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Abstract Background Migraine, a widespread neurological condition, substantially affects the quality of life, particularly for adolescents and young adults. While its impact is significant, there remains a paucity of comprehensive global research on the burden of migraine in younger demographics. Our study sought to elucidate the global prevalence, incidence, and disability-adjusted life-years (DALYs) associated with migraine in the 15–39 age group from 1990 to 2021, utilizing data from the Global Burden of Disease (GBD) 2021 study. Methods Our comprehensive study analyzed migraine data from the GBD 2021 report, examining the prevalence, incidence, and DALYs across 204 countries and territories over a 32-year span. We stratified the information by age, sex, year, geographical region, and Socio-demographic Index (SDI). To evaluate temporal trends in these metrics, we employed the estimated annual percentage change (EAPC) calculation. Results Between 1990 and 2021, the worldwide prevalence of migraine among 15–39 year-olds increased substantially. By 2021, an estimated 593.8 million cases were reported, representing a 39.52% rise from 425.6 million cases in 1990. Global trends showed increases in age-standardized prevalence rate, incidence rate, and DALY rate for migraine during this period. The EAPC were positive for all three metrics: 0.09 for ASPR, 0.03 for ASIR, and 0.09 for DALY rate. Regions with medium SDI reported the highest absolute numbers of prevalent cases, incident cases, and DALYs in 2021. However, high SDI regions demonstrated the most elevated rates overall. Across the globe, migraine prevalence peaked in the 35–39 age group. Notably, female rates consistently exceeded male rates across all age categories. Conclusion The global impact of migraine on youths and young adults has grown considerably from 1990 to 2021, revealing notable variations across SDI regions, countries, age groups, and sexes. This escalating burden necessitates targeted interventions and public health initiatives, especially in areas and populations disproportionately affected by migraine.

Abstract Zika virus, a mosquito-borne arbovirus, has repeatedly caused large pandemics with symptoms worsening from mild and self-limiting diseases to Guillain–Barré syndrome in adults and fetal microcephaly in newborns. In recent years, Zika virus diseases have posed a serious threat to human health. The shortage of susceptible small animal models makes it difficult to study pathogenic mechanisms and evaluate potential therapies for Zika virus infection. Therefore, we chose immunocompromised mice (AG129 mice) deficient in IFN-α/β and IFN-γ receptors, which can abolish the innate immune system that prevents Zika virus infection early. AG129 mice were infected with the Zika virus, and this mouse model exhibited replication dynamics, tissue tropism, pathological lesion and immune activation of the Zika virus. Our results suggest that the inoculum dose of Zika virus can affect the viral replication dynamics, cytokine responses and survival rate in AG129 mice. By testing the potential antiviral drug favipiravir, several critical indicators, including replication dynamics and survival rates, were identified in AG129 mice after Zika virus infection. It is suggested that the model is reliable for drug evaluation. In brief, this model provides a potential platform for studies of the infectivity, virulence, and pathogenesis of the Zika virus. Moreover, the development of an accessible mouse model of Zika virus infection will expedite the research and deployment of therapeutics and vaccines.

Abstract Background Biallelic pathogenic variants in USH2A lead to Usher syndrome or non-syndromic retinitis pigmentosa, and shown to have geographical and ethnical distribution in previous studies. This study provided a deeper understanding of the detailed clinical features using multimodal imaging, genetic spectrum, and genotype–phenotype correlations of USH2A-related retinal dystrophies in Taiwan. Results In our cohort, the mean age at first visit was 47.66 ± 13.54 years, and the mean age at symptom onset, which was referred to the onset of nyctalopia and/or visual field constriction, was 31.21 ± 15.24 years. Among the variants identified, 23 (50%) were missense, 10 (22%) were splicing variants, 8 (17%) were nonsense, and 5 (11%) were frameshift mutations. The most predominant variant was c.2802T>G, which accounted for 21% of patients, and was located in exon 13. Patients with truncated alleles had significantly earlier symptom onset and seemly poorer disease progression regarding visual acuity, ellipsoid zone line length, and hypofluorescent lesions in the macula than those who had the complete gene. However, the clinical presentation revealed similar progression between patients with and without the c.2802T>G variant. During long-term follow-up, the patients had different ellipsoid zone line progression rates and were almost evenly distributed in the fast, moderate, and slow progression subgroups. Although a younger onset age and a smaller baseline intact macular area was observed in the fast progression subgroup, the results showed no significant difference. Conclusions This is the first cohort study to provide detailed genetic and longitudinal clinical analyses of patients with USH2A-related retinal dystrophies in Taiwan. The mutated allele frequency in exon 13 was high in Taiwan due to the predominant c.2802T>G variant. Moreover, truncated variants greatly impacted disease progression and determined the length of therapeutic windows. These findings provide insight into the characteristics of candidates for future gene therapies.

Objective To statistically analyze the perioperative results of patients with ABO-incompatible kidney transplantation (ABOi-KT), in order to explore the changes in blood group antibody of type-A/B recipients. Methods A total of 33 cases of blood group A/B ABOi-KT recipients in our hospital from January 2021 to October 2023 were recruited and divided into two groups of group A(n=18) and group B(n=15) according to the different blood types of recipient. The effects of preoperative plasmapheresis on antibody titer, antibody rebound and renal function after operation(serum urea nitrogen, creatinine and estimated glomerular filtration rate on the 1st, 3rd, 7th and 14th day) were analyzed between the two groups. According to the postoperative rebound of blood type antibodies, 33 recipients were divided into antibody rebound group(n=7) and non rebound group(n=26), and the differences in initial blood type antibody titers between the two groups were analyzed. Results There was no significant difference in the clearance rate of IgM with preoperative plasma exchange between the two groups (Z=-0.26, P>0.05); Levels of serum urea nitrogen and creatinine on the 1st, 3rd, 7th and 14th day after operation between group A and group B were not statistically significant(P>0.05), the same as eGFR. Group B was more prone to rebound antibody compared with group A (P0.05) between the two groups was found. Conclusion The patients type B receiving type AB kidney donors are more prone to rebound antibody after ABOi-KT operation compared to the the patients type A receiving type AB.

Chemokines are small, secreted cytokines crucial in the regulation of a variety of cell functions. The binding of chemokine C-X-C motif chemokine ligand 12 (CXCL12) (stromal cell-derived factor 1) to a G-protein-coupled receptor C-X-C chemokine receptor type 4 (CXCR4) triggers downstream signaling pathways with effects on cell survival, proliferation, chemotaxis, migration, and gene expression. Intensive and extensive investigations have provided evidence suggesting that the CXCL12-CXCR4 axis plays a pivotal role in tumor development, survival, angiogenesis, metastasis, as well as in creating tumor microenvironment, thus implying that this axis is a potential target for the development of cancer therapies. The structures of CXCL12 and CXCR4 have been resolved with experimental methods such as X-ray crystallography, NMR, or cryo-EM. Therefore, it is possible to apply structure-based computational approaches to discover, design, and modify therapeutic molecules for cancer treatments. Here, we summarize the current understanding of the roles played by the CXCL12-CXCR4 signaling axis in cellular functions linking to cancer progression and metastasis. This review also provides an introduction to protein structures of CXCL12 and CXCR4 and the application of computer simulation and analysis in understanding CXCR4 activation and antagonist binding. Furthermore, examples of strategies and current progress in CXCL12-CXCR4 axis-targeted development of therapeutic anticancer inhibitors are discussed.

