RANK-BASED INDICES FOR TESTING INDEPENDENCE BETWEEN TWO HIGH-DIMENSIONAL VECTORS.

To test independence between two high-dimensional random vectors, we propose three tests based on the rank-based indices derived from Hoeffding's D, Blum-Kiefer-Rosenblatt's R and Bergsma-Dassios-Yanagimoto's τ*. Under the null hypothesis of independence, we show that the distributions of the proposed test statistics converge to normal ones if the dimensions diverge arbitrarily with the sample size. We further derive an explicit rate of convergence. Thanks to the monotone transformation-invariant property, these distribution-free tests can be readily used to generally distributed random vectors including heavily tailed ones. We further study the local power of the proposed tests and compare their relative efficiencies with two classic distance covariance/correlation based tests in high dimensional settings. We establish explicit relationships between D,R,τ* and Pearson's correlation for bivariate normal random variables. The relationships serve as a basis for power comparison. Our theoretical results show that under a Gaussian equicorrelation alternative, (i) the proposed tests are superior to the two classic distance covariance/correlation based tests if the components of random vectors have very different scales; (ii) the asymptotic efficiency of the proposed tests based on D,τ* and R are sorted in a descending order.

Projection Test for Mean Vector in High Dimensions.

This paper studies the projection test for high-dimensional mean vectors via optimal projection. The idea of projection test is to project high-dimensional data onto a space of low dimension such that traditional methods can be applied. We first propose a new estimation for the optimal projection direction by solving a constrained and regularized quadratic programming. Then two tests are constructed using the estimated optimal projection direction. The first one is based on a data-splitting procedure, which achieves an exact t-test under normality assumption. To mitigate the power loss due to data-splitting, we further propose an online framework, which iteratively updates the estimation of projection direction when new observations arrive. We show that this online-style projection test asymptotically converges to the standard normal distribution. Various simulation studies as well as a real data example show that the proposed online-style projection test retains the type I error rate well and is more powerful than other existing tests.

The circMYBL2-encoded p185 protein suppresses colorectal cancer progression by inhibiting serine biosynthesis.

Circular RNAs (circRNAs) are a class of covalently closed single-stranded loop RNAs that have been implicated to play a functional role in almost all types of cancers. Previous studies have revealed that circMYBL2 acts as a tumor-promoting circRNA. Here, we found that circMYBL2 in colorectal cancer (CRC) encodes a 185-amino acid protein, p185. Functionally, circMYBL2-encoded p185 suppressed the growth and aggressiveness of CRC cells in vitro and in vivo. Mechanistically, p185 counteracted UCHL3-mediated deubiquitination of phosphoglycerate dehydrogenase (PHGDH) by competitively binding to the C1 domain of UCHL3, resulting in PHGDH degradation and a subsequent reduction in serine and glycine biosynthesis. These data revealed that the circMYBL2-encoded p185 isoform serves as a tumor suppressor to inhibit the progression of CRC by reducing serine biosynthesis.

The role and mechanism of PDZ binding kinase in hypobaric and hypoxic acute lung injury.

Background: Acute lung injury (ALI) caused by hypobaric hypoxia (HH) is frequently observed in high-altitude areas, and it is one of the leading causes of death in high-altitude-related diseases due to its rapid onset and progression. However, the pathogenesis of HH-related ALI (HHALI) remains unclear, and effective treatment approaches are currently lacking. Methods: A new mouse model of HHALI developed by our laboratory was used as the study subject (Chinese patent No. ZL 2021 1 1517241 X). Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the messenger RNA (mRNA) expression levels of PDZ-binding kinase (PBK), sirtuin 1 (SIRT1), and PTEN-induced kinase 1 (PINK1) in mouse lung tissue. Hematoxylin and eosin staining was used to observe the main types of damage and damaged cells in lung tissue, and the lung injury score was used for quantification. The wet-dry (W/D) ratio was used to measure lung water content. Enzyme-linked immunosorbent assay was used to detect changes in inflammatory factors and oxidative stress markers in the lungs. Western blotting verified the expression of various mitochondrial autophagy-related proteins. The 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazoylcarbocyanine iodide (JC-1) method was used determined the health status of mitochondria based on changes in mitochondrial membrane potential. Transmission electron microscopy was used to directly observe the morphology of mitochondria. Multicolor immunofluorescence was used to observe the levels of mitochondrial autophagy markers. Other signaling pathways and molecular mechanisms that may play a role in epithelial cells were analyzed via through RNA sequencing. Results: Low pressure and hypoxia caused pathological changes in mouse lung tissue, mainly ALI, leading to increased levels of inflammatory factors and intensified oxidative stress response in the lungs. Overexpression of PBK was found to alleviate HHALI, and activation of the p53 protein was shown to abrogate this therapeutic effect, while activation of SIRT1 protein reactivated this therapeutic effect. The therapeutic effect of PBK on HHALI is achieved via the activation of mitochondrial autophagy. Finally, RNA sequencing demonstrated that besides mitochondrial autophagy, PBK also exerts other functions in HHALI. Conclusions: Overexpression of PBK inhibits the expression of p53 and activates SIRT1-PINK1 axis mediated mitochondrial autophagy to alleviate HHALI.

