accuracy and avoid unnecessary orchiectomy., (© 2022 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Despite being more transmissible, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant only causes milder diseases in laboratory animals, often accompanied by a lower viral load compared with previous variants of concern. In this study, we report the structural basis for a robust interaction between the receptor-binding domain of the Omicron spike protein and mouse ACE2. We show that pseudovirus bearing the Omicron spike protein efficiently utilizes mouse ACE2 for entry. By comparing viral load and disease severity among laboratory mice infected by a natural Omicron variant or recombinant ancestral viruses bearing either the entire Omicron spike or only the N501Y/Q493R mutations in its spike, we find that mutations outside the spike protein in the Omicron variant may be responsible for the observed lower viral load. Together, our results imply that a post-entry block to the Omicron variant exists in laboratory mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Interleukin 4 (IL-4) plays a major role in T-lymphocyte development and is thought to be a central regulator as a cofactor in resting B-lymphocyte proliferation. Primary infection with porcine reproductive and respiratory syndrome virus (PRRSV) induces minimal IL-4 production, whereas an IL-4 response occurs in the peripheral blood of piglets reinfected by PRRSV. The locations and interaction partners for the massive volume of IL-4 triggered by PRRSV reinfection remain unclear. This study aimed to investigate the characteristics of IL-4 secretion and location changes in peripheral immune organs induced by PRRSV infection and reinfection. Our results show that PRRSV reinfection induced higher levels of IL-4 mRNA and protein expression in the peripheral immune organs (e.g., lymph node and spleen) and peripheral blood compared with PRRSV primary infection. Importantly, we found that, following PRRSV reinfection, an obvious large-scale migration of IL-4 occurred in the lymph nodes. During PRRSV primary infection, IL-4 was mainly concentrated around the lymphoid follicles and paracortical regions of the lymph node and also located in the marginal area and periarterial lymphatic sheath region of the spleen. During PRRSV reinfection, the now abundant IL-4 gathered into the lymphoid follicles of the lymph node and spleen. Notably, IL-4 changed its location state from scattered and sparse during primary infection to clinging to B lymphocytes in the lymphoid follicles during reinfection. During reinfection, IL-4 was often co-localized with T and B lymphocytes; furthermore, the percentages of several T lymphocyte subsets, N protein-specific antibody levels, and viral load in the peripheral blood or lymph tissues underwent remarkable variation. Another important finding of this study was that the numbers of B lymphocytes and T lymphocytes in the lymphoid nodes were significantly reduced after PRRSV infection or reinfection, presumably due to PRRSV-induced acute bone marrow failure and autophagy in thymic epithelial cells. This study revealed the characteristics of IL-4 migration and distribution in the peripheral lymph organs induced by PRRSV reinfection and provides valuable clues for further exploration of the interactions between IL-4, B lymphocytes, and T lymphocytes during PRRSV infection and reinfection., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Diabetic cardiomyopathy (DCM) is described as abnormalities of myocardial structure and function in diabetic patients without other well-established cardiovascular factors. Although multiple pathological mechanisms involving in this unique myocardial disorder, mitochondrial dysfunction may play an important role in its development of DCM. Recently, considerable progresses have suggested that mitochondrial biogenesis is a tightly controlled process initiating mitochondrial generation and maintaining mitochondrial function, appears to be associated with DCM. Nonetheless, an outlook on the mechanisms and clinical relevance of dysfunction in mitochondrial biogenesis among patients with DCM is not completely understood. In this review, hence, we will summarize the role of mitochondrial biogenesis dysfunction in the development of DCM, especially the molecular underlying mechanism concerning the signaling pathways beyond the stimulation and inhibition of mitochondrial biogenesis. Additionally, the evaluations and potential therapeutic strategies regarding mitochondrial biogenesis dysfunction in DCM is also presented.

