A CARM1 Inhibitor Potently Suppresses Breast Cancer Both In Vitro and In Vivo.

CARM1, belonging to the protein arginine methyltransferase (PRMT) family, is intricately associated with the progression of cancer and is viewed as a promising target for both cancer diagnosis and therapy. However, the number of specific and potent CARM1 inhibitors is limited. We herein discovered a CARM1 inhibitor, iCARM1, that showed better specificity and activity toward CARM1 compared to the known CARM1 inhibitors, EZM2302 and TP-064. Similar to CARM1 knockdown, iCARM1 suppressed the expression of oncogenic estrogen/ERα-target genes, whereas activated type I interferon (IFN) and IFN-induced genes (ISGs) in breast cancer cells. Consequently, iCARM1 potently suppressed breast cancer cell growth both in vitro and in vivo. The combination of iCARM1 with either endocrine therapy drugs or etoposide demonstrated synergistic effects in inhibiting the growth of breast tumors. In summary, targeting CARM1 by iCARM1 effectively suppresses breast tumor growth, offering a promising therapeutic approach for managing breast cancers in clinical settings.

Effects of probiotic supplementation on 12 min run performance, mood management, body composition and gut microbiota in amateur marathon runners: A double-blind controlled trial.

Background: Probiotic supplementation has a positive effect on endurance exercise performance and body composition in athletes, but the underlying mechanisms remain unclear. Gut microbiota can provide measurable markers of immune function in athletes, and microbial composition analysis may be sensitive enough to detect stress and metabolic disorders caused by exercise. Methods: Nineteen healthy active amateur marathon runners (15 male and 4 female) with a mean age of 29.11 years volunteered to participate in this double-blind controlled study. Based on the performance of the Cooper 12-min running test (CRT), the participants were allocated into two groups to receive either a probiotic formulation comprising lactobacillus acidophilus and bifidobacterium longum (n = 10) or placebo containing maltodextrin (n = 9) for five weeks. Consistency of diet and exercise was ensured throughout the experimental period. Before and after the intervention, all participants were assessed for CRT, emotional stability and gastrointestinal symptoms, gut microbiota composition, body composition and magnetic resonance imaging (MRI) indicators of skeletal muscle microcirculation. Results: Compared to before the intervention, the probiotics group showed an increase in CRT score (2.88 ± 0.57 vs 3.01 ± 0.60 km, P＜0.05), significant improvement in GSRS and GIQLI (9.20 ± 4.64 vs 7.40 ± 3.24, 118.90 ± 12.30 vs 127.50 ± 9.85, P＜0.05), while these indicators remained unchanged in the control group, with a significant time-group interaction effect on gastrointestinal symptoms. Additionally, some MRI metabolic cycling indicators of the thigh skeletal muscle also changed in the probiotics group (P＜0.05). Regarding microbiota abundance, the probiotics group exhibited a significant increase in the abundance of beneficial bacteria and a significant decrease in the abundance of harmful bacteria post-intervention (P＜0.05). Conclusion: As a sports nutritional supplement, probiotics have the potential to improve athletic performance by optimizing the balance of gut microbiota, alleviating gastrointestinal symptoms.

The Influence of CD40/CD40L, MMP2/MMP9 on Uterine Artery Blood Flow and Their Expression in Recurrent Miscarriage.

Objective: This study aims to investigate the expression levels of soluble CD40L (sCD40L), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) in the serum of patients experiencing recurrent abortion and their impact on uterine artery blood flow. Methods: A cohort of 200 patients with recurrent abortion was selected for this investigation. The levels of sCD40L, MMP2, and MMP9 in serum were assessed using ELISA, while ultrasound was employed to measure the pulsatility index (PI) and resistance index (RI) in uterine artery blood flow. Pregnancy outcomes were observed, and the expression of CD40/CD40L and MMP2/MMP9 in villi tissues was compared between patients experiencing recurrent abortion failure and those with normal pregnancies. Results: In the successful pregnancy group of patients with recurrent spontaneous abortion (RSA), serum levels of sCD40L, MMP2, and MMP9 were significantly lower than those in the failed pregnancy group. Additionally, both RI and PI were notably reduced. The expression of each gene showed a correlation with RI and PI. Furthermore, the expression levels of CD40, CD40L, MMP2, and MMP9 in the pregnancy failure group were significantly higher than in the normal voluntary termination group. Conclusion: Serum levels of sCD40L, MMP2, and MMP9, along with non-invasive and easily accessible indicators such as PI and RI in uterine artery blood flow measured by ultrasound, emerge as potential predictive markers for the outcome of recurrent miscarriage pregnancies. Moreover, these indicators can serve as valuable evaluation markers in clinical practice, facilitating the monitoring of treatment effectiveness for recurrent miscarriage.