Role of LGL1 in cerebellar primordium of embryonic mice.

Lethal giant larvae 1 (LGL1) is originally recognized as a tumor suppressor, implicated in maintaining cell polarity in Drosophila and mammalian cells. Cell polarity plays a crucial role in tumorigenesis. We previously established Pax2-LGL1 -/- conditional knockout mice but did not focus on the tumorigenesis in cerebellar primordium. HE staining was used to detect the morphological structure of the cerebellar primordium during early embryonic development in Pax2-LGL1 -/- mice. Immunofluorescence assays were used to detect the expression of polar molecules. TUNEL staining assessed tissue apoptosis. Our findings reveal that deletion of LGL1 leads to the emergence of neuroblastoma-like tissues within the cerebellum primordium during early embryogenesis. This outcome can be attributed to alterations in expression patterns of polar molecules Cdc42 and ß-catenin following early deletion of LGL1, resulting in loss of cell polarity among neuroepithelial cells and subsequent formation of tumor-like tissues. However, further histological examination demonstrated that these tumor-like tissues disappear from embryonic day 15.5 onwards within the cerebellar primordium of Pax2-LGL1 -/- mice due to apoptosis-mediated cellular compensation. Our data emphasize the importance of LGL1 in maintaining neuroepithelial cell polarity and reveal a novel role for LGL1 in regulating tumorigenesis and ablation in the cerebellar primordium.

Navigating the landscapes of spatial transcriptomics: How computational methods guide the way.

Spatially resolved transcriptomics has been dramatically transforming biological and medical research in various fields. It enables transcriptome profiling at single-cell, multi-cellular, or sub-cellular resolution, while retaining the information of geometric localizations of cells in complex tissues. The coupling of cell spatial information and its molecular characteristics generates a novel multi-modal high-throughput data source, which poses new challenges for the development of analytical methods for data-mining. Spatial transcriptomic data are often highly complex, noisy, and biased, presenting a series of difficulties, many unresolved, for data analysis and generation of biological insights. In addition, to keep pace with the ever-evolving spatial transcriptomic experimental technologies, the existing analytical theories and tools need to be updated and reformed accordingly. In this review, we provide an overview and discussion of the current computational approaches for mining of spatial transcriptomics data. Future directions and perspectives of methodology design are proposed to stimulate further discussions and advances in new analytical models and algorithms. This article is categorized under: RNA Methods > RNA Analyses in Cells RNA Evolution and Genomics > Computational Analyses of RNA RNA Export and Localization > RNA Localization.

The presence of micropapillary and/or solid subtypes is an independent prognostic factor for patients undergoing curative resection for stage I lung adenocarcinoma with ground-glass opacity.

