Eye movement intervention facilitates concurrent perception and memory processing.

A widely used psychotherapeutic treatment for post-traumatic stress disorder (PTSD) involves performing bilateral eye movement (EM) during trauma memory retrieval. However, how this treatment-described as eye movement desensitization and reprocessing (EMDR)-alleviates trauma-related symptoms is unclear. While conventional theories suggest that bilateral EM interferes with concurrently retrieved trauma memories by taxing the limited working memory resources, here, we propose that bilateral EM actually facilitates information processing. In two EEG experiments, we replicated the bilateral EM procedure of EMDR, having participants engaging in continuous bilateral EM or receiving bilateral sensory stimulation (BS) as a control while retrieving short- or long-term memory. During EM or BS, we presented bystander images or memory cues to probe neural representations of perceptual and memory information. Multivariate pattern analysis of the EEG signals revealed that bilateral EM enhanced neural representations of simultaneously processed perceptual and memory information. This enhancement was accompanied by heightened visual responses and increased neural excitability in the occipital region. Furthermore, bilateral EM increased information transmission from the occipital to the frontoparietal region, indicating facilitated information transition from low-level perceptual representation to high-level memory representation. These findings argue for theories that emphasize information facilitation rather than disruption in the EMDR treatment.

Thyroid-stimulating hormone and total bile acids can predict adverse pregnancy outcome among patients with gestational hypertension.

OBJECTIVE: To investigate the correlation between serum thyroid-stimulating hormone (TSH) and total bile acid (TBA) levels in gestational hypertension and their combined predictive value for pregnancy outcome. METHODS: A total of 194 patients with gestational hypertension (GH), treated from June 2020 to May 2022, were included in this study. The patients were divided into two subgroups based on pregnancy outcome: an adverse pregnancy outcome group (77 cases) and a normal pregnancy outcome group (117 cases). Additionally, 50 healthy pregnant women undergoing routine prenatal checkups during the same period served as the control group. In this study, serum TBA and TSH levels were measured and compared between the control and GH groups as well as between adverse pregnancy outcome and normal pregnancy outcome groups. The independent risk factors for adverse pregnancy outcome were screened using logistic regression, and their predictive value for pregnancy outcome in patients with GH was analyzed using receiver operating characteristic (ROC) curves. RESULTS: Serum TSH and TBA levels were significantly higher in the GH group compared to the normal group (both P < 0.001). Logistic regression analysis revealed that age, body mass index (BMI), TSH, and TBA were independent risk factors for adverse pregnancy outcome. ROC curve analysis showed that combined TSH and TBA for predicting adverse pregnancy outcome had an Area Under the Curve (AUC) of 0.896, surpassing the AUCs of each individual index (0.843 for TSH and 0.765 for TBA), which indicates a stronger predictive value (P < 0.001). CONCLUSION: The combined measurement of serum TBA and TSH can serve as a valuable predictive tool for pregnancy outcome in patients with gestational hypertension.

Enantioselective α-Trifluoromethylthiolation of Carbonyl Compounds with AgSCF3 and Trichloroisocyanuric Acid.

We successfully developed an enantioselective trifluoromethylthiolation of structurally diverse carbonyl compounds. Trichloroisocyanuric acid and AgSCF3 were employed to generate active electrophilic trifluoromethylthio species in situ for asymmetric C-SCF3 bond formation. A broad variety of chiral SCF3-carbon nucleophiles (pyrazolones, ß-keto esters, and ß-keto amides) were obtained in excellent yields with high enantioselectivities (up to 92% ee) by Cinchona alkaloid derived squaramide catalysts. The reaction exhibits high efficiency, good enantioselectivity, and high functional group tolerance, which provided a novel and efficient way for asymmetric synthesis of trifluoromethylthiolated carbonyl compounds.

Capmatinib plus nivolumab in pretreated patients with EGFR wild-type advanced non-small cell lung cancer.

