Electrically tunable planar liquid-crystal singlets for simultaneous spectrometry and imaging.

Conventional hyperspectral cameras cascade lenses and spectrometers to acquire the spectral datacube, which forms the fundamental framework for hyperspectral imaging. However, this cascading framework involves tradeoffs among spectral and imaging performances when the system is driven toward miniaturization. Here, we propose a spectral singlet lens that unifies optical imaging and computational spectrometry functions, enabling the creation of minimalist, miniaturized and high-performance hyperspectral cameras. As a paradigm, we capitalize on planar liquid crystal optics to implement the proposed framework, with each liquid-crystal unit cell acting as both phase modulator and electrically tunable spectral filter. Experiments with various targets show that the resulting millimeter-scale hyperspectral camera exhibits both high spectral fidelity ( > 95%) and high spatial resolutions ( ~1.7 times the diffraction limit). The proposed "two-in-one" framework can resolve the conflicts between spectral and imaging resolutions, which paves a practical pathway for advancing hyperspectral imaging systems toward miniaturization and portable applications.

KIF18B: an important role in signaling pathways and a potential resistant target in tumor development.

KIF18B is a key member of the kinesin-8 family, involved in regulating various physiological processes such as microtubule length, spindle assembly, and chromosome alignment. This article briefly introduces the structure and physiological functions of KIF18B, examines its role in malignant tumors, and the associated carcinogenic signaling pathways such as PI3K/AKT, Wnt/ß-catenin, and mTOR pathways. Research indicates that the upregulation of KIF18B enhances tumor malignancy and resistance to radiotherapy and chemotherapy. KIF18B could become a new target for anticancer drugs, offering significant potential for the treatment of malignant tumors and reducing chemotherapy resistance.

Exploring the Birthday Week Effect on Hand, Foot, and Mouth Disease in Yunnan Province, China, From 2008 to 2022: Surveillance Data Analysis.

Background: Hand, foot, and mouth disease (HFMD) is a notable infectious disease predominantly affecting infants and children worldwide. Previous studies on HFMD have primarily focused on natural patterns, such as seasonality, but research on the influence of important social time points is lacking. Several studies have indicated correlations between birthdays and certain disease outcomes. Objective: This study aimed to explore the association between birthdays and HFMD. Methods: Surveillance data on HFMD from 2008 to 2022 in Yunnan Province, China, were collected. We defined the period from 6 days before the birthday to the exact birthday as the "birthday week." The effect of the birthday week was measured by the proportion of cases occurring during this period, termed the "birthday week proportion." We conducted subgroup analyses to present the birthday week proportions across sexes, age groups, months of birth, and reporting years. Additionally, we used a modified Poisson regression model to identify conditional subgroups more likely to contract HFMD during the birthday week. Results: Among the 973,410 cases in total, 116,976 (12.02%) occurred during the birthday week, which is 6.27 times the average weekly proportion (7/365, 1.92%). While the birthday week proportions were similar between male and female individuals (68,849/564,725, 12.19% vs 48,127/408,685, 11.78%; χ21=153.25, P<.001), significant differences were observed among different age groups (χ23=47,145, P<.001) and months of birth (χ211=16,942, P<.001). Compared to other age groups, infants aged 0-1 year had the highest birthday week proportion (30,539/90,709, 33.67%), which is 17.57 times the average weekly proportion. Compared to other months, patients born from April to July and from October to December, the peak months of the HFMD epidemic, had higher birthday week proportions. Additionally, a decreasing trend in birthday week proportions from 2008 to 2022 was observed, dropping from 33.74% (3914/11,600) to 2.77% (2254/81,372; Cochran-Armitage trend test: Z=-102.53, P<.001). The results of the modified Poisson regression model further supported the subgroup analyses findings. Compared with children aged >7 years, infants aged 0-1 year were more likely to contract HFMD during the birthday week (relative risk 1.182, 95% CI 1.177-1.185; P<.001). Those born during peak epidemic months exhibited a higher propensity for contracting HFMD during their birthday week. Compared with January, the highest relative risk was observed in May (1.087, 95% CI 1.084-1.090; P<.001). Conclusions: This study identified a novel "birthday week effect" of HFMD, particularly notable for infants approaching their first birthday and those born during peak epidemic months. Improvements in surveillance quality may explain the declining trend of the birthday week effect over the years. Higher exposure risk during the birthday period and potential biological mechanisms might also account for this phenomenon. Raising public awareness of the heightened risk during the birthday week could benefit HFMD prevention and control.