Background: Non-predominant or even minimal micropapillary and/or solid (MP/S) subtypes have been reported to exert an unfavorable prognostic influence on surgically resected lung adenocarcinoma (ADC). Currently, there is a lack of evidence to demonstrate that high-grade pathological subtypes, including MP/S components, impact the prognosis of patients with surgically resected lung ADCs with ground-glass opacity (GGO). In this investigation, we explored the prognostic implications of minimal MP/S components in lung ADCs with GGO. Methods: A retrospective cohort study was conducted on 1,004 consecutive patients undergoing curative resection for pathologic stage (p-stage) I lung ADCs featuring GGO on computed tomography (CT) scans between January 2014 and December 2016. Tumors were categorized into MP/S positive (MP/S+) group and MP/S negative (MP/S-) group. MP/S+ tumors were defined when MP/S subtypes constituted ≥1% of the entire tumor. The prognostic impact of MP/S subtypes was evaluated using Kaplan-Meier analysis, Cox proportional hazard model and restricted cubic spine (RCS) model. Results: A total of 86 (8.6%) cases with MP/S+ tumors and 918 (91.4%) cases with MP/S- tumors were identified. The solid component tumor diameter and pathological invasive tumor size of MP/S+ tumors were both significantly larger than that of MP/S- tumors (13.0 vs. 4.0 mm, P<0.001, and 18.0 vs. 10.0 mm, P<0.001, respectively). After a median follow-up of 7.3 years, the presence of MP/S components was significantly associated with decreased RFS (5-year RFS, MP/S+ 88.3% vs. MP/S- 97.4%; P<0.001; HR =1.02). The presence of a histologic lepidic (Lep) component demonstrated a prognostic advantage in both MP/S- (5-year RFS, MP/S-Lep+ 98.0% vs. MP/S-Lep- 95.3%; P=0.01; HR =0.89) and MP/S+ subgroups (5-year RFS, MP/S+Lep+ 93.4% vs. MP/S+Lep- 83.2%; P=0.10; HR =0.84). MP/S+ components ≥5% were the only tumor-related factor that independently affected RFS [hazard ratio (HR) =1.77; 95% confidence interval (CI): 1.07-2.94] according to multivariate analysis. There was a progressively negative impact of the proportion of MP/S subtypes on RFS as illustrated by RCS model. Conclusions: The presence of MP/S patterns in stage I GGO-featured lung ADCs exhibit significant prognostic value and may have implications for tailored postoperative treatment and surveillance strategies, especially when the proportion exceeds 5% of the entire tumor.

ESKtides: a comprehensive database and mining method for ESKAPE phage-derived antimicrobial peptides.

'Superbugs' have received increasing attention from researchers, such as ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.), which directly led to about 1 270 000 death cases in 2019. Recently, phage peptidoglycan hydrolases (PGHs)-derived antimicrobial peptides were proposed as new antibacterial agents against multidrug-resistant bacteria. However, there is still a lack of methods for mining antimicrobial peptides based on phages or phage PGHs. Here, by using a collection of 6809 genomes of ESKAPE isolates and corresponding phages in public databases, based on a unified annotation process of all the genomes, PGHs were systematically identified, from which peptides were mined. As a result, a total of 12 067 248 peptides with high antibacterial activities were respectively determined. A user-friendly tool was developed to predict the phage PGHs-derived antimicrobial peptides from customized genomes, which also allows the calculation of peptide phylogeny, physicochemical properties, and secondary structure. Finally, a user-friendly and intuitive database, ESKtides (http://www.phageonehealth.cn:9000/ESKtides), was designed for data browsing, searching and downloading, which provides a rich peptide library based on ESKAPE prophages and phages. Database URL:  10.1093/database/baae022.

Tumor characteristics, brain functional activity, and connectivity of tinnitus in patients with vestibular schwannoma: a pilot study.