Exploration of the Amino Acid Metabolic Profiling and Pathway in Clonorchis sinensis-Infected Rats Revealed by the Targeted Metabolomic Analysis.

Background: Clonorchiasis remains a serious public health problem. However, the molecular mechanism underlying clonorchiasis remains largely unknown. Amino acid (AA) metabolism plays key roles in protein synthesis and energy sources, and improves immunity in pathological conditions. Therefore, this study aimed to explore the AA profiles of spleen in clonorchiasis and speculate the interaction between the host and parasite. Methods: Here targeted ultrahigh performance liquid chromatography multiple reaction monitoring mass spectrometry was applied to discover the AA profiles in spleen of rats infected with Clonorchis sinensis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis (KEGG) was performed to characterize the dysregulated metabolic pathways. Results: Pathway analysis revealed that phenylalanine, tyrosine, and tryptophan biosynthesis and ß-alanine metabolism were significantly altered in clonorchiasis. There were no significant correlations between 14 significant differential AAs and interleukin (IL)-1ß. Although arginine, asparagine, histidine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine were positively correlated with IL-6, IL-10, tumor necrosis factor (TNF)-α as well as aspartate aminotransferase and alanine aminotransferase; ß-alanine and 4-hydroxyproline were negatively correlated with IL-6, IL-10, and TNF-α. Conclusion: This study reveals the dysregulation of AA metabolism in clonorchiasis and provides a useful insight of metabolic mechanisms at the molecular level.

Comparison of the efficacy between the dual therapy of tegoprazan and the quadruple therapy of tegoprazan: A randomized, controlled, multicenter study.

INTRODUCTION: Tegoprazan (TPZ), a potassium-competitive acid blocker, exerts a strong acid-suppression effect and a rapid onset of action. However, research on TPZ-amoxicillin (TA) dual treatment is limited. Here, we compared the safety and efficacy of TPZ-amoxicillin dual treatment and TPZ, bismuth potassium citrate, amoxicillin, and clarithromycin (TBAC) quadruple therapy in patients newly diagnosed with H. pylori infection over a 14-day treatment period. METHODS: A total of 236 patients newly diagnosed with H. pylori were enrolled in this multi-center, prospective, open-label, and randomized controlled study. Patients randomly received either TA dual or TBAC quadruple therapy. The incidence of adverse reactions and treatment compliance were recorded and then analyzed. RESULTS: The intention-to-treat analysis revealed that H. pylori-eradication rates were 83.9% (95% confidence interval [CI] 78.2%-91.3%) and 81.4% (95% CI 74.2%-88.5%) for the TA and TBAC groups, respectively, with no statistically significant difference between them (P = 0.606). The per-protocol analysis revealed that the H. pylori-eradication rates were 88.3% and 84.8% for the TA and TBAC groups, respectively (P = 0.447). The incidence of adverse reactions was significantly lower in the TA group than in the TBAC group (4.2% vs. 15.3%, P = 0.004). Moreover, the TA group demonstrated substantially higher treatment compliance than the TBAC group (94.1% vs. 89.0%, P = 0.020). CONCLUSION: The TA dual therapy successfully eradicated H. pylori with a high eradication rate and a low incidence of adverse reactions. Therefore, this treatment is recommended as an alternative course for patients newly diagnosed with H. pylori infection.

Apoptotic Bodies Derived from Fibroblast-Like Cells in Subcutaneous Connective Tissue Inhibit Ferroptosis in Ischaemic Flaps via the miR-339-5p/KEAP1/Nrf2 Axis.

Preventing and treating avascular necrosis at the distal end of the flaps are critical to surgery success, but current treatments are not ideal. A recent study shows that apoptotic bodies (ABs) generated near the site of apoptosis can be taken up and promote cell proliferation. The study reveals that ABs derived from fibroblast-like cells in the subcutaneous connective tissue (FSCT cells) of skin flaps promoted ischaemic flap survival. It is also found that ABs inhibited cell death and oxidative stress and promoted M1-to-M2 polarization in macrophages. Transcriptome sequencing and protein level testing demonstrated that ABs promoted ischaemic flap survival in endothelial cells and macrophages by inhibiting ferroptosis via the KEAP1-Nrf2 axis. Furthermore, microRNA (miR) sequencing data and in vitro and in vivo experiments demonstrated that ABs inhibited KEAP1 by delivering miR-339-5p to exert therapeutic effects. In conclusion, FSCT cell-derived ABs inhibited ferroptosis, promoted the macrophage M1-to-M2 transition via the miR-339-5p/KEAP1/Nrf2 axis and promoted ischaemic flap survival. These results provide a potential therapeutic strategy to promote ischaemic flap survival by administering ABs.