Campanulaluzhijiangensis (Campanulaceae: Campanuleae) is described and illustrated as a new species from Yunnan, southwest China. The new species is mainly characterized by its relatively gracile stems polyphyllous, small and oblanceolate leaves, and flowers and fruits with small size within Chinese Campanula . It is only known from a single locality in the valley of the Luzhijiang River, usually occurring in the rock crevices, xerophilous scrubs or grasslands. A table of morphological characters comparing the new species with its closest relatives is provided along with a key to the species of Campanula from Yunnan Province, as well as a preliminary conservation assessment of C.luzhijiangensis under the IUCN criteria., (Ting-Ting Wang, Zeng-Yan Dang, Feng Yang, Huan-Chong Wang.)

Despite the remarkable efficacy of COVID-19 vaccines, waning immunity and the emergence of SARS-CoV-2 variants such as Omicron represents a global health challenge. Here, we present data from a study in nonhuman primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, which was recently authorized for use in individuals 18 years or older. Vaccination induced neutralizing antibody (nAb) titers that were maintained at high concentrations for at least 1 year after two doses, with a pseudovirus nAb geometric mean titer (GMT) of 1978 and a live virus nAb GMT of 1331 against the ancestral strain but not against the Omicron BA.1 variant. However, a booster dose at 6 to 12 months with RBD-Wu or RBD-β (RBD from the Beta variant) displayed on I53-50 elicited high neutralizing titers against the ancestral and Omicron variants. In addition, we observed persistent neutralization titers against a panel of sarbecoviruses, including SARS-CoV. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Vaccination resulted in protection against Omicron infection in the lung and suppression of viral burden in the nares at 6 weeks after the final booster immunization. Even at 6 months after vaccination, we observed protection in the lung and rapid control of virus in the nares. These results highlight the durable and cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine.

The effector activity of IgG antibodies is regulated at several levels, including IgG subclass, modifications of the Fc glycan, and the distribution of Type I and II Fcγ receptors (FcγR) on effector cells. Here, we explore how Fc glycosylation, particularly sialylation and fucosylation, tunes cellular responses to immune complexes. We review the current understanding of the pathways and mechanisms underlying this biology, address FcγR in antigen presentation, and discuss aspects of the clinical understanding of Fc glycans in therapies and disease., (Copyright © 2022. Published by Elsevier Ltd.)

In this review, we discuss how IgG antibodies can modulate inflammatory signaling during viral infections with a focus on CD16a-mediated functions. We describe the structural heterogeneity of IgG antibody ligands, including subclass and glycosylation that impact binding by and downstream activity of CD16a, as well as the heterogeneity of CD16a itself, including allele and expression density. While inflammation is a mechanism required for immune homeostasis and resolution of acute infections, we focus here on two infectious diseases that are driven by pathogenic inflammatory responses during infection. Specifically, we review and discuss the evolving body of literature showing that afucosylated IgG immune complex signaling through CD16a contributes to the overwhelming inflammatory response that is central to the pathogenesis of severe forms of dengue disease and coronavirus disease 2019 (COVID-19)., (© 2022 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.)

Argonaute 2 (Ago2) is an essential component of the RNA-induced silencing complex (RISC) and it participates in diverse physiological processes, while dysregulation of Ago2 activity is closely linked to a variety of human diseases including cancers. The reported Ago2 assays often suffer from laborious procedures, complicated reaction schemes, and unsatisfactory sensitivity. Herein, we develop a new gold nanoparticle (AuNP)-based single-molecule biosensor for simple and sensitive detection of Ago2 activity. The Ago2-responsive AuNP nanoprobe is constructed through the self-assembly of multiple Cy5-labeled signal probes onto the AuNP, in which the Cy5 fluorescence is efficiently quenched by the AuNP. Target Ago2 can bind with guide RNA to form an active RISC, inducing the cyclic cleavage of the signal probes and the release of Cy5 moieties from the AuNP nanoprobe. The released Cy5 molecules can be simply quantified by single-molecule counting. This single-molecule biosensor enables detection of Ago2 activity with the involvement of only a single AuNP nanoprobe, eliminating the use of any extra antibodies and protein enzymes. This single-molecule biosensor achieves good specificity and high sensitivity with a detection limit of 9.1 pM, and it can be exploited for the screening of Ago2 inhibitors, Ago2 kinetic analysis, and the imaging of intracellular Ago2 activity in live cells, holding great promise in Ago2-related biomedical research and clinical diagnosis.