Background: The mechanism underlying tinnitus remains unclear, and when it coexists with vestibular schwannoma (VS), it can significantly diminish the quality of life for affected patients. This study aimed to determine the correlation between preoperative clinical characteristics of VS, postoperative changes in brain function, and tinnitus in patients with VS through a cohort study. Methods: We collected data from 80 patients with VS preoperatively and 28 patients with VS preoperatively and postoperatively, and recruited 28 healthy controls. We used Chi-squared tests and unpaired t-tests to identify clinical characteristics with a significant preoperative effect. We used paired t-tests to identify brain regions where patients demonstrated significant changes in amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) postoperatively. Tinnitus severity was evaluated using the Tinnitus Handicap Inventory (THI) and Visual Analogue Scale (VAS). Pearson correlation coefficients were applied to assess the relationship between the changes in ALFF and ReHo and the changes in THI and VAS scores postoperatively. We also conducted seed- and region of interest (ROI)-based functional connectivity (FC) analyses. Results: Before surgery, patients with VS with tinnitus (n=49) had smaller tumors (t=3.293; P<0.001), more solid tumor (χ2=4.559; P=0.033), and less extrusion into the cerebellum brain stem (χ2=10.345; P=0.001) than those without tinnitus (n=31). After surgery, the 28 patients with VS showed a significant reduction in ALFF in the left Cerebellum_Crus2 (a lobule in the cerebellum anatomy) (ROI 1) and a significant reduction in ReHo in the left Cerebellum_Crus1 (a lobule in the cerebellum anatomy) (ROI 2) and the right precuneus (ROI 3). Conversely, ReHo was significantly increased in the right precentral gyrus (ROI 4) [cluster-level P value family-wise error (PFWE) <0.05]. The changes in ALFF values were negatively correlated with changes in the VAS score (r=-0.32; P<0.05). The FC strengths of patients between ROI 2 and the left and right posterior cingulate gyrus were significantly decreased postoperatively [false discovery rate (FDR) correction; P<0.05]. Conclusions: Preoperative tinnitus in patients with VS may be influenced by tumor characteristics. The functional activities of brain regions are possibly altered postoperatively, which may be involved in the maintenance of postoperative tinnitus. Notably, the changes in ALFF are correlated with tinnitus.

The value of musculoskeletal ultrasound in predicting gout flares in index joints: A prospective cohort study of people with gout starting urate-lowering therapy.

OBJECTIVES: To evaluate whether ultrasound findings of monosodium urate (MSU) crystal deposition predict frequent gout flares in index joints over 12 months. METHODS: This single-center study enrolled people with at least one gout flare involving the MTP1, ankle or knee joint. The most painful or most frequently joint was identified as index joint for analysis. All participants were started on urate-lowering therapy and had an ultrasound scan of the index joints at the baseline visit. OMERACT scores (for tophus, double contour sign and aggregates) were used to analyze whether ultrasound scores predicted frequent (≥2) gout flares in the index joint over 12 months. RESULTS: Frequent flares were significantly higher in those with ultrasound findings in all index joints (MTP1: tophus: 85.0% vs 46.0%, P < 0.001, aggregates: 78.8% vs 59.0%, P < 0.01; ankle: tophus: 54.6% vs 20.8%, P < 0.001; aggregates: 60.0% vs 35.9%, P < 0.05; knee: tophus: 68.4% vs 28.6%, P < 0.05). For the MTP1, for each 1-point increase in tophus score, the odds of frequent gout flares increased by 5.19 [(95%CI: 1.26-21.41), 7.91 [(95%CI: 2.23-28.14), and 13.79 [(95%CI: 3.79-50.20)] fold respectively. For the ankle, a tophus score of 3 markedly improved the prediction of the frequent flares [OR= 9.24 (95%CI=2.85-29.91)]. Semi-quantitative sum scores were associated with frequent flares with an OR (95%CI) of 13.66 (3.44-54.18), P < 0.001 at the MTP1, 7.05 (1.98-25.12), P < 0.001 at the ankle. CONCLUSION: Ultrasound features of MSU crystal deposition at the MTP1 and knee predict subsequent risk of frequent gout flares in the same joints following initiation of urate-lowering therapy, with the highest risk in those with high tophus scores.

Development and validation of a clinic-radiological model to predict tumor spread through air spaces in stage I lung adenocarcinoma.

OBJECTIVES: Tumor spread through air spaces (STAS) is associated with poor prognosis and impacts surgical options. We aimed to develop a user-friendly model based on 2-[18F] FDG PET/CT to predict STAS in stage I lung adenocarcinoma (LAC). MATERIALS AND METHODS: A total of 466 stage I LAC patients who underwent 2-[18F] FDG PET/CT examination and resection surgery were retrospectively enrolled. They were split into a training cohort (n = 232, 20.3% STAS-positive), a validation cohort (n = 122, 27.0% STAS-positive), and a test cohort (n = 112, 29.5% STAS-positive) according to chronological order. Some commonly used clinical data, visualized CT features, and SUVmax were analyzed to identify independent predictors of STAS. A prediction model was built using the independent predictors and validated using the three chronologically separated cohorts. Model performance was assessed using ROC curves and calculations of AUC. RESULTS: The differences in age (P = 0.009), lesion density subtype (P < 0.001), spiculation sign (P < 0.001), bronchus truncation sign (P = 0.001), and SUVmax (P < 0.001) between the positive and negative groups were statistically significant. Age ≥ 56 years [OR(95%CI):3.310(1.150-9.530), P = 0.027], lesion density subtype (P = 0.004) and SUVmax ≥ 2.5 g/ml [OR(95%CI):3.268(1.021-1.356), P = 0.005] were the independent factors predicting STAS. Logistic regression was used to build the A-D-S (Age-Density-SUVmax) prediction model, and the AUCs were 0.808, 0.786 and 0.806 in the training, validation, and test cohorts, respectively. CONCLUSIONS: STAS was more likely to occur in older patients, in solid lesions and higher SUVmax in stage I LAC. The PET/CT-based A-D-S prediction model is easy to use and has a high level of reliability in diagnosing.

