Effects of testosterone dose on depression-like behavior among castrated adult male rats.

Previous research has shown a decrease in serum testosterone levels in male patients with depression. In recent years, the results of testosterone replacement therapy (TRT) to improve depression have been mixed. Using the classic CUMS model, we induced depressive-like behaviors in rats and observed a decrease in their serum testosterone levels along with an increase in androgen receptor expression in the hippocampus. We then performed castration and sham surgery on male rats and found that testosterone deprivation led to the manifestation of depressive-like behavior that could be ameliorated by TRT. Through a repeated measures experiment consisting of five blocks over a period of 25 days, we discovered that the reduction in depressive-like behavior in testosterone-deprived rats began 22 days after drug administration (0.5 and 0.25 mg/rat). Furthermore, rats in 0.5mgT group showed the most significant improvements. Subsequently, this dose was used in CUMS rats and reduced the occurrence of depressive-like behaviors. Our study has demonstrated the complex interplay between depression and testosterone, as well as the intricate dose-response relationship between TRT and reduction in depression. Our research supports the use of TRT to alleviate depression, but dosage and duration of treatment are critical factors in determining efficacy.

A novel model based on ubiquitination-related gene to predict prognosis and immunotherapy response in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a common cancer that is increasingly becoming a global health problem and a major public health concern. In order to improve patient outcomes, additional biomarkers and targets must be explored. Ubiquitination-related genes (URGs), as tumor regulators, exhibit multiple functions in tumor development. Our objective was to examine the influence of URGs on the prognosis of patients with HCC. Methods: By utilizing unsupervised cluster analysis, we were able to identify URGs in the database and create a risk score profile for predicting the prognosis of patients with HCC. The model's clinical application was explored using subject operating characteristic curves, survival analysis, and correlation analysis. We additionally examined the variances in clinical traits, immune infiltration, somatic genetic alterations, and responsiveness to treatment among high- and low-risk populations identified by the prognostic model. Scores for immune cell infiltration and immune-related pathway activity were determined by performing ssGSEA enrichment analysis. Additionally, to investigate potential mechanisms, we utilized GO, KEGG and GSVA analyses. Results: We developed a risk scoring model that relies on genes associated with ubiquitination. As the risk score increased, the malignancy and prognosis of the tumor worsened. The high-risk and low-risk groups exhibited notable disparities in relation to the immune microenvironment, genes associated with immune checkpoints, sensitivity to drugs, and response to immunotherapy. Conclusion: The utilization of a risk model that relies on genes associated with ubiquitination can serve as a biomarker to assess the prognosis of patients with HCC, and aid in the selection of suitable therapeutic agents.

Matrix confinement modulates 3D spheroid sorting and burst-like collective migration.

While it is known that cells with differential adhesion tend to segregate and preferentially sort, the physical forces governing sorting and invasion in heterogeneous tumors remain poorly understood. To investigate this, we tune matrix confinement, mimicking changes in the stiffness and confinement of the tumor microenvironment, to explore how physical confinement influences individual and collective cell migration in 3D spheroids. High levels of confinement lead to cell sorting while reducing matrix confinement triggers the collective fluidization of cell motion. Cell sorting, which depends on cell-cell adhesion, is crucial to this phenomenon. Burst-like migration does not occur for spheroids that have not undergone sorting, regardless of the degree of matrix confinement. Using computational Self-Propelled Voronoi modeling, we show that spheroid sorting and invasion into the matrix depend on the balance between cell-generated forces and matrix resistance. The findings support a model where matrix confinement modulates 3D spheroid sorting and unjamming in an adhesion-dependent manner, providing insights into the mechanisms of cell sorting and migration in the primary tumor and toward distant metastatic sites. STATEMENT OF SIGNIFICANCE: The mechanical properties of the tumor microenvironment significantly influence cancer cell migration within the primary tumor, yet how these properties affect intercellular interactions in heterogeneous tumors is not well understood. By utilizing calcium and calcium chelators, we dynamically alter collagen-alginate hydrogel stiffness and investigate tumor cell behavior within co-culture spheroids in response to varying degrees of matrix confinement. High confinement is found to trigger cell sorting while reducing confinement for sorted spheroids facilitates collective cell invasion. Notably, without prior sorting, spheroids do not exhibit burst-like migration, regardless of confinement levels. This work establishes that matrix confinement and intercellular adhesion regulate 3D spheroid dynamics, offering insights into cellular organization and migration within the primary tumor.