Light-responsive adipose-hypothalamus axis controls metabolic regulation.

Light is fundamental for biological life, with most mammals possessing light-sensing photoreceptors in various organs. Opsin3 is highly expressed in adipose tissue which has extensive communication with other organs, particularly with the brain through the sympathetic nervous system (SNS). Our study reveals a new light-triggered crosstalk between adipose tissue and the hypothalamus. Direct blue-light exposure to subcutaneous white fat improves high-fat diet-induced metabolic abnormalities in an Opsin3-dependent manner. Metabolomic analysis shows that blue light increases circulating levels of histidine, which activates histaminergic neurons in the hypothalamus and stimulates brown adipose tissue (BAT) via SNS. Blocking central actions of histidine and denervating peripheral BAT blunts the effects of blue light. Human white adipocytes respond to direct blue light stimulation in a cell-autonomous manner, highlighting the translational relevance of this pathway. Together, these data demonstrate a light-responsive metabolic circuit involving adipose-hypothalamus communication, offering a potential strategy to alleviate obesity-induced metabolic abnormalities.

Hyperglycemia-induced oxidative stress exacerbates mitochondrial apoptosis damage to cochlear stria vascularis pericytes via the ROS-mediated Bcl-2/CytC/AIF pathway.

OBJECTIVES: Diabetes is closely linked to hearing loss, yet the exact mechanisms remain unclear. Cochlear stria vascularis and pericytes (PCs) are crucial for hearing. This study investigates whether high glucose induces apoptosis in the cochlear stria vascularis and pericytes via elevated ROS levels due to oxidative stress, impacting hearing loss. METHODS: We established a type II diabetes model in C57BL/6J mice and used auditory brainstem response (ABR), Evans blue staining, HE staining, immunohistochemistry, and immunofluorescence to observe changes in hearing, blood-labyrinth barrier (BLB) permeability, stria vascularis morphology, and apoptosis protein expression. Primary cultured stria vascularis pericytes were subjected to high glucose, and apoptosis levels were assessed using flow cytometry, Annexin V-FITC, Hoechst 33342 staining, Western blot, Mitosox, and JC-1 probes. RESULTS: Diabetic mice showed decreased hearing thresholds, reduced stria vascularis density, increased oxidative stress, cell apoptosis, and decreased antioxidant levels. High glucose exposure increased apoptosis and ROS content in pericytes, while mitochondrial membrane potential decreased, with AIF and cytochrome C (CytC) released from mitochondria to the cytoplasm. Adding oxidative scavengers reduced AIF and CytC release, decreasing pericyte apoptosis. DISCUSSION: Hyperglycemia may induce mitochondrial apoptosis of cochlear stria vascularis pericytes through oxidative stress.

Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue.

Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.

GJB2 Promotes HCC Progression by Activating Glycolysis Through Cytoplasmic Translocation and Generating a Suppressive Tumor Microenvironment Based on Single Cell RNA Sequencing.

Despite substantial breakthroughs in the treatment of hepatocellular carcinoma (HCC) in recent years, many patients are diagnosed in the middle or late stages, denying them the option for surgical excision. Therefore, it is of great importance to find effective therapeutic targets of HCC. In this study, it is found that Gap junction protein beta-2 (GJB2) is highly enriched in malignant cells based on single-cell RNA sequencing and higher expression of GJB2 indicates a worse prognosis. The localization of GJB2 in HCC cancer cells is changed compared with normal liver tissue. In cancer cells, GJB2 tends to be located in the cytoplasm and nucleus, while in normal tissues, GJB2 is mainly located on the cell membrane. GJB2 is related to glycolysis, promoting NF-κB pathway via inducing the ubiquitination degradation of IκBa, and activating HIF-1α/GLUT-1/PD-L1 pathway. In addition, GJB2 knockdown reshapes tumor immune microenvironment and Salvianolic acid B inhibits the activity of GJB2. In conclusion, GJB2 promotes HCC progression by activating glycolysis through cytoplasmic translocation and generating a suppressive tumor microenvironment. Salvianolic acid B inhibits the expression of GJB2 and enhances the sensitivity of anti-PD1 therapy, which may provide insights into the development of novel combination therapeutic strategies for HCC.