Effect of apple high-methoxyl pectin on heat-induced gelation of silver carp myofibrillar protein.

The effect of adding apple high-methoxy pectin (HMP) (0-3 mg∙mL-1) on heat-induced gel characteristics of low concentration silver carp myofibrillar protein (MP) (15 mg∙mL-1) was studied. It was found that the hardness of gel increased by 20.6 times with adding 2 mg∙mL-1 HMP. Besides, HMP aided in the development of disulfide bonds and the aggregation of hydrophobic groups. During gel formation, the maximal storage modulus (G') of samples supplemented with 2 mg·mL-1 HMP was raised by a factor of 2.7. Of note, the images of SEM showed that protein and water were tightly combined with a proper amount of HMP and made its pores more uniform and dense. Meantime, the addition of moderate amounts of HMP enabled the formation of gels with favorable texture and performance at low concentration of MP was identified, which could provide a theoretical reference for the design and production of flesh low-calorie food gel.

Alteration of White Matter Connectivity for MR-Guided Focused Ultrasound in the Treatment of Essential Tremor.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has been implemented as a therapeutic alternative for the treatment of drug-refractory essential tremor (ET). However, its impact on the brain structural network is still unclear. PURPOSE: To investigate both global and local alterations of the white matter (WM) connectivity network in ET after MRgFUS thalamotomy. STUDY TYPE: Retrospective. SUBJECTS: Twenty-seven ET patients (61 ± 11 years, 19 males) with MRgFUS thalamotomy and 28 healthy controls (HC) (61 ± 11 years, 20 males) were recruited for comparison. FIELD STRENGTH/SEQUENCE: A 3 T/single shell diffusion tensor imaging by using spin-echo-based echo-planar imaging, three-dimensional T1 weighted imaging by using gradient-echo-based sequence. ASSESSMENT: Patients were undergoing MRgFUS thalamotomy and their clinical data were collected from pre-operation to 6-month post-operation. Network topological metrics, including rich-club organization, small-world, and efficiency properties were calculated. Correlation between the topological metrics and tremor scores in ET groups was also calculated to assess the role of neural remodeling in the brain. STATISTICAL TESTS: Two-sample independent t-tests, chi-squared test, ANOVA, Bonferroni test, and Spearman's correlation. Statistical significance was set at P < 0.05. RESULTS: For ET patients, the strength of rich-club connection and clustering coefficient significantly increased vs. characteristic path length decreased at 6-month post-operation compared with pre-operation. The distribution pattern of rich-club regions was different in ET groups. Specifically, the order of the rich-club regions was changed according to the network degree value after MRgFUS thalamotomy. Moreover, the altered nodal efficiency in the right temporal pole of the superior temporal gyrus (R = 0.434-0.596) and right putamen (R = 0.413-0.436) was positively correlated with different tremor improvement. DATA CONCLUSION: These findings might improve understanding of treatment-induced modulation from a network perspective and may work as an objective marker in the assessment of ET tremor control with MRgFUS thalamotomy. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 4.

Atomic Distance Engineering in Metal Catalysts to Regulate Catalytic Performance.