[Clinical value of high frequency ultrasound in the diagnosis of hip joint involvement in patients with ankylosing spondylitis].

OBJECTIVE: To analyze the correlation between hip joint musculoskeletal ultrasound score and ankylosing spondylitis (AS) disease activity, as well as to investigate the value of high frequency ultrasound in the assessment of hip joint involvement in AS. METHODS: The clinical data of 244 patients with AS who were treated in the rheumatology department of from March 2019 to March 2022 were retrospectively analyzed. Among them, there 174 males and 70 females, aged from 19 to 58 years old with an average of (34.22±9.49) years old;the disease duration of AS patients ranged from 8 months to 26 years, with an average of (13.68±4.04) years.The 244 patients were divided into disease group (83 cases) and control group (161 cases) based in the presence of hip joint involuement. According to the the disease activity, patients in the disease group were further categorezed into active phase (45 cases) and stable phase (38 cases). The ultrasound scores of patients in the active and stable phases of the disease group and the control group were compared. Relevant factors of hip joint involvement in AS patients were analyzed, and analyze the correlation between ultrasound score and Bath ankylosing spondylitis disease activity score index(BASDAI), Bath ankylosing spondylitis functional index(BASFI), visual analogue score of pain (VAS), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and the correlation between hip joint capsule score and tendon attachment end score and BASDAI, BASFI, VAS, CRP and ESR. RESULTS: The hip joint capsule score(3.06±1.12), femoral head score(1.45±0.43), tendon attachment end score(3.28±1.30) and total ultrasound score(6.65±2.31) of the disease group were higher than those of the control group(1.51±0.48)、(0.66±0.27)、(1.61±0.53)、(3.81±1.44)scores (P<0.05). Multifactor Logstic regression analysis showed that the course of disease, hip joint capsule score and total ultrasound score were independent risk factors for hip involvement in AS patients.The hip capsule score (3.65±1.22)and total ultrasound score(8.28±2.33) in the active phase of the disease group were higher than those in the stable phase (2.48±1.04)、( 6.82±1.96)scores(P<0.05). The hip joint capsule score and total ultrasonic score of AS patients were positively correlated with BASDAI, BASFI, VAS, CRP, and ESR (P<0.05, P<0.01).The score of tendon attachment end was positively correlated with CRP (P<0.05). The score of joint capsule effusion in AS patients was positively correlated with BASDAI, BASFI and VAS (P<0.05, P<0.01). The synovial blood flow score was positively correlated with BASDAI, VAS, CRP and ESR (P<0.05, P<0.01). The synovial thickening score was positively correlated with BASDAI, BASFI, VAS, CRP and ESR (P<0.05, P<0.01). There was no correlation between the score of tendon attachment end and BASDAI, BASFI, VAS, CRP and ESR. CONCLUSION: There is a correlation between hip joint ultrasonic score of hip joint and clinical indexes in AS patients.Hip joint capsule score and total ultrasonic score were independent risk factors for hip involvement in AS patients. High frequency ultrasound exhibits clinical value in the diagnosis of hip joint involvement in AS patients.

CARM1 hypermethylates the NuRD chromatin remodeling complex to promote cell cycle gene expression and breast cancer development.

Protein arginine methyltransferase CARM1 has been shown to methylate a large number of non-histone proteins, and play important roles in gene transcriptional activation, cell cycle progress, and tumorigenesis. However, the critical substrates through which CARM1 exerts its functions remain to be fully characterized. Here, we reported that CARM1 directly interacts with the GATAD2A/2B subunit in the nucleosome remodeling and deacetylase (NuRD) complex, expanding the activities of NuRD to include protein arginine methylation. CARM1 and NuRD bind and activate a large cohort of genes with implications in cell cycle control to facilitate the G1 to S phase transition. This gene activation process requires CARM1 to hypermethylate GATAD2A/2B at a cluster of arginines, which is critical for the recruitment of the NuRD complex. The clinical significance of this gene activation mechanism is underscored by the high expression of CARM1 and NuRD in breast cancers, and the fact that knockdown CARM1 and NuRD inhibits cancer cell growth in vitro and tumorigenesis in vivo. Targeting CARM1-mediated GATAD2A/2B methylation with CARM1 specific inhibitors potently inhibit breast cancer cell growth in vitro and tumorigenesis in vivo. These findings reveal a gene activation program that requires arginine methylation established by CARM1 on a key chromatin remodeler, and targeting such methylation might represent a promising therapeutic avenue in the clinic.