INTRODUCTION: Dysregulated MET is an established oncogenic driver in non-small cell lung cancer (NSCLC). MET signaling may also suppress anticancer immune responses. Concomitant MET inhibition with capmatinib (a MET inhibitor) synergistically enhanced the efficacy of immunotherapies in murine cancer models, regardless of tumor dependency to MET signaling. Here, we report results of a multicenter, open-label, phase 2 study of capmatinib plus nivolumab (a PD-1 inhibitor) in patients with EGFR wild-type advanced NSCLC, previously treated with platinum-based chemotherapy. METHODS: Patients were allocated into high-MET or low-MET groups according to MET expression determined by immunohistochemistry, MET gene copy number as assessed by fluorescence in-situ hybridization, and presence of MET exon 14 skipping mutation, then received capmatinib 400 mg, oral, twice daily in combination with nivolumab 3 mg/kg intravenously every 2 weeks. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate per RECIST v1.1. RESULTS: The primary endpoint was met in both the high-MET (N = 16) and low-MET (N = 30) groups. In the high-MET and low-MET groups, respectively, the estimated mean 6-month PFS rate (95 % credible interval) by Bayesian analysis was 68.9 % (48.5-85.7) and 50.9 % (35.6-66.4). The Kaplan-Meier median PFS (95 % CI) was 6.2 months (3.5-19.2) and 4.2 months (1.8-7.4). The overall response rate (95 % CI) was 25.0 % (7.3-52.4) and 16.7 % (5.6-34.7). Most frequent treatment-related adverse events (≥30 % any grade, N = 46) were nausea (52.2 %), peripheral edema (34.8 %), and increased blood creatinine (30.4 %). CONCLUSIONS: Capmatinib plus nivolumab showed clinical activity and manageable safety in pretreated patients with advanced EGFR wild-type NSCLC, independent of MET status. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323126.

Aluminum Carboxylate Modification Enabled Efficient and Stable Perovskite-Polystyrene Thin Films for Light-Emitting Applications.

Lead halide perovskite nanocrystals (PNCs) have demonstrated great potential in emerging display technologies. However, the practical application of PNCs is hindered by the inherent instability of their ionic surface. Here, we proposed a surface modification approach to enhance the stability of CsPbBr3 PNCs by postsynthetic treatment with aluminum phenylbutyrate (Al(PA)3). Our study reveals that Al(PA)3 displaces ammonium ligands and binds tightly on surface halide, providing excellent air and moisture resistance while preserving a high quantum efficiency of 81.6%. The modified PNCs maintain a constant photoluminescence intensity under continuous UV light illumination for 500 h. Additionally, the Al(PA)3 ligand is compatible with styrene, enabling homogeneous dispersion of PNCs in polystyrene matrices to form bright and uniform PNC-PS thin films. We demonstrated the application of the composite films for display backlighting, which exhibits a wide color gamut of 125% NTSC. The result highlights the potential of AlPA-modified PNCs in light-emitting and other optoelectronic devices.

High-efficiency and broadband tunable Raman fiber laser in a chalcogenide fiber based on the Fresnel reflection.

A high-efficiency and broadband tunable chalcogenide fiber Raman laser with the Fabry-Perot (F-P) cavity formed by the Fresnel reflection was established. A maximum average power slope efficiency of around 43% and a maximum output peak power of about 2.9 W at 2148 nm were demonstrated by using a 2 µm nanosecond pump source. The laser shows a broadened pulse width of 674 ns and a broadband tunability of the central wavelength from 2100 to 2186 nm. The Raman Fabry-Perot cavity constituted by the Fresnel reflection from chalcogenide fiber endfaces can operate at any wavelength without the aid of any additional optical feedback element. This will facilitate the realization of fiber lasers with excellent performance and compact system, especially in the mid-infrared region.

The m6A reader IGF2BP2 promotes esophageal cell carcinoma progression by enhancing EIF4A1 translation.