Cellular mechanotransduction of human osteoblasts in microgravity.

Astronauts experience significant and rapid bone loss as a result of an extended stay in space, making the International Space Station (ISS) the perfect laboratory for studying osteoporosis due to the accelerated nature of bone loss on the ISS. This prompts the question, how does the lack of load due to zero-gravity propagate to bone-forming cells, human fetal osteoblasts (hFOBs), altering their maturation to mineralization? Here, we aim to study the mechanotransduction mechanisms by which bone loss occurs in microgravity. Two automated experiments, 4 microfluidic chips capable of measuring single-cell mechanics of hFOBs via aspiration and cell spheroids incubated in pressure-controlled chambers, were each integrated into a CubeLab deployed to the ISS National Laboratory. For the first experiment, we report protrusion measurements of aspirated cells after exposure to microgravity at the ISS and compare these results to ground control conducted inside the CubeLab. Our analysis revealed slightly elongated protrusions for space samples compared to ground samples indicating softening of hFOB cells in microgravity. In the second experiment, we encapsulated osteoblast spheroids in collagen gel and incubated the samples in pressure-controlled chambers. We found that microgravity significantly reduced filamentous actin levels in the hFOB spheroids. When subjected to pressure, the spheroids exhibited increased pSMAD1/5/9 expression, regardless of the microgravity condition. Moreover, microgravity reduced YAP expression, while pressure increased YAP levels, thus restoring YAP expression for spheroids in microgravity. Our study provides insights into the influence of microgravity on the mechanical properties of bone cells and the impact of compressive pressure on cell behavior and signaling in space.

A hybrid system for Nickel ions removal from synthesized wastewater using adsorption assisted with electrocoagulation.

The presence of heavy metal ions in water environments has raised significant concerns, necessitating practical solutions for their complete removal. In this study, a combination of adsorption and electrocoagulation (ADS + EC) techniques was introduced as an efficient approach for removing high concentrations of nickel ions (Ni2+) from aqueous solutions, employing low-cost sunflower seed shell biochar (SSSB). The combined techniques demonstrated superior removal efficiency compared to individual methods. The synthesized SSSB was characterized using SEM, FT-IR, XRD, N2-adsorption-desorption isotherms, XPS, and TEM. Batch processes were optimized by investigating pH, adsorbent dosage, initial nickel concentration, electrode effects, and current density. An aluminum (Al) electrode electrocoagulated particles and removed residual Ni2+ after adsorption. Kinetic and isotherm models examined Ni2+ adsorption and electrocoagulation coupling with SSSB-based adsorbent. The results indicated that the kinetic data fit well with a pseudo-second-order model, while the experimental equilibrium adsorption data conformed to a Langmuir isotherm under optimized conditions. The maximum adsorption capacity of the activated sunflower seed shell was determined to be 44.247 mg.g-1. The highest nickel ion removal efficiency of 99.98% was observed at initial pH values of 6.0 for ADS and 4.0 for ADS/EC; initial Ni2+ concentrations of 30.0 mg/L and 1.5 g/L of SSSB; initial current densities of 0.59 mA/cm2 and 1.32 kWh/m3 were also found to be optimal. The mechanisms involved in the removal of Ni2+ from wastewater were also examined in this research. These findings suggest that the adsorption-assisted electrocoagulation technique has a remarkable capacity for the cost-effective removal of heavy metals from various wastewater sources.

Cellular mechanotransduction of human osteoblasts in microgravity.