It has been reported that antibiotics (ATBs) have adverse effect on the efficacy of treatment with immune checkpoint inhibitors (ICIs) in cancer patients. Since different classes of ATBs have different antibacterial spectrum, we aimed to study whether all ATBs had similar or different negative effects on the clinical outcomes of ICIs in patients with advanced non-small cell lung cancer (NSCLC). Patients with advanced NSCLC who received ICIs were included in this retrospective study and grouped by the class of ATBs they had used around the ICIs treatment time. The overall survival (OS) and the progression free survival (PFS) of patients among these groups were compared using Kaplan-Meier method and Cox proportional hazards model. A total of 148 eligible patients were enrolled, and 80 patients used ATBs. The results indicated that quinolones had no significant negative consequence on the clinical outcomes, while β-lactams significantly shortened the OS and PFS of patients. Furthermore, patients exposed to the combination of β-lactams and quinolones suffered the worst OS and PFS. Moreover, the subgroup analysis of β-lactams revealed that only penicillins, but not carbapenems and cephalosporins, markedly reduced both OS and PFS. In addition to the class of ATBs used, the time frame of ATBs used also affected the clinical outcomes of ICIs therapy. Patients receiving ATBs within 60 days prior to and 30 days after the initiation of ICI treatment had significantly shorter OS and PFS compared with those who did not use ATBs. This study demonstrated that different classes of ATBs had disparate negative impacts on the clinical outcomes, and the use of β-lactams, especially penicillins, should be avoided in advanced NSCLC patients who are receiving or scheduled to receive ICIs within 60 days., Competing Interests: None., (AJCR Copyright © 2022.)

Xanthine oxidase (XO) utilizes molecular oxygen as a substrate to convert purine substrates into uric acid, superoxide, and hydrogen peroxide, which is one of the main enzyme pathways to produce reactive oxygen species (ROS) during septic inflammation and oxidative stress. However, it is not clear whether XO inhibition can improve sepsis-induced renal hypoxia in sepsis-induced acute kidney injury (SI-AKI) mice. In this study, pretreatment with febuxostat, an XO-specific inhibitor, or kidney knockdown of XO by shRNA in vivo significantly improved the prognosis of SI-AKI, not only by reducing the levels of blood urea nitrogen, serum creatinine, tumor necrosis factor- α , interleukin-6, and interleukin-1 β in peripheral blood but also by improving histological damage and apoptosis, reducing the production of ROS, and infiltrating neutrophils and macrophages in the kidney. More importantly, we found that pharmacological and genetic inhibition of XO significantly improved renal hypoxia in SI-AKI mice by a hypoxia probe via fluorescence staining. This effect was further confirmed by the decrease in hypoxia-inducible factor-1 α expression in the kidneys of mice with pharmacological and genetic inhibition of XO. In vitro, the change in XO activity induced by lipopolysaccharide was related to the change in hypoxia in HK-2 cells. Febuxostat and XO siRNA significantly relieved the hypoxia of HK-2 cells cultured in 2% oxygen and reversed the decrease in cell viability induced by lipopolysaccharide. Our results provide novel insights into the nephroprotection of XO inhibition in SI-AKI, improving cell hypoxia by inhibiting XO activity and reducing apoptosis, inflammation, and oxidative stress., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Ting-ting Wang et al.)