Esophageal squamous cell carcinoma (ESCC) is one of most prevalent cancers worldwide, especially in China. Lacking in depth mechanism study, effective targets and therapeutics are desperately needed in the clinic. RNA-binding proteins (RBPs) mediate the localization, stability, and translation of the target transcripts and fine-tune the physiological functions of the proteins encoded. Bioinformatics analysis revealed that IGF2BPs were highly expressed in ESCC tissues and at least participated in the regulation of cell proliferation of ESCC cells. Biological researches demonstrated that IGF2BP2 promoted the cell proliferation, migration and invasion of ESCC KYSE30 and KYSE450 cells. IGF2BP2 could bind to EIF4A1 mRNA by recognition of m6A sites and enhanced translation of EIF4A1. IGF2BPs, as m6A reader, IGF2BPs were oncogenic genes in ESCC by regulating the expression of EIF4A1 through m6A sites. IGF2BP2, EIF4A1 and their targets could serve as potential biomarkers and therapeutic targets for ESCC, offering promising novel approaches for the diagnosis and treatment of ESCC.

Absolute and relative outcomes of psychotherapies for eight mental disorders: a systematic review and meta-analysis.

Psychotherapies are first-line treatments for most mental disorders, but their absolute outcomes (i.e., response and remission rates) are not well studied, despite the relevance of such information for health care users, providers and policy makers. We aimed to examine absolute and relative outcomes of psychotherapies across eight mental disorders: major depressive disorder (MDD), social anxiety disorder, panic disorder, generalized anxiety disorder (GAD), specific phobia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and borderline personality disorder (BPD). We used a series of living systematic reviews included in the Metapsy initiative (www.metapsy.org), with a common strategy for literature search, inclusion of studies and extraction of data, and a common format for the analyses. Literature search was conducted in major bibliographical databases (PubMed, PsycINFO, Embase, and the Cochrane Register of Controlled Trials) up to January 1, 2023. We included randomized controlled trials comparing psychotherapies for any of the eight mental disorders, established by a diagnostic interview, with a control group (waitlist, care-as-usual, or pill placebo). We conducted random-effects model pairwise meta-analyses. The main outcome was the absolute rate of response (at least 50% symptom reduction between baseline and post-test) in the treatment and control conditions. Secondary outcomes included the relative risk (RR) of response, and the number needed to treat (NNT). Random-effects meta-analyses of the included 441 trials (33,881 patients) indicated modest response rates for psychotherapies: 0.42 (95% CI: 0.39-0.45) for MDD; 0.38 (95% CI: 0.33-0.43) for PTSD; 0.38 (95% CI: 0.30-0.47) for OCD; 0.38 (95% CI: 0.33-0.43) for panic disorder; 0.36 (95% CI: 0.30-0.42) for GAD; 0.32 (95% CI: 0.29-0.37) for social anxiety disorder; 0.32 (95% CI: 0.23-0.42) for specific phobia; and 0.24 (95% CI: 0.15-0.36) for BPD. Most sensitivity analyses broadly supported these findings. The RRs were significant for all disorders, except BPD. Our conclusion is that most psychotherapies for the eight mental disorders are effective compared with control conditions, but absolute response rates are modest. More effective treatments and interventions for those not responding to a first-line treatment are needed.

Altered static and dynamic cerebellar-cerebral functional connectivity in acute pontine infarction.

This study investigates abnormalities in cerebellar-cerebral static and dynamic functional connectivity among patients with acute pontine infarction, examining the relationship between these connectivity changes and behavioral dysfunction. Resting-state functional magnetic resonance imaging was utilized to collect data from 45 patients within seven days post-pontine infarction and 34 normal controls. Seed-based static and dynamic functional connectivity analyses identified divergences in cerebellar-cerebral connectivity features between pontine infarction patients and normal controls. Correlations between abnormal functional connectivity features and behavioral scores were explored. Compared to normal controls, left pontine infarction patients exhibited significantly increased static functional connectivity within the executive, affective-limbic, and motor networks. Conversely, right pontine infarction patients demonstrated decreased static functional connectivity in the executive, affective-limbic, and default mode networks, alongside an increase in the executive and motor networks. Decreased temporal variability of dynamic functional connectivity was observed in the executive and default mode networks among left pontine infarction patients. Furthermore, abnormalities in static and dynamic functional connectivity within the executive network correlated with motor and working memory performance in patients. These findings suggest that alterations in cerebellar-cerebral static and dynamic functional connectivity could underpin the behavioral dysfunctions observed in acute pontine infarction patients.