Astronauts experience significant and rapid bone loss as a result of an extended stay in space, making the International Space Station (ISS) the perfect laboratory for studying osteoporosis due to the accelerated nature of bone loss on the ISS. This prompts the question, how does the lack of load due to zero-gravity propagate to bone-forming cells, human fetal osteoblasts (hFOBs), altering their maturation to mineralization? Here, we aim to study the mechanotransduction mechanisms by which bone loss occurs in microgravity. Two automated experiments, microfluidic chips capable of measuring single-cell mechanics via aspiration and cell spheroids incubated in pressure-controlled chambers, were each integrated into a CubeLab deployed to the ISS National Laboratory. For the first experiment, we report protrusion measurements of aspirated cells after exposure to microgravity at the ISS and compare these results to ground control conducted inside the CubeLab. We found slightly elongated protrusions for space samples compared to ground samples indicating softening of hFOB cells in microgravity. In the second experiment, we encapsulated osteoblast spheroids in collagen gel and incubated the samples in pressure-controlled chambers. We found that microgravity significantly reduced filamentous actin levels in the hFOB spheroids. When subjected to pressure, the spheroids exhibited increased pSMAD1/5/9 expression, regardless of the microgravity condition. Moreover, microgravity reduced YAP expression, while pressure increased YAP levels, thus restoring YAP expression for spheroids in microgravity. Our study provides insights into the influence of microgravity on the mechanical properties of bone cells and the impact of compressive pressure on cell signaling in space.

Optimized New Shengmai Powder modulation of cAMP/Rap1A signaling pathway attenuates myocardial fibrosis in heart failure.

BACKGROUND: Optimized New Shengmai Powder (ONSMP) is a traditional Chinese medicine formula with significant anti-heart failure and myocardial fibrosis effects, but the specific molecular biological mechanisms are not fully understood. METHODS: In this study, we first used network pharmacology to analyze the ONSMP's active ingredients, core signaling pathways, and core targets. Second, calculate the affinity and binding modes of the ONSMP components to the core targets using molecular docking. Finally, the heart failure rat model was established by ligating the left anterior descending branch of the coronary artery and assessing the effect of ONSMP on myocardial fibrosis in heart failure using echocardiography, cardiac organ coefficients, heart failure markers, and pathological sections after 4 weeks of drug intervention. The cAMP level in rat myocardium was determined using Elisa, the α-SMA and FSP-1 positive expression determined by immunohistochemistry, and the protein and mRNA levels of the cAMP/Rap1A signaling pathway were detected by Western Blotting and quantitative real-time PCR, respectively. RESULTS: The result shows that the possible mechanism of ONSMP in reducing myocardial fibrosis also includes the use of 12 active ingredients such as baicalin, vitamin D, resveratrol, tanshinone IIA, emodin, 15,16-dihydrotanshinone-i to regulate ß1-AR, AC6, EPAC1, Rap1 A, STAT3, and CCND1 on the cAMP/Rap1A signaling pathway, thereby inhibiting the proliferation of cardiac fibroblasts and reduce the excessive secretion of collagen, effectively improve cardiac function and ventricular remodeling in heart failure rats. CONCLUSION: This research shows that ONSMP can inhibit myocardial fibrosis and delay heart failure through the cAMP/Rap1A signaling pathway.

Assessment of the U.S. Food and Drug Administration's risk evaluation and mitigation strategy (REMS) for prasugrel (EFFIENT): A narrative review.

Background: Prasugrel, first approved in 2009, was subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to mitigate the risk of bleeding associated with its use. Methods: We performed a narrative review of FDA documents obtained through a Freedom of Information Act request. Document classification and primary evidence extraction was performed by three authors (TM, JC, and SL). Results: The prasugrel REMS consists of a medication guide and a communication plan. Assessment of the REMS was via patient and clinician surveys. 1560 patients were invited to participate and 212 individuals (13.6 %) completed the survey. Rates of awareness among respondents varied across key messages and were highest for those examining the risks of premature discontinuation (96 % and 88 % of respondents), while lower for those regarding the importance of perioperative discontinuation (66 %) and contraindications posed by a history of stroke (16 %) or transient ischemic attack (17 %). Of the 6000 clinicians invited to participate in the survey, 201 (3.4 %) agreed to take part. Four of 11 key risk messages did not meet prespecified acceptable levels of comprehension. No prespecified levels of patient or provider knowledge were required for the retirement of the REMS, which took place on March 23, 2012 based on the sponsor's request. Conclusions: The prasugrel REMS consisted of passive educational materials whose adequacy was evaluated using highly limited, one-time, cross-sectional surveys. Our assessment adds to evidence suggesting the importance of improving the quality and impact of the FDA's post-approval activities to maximize drug safety.