Current perspectives and trends of CD39-CD73-eAdo/A2aR research in tumor microenvironment: a bibliometric analysis.

Background and objective: Extracellular adenosine (eAdo) bridges tumor metabolism and immune regulation. CD39-CD73-eAdo/A2aR axis regulates tumor microenvironment (TME) and immunotherapy response. In the era of immunotherapy, exploring the impact of the CD39-CD73-eAdo/A2aR axis on TME and developing targeted therapeutic drugs to enhance the efficacy of immunotherapy are the current research hotspots. This study summarizes and explores the research trends and hotspots of the adenosine axis in the field of TME to provide ideas for further in-depth research. Methods: Literature information was obtained from the Web of Science core collection database. The VOS viewer and the bibliometric tool based on R were used to quantify and identify cooperation information and individual influence by analyzing the detailed information of the global annual publication volume, country/region and institution distribution, article authors and co-cited authors, and journal distribution of these articles. At the same time, the distribution of author keywords and the co-occurrence of author keywords, highly cited articles, and highly co-cited references of CD39-CD73-eAdo/A2aR in the field of TME were analyzed to determine research hotspots and trends. Result: 1,721 articles published in the past ten years were included in this study. Through bibliometric analysis, we found that (1) 69 countries and regions explored the effect of the CD39-CD73-eAdo/A2aR on TME, and the research was generally on the rise. Researchers in the United States dominated research in this area, with the highest total citation rate. China had the most significant number of publications. (2) Harvard University has published the most articles in this field. (3) 12,065 authors contributed to the publication of papers in this field, of which 23 published at least eight papers. STAGG J had significant academic influence, with 24 published articles and 2,776 citations. Co-cited authors can be clustered into three categories. Stagg J, Allard B, Ohta A, and Antonioli, L occupied a central position in the network. (4) 579 scholarly journals have published articles in this field. The journal FRONTIERS IN IMMUNOLOGY published the most significant number of papers, with 97 articles and a total of 2,317 citations, and the number of publications increased year by year. (5) "The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets" was the most frequently local cited article (163 times). The "A2A adenosine receptor protects tumors from antitumor T cells" was the most co-cited reference (224 times). (6) Through the analysis of author keywords, we found that the relationship between adenosine and immunotherapy was a core concept for many researchers in this field. Breast cancer, melanoma, colorectal cancer, ovarian cancer, glioblastoma, pancreatic cancer, hepatocellular carcinoma, and lung cancer were the most frequent cancer types in adenosine-related tumor studies. Immunotherapy, immunosuppression, immune checkpoint, and immune checkpoint inhibitors were the hot keywords in the research, reflecting the importance of the adenosine metabolic pathway in tumor immunotherapy. The keywords such as Immunogenic cell death, T cells, Sting, regulatory T cells, innate immunity, and immune infiltration demonstrated the pathways by which adenosine affected the TME. The famous author keywords in recent years have been immunotherapy, immunogenic cell death, inflammation, lung cancer, and gastric cancer. Conclusion: The effect of CD39-CD73-eAdo/A2aR on the infiltration and function of various immune cells in TME, tumor immunotherapy response, and patient prognosis has attracted the attention of researchers from many countries/regions. American scholars still dominate the research in this field, but Chinese scholars produce the most research results. The journal FRONTIERS IN IMMUNOLOGY has published the wealthiest research in the field. Stagg J was a highly influential researcher in this field. Further exploration of targeted inhibition of CD39-CD73-eAdo/A2aR alone or in combination with other immunotherapy, radiotherapy, and chemotherapy in treating various cancer types and developing effective clinical therapeutic drugs are continuous research hotspots in this field.