Differences in tourism economic development and its influencing factors among three major city clusters along the middle reaches of the Yangtze River.

An in-depth study of the mechanisms governing the generation, evolution, and regulation of differences in tourism economics holds significant value for the rational utilization of tourism resources and the promotion of synergistic tourism economic development. This study utilizes mathematical statistical analysis and GIS spatial analysis to construct a single indicator measure and a comprehensive indicator measure to analyze tourism-related data in the research area from 2004 to 2019. The main factors influencing the spatial and temporal differences in the tourism economy are analyzed using two methods, namely, multiple linear regression and geodetector. The temporal evolution, overall differences and differences within each city group fluctuate downwards, while the differences between groups fluctuate upwards. Domestic tourism economic differences contribute to over 90% of the overall tourism economic differences. Spatial divergence, the proportion of the tourism economy accounted for by spatial differences is obvious, the comprehensive level of the tourism economy can be divided into five levels. The dominant factors in the formation of the pattern of spatial and temporal differences in the tourism economy are the conditions of tourism resources based on class-A tourist attractions and the level of tourism industry and services based on star hotels and travel agencies. This study addresses the regional imbalance of tourism economic development in city clusters and with the intent of promoting balanced and high-quality development of regional tourism economies.

An orally administered bacterial membrane protein nanodrug ameliorates doxorubicin cardiotoxicity through alleviating impaired intestinal barrier.

The cardiotoxicity caused by Dox chemotherapy represents a significant limitation to its clinical application and is a major cause of late death in patients undergoing chemotherapy. Currently, there are no effective treatments available. Our analysis of 295 clinical samples from 132 chemotherapy patients and 163 individuals undergoing physical examination revealed a strong positive correlation between intestinal barrier injury and the development of cardiotoxicity in chemotherapy patients. We developed a novel orally available and intestinal targeting protein nanodrug by assembling membrane protein Amuc_1100 (obtained from intestinal bacteria Akkermansia muciniphila), fluorinated polyetherimide, and hyaluronic acid. The protein nanodrug demonstrated favorable stability against hydrolysis compared with free Amuc_1100. The in vivo results demonstrated that the protein nanodrug can alleviate Dox-induced cardiac toxicity by improving gut microbiota, increasing the proportion of short-chain fatty acid-producing bacteria from the Lachnospiraceae family, and further enhancing the levels of butyrate and pentanoic acids, ultimately regulating the homeostasis repair of lymphocytes in the spleen and heart. Therefore, we believe that the integrity of the intestinal barrier plays an important role in the development of chemotherapy-induced cardiotoxicity. Protective interventions targeting the intestinal barrier may hold promise as a general clinical treatment regimen for reducing Dox-induced cardiotoxicity.

Development of real-time recombinase polymerase amplification (RPA) and RPA combined with lateral flow dipstick (LFD) assays for the rapid and sensitive detection of cyprinid herpesvirus 3.

In this issue, we established rapid, cost-effective, and simple detection methods including recombines polymerase amplification with lateral flow dipstick (RPA-LFD) and real-time RPA for cyprinid herpesvirus 3(CyHV-3), and evaluated their sensitivity, specificity, and applicability, the real-time RPA method could achieve sensitive diagnosis of CyHV-3 within 1.3 copies per reaction, respectively. The real-time RPA method is 10-fold more sensitive than RPA-LFD method. The exact number of CyHV-3 can be calculated in each sample by real-time RPA. The sera from koi also can be tested in these methods. In addition, no cross-reaction was observed with other related pathogens, including carp oedema virus (CEV), spring viraemia of carp virus (SVCV), cyprinid herpesvirus 1(CyHV-1), cyprinid herpesvirus 2(CyHV-2), type I grass carp reovirus (GCRV-I), type II GCRV (GCRV-II), type III GCRV (GCRV-III), and Aeromonas hydrophila.

Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer.

Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines are constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines are identified. The expression of SOX13/SCAF1 is manipulated in GC cell lines where relevant biological and molecular analyses are performed. Molecular docking and computational screening are performed to screen potential inhibitors of SOX13. We show that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics and chemo- and immune-resistance. Zanamivir, reverts the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Here we show, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential.

The nematode Caenorhabditis elegans enhances tolerance to landfill leachate stress by increasing trehalose synthesis.

The burgeoning issue of landfill leachate, exacerbated by urbanization, necessitates evaluating its biological impact, traditionally overshadowed by physical and chemical assessments. This study harnesses Caenorhabditis elegans, a model organism, to elucidate the physiological toxicity of landfill leachate subjected to different treatment processes: nanofiltration reverse osmosis tail water (NFRO), membrane bioreactor (MBR), and raw leachate (RAW). Our investigation focuses on the modulation of sugar metabolism, particularly trehalose-a disaccharide serving dual functions as an energy source and an anti-adversity molecule in invertebrates. Upon exposure, C. elegans showcased a 60-70% reduction in glucose and glycogen levels alongside a significant trehalose increase, highlighting an adaptive response to environmental stress by augmenting trehalose synthesis. Notably, trehalose-related genes in the NFRO group were up-regulated, contrasting with the MBR and RAW groups, where trehalose synthesis genes outpaced decomposition genes by 20-30 times. These findings suggest that C. elegans predominantly counters landfill leachate-induced stress through trehalose accumulation. This research not only provides insights into the differential impact of leachate treatment methods on C. elegans but also proposes a molecular framework for assessing the environmental repercussions of landfill leachate, contributing to the development of novel strategies for pollution mitigation and environmental preservation.

Metagenomics analysis reveals effects of salinity fluctuation on diversity and ecological functions of high and low nucleic acid content bacteria.

Salinity is a critical environmental factor in marine ecosystems and has complex and wide-ranging biological effects. However, the effects of changing salinity on diversity and ecological functions of high nucleic acid (HNA) and low nucleic acid (LNA) bacteria are not well understood. In this study, we used 16S rRNA sequencing and metagenomic sequencing analysis to reveal the response of HNA and LNA bacterial communities and their ecological functions to salinity, which was decreased from 26 ‰ to 16 ‰. The results showed that salinity changes had significant effects on the community composition of HNA and LNA bacteria. Among LNA bacteria, 14 classes showed a significant correlation between relative abundance and salinity. Salinity changes can lead to the transfer of some bacteria from HNA bacteria to LNA bacteria. In the network topology relationship, the complexity of the network between HNA and LNA bacterial communities gradually decreased with decreased salinity. The abundance of some carbon and nitrogen cycling genes in HNA and LNA bacteria varied with salinity. Overall, this study demonstrates the effects of salinity on diversity and ecological functions and suggests the importance of salinity in regulating HNA and LNA bacterial communities and functions.

Genomic and Transcriptomic Significance of Multiple Primary Lung Cancers Detected by Next-Generation Sequencing in Clinical Settings.