The photo- and microbial degradation kinetics and pathways of sulfadoxine in seawater elucidated by liquid chromatography coupled with time-of-flight mass spectrometry.

Sulfadoxine (SDX) is a broad-spectrum veterinary antibiotic, which was used alone for the treatment of various infections in the past, and detected ubiquitously in the aqueous environment. However, understanding SDX's photo- and microbial degradation within the environment, especially in marine matrixes, remains limited. This research hones in on SDX's degradation dynamics in seawater. Photodegradation emerges as the dominant process, surpassing microbial degradation in speed and efficiency. Notably, 90% of SDX is photo-degraded within 12 h, while only 52% is removed via microbial degradation over two weeks. Time-of-flight mass spectrometry provides high-resolution molecular mass information on degradation products. The molecular structures of hydrolysis, photo-, and microbial degradation products are deduced from accurate precursor and fragment ion masses, alongside an integrated data processing workflow. Six hydrolysis products arise from the treatment, and photodegradation and microbial degradation yield nine and eighteen products, respectively. Molecular insights from these products inform plausible degradation pathways involving hydrolysis, photodegradation, and microbial degradation. Processes like bond cleavage, methylation, hydroxylation, oxidation, reduction, and methoxylation are identified and associated with degradation. This study presents a comprehensive workflow for acquiring and processing degradation product data linked to emerging organic pollutants. Moreover, it contributes to our comprehension of the environmental fate of veterinary drugs in marine ecosystems.

STAT3-Mediated Ferroptosis is Involved in Sepsis-Associated Acute Respiratory Distress Syndrome.

Sepsis-induced acute respiratory distress syndrome (ARDS) poses a grave danger to life, resulting from sepsis-induced multi-organ failure. Although ferroptosis, a form of iron-dependent lipid peroxidative cell death, has been associated with sepsis-induced ARDS, the specific mechanisms are not fully understood. In this study, we utilized WGCNA, PPI, friends analysis, and six machine learning techniques (Lasso, SVM, RFB, XGBoost, AdaBoost, and LightGBM) to pinpoint STAT3 as a potential diagnostic marker. A significant increase in monocyte and neutrophil levels was observed in patients with sepsis-induced ARDS, as revealed by immune infiltration analyses, when compared to controls. Moreover, there was a positive correlation between STAT3 expression and the level of infiltration. Single-cell analysis uncovered a notable disparity in B-cell expression between sepsis and sepsis-induced ARDS. Furthermore, in vitro experiments using LPS-treated human bronchial epithelial cells (BEAS-2B) and THP1 cells demonstrated a significant increase in STAT3 phosphorylation expression. Additionally, the inhibition of STAT3 phosphorylation by Stattic effectively prevented LPS-induced ferroptosis in both BEAS-2B and THP1 cells. This indicates that the activation of STAT3 phosphorylation promotes ferroptosis in human bronchial epithelial cells in response to LPS. In summary, this research has discovered and confirmed STAT3 as a potential biomarker for the diagnosis and treatment of sepsis-induced ARDS.

Distinct mechanisms by which Nrf1 and Nrf2 as drug targets contribute to the anticancer efficacy of cisplatin on hepatoma cells.