Characteristics, Influence, Prevention, and Control Measures of the Mpox Infodemic: Scoping Review of Infodemiology Studies.

BACKGROUND: The mpox pandemic has caused widespread public concern around the world. The spread of misinformation through the internet and social media could lead to an infodemic that poses challenges to mpox control. OBJECTIVE: This review aims to summarize mpox-related infodemiology studies to determine the characteristics, influence, prevention, and control measures of the mpox infodemic and propose prospects for future research. METHODS: The scoping review was conducted based on a structured 5-step methodological framework. A comprehensive search for mpox-related infodemiology studies was performed using PubMed, Web of Science, Embase, and Scopus, with searches completed by April 30, 2024. After study selection and data extraction, the main topics of the mpox infodemic were categorized and summarized in 4 aspects, including a trend analysis of online information search volume, content topics of mpox-related online posts and comments, emotional and sentiment characteristics of online content, and prevention and control measures for the mpox infodemic. RESULTS: A total of 1607 articles were retrieved from the databases according to the keywords, and 61 studies were included in the final analysis. After the World Health Organization's declaration of an mpox public health emergency of international concern in July 2022, the number of related studies began growing rapidly. Google was the most widely used search engine platform (9/61, 15%), and Twitter was the most used social media app (32/61, 52%) for researchers. Researchers from 33 countries were concerned about mpox infodemic-related topics. Among them, the top 3 countries for article publication were the United States (27 studies), India (9 studies), and the United Kingdom (7 studies). Studies of online information search trends showed that mpox-related online search volume skyrocketed at the beginning of the mpox outbreak, especially when the World Health Organization provided important declarations. There was a large amount of misinformation with negative sentiment and discriminatory and hostile content against gay, bisexual, and other men who have sex with men. Given the characteristics of the mpox infodemic, the studies provided several positive prevention and control measures, including the timely and active publishing of professional, high-quality, and easy-to-understand information online; strengthening surveillance and early warning for the infodemic based on internet data; and taking measures to protect key populations from the harm of the mpox infodemic. CONCLUSIONS: This comprehensive summary of evidence from previous mpox infodemiology studies is valuable for understanding the characteristics of the mpox infodemic and for formulating prevention and control measures. It is essential for researchers and policy makers to establish prediction and early warning approaches and targeted intervention methods for dealing with the mpox infodemic in the future.

RBM25 depletion suppresses the growth of colon cancer cells through regulating alternative splicing of MNK2.

Increasing evidence suggests that deregulated RNA splicing factors play critical roles in tumorigenesis; however, their specific involvement in colon cancer remains largely unknown. Here we report that the splicing factor RBM25 is overexpressed in colon cancer, and this increased expression correlates with a poor prognosis of patients with colon cancer. Functionally, RBM25 ablation suppresses the growth of colon cancer cells both in vitro and in vivo. Mechanistically, our transcriptome-wide analysis of splicing events revealed that RBM25 regulates a large number of cancer-related alternative splicing events across the human genome in colon cancer. Particularly, RBM25 regulates the splicing of MNK2 by interacting with the poly G rich region in exon 14a, thereby inhibiting the selection of the proximal 3' splice site (ss), resulting in the production of the oncogenic short isoform, MNK2b. Knockdown of RBM25 leads to an increase in the MNK2a isoform and a decrease in the MNK2b isoform. Importantly, re-expression of MNK2b or blocking the 3' ss of the alternative exon 14a with ASO partially reverses the RBM25 knockdown mediated tumor suppression. Moreover, MNK2b levels were significantly increased in colon cancer tissues, which is positively correlated with the expression level of RBM25. Collectively, our findings uncover the critical role of RBM25 as a key splicing factor in colon cancer, suggesting its potential as a prognostic marker and therapeutic target.

Effects of 6-Week Weighted-Jump-Squat Training With and Without Eccentric Load Reduction on Explosive Performance.