Effective diagnosis and understanding of the mechanism of intrapulmonary metastasis (IM) from multiple primary lung cancers (MPLC) aid clinical management. However, the actual detection panels used in the clinic are variable. Current research on tumor microenvironment (TME) of MPLC and IM is insufficient. Therefore, additional investigation into the differential diagnosis and discrepancies in TME between two conditions is crucial. 214 non-small cell lung cancer patients with multiple tumors were enrolled, and 507 samples were subjected to DNA sequencing (NGS 10). Then, DNA and RNA sequencing (master panel) were performed on the specimens from 32 patients, the TME profiles between tumors within each patient and across patients and the differentially expressed genes were compared. 4 patients were regrouped with NGS 10 results. Master panel resolved the classifications of 6 undetermined patients. The TME in MPLC exhibited a high degree of infiltration by natural killer (NK) cells, CD56dim NK cells, endothelial cells etc., P < 0.05. Conversely, B cells, activated B cells, regulatory cells, immature dendritic cells etc., P < 0.001, were heavily infiltrated in the IM. NECTIN4 and LILRB4 mRNA were downregulated in the MPLC (P < 0.0001). Additionally, NECTIN4 (P < 0.05) and LILRB4 were linked to improved disease-free survival in the MPLC. In conclusion, IM is screened from MPLC by pathology joint NGS 10 detections, followed by a large NGS panel for indistinguishable patients. A superior prognosis of MPLC may be associated with an immune-activating TME and the downregulation of NECTIN4 and LILRB4 considered as potential drug therapeutic targets.

Phycospheric bacteria limits the effect of nitrogen and phosphorus imbalance on diatom bloom.

Human activities have caused an imbalance in the input nitrogen and phosphorus (N/P) in the biosphere. The imbalance of N/P is one of the characteristics of water eutrophication, which is the fundamental factor responsible for the blooms. The effects of the N/P imbalance on diatom and phycospheric bacteria in blooms are poorly understood. In this study, the N/P molar ratio in real water (14:1) and the predicted N/P molar ratio in future water (65:1) were simulated to analyze the response of Cyclotella sp. and phycospheric bacteria to the N/P imbalance. The results showed that the N/P imbalance inhibited the growth of Cyclotella sp., but prolonged diatom bloom duration. The resistance of Cyclotella sp. to the N/P imbalance is related to phycospheric bacteria, and there are dynamic regulatory mechanisms within the phycospheric bacteria community to resist the N/P imbalance: (1) the increase of HNA bacterial density, the decrease of LNA bacterial density, (2) the increase of phycospheric bacterial diversity and eutrophic bacteria abundance, and the change of denitrifying bacteria abundance, (3) the activity of nitrogen and phosphorus metabolism of HNA bacteria enhanced, while that of LNA bacteria decreased. And the gene hosts of nitrogen and phosphorus metabolism were most enriched in Proteobacteria, indicating that Proteobacteria played an important role in maintaining the stability of phycospheric bacteria and was the dominant phylum resistant to the N/P imbalance. This study clarified that the algal-bacteria system was resistant to the N/P imbalance and implied that the N/P imbalance had little effect on the occurrence of diatom bloom events due to the presence of phycospheric bacteria.

Changes in water-soluble taste compounds of tilapia (Oreochromis niloticus) fillets subjected to different thawing methods during long-term frozen storage.

BACKGROUND: The taste of fish is highly dependent on the composition of free amino acids (FAAs) and nucleotides. The present study aimed to investigate the effect of long-term frozen storage periods (-18 °C, up to 6 months) and thawing methods [water thawing (WT, 25 °C), air thawing (AT, 25 °C), and chilled air thawing (CAT, 4 °C)] on the taste quality of tilapia (Oreochromis niloticus) fillets. RESULTS: The results showed that increase in bitter FAAs of CAT samples was 150.57% at 6 months of storage, which was lower than that of AT and WT. Glycine was the most abundant FAA and CAT maintained the highest sweet FAAs (249.90 mg/100 g). Additionally, the inosine monophosphate (IMP) of CAT samples were 1.18 and 1.09 times higher than that of WT and AT, respectively, at a frozen period of 6 months. In particular, the increase in equivalent umami concentration (EUC) values ranged from 24.25% to 103.16% in the three groups during the first 2 months. Data from principal component analysis (PCA) and orthogonal partial least-squares discrimination analysis (OPLS-DA) indicated that the taste quality was highly correlated with high levels of FAAs, hypoxanthine inosine (HxR) and hypoxanthine (Hx) as the storage time progressed. CONCLUSION: In general, CAT is beneficial in maintaining the taste quality of tilapia fillets during frozen storage, and frozen durations for 2 months enhances the umami flavor. This study provides useful information for the preservation of frozen aquatic products during the storage and thawing, and enrich the theoretical knowledge of the flavor chemistry of fish products. © 2024 Society of Chemical Industry.