Objectives: To study the association of maternal methylenetetrahydrofolate dehydrogenase 1 ( MTHFD1 ) and methylenetetrahydrofolate dehydrogenase 2 ( MTHFD2 ) gene polymorphisms with congenital heart disease (CHD) in offspring., Methods: A hospital-based case-control study was conducted. The mothers of 683 children with CHD alone who attended Hunan Children's Hospital, from November 2017 to March 2020 were enrolled as the case group, and the mothers of 740 healthy children who attended the same hospital during the same period and did not have any deformity were enrolled as the control group. A questionnaire survey was performed to collect related exposure data, and then venous blood samples (5 mL) were collected from the mothers to detect MTHFD1 and MTHFD2 gene polymorphisms. A multivariate logistic regression analysis was used to evaluate the association of MTHFD1 and MTHFD2 gene polymorphisms with CHD. The four-gamete test in Haploview 4.2 software was used to construct haplotypes and evaluate the association between haplotypes and CHD. The generalized multifactor dimensionality reduction method and logistic regression analysis were used to examine gene-gene interaction and its association with CHD., Results: The multivariate logistic regression analysis showed that maternal MTHFD1 gene polymorphisms at rs11849530 (GA vs AA: OR =1.49; GG vs AA: OR =2.04) andat rs1256142 (GA vs GG: OR =2.34; AA vs GG: OR =3.25) significantly increased the risk of CHD in offspring ( P <0.05), while maternal MTHFD1 gene polymorphisms at rs1950902 (AA vs GG: OR =0.57) and MTHFD2 gene polymorphisms at rs1095966 (CA vs CC: OR =0.68) significantly reduced the risk of CHD in offspring ( P <0.05). The haplotypes of G-G-G ( OR =1.86) and G-A-G ( OR =1.35) in mothers significantly increased the risk of CHD in offspring ( P <0.05). The gene-gene interaction analyses showed that the first-order interaction between MTHFD1 rs1950902 and MTHFD1 rs2236222 and the second-order interaction involving MTHFD1 rs1950902, MTHFD1 rs1256142, and MTHFD2 rs1095966 might be associated with risk of CHD ( P <0.05)., Conclusions: Maternal MTHFD1 and MTHFD2 gene polymorphisms and their haplotypes, as well as the interaction between MTHFD1 rs1950902 and MTHFD1 rs2236222 and between MTHFD1 rs1950902, MTHFD1 rs1256142, and MTHFD2 rs1095966, are associated with the risk of CHD in offspring.

BACKGROUNDProlonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive.METHODSAdult SARS-CoV-2 reverse transcription PCR-positive (RT-PCR-positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1-3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit.RESULTSOur cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution.CONCLUSIONWe found that all disease severities had a similar risk of developing post-COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration.TRIAL REGISTRATIONClinicalTrials.gov, NCT04373148.FUNDINGNIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research., (© 2022. Springer Nature Limited.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4 + T cells are likely important in immunity against coronavirus 2019 (COVID-19), but our understanding of CD4 + longitudinal dynamics following infection and of specific features that correlate with the maintenance of neutralizing antibodies remains limited. Here, we characterize SARS-CoV-2-specific CD4 + T cells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4 + response shifts from cells producing interferon gamma (IFNγ) to tumor necrosis factor alpha (TNF-α) from 5 days to 4 months post-enrollment, with IFNγ - IL-21 - TNF-α + CD4 + T cells the predominant population detected at later time points. Greater percentages of IFNγ - IL-21 - TNF-α + CD4 + T cells on day 28 correlate with SARS-CoV-2-neutralizing antibodies measured 7 months post-infection (⍴ = 0.4, p = 0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNγ- and TNF-α-producing, spike-protein-specific CD4 + T cells. These data suggest that SARS-CoV-2-specific, TNF-α-producing CD4 + T cells may play an important role in antibody maintenance following COVID-19., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Study Objectives: The physical and mental health of adolescents is an important study area. This study aims to examine the occurrence of aggression, sleep disturbances, and suicide risk among Chinese adolescents, along with the relationships between these factors., Methods: This is a cross-sectional study conducted through an online survey. Of the original 7011 Chinese adolescent respondents, the analysis included data from 6122 adolescents, aged between 12 and 18 years, from 23 regions, whose average age was 16.12 (±1.44) years, with 48.8% being male. While the chi-square test and t-test were used for analyzing demographic data and continuous variables, respectively, mediation analysis was used to explore the mechanism of experiencing aggression on suicide risk. The respondents' sleep quality, nightmare distress, daytime sleepiness, fatigue, and suicide risk were assessed using the Pittsburgh Sleep Quality Index (PSQI), Nightmare Distress Questionnaire-Chinese version (NDQ-CV), Chinese Adolescent Daytime Sleepiness Scale (CADSS), Multidimensional Fatigue Inventory (MFI-20), and the suicide risk module of the Mini-International Neuropsychiatric Interview (MINI), respectively. Four items were used to assess adolescents' experiences with aggression., Results: Of the respondents, 42% reported experiencing aggression by others, especially parental physical maltreatment. Furthermore, 26.9% of adolescents in school, and in particular, 31.8% in senior high school experienced insomnia symptoms. Adolescents who reported experiences of aggression had more severe insomnia symptoms, nightmare distress, fatigue, and a higher risk of suicide when compared with those who did not (all ps < 0.001). Insomnia symptoms, nightmare distress, and fatigue all mediated the relationship between aggression and suicide risk, and there was a chain of mediating effects between these factors [for total indirect effect β = 1.1512, 95% CI (0.9671 to 1.3426), direct effect β = 0.4934, 95% CI (0.1978 to 0.7891), and total effect β = 1.6446, 95% CI (1.3479 to 1.9414)]., Conclusions: Our findings indicate that among adolescents, experiencing aggression is associated with an increased suicide risk. In addition to the direct effect of aggression on suicide risk, insomnia, nightmare distress, and fatigue mediate the relationship between aggression and suicide risk. More attention should be paid to adolescents experiencing aggression, and interventions should be implemented and strengthened., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Realizing quantum speedup for practically relevant, computationally hard problems is a central challenge in quantum information science. Using Rydberg atom arrays with up to 289 qubits in two spatial dimensions, we experimentally investigate quantum algorithms for solving the maximum independent set problem. We use a hardware-efficient encoding associated with Rydberg blockade, realize closed-loop optimization to test several variational algorithms, and subsequently apply them to systematically explore a class of graphs with programmable connectivity. We find that the problem hardness is controlled by the solution degeneracy and number of local minima, and we experimentally benchmark the quantum algorithm's performance against classical simulated annealing. On the hardest graphs, we observe a superlinear quantum speedup in finding exact solutions in the deep circuit regime and analyze its origins.