PURPOSE: To compare the effects of 6-week barbell weighted-jump-squat (WJS) training with and without eccentric load reduction on explosive performance. METHODS: Twenty well-trained male athletes were randomly assigned to either an experimental group (n = 10) or a control group (n = 10). Participants completed 12 WJS training sessions (6 sets of 5 repetitions of barbell back squat at 30% of 1-repetition maximum [1RM]) twice a week over a 6-week period. While the control group used 0% eccentric loading (ie, traditional WJS), the experimental group utilized a 50% eccentric loading reduction with a mechanical braking unit (ie, eccentric load set at 15% of 1RM). Performance assessments, including countermovement jump, 20-m sprint, standing long jump, and 1RM barbell back squat, were conducted both before (pretests) and after (posttests) the intervention. RESULTS: Both the experimental group and the control group demonstrated a significant increase in countermovement-jump height (+6.4% [4.0%] vs +4.9% [5.7%]; P < .001) and peak power output (+2.3% [2.7%] vs +1.9% [5.1%]; P = .017), faster 20-m sprint times (+9.4% [4.8%] vs +9.2% [5.5%]; P < .001), longer standing long jump (+3.1% [2.5%] vs +3.0% [3.3%]; P < .001), and higher 1RM back squat (+6.4% [4.0%] vs +4.9% [5.7%]; P < .001) from pretests to posttests. However, there was no significant condition × time interaction for any variable (all P ≥ .294). CONCLUSIONS: Both WJS training methods, with and without load reduction in the eccentric phase, effectively enhance explosive performance. Nevertheless, athletes in later stages of injury rehabilitation or intense training may find reducing eccentric load a more tolerable strategy for achieving similar performance gains compared with traditional isoinertial loading.

miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization.

BACKGROUND: Colorectal cancer is among the most common malignant tumors affecting the gastrointestinal tract. Liver metastases, a complication present in approximately 50% of colorectal cancer patients, are a considerable concern. Recently, studies have revealed the crucial role of miR-455 in tumor pathogenesis. However, the effect of miR-455 on the progression of liver metastases in colorectal cancer remains controversial. As an antagonist of bone morphogenetic protein(BMP), Gremlin 1 (GREM1) may impact organogenesis, body patterning, and tissue differentiation. Nevertheless, the role of miR-455 in regulating GREM1 in colorectal cancer liver metastases and how miR-455/GREM1 axis influences tumour immune microenvironment is unclear. METHODS: Bioinformatics analysis shows that miR-455/GREM1 axis plays crucial role in liver metastasis of intestinal cancer and predicts its possible mechanism. To investigate the impact of miR-455/GREM1 axis on the proliferation, invasion, and migration of colorectal cancer cells, colony formation assay, wound healing and transwell assay were examined in vitro. The Dual-Luciferase reporter gene assay and RNA pull-down assay confirmed a possible regulatory effect between miR-455 and GREM1. In vivo, colorectal cancer liver metastasis(CRLM) model mice was established to inquiry the effect of miR-455/GREM1 axis on tumor growth and macrophage polarization. The marker of macrophage polarization was tested using immunofluorescence(IF) and quantitative real-time polymerase chain reaction(qRT-PCR). By enzyme-linked immunosorbent assay (ELISA), cytokines were detected in culture medium supernatants. RESULTS: We found that miR-455 and BMP6 expression was increased and GREM1 expression was decreased in liver metastase compared with primary tumor. miR-455/GREM1 axis promotes colorectal cancer cells proliferation, migration, invasion via affected PI3K/AKT pathway. Moreover, downregulating GREM1 augmented BMP6 expression in MC38 cell lines, inducing M2 polarization of macrophages, and promoting liver metastasis growth in CRLM model mice. CONCLUSION: These data suggest that miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization. These results offer valuable insights and direction for future research and treatment of CRLM.

CircCHSY1 protects hearts against ischemia/reperfusion injury by enhancing heme oxygenase 1 expression via miR-24-3p.