Mechanical activation opens a lipid-lined pore in OSCA ion channels.

OSCA/TMEM63 channels are the largest known family of mechanosensitive channels1-3, playing critical roles in plant4-7 and mammalian8,9 mechanotransduction. Here we determined 44 cryogenic electron microscopy structures of OSCA/TMEM63 channels in different environments to investigate the molecular basis of OSCA/TMEM63 channel mechanosensitivity. In nanodiscs, we mimicked increased membrane tension and observed a dilated pore with membrane access in one of the OSCA1.2 subunits. In liposomes, we captured the fully open structure of OSCA1.2 in the inside-in orientation, in which the pore shows a large lateral opening to the membrane. Unusually for ion channels, structural, functional and computational evidence supports the existence of a 'proteo-lipidic pore' in which lipids act as a wall of the ion permeation pathway. In the less tension-sensitive homologue OSCA3.1, we identified an 'interlocking' lipid tightly bound in the central cleft, keeping the channel closed. Mutation of the lipid-coordinating residues induced OSCA3.1 activation, revealing a conserved open conformation of OSCA channels. Our structures provide a global picture of the OSCA channel gating cycle, uncover the importance of bound lipids and show that each subunit can open independently. This expands both our understanding of channel-mediated mechanotransduction and channel pore formation, with important mechanistic implications for the TMEM16 and TMC protein families.

DIREN mitigates DSS-induced colitis in mice and attenuates collagen deposition via inhibiting the Wnt/ß-catenin and focal adhesion pathways.

BACKGROUND: DIREN is a SHE ethnic medicine with stasis-resolving, hemostasis, clearing heat, and removing toxin effects. It is clinically used in the treatment of gastrointestinal bleeding, such as ulcerative colitis (UC). AIM OF THE STUDY: Fibrosis is one of the pathological changes in the progression of UC, which can make it challenging to respond to a treatment. We aimed to illuminate the role of DIREN in DSS-induced UC and tried to unveil its related mechanisms from two perspectives: intestinal inflammation and collagen deposition. MATERIALS AND METHODS: A 2.5 % dextran sulfate sodium (DSS) water solution was used to induce colitis in mice. The therapeutic effect of DIREN was assessed using the disease activity index, histopathological score, and colon length. Masson and Sirius Red staining was used to observe the fibrosis in the colon. Apoptosis of colonic epithelial cells was observed by TUNEL immunofluorescence staining. RNA-seq observed differential genes and enrichment pathways. Immunohistochemistry and RT-qPCR were used to detect the expression of molecules related to fibrosis and focal adhesion signaling in colon tissue. RESULTS: The administration of DIREN resulted in a reduction of disease activity index (DAI) in mice with UC while simultaneously promoting an increase in colon length. DIREN mitigated the loss of goblet cells in the colon of UC mice and maintained the integrity of the intestinal mucosa barrier. Masson staining revealed a reduction in colonic fibrosis with DIREN treatment, while Sirius red staining demonstrated a decrease in collagen Ⅰ deposition. DIREN reduced apoptosis of colonic epithelial cells and the expression of genes, such as CDH2, ITGA1, and TGF-ß2. Additionally, the results of GSEA analysis of colon tissue transcriptome showed that the differentially expressed genes were enriched in the focal adhesion pathway. DIREN was found to downregulate the protein expression of BAX, N-cadherin, ß-catenin, Integrin A1, and Vinculin while upregulating the protein expression of BCL2. Additionally, it led to the co-expression of N-cadherin and α-SMA. CONCLUSION: DIREN exerts a protective effect against DSS-induced UC by ameliorating colonic fibrosis via regulation of focal adhesion and the WNT/ß-catenin signaling pathway, thereby inhibiting fibroblast migration and reducing collagen secretion.