Abstract This study investigated the correlation of newly identified inflammatory and insulin resistance indices with cerebral amyloid angiopathy (CAA), and explored their potential to differentiate CAA from hypertensive arteriopathy (HA). We retrospectively analyzed 514 consecutive patients with cerebral small vessel disease (CSVD)-related haemorrhage, comparing the differences in novel inflammatory and insulin resistance indices between patients with CAA and HA. Univariate regression, LASSO and multivariate regression were used to screen variables and construct a classification diagnosis nomogram. Additionally, these biomarkers were explored in patients with mixed haemorrhagic CSVD. Inflammatory indices were higher in CAA patients, whereas insulin resistance indices were higher in HA patients. Further analysis identified neutrophil-to-lymphocyte ratio (NLR, OR 1.17, 95% CI 1.07–1.30, P

Abstract Background Childhoods in urban or rural environments may differentially affect the risk of neuropsychiatric disorders, possibly through memory processing and neural response to emotional stimuli. Genetic factors may not only influence individuals’ choices of residence but also modulate how the living environment affects responses to episodic memory. Methods We investigated the effects of childhood urbanicity on episodic memory in 410 adults (discovery sample) and 72 adults (replication sample) with comparable socioeconomic statuses in Beijing, China, distinguishing between those with rural backgrounds (resided in rural areas before age 12 and relocated to urban areas at or after age 12) and urban backgrounds (resided in cities before age 12). We examined the effect of childhood urbanicity on brain function across encoding and retrieval sessions using an fMRI episodic memory paradigm involving the processing of neutral or aversive pictures. Moreover, genetic association analyses were conducted to understand the potential genetic underpinnings that might contribute to memory processing and neural mechanisms influenced by early-life urban or rural environments. Results Episodic memory retrieval accuracy for more difficult neutral stimuli was similar between those with urban and rural childhoods, whereas aversive stimuli elicited higher retrieval accuracy in the urban group (P = 0.023). For aversive stimuli, subjects with urban childhood had relatively decreased engagement of the striatum at encoding and decreased engagement of the hippocampus at retrieval. This more efficient striatal encoding of aversive stimuli in those with urban childhoods was associated with common variation in neurotrophic tyrosine kinase receptor type 2 (NTRK2) (right striatum: P = 1.58×10−6). These findings were confirmed in the replication sample. Conclusions We suggest that this differential striatal processing of aversive stimuli observed in individuals with urban or rural childhoods may represent mechanisms by which childhood urbanicity may affect brain circuits, heightening behavioral responses to negative stressors associated with urban environments. NTRK2-associated neural processes in the striatum may play a role in these processes.

Abstract Background To investigate the knowledge, attitudes, and practice (KAP) toward postoperative cognitive dysfunction (POCD) among anesthesiologists in China. Methods This cross-sectional study was conducted nationwide among Chinese anesthesiologists between December 2022 and January 2023. The demographic information and KAP scores of the respondents were collected using a web-based questionnaire. The mean KAP dimension scores ≥ 60% were considered good. Results This study enrolled 1032 anesthesiologists (51.2% male). The mean total scores of knowledge, positive attitude, and positive practice were 9.3 ± 1.2 (max 12), 34.8 ± 3.3 (max 40), and 30.6 ± 6.7 (max 40), respectively. The knowledge items with correctness scores

Abstract Radix Fici Simplicissimae (RFS) is widely studied, and is in demand for its value in medicines and food products, with increased scientific focus on its cultivation and breeding. We used ultra-high-performance liquid chromatography quadrupole-orbitrap mass spectrometry-based metabolomics to elucidate the similarities and differences in phytochemical compositions of wild Radix Fici Simplicissimae (WRFS) and cultivated Radix Fici Simplicissimae (CRFS). Untargeted metabolomic analysis was performed with multivariate statistical analysis and heat maps to identify the differences. Eighty one compounds were identified from WRFS and CRFS samples. Principal component analysis and orthogonal partial least squares discrimination analysis indicated that mass spectrometry could effectively distinguish WRFS from CRFS. Among these, 17 potential biomarkers with high metabolic contents could distinguish between the two varieties, including seven phenylpropanoids, three flavonoids, one flavonol, one alkaloid, one glycoside, and four organic acids. Notably, psoralen, apigenin, and bergapten, essential metabolites that play a substantial pharmacological role in RFS, are upregulated in WRFS. WRFS and CRFS are rich in phytochemicals and are similar in terms of the compounds they contain. These findings highlight the effects of different growth environments and drug varieties on secondary metabolite compositions and provide support for targeted breeding for improved CRFS varieties.

Abstract The purpose of this study was to explore whether dietary live microbe intake is associated with various cognitive domains using data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. And the specific relationship between low, medium and high dietary live microbe intake groups and cognitive ability of the elderly. Dietary live microbe intake was calculated from 24-h diet recall interviews. Cognitive function was assessed using the number symbol substitution test (DSST, which measures processing speed), the animal fluency test (AFT, which measures executive function), the Alzheimer's Registry sub-test (CERAD, which measures memory), and the Composite Z-score, which adds the Z-values of individual tests. Multiple linear regression models and restricted cubic bar graphs were used to investigate the relationship between live microbe intake and cognitive performance. A total of 2,450 participants aged 60 or older were included. Live microbe intake was positively correlated with cognitive ability on the whole. Specifically, when the intake of low, medium and high live microbe was > 2640 g, > 39 g and > 0 g respectively, the CERAD, DSST, AFT and compositive-Z score of the subjects increased with the increase of microbial intake (P

Abstract Microglia/macrophages are major contributors to neuroinflammation in the central nervous system (CNS) injury and exhibit either pro- or anti-inflammatory phenotypes in response to specific microenvironmental signals. Our latest in vivo and in vitro studies demonstrated that curcumin-treated olfactory ensheathing cells (aOECs) can effectively enhance neural survival and axonal outgrowth, and transplantation of aOECs improves the neurological outcome after spinal cord injury (SCI). The therapeutic effect is largely attributed to aOEC anti-inflammatory activity through the modulation of microglial polarization from the M1 to M2 phenotype. However, very little is known about what viable molecules from aOECs are actively responsible for the switch of M1 to M2 microglial phenotypes and the underlying mechanisms of microglial polarization. Herein, we show that Interleukin-4 (IL-4) plays a leading role in triggering the M1 to M2 microglial phenotype, appreciably decreasing the levels of M1 markers IL‑1β, IL‑6, tumour necrosis factor-alpha (TNF-α) and inducible nitric oxide synthase (iNOS) and elevating the levels of M2 markers Arg-1, TGF-β, IL-10, and CD206. Strikingly, blockade of IL-4 signaling by siRNA and a neutralizing antibody in aOEC medium reverses the transition of M1 to M2, and the activated microglia stimulated with the aOEC medium lacking IL-4 significantly decreases neuronal survival and neurite outgrowth. In addition, transplantation of aOECs improved the neurological function deficits after SCI in rats. More importantly, the crosstalk between JAK1/STAT1/3/6-targeted downstream signals and NF-κB/SOCS1/3 signaling predominantly orchestrates IL-4-modulated microglial polarization event. These results provide new insights into the molecular mechanisms of aOECs driving the M1-to-M2 shift of microglia and shed light on new therapies for SCI through the modulation of microglial polarization.

Abstract We conducted a systematic review and meta-analysis to evaluate the visual, anatomical, and safety outcomes of the intravitreal faricimab, a novel vascular endothelial growth factor (VEGF)/angiopoietin-2 (Ang-2) bispecific agent, in neovascular age-related macular degeneration (nAMD) patients. The follow-up times in the included studies ranged from a minimum of 36 weeks to a maximum of 52 weeks. EMBASE, Ovid-Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, the WHO ICTRP, ClinicalTrial.gov, the EU Clinical Trials Register, and Chinese Clinical Trial Registry (ChiCTR) were searched (The last literature search was performed on August 17, 2023) for randomized controlled trials (RCTs) comparing faricimab with control groups for neovascular age-related macular degeneration (nAMD). The risk of bias for eligible RCTs was independently assessed using the Cochrane Risk of Bias Tool by two authors (W.-T.Y. and C.-S.W.). The meta-analysis was conducted using Review Manager 5.4 software. The mean best corrected visual acuity (BCVA), central subfield thickness (CST), total choroidal neovascularization (CNV) area, and total lesion leakage were analyzed as continuous variables and the outcome measurements were reported as the weighted mean difference (WMD) with a 95% confidence interval (CI). The ocular adverse events and ocular serious adverse events were analyzed as dichotomous variables and the outcome measurements were analyzed as the odds ratios (ORs) with a 95% CI. Random-effects model was used in our study for all outcome synthesizing due to different clinical characteristics. Four RCTs with 1,486 patients were eligible for quantitative analysis. There was no statistically significant difference between intravitreal faricimab and anti-VEGF in BCVA [weighted mean difference (WMD) = 0.47; 95% CI: (− 0.17, 1.11)]. The intravitreal faricimab group showed numerically lower CST [WMD = − 5.96; 95% CI = (− 7.11, − 4.82)], total CNV area [WMD = − 0.49; 95% CI = (− 0.68, − 0.30)], and total lesion leakage [WMD = − 0.88; 95% CI = (− 1.08, − 0.69)] after intravitreal therapy compared with the intravitreal anti-VEGF group. There were no statistically significant differences between intravitreal faricimab and anti-VEGF in ocular adverse events (AEs) [pooled odds ratio (OR) = 1.10; 95% CI = (0.81, 1.49)] and serious adverse events (SAEs) [pooled OR = 0.84; 95% CI = (0.37, 1.90)]. The intravitreal bispecific anti-VEGF/angiopoietin 2 (Ang2) antibody faricimab with a extended injection interval was non-inferior to first-line anti-VEGF agents in BCVA. It was safe and had better anatomical recovery. Large, well-designed RCTs are needed to explore the potential benefit of extended faricimab for nAMD. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022327450).

Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits. Cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following TBI. ROS often damage DNA, lipids, proteins, and carbohydrates while RNS attack proteins. The products of lipid peroxidation 4-hydroxynonenal (4-HNE) and protein nitration 3-nitrotyrosine (3-NT) are often used as indicators of oxidative and nitrosative damages, respectively. Increasing evidence has shown that striatum is vulnerable to damage from TBI with a disturbed dopamine neurotransmission. TBI results in neurodegeneration, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy in the striatum and contribute to motor or behavioral deficits. Pomalidomide (Pom) is a Food and Drug Administration (FDA)-approved immunomodulatory drug clinically used in treating multiple myeloma. We previously showed that Pom reduces neuroinflammation and neuronal death induced by TBI in rat cerebral cortex. Here, we further compared the effects of Pom in cortex and striatum focusing on neurodegeneration, oxidative and nitrosative damages, as well as neuroinflammation following TBI. Sprague–Dawley rats subjected to a controlled cortical impact were used as the animal model of TBI. Systemic administration of Pom (0.5 mg/kg, intravenous [i.v.]) at 5 h post-injury alleviated motor behavioral deficits, contusion volume at 24 h after TBI. Pom alleviated TBI-induced neurodegeneration stained by Fluoro-Jade C in both cortex and striatum. Notably, Pom treatment reduces oxidative and nitrosative damages in cortex and striatum and is more efficacious in striatum (93% reduction in 4-HNE-positive and 84% reduction in 3-NT-positive neurons) than in cerebral cortex (42% reduction in 4-HNE-positive and 55% reduction in 3-NT-positive neurons). In addition, Pom attenuated microgliosis, astrogliosis, and elevations of proinflammatory cytokines in cortical and striatal tissue. We conclude that Pom may contribute to improved motor behavioral outcomes after TBI through targeting oxidative/nitrosative damages and neuroinflammation.

Abstract Existing knowledge distillation (KD) methods are mainly based on features, logic, or attention, where features and logic represent the results of reasoning at different stages of a convolutional neural network, and attention maps symbolize the reasoning process. Because of the continuity of the two in time, transferring only one of them to the student network will lead to unsatisfactory results. We study the knowledge transfer between the teacher-student network to different degrees, revealing the importance of simultaneously transferring knowledge related to the reasoning process and reasoning results to the student network, providing a new perspective for the study of KD. On this basis, we proposed the knowledge distillation method based on attention and feature transfer (AFT-KD). First, we use transformation structures to transform intermediate features into attentional and feature block (AFB) that contain both inference process information and inference outcome information, and force students to learn the knowledge in AFBs. To save computation in the learning process, we use block operations to align the teacher-student network. In addition, in order to balance the attenuation ratio between different losses, we design an adaptive loss function based on the loss optimization rate. Experiments have shown that AFT-KD achieves state-of-the-art performance in multiple benchmark tests.

Abstract This study aimed to assess the accuracy of cortical bone trajectory (CBT) screws placement guided by a spinous process clamp (SPC) guide. A total of 32 patients who received single-level midline lumbar fusion (MIDLF) surgery between June 2019 and January 2020 were retrospectively analyzed and divided into free-hand (FH) and SPC-guided groups according to the surgical approach. In the FH group, CBT screws was implanted with the assistance of fluoroscopy, while in the SPC group, CBT screws was implanted using the SPC navigator hardwire. A total of 128 screws were assessed in this study, with higher rates of clinically acceptable screw placement (grades A and B) and grade A screws in the SPC group than in the FH guide group (92.2% vs. 79.7%, P = 0.042 and 54.7% vs. 35.9%, P = 0.033, respectively). Misplacement screws (grades C, D, and E) occurred more often in the FH group than in the SPC guide group (20.3% vs. 7.8%, P = 0.042). The incidence of proximal facet joint violation (FJV) was higher in the FH group than in the SPC group (15.6% vs. 3.1%, P = 0.030). The radiation dose and time in the SPC guide group were comparable to those in the FH group (P = 0.063 and P = 0.078). The average operative time was significantly longer in the SPC guide group than in the FH group (267.8 ± 45.5 min vs. 210.9 ± 44.5 min, P = 0.001). Other clinical parameters, such as the average bone mineral density (BMD), intraoperative blood loss, and postoperative hospital stay, were not significantly different. Oswestry disability index (ODI) and back pain visual analogue scale (VAS) scores were significantly improved in both groups compared with preoperatively. SPC guided screw placement was more accurate than the fluoroscopy-assisted FH technique for single-level MIDLF at L4/5. Patients undergoing SPC-guided screw placement can achieve similar clinical outcomes as the fluoroscopy-assisted FH technique.

Abstract Objective To design a teaching model of innovative nursing practice workshop for new nurses based on creativity component theory and OBE concept, and to explore its implementation effect and application evaluation. Methods Using convenience sampling, 50 newly recruited nurses in 2021 from a tertiary hospital in Chengdu were selected as the study subjects and taught using the new nurses’ innovative practice workshop based on creativity component theory and the OBE concept. Results Before and after the implementation of the teaching, the new nurses’ creativity scale scores were significantly improved, and the effects of practice demonstration, teaching satisfaction results, and research output (one-year follow-up) were better. All 50 new nurses (100%) expressed willingness to participate in the course again. Conclusions Based on creativity component theory and the OBE concept, the innovative practice workshop for new nurses integrates theory and practice, and fully mobilizes students’ thinking, interest, and subjective initiative; during the teaching process, students’ creative thinking and problem-solving skills are improved, in addition, teamwork, literature review, communication and other skills are improved to different degrees, which is conducive to the research results. In addition, students’ abilities in teamwork, literature review, communication, and other aspects have been improved to different degrees, which is conducive to producing scientific research results and lays a good foundation for their future career development. No patient or public contribution No patient or public contribution is involved in this study.

Abstract Background In recent years, headache disorders have garnered significant attention as a pressing global health issue. This concern is especially pronounced in low- to middle-income countries and exhibits a notable increase in prevalence among adolescents and young adults. Such a surge in these disorders has invariably diminished the quality of life for affected individuals. Despite its global impact, comprehensive studies exploring the ramifications of headache disorders in the younger population remain scant. Our study endeavored to quantify the global prevalence of headache disorders in individuals between the ages of 15 and 39, over a three-decade span from 1990 to 2019. Methods Our study, conducted from 1990 to 2019, evaluated the impact of headache disorders, specifically migraines and tension-type headaches (TTH), in 204 different countries and territories. This comprehensive assessment included a detailed analysis of incidence rates, prevalence, and disability-adjusted life-years (DALYs) across various demographics such as age, gender, year, geographical location, and Socio-demographic Index (SDI). Results In 2019, there were an estimated 581,761,847.2 migraine cases globally (95% UI: 488,309,998.1 to 696,291,713.7), marking a 16% increase from 1990. Concurrently, TTH cases numbered at 964,808,567.1 (95% UI: 809,582,531.8 to 1,155,235,337.2), reflecting a 37% rise since 1990. South Asia reported the highest migraine prevalence with 154,490,169.8 cases (95% UI: 130,296,054.6 to 182,464,065.6). High SDI regions exhibited the most substantial migraine prevalence rates both in 1990 (22,429 per 100,000 population) and 2019 (22,606 per 100,000 population). Among the five SDI classifications, the middle SDI region recorded the highest tally of TTH cases in both 1990 (210,136,691.6 cases) and 2019 (287,577,250 cases). Over the past 30 years, East Asia experienced the most pronounced surge in the number of migraine cases. On the whole, there was a discernible positive correlation between the disease burden of migraine and TTH and the SDI. Conclusion Migraine and TTH represent formidable challenges in global health. The intensity of their impact exhibits marked disparities across nations and is distinctly elevated among women, individuals within the 30–39 age bracket, and populations characterized by a high SDI. The results of our research emphasize the imperative of assimilating migraine and TTH management into contemporary healthcare paradigms. Such strategic integration holds the potential to amplify public cognizance regarding pertinent risk factors and the spectrum of therapeutic interventions at hand.