Cisplatin (cis-Dichlorodiamineplatinum[II], CDDP) is generally accepted as a platinum-based alkylating agent type of the DNA-damaging anticancer drug, which is widely administrated in clinical treatment of many solid tumors. The pharmacological effect of CDDP is mainly achieved by replacing the chloride ion (Cl-) in its structure with H2O to form active substances with the strong electrophilic properties and then react with any nucleophilic molecules, primarily leading to genomic DNA damage and subsequent cell death. In this process, those target genes driven by the consensus electrophilic and/or antioxidant response elements (EpREs/AREs) in their promoter regions are also activated or repressed by CDDP. Thereby, we here examined the expression profiling of such genes regulated by two principal antioxidant transcription factors Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) in diverse cellular signaling responses to this intervention. The results demonstrated distinct cellular metabolisms, molecular pathways and signaling response mechanisms by which Nrf1 and Nrf2 as the drug targets differentially contribute to the anticancer efficacy of CDDP on hepatoma cells and xenograft tumor mice. Interestingly, the role of Nrf1, rather than Nrf2, is required for the anticancer effect of CDDP, to suppress malignant behavior of HepG2 cells by differentially monitoring multi-hierarchical signaling to gene regulatory networks. To our surprise, it was found there exists a closer relationship of Nrf1α than Nrf2 with DNA repair, but the hyperactive Nrf2 in Nrf1α-∕- cells manifests a strong correlation with its resistance to CDDP, albeit their mechanistic details remain elusive.

The Born in Guangzhou Cohort Study enables generational genetic discoveries.

Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health1. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study2 (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.

Structural insights of a SusD-like protein in marine Bacteroidetes bacteria reveal the molecular basis for chitin recognition and acquisition.

Efficient recognition and transportation of chitin oligosaccharides are crucial steps for the utilization of chitin by heterotrophic bacteria. In this study, we employed structural biological and biochemical approaches to investigate the substrate recognition and acquisition mechanism of a novel chitin-binding SusD-like protein, AqSusD, which is derived from the chitin utilization gene cluster of a marine Bacteroides strain (Aquimarina sp. SCSIO 21287). We resolved the crystal structures of the AqSusD apo-protein and its complex with chitin oligosaccharides. Our results revealed that some crucial residues (Gln67, Phe87, and Asp276) underwent significant conformational changes to form tighter substrate binding sites for ligand binding. Moreover, we identified the functions of key amino acid residues and discovered that π-π stacking and hydrogen bonding between AqSusD and the ligand played significant roles in recognition of the protein for chitin oligosaccharide binding. Based on our findings and previous investigations, we put forward a model for the mechanism of chitin oligosaccharide recognition, capture, and transport by AqSusD, in collaboration with the membrane protein AqSusC. Our study deepens the understanding of the molecular-level "selfish" use of polysaccharides such as chitin by Bacteroides.

Matrix confinement modulates 3D spheroid sorting and burst-like collective migration.

While it is known that cells with differential adhesion tend to segregate and preferentially sort, the physical forces governing sorting and invasion in heterogeneous tumors remain poorly understood. To investigate this, we tune matrix confinement, mimicking changes in the stiffness and confinement of the tumor microenvironment, to explore how physical confinement influences individual and collective cell migration in 3D spheroids. High levels of confinement lead to cell sorting while reducing matrix confinement triggers the collective fluidization of cell motion. Cell sorting, which depends on cell-cell adhesion, is crucial to this phenomenon. Burst-like migration does not occur for spheroids that have not undergone sorting, regardless of the degree of matrix confinement. Using computational Self-Propelled Voronoi modeling, we show that spheroid sorting and invasion into the matrix depend on the balance between cell-generated forces and matrix resistance. The findings support a model where matrix confinement modulates 3D spheroid sorting and unjamming in an adhesion-dependent manner, providing insights into the mechanisms of cell sorting and migration in the primary tumor and toward distant metastatic sites.

How to enhance the applicability of a risk prediction model for term small-for-gestational-age neonates in clinical settings?