In this work a flexible multi-dentate 4,4'-(1H-1,2,4-triazole-1-yl) methylene-bis(benzonic acid) (H 2 L) ligand has been employed, a unique cluster-based nano-porous luminescent zinc(II) metal-organic framework {[Zn(μ 6 -L)]·(DMAC) 2 } n (1) (DMAC = Dimethylacetamide) has been isolated under solvo-thermal conditions. The H 2 L ligand adopts hexa-dentate coordination modes via one triazole nitrogen atom and four aromatic carboxylate oxygen atoms, which bridge the neighboring six-coordinated Zn II centers, leading to a three-dimensional (3D) nano-porous metal organic framework. A PLATON program analysis suggests the total potential solvent area volume is 2028.9 Å 3 , which occupy 62.5% percent of the unit cell volume (3248.4 Å 3 ). PXRD Patterns of the as-synthesized samples 1 have been determined confirming the purity of the bulky samples. Photo-luminescent properties indicate strong fluorescent emissions of 1 at the room temperature. Further photo-luminescent measurements show that 1 can exhibit highly sensitive real-time luminescence sensing of anthrax biomarker dipicolinic acid (DPA) with high quenching efficiency (K SV  = 1.48 × 10 5 M -1 ) and low detection limit (0.298 μM (S/N = 3)). Meanwhile 1 also exhibits highly selective and sensitive luminescence sensing for Cr 2 O 7 2- ions in aqueous solutions with high quenching efficiency K SV  = 1.22 × 10 4 L·mol -1 and low detection limit (0.023 μM (S/N = 3)). Therefore 1 can be used a unique multi-functional 3D cluster-based metal organic material in sensitive detection and effective detection of environment pollutants and biomarker molecules., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to measure the association between age and adverse outcomes in patients undergoing open reduction internal fixation (ORIF) of mandibular fractures., Methods: This was a retrospective cohort study utilizing the American College of Surgeons National Surgical Quality Improvement Program databases (2011 to 2019) to identify patients with mandibular fractures treated with ORIF. The primary predictor variable was age (<45 years, 45 to 54 years, 55 to 64 years, 65 to 74 years, and ≥75 years). The primary outcome variable was surgical complications. Secondary outcome variables included any complication, extended length of stay (LOS ≥95 th percentile), and adverse discharge destination. Covariates included demographic, medical, and perioperative covariates. Descriptive, bivariate, and multiple logistic regression statistics were utilized to evaluate the association between age and adverse outcomes., Results: During the study period, 2,843 patients underwent ORIF of a mandibular fracture, and 2,168 subjects were included. There were 1,673 subjects aged <45 years (77.2%), 240 subjects aged 45 to 54 years (11.1%), 155 subjects aged 55 to 64 years (7.10%), 53 subjects aged 65 to 74 years (2.40%), and 47 subjects aged ≥75 years (2.20%). A total of 148 subjects (6.83%) experienced a surgical complication; the incidence of surgical complications increased in a step-wise fashion with each decade of life (P ≤ .001). In bivariate analysis, subjects aged 65 to 74 years were more likely to experience extended LOS (P = .004), whereas subjects aged ≥75 years were more likely to have an extended LOS (P ≤ .001) and an adverse discharge destination (P ≤ .001). In multivariate analysis, age 65 to 74 years was an independent predictor of any complication (P = .032, 95% confidence interval [CI] = 1.08 to 5.37), extended LOS (P = .001, 95% CI = 1.72 to 8.79), and adverse discharge destination (P = .050, 95% CI = 1.00 to 14.4), whereas age ≥75 years was an independent predictor of surgical complications (P = .043, 95% CI = 1.03 to 6.68), any complication (P = .018, 95% CI = 1.20 to 6.75), extended LOS (P = .001, 95% CI = 2.35 to 12.3), and an adverse discharge destination (P ≤ .001, 95% CI = 3.01 to 33.2)., Conclusions: The elderly are at increased risk of adverse outcomes with step-wise increases in the odds of select outcomes with increasing age., (Copyright © 2022 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

P2X receptors are a class of nonselective cation channels widely distributed in the immune and nervous systems, and their dysfunction is a significant cause of tumors, inflammation, leukemia, and immune diseases. P2X7 is a unique member of the P2X receptor family with many properties that differ from other subtypes in terms of primary sequence, the architecture of N- and C-terminals, and channel function. Here, we suggest that the observed lengthened β2- and β3-sheets and their linker (loop β2,3), encoded by redundant sequences, play an indispensable role in the activation of the P2X7 receptor. We show that deletion of this longer structural element leads to the loss of P2X7 function. Furthermore, by combining mutagenesis, chimera construction, surface expression, and protein stability analysis, we found that the deletion of the longer β2,3-loop affects P2X7 surface expression but, more importantly, that this loop affects channel gating of P2X7. We propose that the longer β2,3-sheets may have a negative regulatory effect on a loop on the head domain and on the structural element formed by E171 and its surrounding regions. Understanding the role of the unique structure of the P2X7 receptor in the gating process will aid in the development of selective drugs targeting this subtype., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)