Contrast-enhanced computed tomography scans (CECT) are routinely used in the evaluation of different clinical scenarios, including the detection and characterization of hepatocellular carcinoma (HCC). Quantitative medical image analysis has been an exponentially growing scientific field. A number of studies reported on the effects of variations in the contrast enhancement phase on the reproducibility of quantitative imaging features extracted from CT scans. The identification and labeling of phase enhancement is a time-consuming task, with a current need for an accurate automated labeling algorithm to identify the enhancement phase of CT scans. In this study, we investigated the ability of machine learning algorithms to label the phases in a dataset of 59 HCC patients scanned with a dynamic contrast-enhanced CT protocol. The ground truth labels were provided by expert radiologists. Regions of interest were defined within the aorta, the portal vein, and the liver. Mean density values were extracted from those regions of interest and used for machine learning modeling. Models were evaluated using accuracy, the area under the curve (AUC), and Matthew's correlation coefficient (MCC). We tested the algorithms on an external dataset (76 patients). Our results indicate that several supervised learning algorithms (logistic regression, random forest, etc.) performed similarly, and our developed algorithms can accurately classify the phase of contrast enhancement.

Asthma is a common chronic respiratory disease, with onset usually occurring during childhood or adolescence. The aim of this study was to estimate the dynamic changes in the burden of asthma disease among adolescents (aged 15–39 years). Between 1990 and 2019, our comprehensive analysis spanned 204 nations and territories to ascertain the global prevalence of asthma. This extensive evaluation meticulously quantified the disease's burden by examining a range of critical metrics—including mortality rates, prevalence figures, and disability-adjusted life-years (DALYs)—across diverse demographics. Our investigation systematically segmented the data by age, gender, and year, as well as by geographical regions and the Socio-demographic Index (SDI), offering an in-depth perspective on the multifaceted impact of asthma worldwide. From 1990 to 2019, there was a global increase in the incidence cases of asthma among young adults, with the number rising from 6487957.18 (95 %UI: 4578735.08–8736387.55) to 7604488.39 (95 % UI:5428024.98–10177808.25). The prevalence rate of asthma among young adults exhibited a decline from 580.09 per 1,00,000 (95 %UI:481.37–757.28) to 504.28 per 1,00,000 (95 %UI:400.64–633.26). It is also noteworthy that the incidence rates in the remaining SDI regions, although lower, also showed varying degrees of increase in 2015. The age-standardized disease burden rate for asthma among young adults has exhibited a decline over the course of the previous three decades. Nevertheless, regions characterized by lower SDI demonstrate elevated age-standardized mortality rates for asthma, thereby warranting focused attention and prioritized allocation of medical resources.

Abstract Immune responses induced by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection play a critical role in the pathogenesis and outcome of coronavirus disease 2019 (COVID‐19). However, the dynamic profile of immune responses postinfection by SARS‐CoV‐2 variants of concern (VOC) is not fully understood. In this study, peripheral blood mononuclear cells single‐cell sequencing was performed to determine dynamic profiles of immune response to Prototype, Alpha, Beta, and Delta in a rhesus monkey model. Overall, all strains induced dramatic changes in both cellular subpopulations and gene expression levels at 1 day postinfection (dpi), which associated function including adaptive immune response, innate immunity, and IFN response. COVID‐19‐related genes revealed different gene profiles at 1 dpi among the four SARS‐CoV‐2 strains, including genes reported in COVID‐19 patients with increased risk of autoimmune disease and rheumatic diseases. Delta‐infected animal showed inhibition of translation pathway. B cells, T cells, and monocytes showed much commonality rather than specificity among the four strains. Monocytes were the major responders to SARS‐CoV‐2 infection, and the response lasted longer in Alpha than the other strains. Thus, this study reveals the early immune responses induced by SARS‐CoV‐2 Proto or its variants in nonhuman primates, which is important information for controlling rapidly evolving viruses.

Epilepsy is a profound disorder, accounting for roughly 1% of the global disease burden. It can result in premature death and significant disability. To comprehensively understand the current dynamics and trends of idiopathic epilepsy, a deep insight into its epidemiological attributes is vital. We evaluated the incidence, prevalence, mortality, and disability-adjusted life years associated with idiopathic epilepsy from 1990 to 2019 using data and methodologies from the Global Burden of Disease Study.In 2019, there were approximately 2,898,222 individuals diagnosed with idiopathic epilepsy. Intriguingly, from 1990 to 2019, the age-standardized incidence rate of idiopathic epilepsy was consistently lower in women compared to men. Over these three decades, global mortality connected to idiopathic epilepsy increased by 13.95%. However, within the same period, age-standardized death rates for idiopathic epilepsy decreased from 1.94 per 100,000 population to 1.46 per 100,000 population. Predictions indicate an increase in the incidence of idiopathic epilepsy across all age brackets through 2035, especially among the elderly aged 80 and above. Mortality rates are projected to climb for those aged 80 and above while remaining relatively unchanged in other age demographics. Idiopathic epilepsy continues to be a significant contributor to both disability and death. The findings of our study underscore the critical importance of incorporating idiopathic epilepsy management into modern healthcare frameworks. Such strategic inclusion can enhance public awareness of relevant risk factors and the range of available therapeutic interventions.

Abstract Knowledge graphs (KGs) are of great importance to many artificial intelligence applications, but they usually suffer from the incomplete problem. Knowledge graph embedding (KGE), which aims to represent entities and relations in low-dimensional continuous vector spaces, has been proved to be a promising approach for KG completion. Traditional KGE methods only concentrate on structured triples, while paying less attention to the type information of entities. In fact, incorporating entity types into embedding learning could further improve the performance of KG completion. To this end, we propose a universal Type-augmented Knowledge graph Embedding framework (TaKE) which could utilize type features to enhance any traditional KGE models. TaKE automatically captures type features under no explicit type information supervision. And by learning different type representations of each entity, TaKE could distinguish the diversity of types specific to distinct relations. We also design a new type-constrained negative sampling strategy to construct more effective negative samples for the training process. Extensive experiments on four datasets from three real-world KGs (Freebase, WordNet and YAGO) demonstrate the merits of our proposed framework. In particular, combining TaKE with the recent tensor factorization KGE model SimplE can achieve state-of-the-art performance on the KG completion task.