Oxidation Behavior of Pre-Strained Polycrystalline Ni3Al-Based Superalloy.

The harsh service environment of aeroengine hot-end components requires superalloys possessing excellent antioxidant properties. This study investigated the effect of pre-strain on the oxidation behavior of polycrystalline Ni3Al-based superalloys. The growth behaviors of oxidation products were analyzed by scanning electron microscope, transmission electron microscope, X-ray Photoelectron Spectroscopy and Raman spectroscopy. The results indicated that the 5% pre-strained alloys exhibited lower mass gain, shallower oxidation depth and more compact oxide film structures compared to the original alloy. This is mainly attributed to the formation of rapid diffusion paths for Al atoms diffusing to the surface under 5% pre-strain, which promotes the faster formation of protective Al2O3 film while continuing to increase the pre-strain to 25% results in less protective transient oxidation behavior being aggravated due to the increase in dislocation density within the alloy, which prevents the timely formation of the protective Al2O3 film, resulting in uneven oxidation behavior on the alloy.

A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease.

IRAK4 is a critical mediator in NF-κB-regulated inflammatory signaling and has emerged as a promising therapeutic target for the treatment of autoimmune diseases; however, none of its inhibitors have received FDA approval. In this study, we identified a novel small-molecule IRAK4 kinase inhibitor, DW18134, with an IC50 value of 11.2 nM. DW18134 dose-dependently inhibited the phosphorylation of IRAK4 and IKK in primary peritoneal macrophages and RAW264.7 cells, inhibiting the secretion of TNF-α and IL-6 in both cell lines. The in vivo study demonstrated the efficacy of DW18134, significantly attenuating behavioral scores in an LPS-induced peritonitis model. Mechanistically, DW18134 reduced serum TNF-α and IL-6 levels and attenuated inflammatory tissue injury. By directly blocking IRAK4 activation, DW18134 diminished liver macrophage infiltration and the expression of related inflammatory cytokines in peritonitis mice. Additionally, in the DSS-induced colitis model, DW18134 significantly reduced the disease activity index (DAI) and normalized food and water intake and body weight. Furthermore, DW18134 restored intestinal damage and reduced inflammatory cytokine expression in mice by blocking the IRAK4 signaling pathway. Notably, DW18134 protected DSS-threatened intestinal barrier function by upregulating tight junction gene expression. In conclusion, our findings reported a novel IRAK4 inhibitor, DW18134, as a promising candidate for treating inflammatory diseases, including peritonitis and IBD.

Dihydrocapsaicin suppresses the STING-mediated accumulation of ROS and NLRP3 inflammasome and alleviates apoptosis after ischemia-reperfusion injury of perforator skin flap.

Avascular necrosis frequently occurs as a complication following surgery involving the distal perforator flap. Dihydrocapsaicin (DHC) can protect tissue from ischemia-reperfusion (I/R) injury, but its specific role in multizone perforator flaps remains unclear. In this study, the prospective target of DHC in the context of I/R injury was predicted using network pharmacology analysis. Flap viability was determined through survival area analysis, laser Doppler blood flow, angiograms, and histological examination. The expressions of angiogenesis, apoptosis, NLR family pyrin domain containing 3 (NLRP3) inflammasome, oxidative stress, and molecules related to cyclic guanosine monophosphate (GMP)-adenosine monophosphate synthase (cGAS)-interferon gene stimulant (STING) pathway were assessed using western blotting, immunofluorescence, TUNEL staining, and dihydroethidium (DHE) staining. Our finding revealed that DHC promoted the perforator flap survival, which involves the cGAS-STING pathway, oxidative stress, NLRP3 inflammasome, apoptosis, and angiogenesis. DHC induced oxidative stress resistance and suppressed the NLRP3 inflammasome, preventing apoptosis in vascular endothelial cells. Through regulation of STING pathway, DHC controlled oxidative stress in endothelial cells and NLRP3 levels in ischemic flaps. However, activation of the cGAS-STING pathway led to the accumulation of reactive oxygen species (ROS) and NLRP3 inflammasome, thereby diminishing the protective role of DHC. DHC enhanced the survival of multidomain perforator flaps by suppressing the cGAS-STING pathway, oxidative stress, and the formation of NLRP3 inflammasome. These findings unveil a potentially novel mechanism with clinical significance for promoting the survival of multidomain perforator flaps.