It is very important to understand the structure-performance relationship of metal catalysts by adjusting the microstructure of catalysts at the atomic scale. The atomic distance has an essential influence on the composition of the environment of active metal atom, which is a key factor for the design of targeted catalysts with desired function. In this review, we discuss and summarize strategies for changing the atomic distance from three aspects and relate their effects on the reactivity of catalysts. First, the effects of regulating bond length between metal and coordination atom at one single-atom site on the catalytic performance are introduced. The bond lengths are affected by the strain effect of the support and high-shell doping and can evolve during the reaction. Next, the influence of the distance between single-atom sites on the catalytic performance is discussed. Due to the space matching of adsorption and electron transport, the catalytic performance can be adjusted with the shortening of site distance. In addition, the effect of the arrangement spacing of the surface metal active atoms on the catalytic performance of metal nanocatalysts is studied. Finally, a comprehensive summary and outlook of the relationship between atomic distance and catalytic performance is given.

Quantitative Optical Coherence Elastography of the Optic Nerve Head In Vivo.

OBJECTIVE: Optical coherence elastography (OCE) was used to demonstrate the relationship between the elasticity of the optic nerve head (ONH) and different intraocular pressure (IOP) levels in an in-vivo rabbit model for the first time. METHOD: Both ex-vivo and in-vivo rabbit ONH were imaged using OCE system. A mechanical shaker initiated the propagation of elastic waves, and the elasticity of the ONH was determined by tracking the wave propagation speed. The elasticity of the ONH under varying IOP levels was reconstructed based on the wave speed. Notably, the ONH exhibited increased stiffness with elevated IOP. RESULTS: In the in-vivo rabbit models, the Young's modulus of ONH increased from 14 kPa to 81 kPa with the IOP increased from 15 mmHg to 35 mmHg. This revealed a positive correlation between the Young's modulus of the ONH and intraocular pressure. CONCLUSION: The OCE system proved effective in measuring the mechanical properties of ONH at different IOP levels, with validation in an in-vivo rabbit model. SIGNIFICANCE: Considering ONH plays a critical role in vision and eye diseases, the capability to image and quantify in vivo ONH biomechanical properties has great potential to advance vision science research and improve the clinical management of glaucoma patients.

Magnetic graphene oxide nanocomposites induce cytotoxicity in ADSCs via GPX4 regulating ferroptosis.

Magnetic graphene oxide nanocomposites (MGO NPs) have been widely studied in biomedical applications. However, their cytotoxicity and underlying mechanisms remain unclear. In this study, the biosafety of MGO NPs was investigated, and the mechanism involved in ferroptosis was further explored. MGO can produce cytotoxicity in ADSCs, which is dependent on their concentration. Ferroptosis was involved in MGO NP-induced ADSC survival inhibition by increasing total ROS and lipid ROS accumulation as well as regulating the expression levels of ferroptosis-related genes and proteins. GPX4 played a critical role in the MGO NP-induced ADSC ferroptosis process, and overexpressing GPX4 suppressed ferroptosis to increase cell survival. This study provides a theoretical basis for the biosafety management of MGO NPs used in the field of biomedical treatment.

Gss deficiency causes age-related fertility impairment via ROS-triggered ferroptosis in the testes of mice.

Glutathione synthetase (GSS) catalyzes the final step in the synthesis of glutathione (GSH), a well-established antioxidant. Research on the specific roles of the Gss gene during spermatogenesis remains limited due to the intricate structure of testis. In this study, we identified pachytene spermatocytes as the primary site of GSS expression and generated a mouse model with postnatal deletion of Gss using Stra8-Cre (S8) to investigate the role of GSS in germ cells. The impact of Gss knockout on reducing male fertility is age-dependent and caused by ferroptosis in the testis. The 2-month-old S8/Gss-/- male mice exhibited normal fertility, due to a compensatory increase in GPX4, which prevented the accumulation of ROS. With aging, there was a decline in GPX4 and an increase in ALOX15 levels observed in 8-month-old S8/Gss-/- mice, resulting in the accumulation of ROS, lipid peroxidation, and ultimately testicular ferroptosis. We found that testicular ferroptosis did not affect spermatogonia, but caused meiosis disruption and acrosome heterotopia. Then the resulting aberrant sperm showed lower concentration and abnormal morphology, leading to reduced fertility. Furthermore, these injuries could be functionally rescued by inhibiting ferroptosis through intraperitoneal injection of GSH or Fer-1. In summary, Gss in germ cells play a crucial role in the resistance to oxidative stress injury in aged mice. Our findings deepen the understanding of ferroptosis during spermatogenesis and suggest that inhibiting ferroptosis may be a potential strategy for the treatment of male infertility.