Abstract Although antiangiogenic therapy has been used in gastric cancer, disease progression due to drug resistance remains common. Neutrophils play an important role in the occurrence and progression of cancer via neutrophil extracellular traps (NETs). However, few studies have investigated angiogenic regulation in gastric cancer. We aimed to determine the role of NETs in promoting angiogenesis in gastric cancer. Multiple immunohistochemical staining was used to analyze the spatial distribution of NETs and microvessels in patient tissue samples. A mouse subcutaneous tumor model was established to determine the effect of NETs on tumor growth, and changes in microvessel density were observed via immunohistochemical staining. We screened differentially expressed proteins in HUVECs stimulated by NETs via proteomics. Cell Counting Kit-8, EdU labeling, and tubule formation assays were used to verify the effect of NETs on HUVEC proliferation, migration, and tubule formation. Blocking NETs, which was related to decreased microvessel density, significantly inhibited tumor growth in the murine subcutaneous tumor model. Compared with those of the control group, tumor volume and mass among mice in the inhibition group decreased by 61.3% and 77.9%, respectively. The NET-DNA receptor CCDC25 was expressed in HUVECs, providing a platform for NETs to promote HUVEC proliferation, migration, and tubulation. In an in vitro rat aortic explant model, NETs induced HUVEC proliferation, survival, and chemotaxis, which were not significantly different from those observed in the VEGF stimulation group. Our results confirm that NETs promote angiogenesis in gastric cancer, providing a theoretical basis for identifying new anti-vascular therapeutic targets. Graphical Abstract Video Abstract

Purpose: To investigate the associations between fluid accumulation at different levels in the retina and visual outcome in polypoidal choroidal vasculopathy (PCV). Design: A retrospective observational study. Institutional setting. Study Population: A total of 91 eyes from 91 patients of PCV were included, with 65 receiving intravitreal aflibercept monotherapy and 26 receiving combined intravitreal ranibizumab and photodynamic therapy (PDT). Observation Procedures: Best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) examination results were recorded at baseline and 3, 6, and 12 months after treatment. Main Outcome Measures: The correlations between visual outcomes and fluid biomarkers including intraretinal fluid (IRF), subretinal fluid (SRF), serous pigment epithelium detachment (PED), and hemorrhage at fovea were analyzed. Results: No differences in treatment outcomes were noted between patients receiving aflibercept and those receiving combined ranibizumab and PDT. IRF and hemorrhage at baseline predicted poorer vision at 3, 6, and 12 months. The presence of IRF was associated with poorer vision at 6 months and 12 months (p < 0.05 for all). The presence of SRF or PED was not associated with better vision at any time point. No differences in the correlations between fluid markers and visual outcomes were noted between thin and thick subfoveal choroidal thickness groups. Conclusions: For PCV, IRF and hemorrhage at baseline served as surrogates for poor visual prognosis after treatment, and IRF was a biomarker for poor vision during the treatment course. No fluid markers predicted good visual prognosis or had a positive impact on vision at any time point.

Abstract This study aimed to explore how kinesin family member 2C (KIF2C) influences the progression of non-small cell lung cancer (NSCLC). The levels of KIF2C and microRNA-186-3p (miR-186-3p) were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Through the utilization of cell counting kit-8 (CCK-8) assay, colony formation assay, wound closure assay, and Transwell assay, NSCLC cell proliferation, migration, and invasion were identified, respectively. NSCLC cell apoptosis was assessed using the TUNEL assay and flow cytometry (FCM) assay. Luciferase reporter analysis was used to investigate the relationship between KIF2C and miR-186-3p. Western blot assays were conducted to investigate the influence of KIF2C on the AKT-GSK3β-β-catenin pathway. The results showed that KIF2C was up‐regulated in NSCLC cells, which predicted poor prognosis. KIF2C overexpression promoted the proliferation, migration, and invasion of NSCLC cells as well as inhibited NSCLC cell apoptosis. KIF2C was as a key target of miR-186-3p. High expression of KIF2C, meanwhile, increased the levels of β-catenin, p-GSK-3β and phosphorylated protein kinase B (p-AKT). KIF2C downregulation and miR-186-3p upregulation reversed these outcomes. As an oncogenic factor, KIF2C is negatively regulated by miR-186-3p and participates in the progression of NSCLC through the AKT-GSK3β-β-catenin pathway.

Abstract Decreased coherence in electroencephalogram (EEG) has been reported in Alzheimer’s disease (AD) experimentally, which could be considered as a typical electrophysiological characteristic in AD. This work aimed to investigate the effect of AD on coherence in the dorsal visual pathway by the technique of neurocomputation. Firstly, according to the hierarchical organization of the cerebral cortex and the information flows of the dorsal visual pathway, a more physiologically plausible neural mass model including cortical areas v1, v2, and v5 was established in the dorsal visual pathway. The three interconnected cortical areas were connected by ascending and descending projections. Next, the pathological condition of loss of long synaptic projections in AD was simulated by reducing the parameters of long synaptic projections in the model. Then, the loss of long synaptic projections on coherence among different visual cortex areas was explored by means of power spectral analysis and coherence function. The results demonstrate that the coherence between these interconnected cortical areas showed an obvious decline with the gradual decrease of long synaptic projections, i.e. decrease in descending projections from area v2 to v1 and v5 to v2 and ascending projection from area v2 to v5. Hopefully, the results of this study could provide theoretical guidance for understanding the dynamical mechanism of AD.

Abstract Background A global plan has been set to end human deaths from dog-mediated rabies by 2030 ("Zero-by-30"), but whether it could be achieved in some countries, such as China, remains unclear. Although elimination strategies through post-exposure prophylaxis (PEP) use, dog vaccination, and patient risk assessments with integrated bite case management (IBCM) were proposed to be cost-effective, evidence is still lacking in China. We aim to evaluate the future burdens of dog-mediated human rabies deaths in the next decade and provide quantitative evidence on the cost-effectiveness of different rabies-control strategies in China. Methods Based on data from China's national human rabies surveillance system, we used decision-analytic modelling to estimate dog-mediated human rabies death trends in China till 2035. We simulated and compared the expected consequences and costs of different combination strategies of the status quo, improved access to PEP, mass dog vaccination, and use of IBCM. Results The predicted human rabies deaths in 2030 in China will be 308 (95%UI: 214–411) and remain stable in the next decade under the status quo. The strategy of improved PEP access alone could only decrease deaths to 212 (95%UI: 147–284) in 2028, remaining unchanged till 2035. In contrast, scaling up dog vaccination to coverage of 70% could eliminate rabies deaths by 2033 and prevent approximately 3,265 (95%UI: 2,477–3,687) extra deaths compared to the status quo during 2024–2035. Moreover, with the addition of IBCM, the "One Health" approach through mass dog vaccination could avoid unnecessary PEP use and substantially reduce total cost from 12.53 (95%UI: 11.71–13.34) to 8.73 (95%UI: 8.09–9.85) billion US dollars. Even if increasing the total costs of IBCM from 100 thousand to 652.10 million US dollars during 2024–2035, the combined strategy of mass dog vaccination and use of IBCM will still dominate, suggesting the robustness of our results. Conclusions The combined strategy of mass dog vaccination and IBCM requires collaboration between health and livestock/veterinary sectors, and it could eliminate Chinese rabies deaths as early as 2033, with more deaths averted and less cost, indicating that adding IBCM could reduce unnecessary use of PEP and make the "One Health" rabies-control strategy most cost-effective.

Viruses existed in wastewaters might pose a biosecurity risk to human and animal health. However, it is generally difficult to detect viruses in wastewater directly as they usually occur in low numbers in water. Therefore, processing large volumes of water to concentrate viruses in a much smaller final volume for detection is necessary. Glass wool has been recognized as an effective material to concentrate multiple in water, and in this study, we assessed the use of glass wools on concentrating pseudorabies virus (PRV), African swine fever virus (ASFV), and porcine epidemic diarrhea virus (PEDV) in water samples. The influence of pH values, water matrix, water volume, filtration rate, temperature on the effect of the method concentrating these viruses for detection was evaluated in laboratory. Our results revealed that glass wool was suitable for the concentration of above-mentioned viruses from different water samples, and demonstrated a good application effect for water with pH between 6.0–9.0. Furthermore, glass wool also showed a good recovery effect on concentrating viral nucleic acids and viral particles, as well as living viruses. In addition, combining use of glass wool with skim milk, polyethylene glycol (PEG)-NaCl, or ultracentrifuge had good effects on concentrating ASFV, PRV, and PEDV. Detection of wastewater samples (n = 70) collected from 70 pig farms in 13 regions across Hubei Province in Central China after glass-wool-concentration determined one sample positive for ASFV, eighteen samples positive for PRV, but no sample positive for PEDV. However, these positive samples were detected to be negative before glass wool enrichment was implemented. Our results suggest that glass wool-based water concentration method developed in this study represents an effective tool for detecting viruses in wastewater.