AIMS: Circular RNAs are important players involving in a variety of physiological and pathological processes. However, their functions and mechanisms during myocardial ischemic injury and protection remain largely unknown. We recently found significant alterations of many circRNAs including circCHSY1 following myocardial ischemia/reperfusion (I/R) injury, whereas their exact functions are unclear. Here, we investigated roles of circCHSY1 in the acute myocardial I/R injury and the potential mechanisms involved. METHODS AND RESULTS: The expression of circCHSY1 was detected in cardiomyocytes from mouse, rat and human embryonic stem cells (hESC-CMs). It was further upregulated in mouse I/R (30 min/24 h) hearts, oxygen glucose deprivation/reperfused (OGD/R, 6 h/2 h) primary neonatal rat ventricular cardiomyocytes (NRCMs) and OGD/R (48 h/2 h) hESC-CMs. Adenovirus-mediated circCHSY1-overexpression significantly decreased infarct size and lactate dehydrogenase (LDH) release in mouse I/R hearts. Consistently, circCHSY1 overexpression reduced the LDH release in the OGD/R NRCMs and hESC-CMs, improved cell viability, and preserved mitochondrial function in the OGD/R NRCMs, whereas there were no significant differences in cell viability and LDH release between the OGD/R NRCMs with and without siRNA-mediated circCHSY1 knockdown. Mechanistically, circCHSY1 was detected to bind with miR-24-3p analyzed by dual luciferase assay and RNA pull-down assays. CircCHSY1 overexpression-mediated protective effects on cells and mitochondria in OGD/R NRCMs were reversed by the miR-24-3p mimic. Further, dual luciferase assay showed that miR-24-3p directly bound to heme oxygenase 1 (HO1) via its 3'UTR. The protein level of HO1 was downregulated by miR-24-3p mimic in OGD/R NRCMs but enhanced by the circCHSY1 overexpression in vitro and in vivo. Functionally, the HO1 knockdown by adenovirus in vivo and by siRNA in vitro eliminated cardioprotective effects of circCHSY1 overexpression. CONCLUSION: CircCHSY1 is upregulated following myocardial I/R injury. The higher level of circCHSY1 protects I/R hearts and cardiomyocytes. The protection of circCHSY1 is mediated through enhancement of the HO1 level, resulting in preserving mitochondrial homeostasis via targeting miR-24-3p in cardiomyocytes. These findings suggest circCHSY1 as a protective factor.

Hypericum perforatum L. attenuates depression by regulating Akkermansia muciniphila, tryptophan metabolism and NFκB-NLRP2-Caspase1-IL1ß pathway.

BACKGROUND: Gut microbiota dysbiosis significantly contributes to progression of depression. Hypericum perforatum L. (HPL) is traditionally used in Europe for treating depression. However, its mechanism remains largely underexplored. PURPOSE: This study aims to investigate the pivotal gut microbiota species and microbial signaling metabolites associated with the antidepressant effects of HPL. METHODS: Fecal microbiota transplantation was used to assess whether HPL mitigates depression through alterations in gut microbiota. Microbiota and metabolic profiling of control, chronic restraint stress (CRS)-induced depression, and HPL-treated CRS mice were examined using 16S rRNA gene sequencing and metabolomics analysis. The influence of gut microbiota on HPL's antidepressant effects was assessed by metabolite and bacterial intervention experiments. RESULTS: HPL significantly alleviated depression symptoms in a manner dependent on gut microbiota and restored gut microbial composition by enriching Akkermansia muciniphila (AKK). Metabolomic analysis indicated that HPL regulated tryptophan metabolism, reducing kynurenine (KYN) levels derived from microbiota and increasing 5-hydroxytryptophan (5-HTP) levels. Notably, supplementation with KYN activated the NFκB-NLRP2-Caspase1-IL1ß pathway and increased proinflammatory IL1ß in the hippocampus of mice with depression. Interestingly, mono-colonization with AKK notably increased 5-hydroxytryptamine (5-HT) and decreased KYN levels, ameliorating depression symptoms through modulation of the NFκB-NLRP2-Caspase1-IL1ß pathway. CONCLUSIONS: The promising therapeutic role of HPL in treating depression is primarily attributed to its regulation of the NFκB-NLRP2-Caspase1-IL1ß pathway, specifically by targeting AKK and tryptophan metabolites.

MAL2 reprograms lipid metabolism in intrahepatic cholangiocarcinoma via EGFR/SREBP-1 pathway based on single-cell RNA sequencing.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/AKT/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.