ESRP1-driven alternative splicing of CLSTN1 inhibits the metastasis of gastric cancer.

Tumor metastasis severely limits the prognosis of gastric cancer patients. RNA-binding proteins (RBPs) are crucial in tumor metastasis, yet there is limited research into their involvement in gastric cancer. Here, we found that ESRP1, a RBP specific in epithelial cells, is important in regulating the metastasis of gastric cancer cells. ESRP1 is negatively correlated with distant metastasis and lymph node metastasis in gastric cancer patients. And we demonstrated that ESRP1 inhibit migration and invasion of gastric cancer in vitro and in vivo. Mechanistically, ESRP1 promotes exon 11 alternative splicing of CLSTN1 pre-mRNA. The post-splicing short CLSTN1 stabilizes the Ecadherin/ß-catenin binding structure, and promotes ß-catenin protein ubiquitination and degradation, thereby inhibiting the migration and invasion of gastric cancer cells. Our study highlights the role of ESRP1 in regulating metastasis of gastric cancer and extends its mechanism. These results provide a possibility for ESRP1 and CLSTN1 to become therapeutic targets for metastasis of gastric cancer.

[Study on effects of 40 Hz light flicker stimulation on spatial working memory in rats and its neural mechanism].

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment, with the predominant clinical diagnosis of spatial working memory (SWM) deficiency, which seriously affects the physical and mental health of patients. However, the current pharmacological therapies have unsatisfactory cure rates and other problems, so non-pharmacological physical therapies have gradually received widespread attention. Recently, a novel treatment using 40 Hz light flicker stimulation (40 Hz-LFS) to rescue the cognitive function of model animals with AD has made initial progress, but the neurophysiological mechanism remains unclear. Therefore, this paper will explore the potential neural mechanisms underlying the modulation of SWM by 40 Hz-LFS based on cross-frequency coupling (CFC). Ten adult Wistar rats were first subjected to acute LFS at frequencies of 20, 40, and 60 Hz. The entrainment effect of LFS with different frequency on neural oscillations in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was analyzed. The results showed that acute 40 Hz-LFS was able to develop strong entrainment and significantly modulate the oscillation power of the low-frequency gamma (lγ) rhythms. The rats were then randomly divided into experimental and control groups of 5 rats each for a long-term 40 Hz-LFS (7 d). Their SWM function was assessed by a T-maze task, and the CFC changes in the HPC-mPFC circuit were analyzed by phase-amplitude coupling (PAC). The results showed that the behavioral performance of the experimental group was improved and the PAC of θ-lγ rhythm was enhanced, and the difference was statistically significant. The results of this paper suggested that the long-term 40 Hz-LFS effectively improved SWM function in rats, which may be attributed to its enhanced communication of different rhythmic oscillations in the relevant neural circuits. It is expected that the study in this paper will build a foundation for further research on the mechanism of 40 Hz-LFS to improve cognitive function and promote its clinical application in the future.

A film-linked electrostatic self-assembly microfluidic chip.

This article proposes a film-linked electrostatic self-assembly microfluidic chip for the first time, designed to be ready-to-use. Barrier films are used to isolate the gas/liquid path microchannels and the pre-stored reagents of the chip before use. Through the linkage design between the film materials, the motion of barrier films is linked to the structural changes inside the chip. Under the combined action of the rebound force of the elastic substrate, the electrostatic adsorption force between the substrates, and the reaction force of the elastic film, the elastic substrate and the liquid storage substrate are instantly bonded, and the self-assembly of the chip is completed within 1 s. By using six independently output programmable sequences to perform the sequential quantitative pumping of pre-stored reagents, the transfer and mixing of samples and pre-stored reagents are automatically driven in a confined space, which greatly reduces the contamination risk and loss rate of samples/reagents, and improves the accuracy and reproducibility of test results. In addition, the microfluidic multi-step reaction driven in parallel can avoid liquid reflux, accurately control the amount of reactant transfer, and realize the quantitative detection of samples. Multiple reactions can be performed synchronously without interference, saving the test time. Since each gas path is independently controllable, the chip can be extended to a variety of biochemical reactions and has the potential to detect a variety of substances.