Abstract Background Previous studies have shown that depression is often accompanied by an increase in mtDNA copy number and a decrease in ATP levels; however, the exact regulatory mechanisms remain unclear. Methods In the present study, Western blot, cell knockdown, immunofluorescence, immunoprecipitation and ChIP-qPCR assays were used to detect changes in the Ahi1/GR-TFAM-mtDNA pathway in the brains of neuronal Abelson helper integration site-1 (Ahi1) KO mice and dexamethasone (Dex)-induced mice to elucidate the pathogenesis of depression. In addition, a rescue experiment was performed to determine the effects of regular exercise on the Ahi1/GR-TFAM-mtDNA-ATP pathway and depression-like behavior in Dex-induced mice and Ahi1 KO mice under stress. Results In this study, we found that ATP levels decreased and mitochondrial DNA (mtDNA) copy numbers increased in depression-related brain regions in Dex-induced depressive mice and Ahi1 knockout (KO) mice. In addition, Ahi1 and glucocorticoid receptor (GR), two important proteins related to stress and depressive behaviors, were significantly decreased in the mitochondria under stress. Intriguingly, GR can bind to the D-loop control region of mitochondria and regulate mitochondrial replication and transcription. Importantly, regular exercise significantly increased mitochondrial Ahi1/GR levels and ATP levels and thus improved depression-like behaviors in Dex-induced depressive mice but not in Ahi1 KO mice under stress. Conclusions In summary, our findings demonstrated that the mitochondrial Ahi1/GR complex and TFAM coordinately regulate mtDNA copy numbers and brain ATP levels by binding to the D-loop region of mtDNA Regular exercise increases the levels of the mitochondrial Ahi1/GR complex and improves depressive behaviors. Video Abstract

Abstract To analyze alterations of the liver appearance during the hepatobiliary phase of individuals with type 2 diabetes who are receiving gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI). Fifty-seven individuals who received Gd-EOB-DTPA-enhanced MRI and had normal liver and renal function but did not have (control group) or have type 2 diabetes (observation group) were retrospectively included in this study. The liver enhancement ratio (LER) and contrast between liver parenchyma and portal vein (LPC) were calculated from hepatobiliary phase images. Utilizing liver to kidney signal intensity, signs of the biliary system, and signs of the portal vein, a functional liver imaging score (FLIS) was calculated. Wilcoxon rank-sum test was used to assess the between-group differences in LER, LPC, and FLIS. FLIS constituent ratios between the two groups were tested using the χ 2 test. The effectiveness of LER, LPC, and FLIS for identifying type 2 diabetes was assessed by receiver operating characteristic curves (ROCs). The interobserver consistency of FLIS was evaluated using the intraclass correlation coefficients. The observation group’s LER and LPC were lower than the control group. The constituent ratio of the FLIS score (liver to kidney signal intensity, p = 0.011) showed a significant between-group difference. According to ROCs, LER and LPC were associated with the identification of type 2 diabetes. LER = 0.54 and LPC = 1.46 were the optimal cutoff for identifying type 2 diabetes, respectively. FLIS demonstrated excellent inter-reader agreement. The relative signal intensity of the liver during the hepatobiliary phase is decreased in patients with type 2 diabetes. This should be considered when individuals with type 2 diabetes undergo Gd-EOB-DTPA-enhanced MRI to avoid misdiagnoses, such as small hepatocellular carcinoma or abnormal liver function.

Abstract Backgrounds Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed. Methods Surgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively. Results We established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone. Conclusions These data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations.

Abstract Background To investigate the association between computed tomography (CT)-detected extramural venous invasion (EMVI)-related genes and immunotherapy resistance and immune escape in patients with gastric cancer (GC). Methods Thirteen patients with pathologically proven locally advanced GC who had undergone preoperative abdominal contrast-enhanced CT and radical resection surgery were included in this study. Transcriptome sequencing was multidetector performed on the cancerous tissue obtained during surgery, and EMVI-related genes (P value for association

Abstract Isodon rubescens (Hemsley) H. Hara (Lamiaceae) is a traditional Chinese medicine plant that has been used to treat various human diseases. Oridonin is one of the main active ingredients, and the route of its molecular biosynthesis remains to be determined. The study of gene expression patterns can provide clues toward the understanding of its biological functions. The selection of suitable reference genes for normalizing target gene expression is the first steps in any quantitative real-time PCR (RT-qPCR) gene expression study. Therefore, validation of suitable reference genes is necessary for obtaining reliable results in RT-qPCR analyses of I. rubescens. Here, 12 candidate reference genes were chosen, and their expression stability in different tissues of I. rubescens and in leaves under different abiotic stresses (NaCl, dehydration, SA, MeJA, and ABA) was evaluated using the ∆Ct, NormFinder, GeNorm, BestKeeper, and RankAggreg statistical tools. Analysis using the comprehensive tools of RankAggreg algorithm showed that GADPH, 18S and eIF were stably expressed in different tissues; UBQ, Apt, and HIS; Cycl, UBQ, and PP2A; GADPH, 18S, and eIF; eIF, UBQ, and PP2A; TUB, Cycl, and UBQ; were the best three candidate reference genes for the samples of Dehydration, NaCl, SA, MeJA, and ABA treatment, respectively. While for the concatenated sets of ND (NaCl and dehydration) and SMA (SA, MeJA, and ABA), UBQ, HIS, and TUA; UBQ, eIF and Apt were the three appropriate candidate reference genes, respectively. In addition, the expression patterns of HMGR in different tissues and under different treatments were used to confirm the reliability of the selected reference genes, indicating that the use of an inappropriate reference gene as the internal control will cause results with a large deviation. This work is the first study on the expression stability of reference genes in I. rubescens and will be particularly useful for gene functional research in this species.

Abstract Neutrophil extracellular traps (NETs) has been demonstrated to regulate the metastasis of breast cancer. In this study, we showed that de novo cholesterol biosynthesis induced by ASPP2 depletion in mouse breast cancer cell 4T1 and human breast cancer cell MDA-MB-231 promoted NETs formation in vitro, as well as in lung metastases in mice intravenously injected with ASPP2-deficient 4T1 cells. Simvastatin and berberine (BBR), cholesterol synthesis inhibitors, efficiently blocked ASPP2-depletion induced NETs formation. Cholesterol biosynthesis greatly enhanced Coiled-coil domain containing protein 25 (CCDC25) expression on cancer cells as well as in lung metastases. CCDC25 expression was co-localized with caveolin-1, a lipid raft molecule, and was damped by inhibitor of lipid rafts formation. Our data suggest that cholesterol biosynthesis promotes CCDC25 expression in a lipid raft-dependent manner. Clinically, the expression of CCDC25 was positively correlated with the expression of 3-hydroxy-3-methylglutaryl-CoAreductase (HMRCG), and citrullinated histone H3 (H3cit), in tissues from breast cancer patients. High expression of CCDC25 and HMGCR was related with worse prognosis in breast cancer patients. In conclusion, our study explores a novel mechanism for de novo cholesterol biosynthesis in the regulation of CCDC25 expression, NETs formation and breast cancer metastasis. Targeting cholesterol biosynthesis may be promising therapeutic strategies to treat breast cancer metastasis.

Abstract Sperm-oocyte membrane fusion is necessary for mammalian fertilization. The factors that determine the fusion of sperm with oocytes are largely unknown. So far, spermatozoon factor IZUMO1 and the IZUMO1 counter-receptor JUNO on the oocyte membrane has been identified as a protein requiring fusion. Some sperm membrane proteins such as FIMP, SPACA6 and TEME95, have been proved not to directly regulate fusion, but their knockout will affect the fusion process of sperm and oocytes. Here, we identified a novel gene C11orf94 encoding a testicular-specific small transmembrane protein that emerges in vertebrates likely acquired via horizontal gene transfer from bacteria and plays an indispensable role in sperm-oocyte binding. We demonstrated that the deletion of C11orf94 dramatically decreased male fertility in mice. Sperm from C11orf94-deficient mice could pass through the zona pellucida, but failed to bind to the oocyte membrane, thus accumulating in the perivitelline space. In consistence, when the sperm of C11orf94-deficient mice were microinjected into the oocyte cytoplasm, fertilized oocytes were obtained and developed normally to blastocysts. Proteomics analysis revealed that C11orf94 influenced the expression of multiple gene products known to be indispensable for sperm-oocyte binding and fusion, including IZUMO1, EQTN and CRISP1. Thus, our study indicated that C11ORF94 is a vertebrate- and testis-specific small transmembrane protein that plays a critical role in sperm binding to the oolemma.