OBJECTIVE: To construct a simple term small-for-gestational-age (SGA) neonate prediction model that is clinically practical. METHODS: This analysis was based on the Born in Guangzhou Cohort Study (BIGCS). Mothers who had a singleton pregnancy, delivered a term neonate, and had an ultrasonography within 30 + 0 to 32 + 6 weeks of gestation were included. Term SGA was defined with customized population percentiles. Prediction models were constructed with backward selection logistic regression in a four-step approach, where model 1 contained fetal biometrics only, models 2 and 3 included maternal features and a time factor (weeks between ultrasonography and delivery), respectively; and model 4 contained all features mentioned. The prediction performance of individual models was evaluated based on area under the curve (AUC) and a calibration test was performed. RESULTS: The prevalence of SGA in the study population of 21 346 women was 11.5%. With a complete-case analysis approach, data of 19 954 women were used for model construction and validation. The AUC of the four models were 0.781, 0.793, 0.823, and 0.834, respectively, and all were well-calibrated. Model 3 consisted of fetal biometrics and corrected for time to delivery was chosen as the final model to build risk prediction graphs for clinical use. CONCLUSION: A prediction model derived from fetal biometrics in early third trimester is satisfactory to predict SGA.

Formation ability and drug resistance mechanism of Klebsiella pneumoniae biofilm and capsule for multidrug-resistant.

This study was to explore the formation ability of biofilm and capsule and the drug resistance mechanism for multidrug-resistant Klebsiella pneumoniae. firstly, 55 strains of K. pneumoniae were screened out from the body fluid specimens of the laboratory. The strains were drug-resistant, and the characteristics of clinical infections of these strains were analyzed. Secondly, all strains were tested for the presence of biofilms and capsules, and then the deoxyribonucleic acid (DNA) genomes of the strains extracted were detected using polymerase chain reaction (PCR) technology. Finally, the serotype genes and virulence genes of the strains were screened, and the relationship between these two genes and the formation of capsules and biofilms was analyzed and compared. A new generation of sequencing technology was applied to analyze the genome structure of K. pneumoniae, comparative genomics technology was adopted to analyze the drug resistance plasmids, and molecular cloning and other methods were utilized to clone the drug resistance-related genes. of the 55 strains of K. pneumoniae isolated clinically, 61.8% came from blood with a total number of 34 strains; 8 strains were from secretion specimens (accounting for 14.5% of the total); and 7 strains were from drainage fluid (accounting for 12.7% of the total), including 2 strains from pus, bile, and pleural fluid, respectively. The strains were tested by PCR, of which iroN virulence genes were the most (34 strains), accounting for 61.8%, followed by wabG and fimH (33 strains, accounting for 60% of the total), followed by magA, K2, K20, K1, and K57. The positive rates of the two virulence genes (fimH and wabG) were higher in positive strains of biofilm. The drug susceptibility results showed that ampicillin and amoxicillin were more resistant to capsule-positive strains than the capsule-negative strains. K. pneumoniae had been able to form a complete capsule and biofilm, the formation rate of biofilm was higher than that of the capsule, and there was an increasing trend. The two serotype genes (K20 and K2) accounted for relatively high proportions, and K. pneumoniae carried relatively more virulence genes (wabG and fimH), which may be closely related to the capsule production of K. pneumoniae. In addition, resistance-related genes were also transferred horizontally in different strains of bacteria, forming a wide range of drug resistance, which brought great difficulties to clinical work.

Speckle-based optical encryption with complex-amplitude coding and deep learning.

We propose a speckle-based optical encryption scheme by using complex-amplitude coding and deep learning, which enables the encryption and decryption of complex-amplitude plaintext containing both amplitude and phase images. During encryption, the amplitude and phase images are modulated using a superpixel-based coding technique and feded into a digital micromirror device. After passing through a 4f system, the information undergoes disturbance modulation by a scattering medium, resulting in a diffracted speckle pattern serving as the ciphertext. A Y-shaped convolutional network (Y-Net) model is constructed to establish the mapping relationship between the complex-amplitude plaintext and ciphertext through training. During decryption, the Y-Net model is utilized to quickly extract high-quality amplitude and phase images from the ciphertext. Experimental results verify the feasibility and effectiveness of our proposed method, demonstrating that the potential of integrating speckle encryption and deep learning for optical complex-amplitude encryption.

INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control.

The immune synapse, a highly organized structure formed at the interface between T lymphocytes and antigen-presenting cells (APCs), is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although the roles of ciliary proteins on the immune synapse remain elusive. Here, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, is enriched at the immune synapse in Jurkat T-cells during superantigen-mediated conjugation or antibody-mediated crosslinking of TCR complexes, and forms a complex with CD3ζ, ZAP-70, and Lck. Silencing INPP5E in Jurkat T-cells impairs the polarized distribution of CD3ζ at the immune synapse and correlates with a failure of PI(4,5)P2 clearance at the center of the synapse. Moreover, INPP5E silencing decreases proximal TCR signaling, including phosphorylation of CD3ζ and ZAP-70, and ultimately attenuates IL-2 secretion. Our results suggest that INPP5E is a new player in phosphoinositide manipulation at the synapse, controlling the TCR signaling cascade.

Identification and verification of diagnostic biomarkers in recurrent pregnancy loss via machine learning algorithm and WGCNA.

Background: Recurrent pregnancy loss defined as the occurrence of two or more pregnancy losses before 20-24 weeks of gestation, is a prevalent and significant pathological condition that impacts human reproductive health. However, the underlying mechanism of RPL remains unclear. This study aimed to investigate the biomarkers and molecular mechanisms associated with RPL and explore novel treatment strategies for clinical applications. Methods: The GEO database was utilized to retrieve the RPL gene expression profile GSE165004. This profile underwent differential expression analysis, WGCNA, functional enrichment, and subsequent analysis of RPL gene expression using LASSO regression, SVM-RFE, and RandomForest algorithms for hub gene screening. ANN model were constructed to assess the performance of hub genes in the dataset. The expression of hub genes in both the RPL and control group samples was validated using RT-qPCR. The immune cell infiltration level of RPL was assessed using CIBERSORT. Additionally, pan-cancer analysis was conducted using Sangerbox, and small-molecule drug screening was performed using CMap. Results: A total of 352 DEGs were identified, including 198 up-regulated genes and 154 down-regulated genes. Enrichment analysis indicated that the DEGs were primarily associated with Fc gamma R-mediated phagocytosis, the Fc epsilon RI signaling pathway, and various metabolism-related pathways. The turquoise module, which showed the highest relevance to clinical symptoms based on WGCNA results, contained 104 DEGs. Three hub genes, WBP11, ACTR2, and NCSTN, were identified using machine learning algorithms. ROC curves demonstrated a strong diagnostic value when the three hub genes were combined. RT-qPCR confirmed the low expression of WBP11 and ACTR2 in RPL, whereas NCSTN exhibited high expression. The immune cell infiltration analysis results indicated an imbalance of macrophages in RPL. Meanwhile, these three hub genes exhibited aberrant expression in multiple malignancies and were associated with a poor prognosis. Furthermore, we identified several small-molecule drugs. Conclusion: This study identifies and validates hub genes in RPL, which may lead to significant advancements in understanding the molecular mechanisms and treatment strategies for this condition.

Effects of Early Adverse Life Events on Depression and Cognitive Performance from the Perspective of the Heart-Brain Axis.

Early adverse life events (EALs) increase susceptibility to depression and impair cognitive performance, but the physiological mechanisms are still unclear. The target of this article is to clarify the impact of adverse childhood experiences on emotional and cognitive performance from the perspective of the heart-brain axis. We used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to test cognitive function and the Childhood Trauma Questionnaire (CTQ) to assess adverse childhood experiences. Heart rate variability (HRV) and electroencephalograms (EEG) were acquired at rest. We observed that subjects with depression had experienced more traumatic events during their childhood. Furthermore, they exhibited lower heart rate variability and higher power in the delta, theta, and alpha frequency bands. Moreover, heart rate variability partially mediated the association between childhood trauma exposure and depressive symptoms. Our findings suggested that adverse life events in childhood could influence the development of depression in adulthood, which might be linked to cardiac autonomic dysfunction and altered brain function.