Identification of diabetic retinopathy classification using machine learning algorithms on clinical data and optical coherence tomography angiography.

BACKGROUND: To apply machine learning (ML) algorithms to perform multiclass diabetic retinopathy (DR) classification using both clinical data and optical coherence tomography angiography (OCTA). METHODS: In this cross-sectional observational study, clinical data and OCTA parameters from 203 diabetic patients (203 eye) were used to establish the ML models, and those from 169 diabetic patients (169 eye) were used for independent external validation. The random forest, gradient boosting machine (GBM), deep learning and logistic regression algorithms were used to identify the presence of DR, referable DR (RDR) and vision-threatening DR (VTDR). Four different variable patterns based on clinical data and OCTA variables were examined. The algorithms' performance were evaluated using receiver operating characteristic curves and the area under the curve (AUC) was used to assess predictive accuracy. RESULTS: The random forest algorithm on OCTA+clinical data-based variables and OCTA+non-laboratory factor-based variables provided the higher AUC values for DR, RDR and VTDR. The GBM algorithm produced similar results, albeit with slightly lower AUC values. Leading predictors of DR status included vessel density, retinal thickness and GCC thickness, as well as the body mass index, waist-to-hip ratio and glucose-lowering treatment. CONCLUSIONS: ML-based multiclass DR classification using OCTA and clinical data can provide reliable assistance for screening, referral, and management DR populations.

T-DNA insertion in Arabidopsis caused coexisting chromosomal inversion and duplication at megabase level.

Agrobacteria-mediated transformation is widely used in plant genetic engineering to introduce exogenous genes and create mutant lines through random T-DNA insertion and gene disruption. When T-DNA fragments are inserted into the plant genome, it could cause chromosomal abnormalities. In this study, we investigated the genetic basis of pleiotropic phenotypes observed in the T-DNA insertion mutant lnc161. We discovered that there are four T-DNA insertions present in the lnc161 genome, which disrupted the genes LNC161 (AT3G05035), AT3G57400, AT5G05630, and AT5G16450, respectively. However, none of these insertions were the causative mutation that leads to the lnc161 phenotypes. Strikingly, through genetic analyses and high throughput sequencing, we found an inversion of about 19.8 Mb sequences between LNC161 and AT3G57400. Moreover, the sequences between AT5G05630 and AT5G16450 (about 3.7 Mb) were translocated from chromosome 5 to chromosome 3, adjacent to the inversion sequences, and were duplicated. This duplication led to an up-regulation of genes expression in this region, potentially resulting in pleiotropic morphological traits in lnc161. Overall, this study provides a case showing complex chromosomal re-arrangement induced by T-DNA insertion.

Metabolomics reveals ascorbic acid inhibits ferroptosis in hepatocytes and boosts the effectiveness of anti-PD1 immunotherapy in hepatocellular carcinoma.

BACKGROUND: Immunotherapy combined with molecular targeted therapy is increasingly popular in patients with advanced hepatocellular carcinoma (HCC). However, immune-related adverse events(irAEs) brought on by immunotherapy increase the likelihood of side effects, thus it is important to look into ways to address this issue. METHODS: Different metabolite patterns were established by analyzing metabolomics data in liver tissue samples from 10 patients(divided into severe and mild liver injury) before and after immuno-targeted therapy. After establishing a subcutaneous tumor model of HCC, the mice were divided into PBS group, ascorbic acid(AA) group, and anti-PD1 + tyrosine kinase inhibitor (TKI) group, anti-PD1 + TKI + AA group. Liver tissue were stained with hematoxylin-eosin staining(HE) and the content of aspartate transaminase (AST) and alanine transaminase(ALT) in blood were determined. The mechanism was confirmed by western blotting, mass cytometry, and other techniques. RESULTS: Through metabolomics analysis, AA was significantly reduced in the sample of patients with severe liver injury caused by immuno-targeted therapy compared to patients with mild liver injury. The addition of AA in vivo experiments demonstrated a reduction in liver injury in mice. In the liver tissues of the anti-PD1 + TKI + AA group, the protein expressions of SLC7A11,GPX4 and the level of glutathione(GSH) were found to be higher compared to the anti-PD1 + TKI group. Mass cytometry analysis revealed a significant increase in the CD11b+CD44+ PD-L1+ cell population in the AA group when compared to the PBS group. CONCLUSIONS: AA could reduce liver injury by preventing hepatocyte SLC7A11/GPX4 ferroptosis and improve the immunotherapy effect of anti-PD1 by boosting CD11b+CD44+PD-L1+cell population in HCC.