Abstract Previous works imply that involving brainstem in neuropathological studies of Alzheimer’s disease (AD) is of clinically significant. This work constructs a comprehensive neural mass model for cholinergic neuropathogenesis that involves brainstem, thalamus and cortex, wherein how acetylcholine deficiency in AD affects neural oscillation of the model output is systematically explored from the perspective of neurocomputation. By decreasing synapse connectivity parameters in direct cholinergic pathway from brainstem to thalamus or in indirect glutamatergic synapse pathway from cortex to brainstem to mimic the pathological condition of reduced acetylcholine release in patients with AD, the property of neural oscillation in this model is numerically investigated by means of power spectrum in frequency domain and amplitude distribution in time domain. Simulated results demonstrate that decreasing synapse connectivity whether in the direct cholinergic pathway or in the indirect glutamatergic synapse pathway can alter the neural oscillation significantly in three aspects: it induces an obvious decrease of dominant frequency; it leads to a degraded rhythmic activity in the alpha frequency band as well as an enhanced rhythmic activity in the theta frequency band; it results in reduced oscillation amplitude of the model output. These results are agreement with the characteristic of electrophysiological EEG measurement recorded in AD, especially support the hypothesis that cholinergic deficiency is a promising pathophysiological origin of EEG slowing in AD. Our analysis indicates that targeting the cholinergic system may have potential prospects in early diagnosis and treatment of AD.

Abstract Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar IV/V lobe that projected to CaMKIIα+ neurons in the fastigial nucleus (FN), which regulated sensorimotor coordination. Furthermore, transcriptomics profiling analysis revealed various cerebellar neuronal identities, and we validated that biorientation defective 1 (BOD1) played an important role in the circuit of IV/V lobe to FN. BOD1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs, accompany with ataxia behaviors. Instead, BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα+ neurons in the FN and ameliorated ataxia behaviors in L7-Cre; BOD1 f/f mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobePCs → FNCaMKIIα+ circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.

Summary: Background: Liquid biopsy is a promising non-invasive alternative for cancer screening and minimal residual disease (MRD) detection, although there are some concerns regarding its clinical applications. We aimed to develop an accurate detection platform based on liquid biopsy for both cancer screening and MRD detection in patients with lung cancer (LC), which is also applicable to clinical use. Methods: We applied a modified whole-genome sequencing (WGS) -based High-performance Infrastructure For MultIomics (HIFI) method for LC screening and postoperative MRD detection by combining the hyper-co-methylated read approach and the circulating single-molecule amplification and resequencing technology (cSMART2.0). Findings: For early screening of LC, the LC score model was constructed using the support vector machine, which showed sensitivity (51.8%) at high specificity (96.3%) and achieved an AUC of 0.912 in the validation set prospectively enrolled from multiple centers. The screening model achieved detection efficiency with an AUC of 0.906 in patients with lung adenocarcinoma and outperformed other clinical models in solid nodule cohort. When applied the HIFI model to real social population, a negative predictive value (NPV) of 99.92% was achieved in Chinese population. Additionally, the MRD detection rate improved significantly by combining results from WGS and cSMART2.0, with sensitivity of 73.7% at specificity of 97.3%. Interpretation: In conclusion, the HIFI method is promising for diagnosis and postoperative monitoring of LC. Funding: This study was supported by CAMS Innovation Fund for Medical Sciences, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Beijing Natural Science Foundation and Peking University People's Hospital.

Abstract Background Depression is one of the most common psychiatric diseases. The monoamine transmitter theory suggests that neurotransmitters are involved in the mechanism of depression; however, the regulation on serotonin production is still unclear. We previously showed that Ahi1 knockout (KO) mice exhibited depression-like behavior accompanied by a significant decrease in brain serotonin. Methods In the present study, western blot, gene knockdown, immunofluorescence, dual-luciferase reporter assay, and rescue assay were used to detect changes in the Ahi1/GR/ERβ/TPH2 pathway in the brains of male stressed mice and male Ahi1 KO mice to explain the pathogenesis of depression-like behaviors. In addition, E2 levels in the blood and brain of male and female mice were measured to investigate the effect on the ERβ/TPH2 pathway and to reveal the mechanisms for the phenomenon of gender differences in depression-like behaviors. Results We found that the serotonin-producing pathway-the ERβ/TPH2 pathway was inhibited in male stressed mice and male Ahi1 KO mice. We further demonstrated that glucocorticoid receptor (GR) as a transcription factor bound to the promoter of ERβ that contains glucocorticoid response elements and inhibited the transcription of ERβ. Our recent study had indicated that Ahi1 regulates the nuclear translocation of GR upon stress, thus proposing the Ahi1/GR/ERβ/TPH2 pathway for serotonin production. Interestingly, female Ahi1 KO mice did not exhibit depressive behaviors, indicating sexual differences in depressive behaviors compared with male mice. Furthermore, we found that serum 17β-estradiol (E2) level was not changed in male and female mice; however, brain E2 level significantly decreased in male but not female Ahi1 KO mice. Further, ERβ agonist LY-500307 increased TPH2 expression and 5-HT production. Therefore, both Ahi1 and E2 regulate the ERβ/TPH2 pathway and involve sexual differences in brain serotonin production and depressive behaviors. Conclusions In conclusion, although it is unclear how Ahi1 controls E2 secretion in the brain, our findings demonstrate that Ahi1 regulates serotonin production by the GR/ERβ/TPH2 pathway in the brain and possibly involves the regulation on sex differences in depressive behaviors. Video Abstract

Abstract Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics, and currently used drugs cannot reverse the disease progress. Worse still, there are still challenges to be addressed to fully decipher the intricated pathogenesis. Thus, specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed. In this work, multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents. By utilizing an unbiased and time-resolved analysis of the transcriptome, proteome and phosphoproteome of a silicosis mouse model, we have verified the significant differences in transcript, protein, kinase activity and signaling pathway level during silicosis progression, in which the importance of essential biological processes such as macrophage activation, chemotaxis, immune cell recruitment and chronic inflammation were emphasized. Notably, the phosphorylation of EGFR (p-EGFR) and SYK (p-SYK) were identified as potential therapeutic targets in the progression of silicosis. To inhibit and validate these targets, we tested fostamatinib (targeting SYK) and Gefitinib (targeting EGFR), and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis. Overall, our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.

Abstract To alleviate the social contradiction between limited medical resources and increasing medical needs, the medical image-assisted diagnosis based on deep learning has become the research focus in Wise Information Technology of med. Most of the existing medical segmentation models based on Convolution or Transformer have achieved relatively sound effects. However, the Convolution-based model with a limited receptive field cannot establish long-distance dependencies between features as the Network deepens. The Transformer-based model produces large computation overhead and cannot generalize the bias of local features and perceive the position feature of medical images, which are essential in medical image segmentation. To address those issues, we present Triple Gate MultiLayer Perceptron U-Net (TGMLP U-Net), a medical image segmentation model based on MLP, in which we design the Triple Gate MultiLayer Perceptron (TGMLP), composed of three parts. Firstly, considering encoding the position information of features, we propose the Triple MLP module based on MultiLayer Perceptron in this model. It uses linear projection to encode features from the high, wide, and channel dimensions, enabling the model to capture the long-distance dependence of features along the spatial dimension and the precise position information of features in three dimensions with less computational overhead. Then, we design the Local Priors and Global Perceptron module. The Global Perceptron divides the feature map into different partitions and conducts correlation modelling for each partition to establish the global dependency between partitions. The Local Priors uses multi-scale Convolution with high local feature extraction ability to explore further the relationship of context feature information within the structure. At last, we suggest a Gate-controlled Mechanism to effectively solves the problem that the dependence of position embeddings between Patches and within Patches in medical images cannot be well learned due to the relatively small number of samples in medical images segmentation data. Experimental results indicate that the proposed model outperforms other state-of-the-art models in most evaluation indicators, demonstrating its excellent performance in segmenting medical images.

Abstract To investigate optical coherence tomography (OCT) and OCT angiography (OCTA) biomarkers for good visual outcomes in eyes with myopic choroidal neovascularization (mCNV) following anti-vascular endothelial growth factor (anti-VEGF) therapy. Patients diagnosed with mCNV via multimodal imaging were retrospectively reviewed. Baseline demographic data and biomarkers were collected. Anti-VEGF treatment based on a pro re nata (PRN) regimen was conducted on all eyes. The visual gains of ≥ 15 ETDRS letters or

Abstract Foxtail millet (Setaria italica) is rich in nutrients and extremely beneficial to human health. We identified and comprehensively analyzed 89 MADS-box genes in the foxtail millet genome. According to the classification of MADS-box genes in Arabidopsis thaliana and rice, the SiMADS-box genes were divided into M-type (37) and MIKC-type (52). During evolution, the differentiation of MIKC-type MADS-box genes occurred before that of monocotyledons and dicotyledons. The SiMADS-box gene structure has undergone much differentiation, and the number of introns in the MIKC-type subfamily is much greater than that in the M-type subfamily. Analysis of gene duplication events revealed that MIKC-type MADS-box gene segmental duplication accounted for the vast majority of gene duplication events, and MIKC-type MADS-box genes played a major role in the amplification of SiMADS-box genes. Collinearity analysis showed highest collinearity between foxtail millet and maize MADS-box genes. Analysis of tissue-specific expression showed that SiMADS-box genes are highly expressed throughout the grain-filling process. Expression analysis of SiMADS-box genes under eight different abiotic stresses revealed many stress-tolerant genes, with induced expression of SiMADS33 and SiMADS78 under various stresses warranting further attention. Further, some SiMADS-box proteins may interact under external stress. This study provides insights for MADS-box gene mining and molecular breeding of foxtail millet in the future.

Objective To explore the regularity of external-use Chinese medicine agents for curing freckle and chloasma.Methods To screening the external prescriptions for freckles and chloasma recorded in ancient books. The Excel data recording system was used to build an external prescription database of Chinese medicines for facial pigmentation skin disease. The frequency analysis and correlation analysis of 115 external prescriptions were carried out to summarize the common herbs, external application method, matrix, common Chinese medicine pairs and drug groups in the treatment of freckle and chloasma. Results Although with different causes of disease and different western medicine methods for freckles and chloasma, the external prescriptions of Chinese medicine were similar in ancient literature, Mainly including Baizhi, Baifuzi, Baiji, Bailian and Fuling, etc. Common drug pairs and drug groups included Baidingxiang, Baizhi, Baiji, Baifuzi, Bailian and Gansong, etc. The most commonly external-used method was rubbing and cleansing,with chicken egg white and honey as most popular drug matrix.Conclusion Common drugs, matrix drugs, drug pairs and external application methods for freckles and chloasma found by data mining analysis can provide ideas and references for clinical treatment and developing beauty products.

Objective To explore the influence of resin modified glass ionomer cement (RMGIC) adhesives containing protein-repellent and quaternary ammonium salt agents on supragingival microbiome, enamel and gingival health around brackets. Materials and Methods Ten patients (21.4 ± 3.5 years) about to receive fixed orthodontics were enrolled in this study. Unilateral upper teeth bonded with RMGIC incorporating 2-Methacryloyloxyethyl phosphorylcholine (MPC) and Dimethylaminohexadecyl methacrylate (DMAHDM) were regarded as experimental group (RMD), while contralateral upper teeth bonded with RMGIC were control group (RMGIC), using a split-mouth design. Supragingival plaque was collected from both groups before treatment (T0), and at 1 month (T1) and 3 months (T2) of treatment. High-throughput sequencing was performed targeting v3–v4 of 16S rRNA gene. Streptococcus mutans and Fusobacterium nucleatum quantification was done by qPCR analysis. Bracket failures, enamel decalcification index (EDI), DIAGNODent scores (Dd), plaque index (PI) and gingival index (GI) were monitored at indicated time points. Results Within 3 months, alpha and beta diversity of supragingival plaque had no difference between RMGIC and RMD groups. From T0 to T2, the relative abundance of Streptococcus depleted in RMD but remained steady in RMGIC group. Streptococcus, Prevotella, and Fusobacterium became depleted in RMD, Haemophilus and Capnocytophaga became depleted in RMGIC group but Prevotella enriched. Quantification of Fusbacterium nucleatum and Streptococcus mutans showed significant difference between RMGIC and RMD groups at T2. Teeth bonded with RMD had significant lower plaque index (PI) and DIAGNODent (Dd) score at T2, compared with teeth bonded with RMGIC (p < 0.05). No difference in bracket failure rate was examined between both groups (p > 0.05). Conclusion By incorporating MPC and DMAHDM into RMGIC, the material could affect the supragingival microbial composition, inhibit the progress of plaque accumulation as well as the key pathogens S. mutans and F. nucleatum in the early stage of orthodontic treatment.

Previous studies have shown that deep models are often over-parameterized, and this parameter redundancy makes deep compression possible. The redundancy of model weight is often manifested as low rank and sparsity. Ignoring any part of the two or the different distributions of these two characteristics in the model will lead to low accuracy and a low compression rate of deep compression. To make full use of the difference between low-rank and sparsity, a unified framework combining low-rank tensor decomposition and structured pruning is proposed: a hybrid model compression method based on sensitivity grouping (HMC). This framework unifies the existing additive hybrid compression method (AHC) and the non-additive hybrid compression method (NaHC) proposed by us into one model. The latter group the network according to the sensitivity difference of the convolutional layer to different compression methods, which can better integrate the low rank and sparsity of the model compared with the former. Experiments show that our approach achieves a better trade-off between test accuracy and compression ratio when compressing the ResNet family of models than other recent compression methods using a single strategy or additive hybrid compression.

Abstract Variants are globally emerging very quickly following pandemic prototypic SARS-CoV-2. To evaluate the cross-protection of prototypic SARS-CoV-2 vaccine against its variants, we vaccinated rhesus monkeys with three doses of prototypic SARS-CoV-2 inactivated vaccine, followed by challenging with emerging SARS-CoV-2 variants of concern (VOCs). These vaccinated animals produced neutralizing antibodies against Alpha, Beta, Delta, and Omicron variants, although there were certain declinations of geometric mean titer (GMT) as compared with prototypic SARS-CoV-2. Of note, in vivo this prototypic vaccine not only reduced the viral loads in nasal, throat and anal swabs, pulmonary tissues, but also improved the pathological changes in the lung infected by variants of Alpha, Beta, and Delta. In summary, the prototypic SARS-CoV-2 inactivated vaccine in this study protected against VOCs to certain extension, which is of great significance for prevention and control of COVID-19.

Abstract Patients with hepatocellular carcinoma (HCC) have poor long-term survival following curative resection because of the high rate of tumor early recurrence. Little is known about the trajectory of genomic evolution from primary to early-recurrent HCC. In this study, we performed whole-genome sequencing (WGS) on 40 pairs of primary and early-recurrent hepatitis B virus (HBV)-related HCC tumors from patients who received curative resection, and from four patients whose primary and recurrent tumor were extensively sampled. We identified two recurrence patterns: de novo recurrence (18/40), which developed genetically independently of the primary tumor and carried different HCC drivers, and ancestral recurrence (22/40), which was clonally related to the primary tumor and progressed more rapidly than de novo recurrence. We found that the recurrence location was predictive of the recurrence pattern: distant recurrence tended to display the de novo pattern, whereas local recurrence tended to display the ancestral pattern. We then uncovered the evolutionary trajectories based on the subclonal architecture, driver-gene mutations, and mutational processes observed in the primary and recurrent tumors. Multi-region WGS demonstrated spatiotemporal heterogeneity and polyclonal, monophyletic dissemination in HCC ancestral recurrence. In addition, we identified recurrence-specific mutations and copy-number gains in BCL9, leading to WNT/β-catenin signaling activation and an immune-excluded tumor microenvironment, which suggests that BCL9 might serve as a new therapeutic target for recurrent HCC. Collectively, our results allow us to view with unprecedented clarity the genomic evolution during HBV-related HCC early recurrence, providing an important molecular foundation for enhanced understanding of HCC with implications for personalized therapy to improve patient survival.