Oxygen vacancy-rich nickel oxide nanoplatforms for enhanced photothermal and chemodynamic therapy combat methicillin-resistant Staphylococcus aureus.

Bacterial infections pose a global concern due to high fatality rates, particularly with the rise of drug-resistant bacteria and biofilm formation. There is an urgent need for innovative strategies to combat this issue. A study on chemodynamic therapy (CDT) using nanozymes in conjunction with photothermal therapy (PTT) has displayed potential in addressing drug-resistant bacterial infections. However, the effectiveness of this combined approach is limited by inadequate light absorption. This work suggests the NiOx nanoparticles enriched with oxygen vacancies enhance CDT and PTT to overcome this challenge. The presence of oxygen vacancies in NiOx can reduce the energy gap between its valence band and conduction band, facilitating oxygen adsorption. NiOx has exhibited notable antibacterial properties and complete eradication of biofilms in both laboratory and animal trials. In animal abscess models, NiOx demonstrated antibacterial and anti-inflammatory effects in the initial stages, while also promoting wound healing and tissue regeneration by influencing immune factors and encouraging collagen deposition and neovascularization. With positive biosafety and biocompatibility profiles, the oxygen vacancy-enhanced CDT and PTT therapy proposed in this article hold promise for effective sterilization, deep biofilm removal, and treatment of infections caused by drug-resistant bacteria. STATEMENT OF SIGNIFICANCE: This study constructs oxygen vacancies NiOx nanoparticles (NiOx NPs) to improve the efficacy of photothermal therapy and chemodynamic therapy. The presence of oxygen vacancies in NiOx NPs helps bridge the energy gap between its valence band and conduction band, facilitating oxygen adsorption and improving catalytic efficiency. In both in vivo and in vitro antibacterial experiments, NiOx NPs demonstrate effective antibacterial and anti-inflammatory properties. Furthermore, it aids in wound healing and tissue regeneration by modulating immune factors, collagen deposition, and angiogenesis. This approach presents a promising collaborative strategy for utilizing nickel-based defective nanomaterials in combating deep drug-resistant bacterial infections.

Functional dissection of parabrachial substrates in processing nociceptive information.

Painful stimuli elicit first-line reflexive defensive reactions and, in many cases, also evoke second-line recuperative behaviors, the latter of which reflects the sensing of tissue damage and the alleviation of suffering. The lateral parabrachial nucleus (lPBN), composed of external- (elPBN), dorsal- (dlPBN), and central/superior-subnuclei (jointly referred to as slPBN), receives sensory inputs from spinal projection neurons and plays important roles in processing affective information from external threats and body integrity disruption. However, the organizational rules of lPBN neurons that provoke diverse behaviors in response to different painful stimuli from cutaneous and deep tissues remain unclear. In this study, we used region-specific neuronal depletion or silencing approaches combined with a battery of behavioral assays to show that slPBN neurons expressing substance P receptor ( NK1R) (lPBN NK1R) are crucial for driving pain-associated self-care behaviors evoked by sustained noxious thermal and mechanical stimuli applied to skin or bone/muscle, while elPBN neurons are dispensable for driving such reactions. Notably, lPBN NK1R neurons are specifically required for forming sustained somatic pain-induced negative teaching signals and aversive memory but are not necessary for fear-learning or escape behaviors elicited by external threats. Lastly, both lPBN NK1R and elPBN neurons contribute to chemical irritant-induced nocifensive reactions. Our results reveal the functional organization of parabrachial substrates that drive distinct behavioral outcomes in response to sustained pain versus external danger under physiological conditions.