Lasiokaurin Regulates PLK1 to Induce Breast Cancer Cell G2/M Phase Block and Apoptosis.

Aim of the study: To investigate the anti-tumor effects of Lasiokaurin on breast cancer and explore its underlying molecular mechanism. Materials and methods: In this study, MTT assay, plate colony formation assays, soft agar assay, and EdU assay were employed to evaluate the anti-proliferation effects of LAS. Apoptosis and cell cycle distribution were detected by flow cytometry. The molecular mechanism was predicted by performing RNA sequencing and verified by using immunoblotting assays. Breast cancer organiods derived from patient-derived xenografts model and MDA-MB-231 xenograft mouse model were established to assess the effect of LAS. Results: Our study showed that LAS treatment significantly suppressed cell viability of 5 breast cancer cell lines, with the IC50 value of approximately 1-5 µM. LAS also inhibitied the clonogenic ability and DNA synthesis of breast cancer cells, Moreover, LAS induced apoptosis and G2/M cell cycle arrest in SK-BR-3 and MDA-MB-231 cells. Notably, transcriptomic analysis predicted the mechanistic involvement of PLK1 in LAS-suppressed breast cancer progression. Our experiment data further verified that LAS reduced PLK1 mRNA and protein expression in breast cancer, accompanied by downregulating CDC25C and AKT phosphorylation. Ultimately, we confirmed that LAS inhibit breast cancer growth via inhibiting PLK1 pathway in vivo. Conclusions: Collectively, our findings revealed that LAS inhibits breast cancer progression via regulating PLK1 pathway, which provids scientific evidence for the use of traditional Chinese medicine in cancer therapy.

Long noncoding RNA MALAT-1: A versatile regulator in cancer progression, metastasis, immunity, and therapeutic resistance.

Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that do not code for proteins but have been linked to cancer development and metastasis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) influences crucial cancer hallmarks through intricate molecular mechanisms, including proliferation, invasion, angiogenesis, apoptosis, and the epithelial-mesenchymal transition (EMT). The current article highlights the involvement of MALAT-1 in drug resistance, making it a potential target to overcome chemotherapy refractoriness. It discusses the impact of MALAT-1 on immunomodulatory molecules, such as major histocompatibility complex (MHC) proteins and PD-L1, leading to immune evasion and hindering anti-tumor immune responses. MALAT-1 also plays a significant role in cancer immunology by regulating diverse immune cell populations. In summary, MALAT-1 is a versatile cancer regulator, influencing tumorigenesis, chemoresistance, and immunotherapy responses. Understanding its precise molecular mechanisms is crucial for developing targeted therapies, and therapeutic strategies targeting MALAT-1 show promise for improving cancer treatment outcomes. However, further research is needed to fully uncover the role of MALAT-1 in cancer biology and translate these findings into clinical applications.

Oncogenic KRAS induces arginine auxotrophy and confers a therapeutic vulnerability to SLC7A1 inhibition in non-small cell lung cancer.

The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypo-acetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3 (HDAC3)-dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC.

Modeling and optimization of sporulation by Bacillus licheniformis BF-002 based on dynamics and recurrent neural networks.

Bacillus licheniformis is widely utilized in disease prevention and environmental remediation. Spore quantity is a critical factor in determining the quality of microbiological agents containing vegetative cells. To improve the understanding of Bacillus licheniformis BF-002 strain culture, a hybrid model integrating traditional dynamic modeling and recurrent neural network was developed. This model enabled the optimization of carbon/nitrogen source feeding rates, pH, temperature and agitation speed using genetic algorithms. Carbon and nitrogen source consumption in the optimal duplicate batches showed no significant difference compared to the control batch. However, the spore quantity in the broth increased by 16.2% and 35.2% in the respective duplicate batches. Overall, the hybrid model outperformed the traditional dynamic model in accurately tracking the cultivation dynamics of Bacillus licheniformis, leading to increased spore production when used for optimizing cultivation conditions.

LncRNA LUESCC promotes esophageal squamous cell carcinoma by targeting the miR-6785-5p/NRSN2 axis.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent gastrointestinal malignancies with high mortality worldwide. Emerging evidence indicates that long noncoding RNAs (lncRNAs) are involved in human cancers, including ESCC. However, the detailed mechanisms of lncRNAs in the regulation of ESCC progression remain incompletely understood. LUESCC was upregulated in ESCC tissues compared with adjacent normal tissues, which was associated with gender, deep invasion, lymph node metastasis, and poor prognosis of ESCC patients. LUESCC was mainly localized in the cytoplasm of ESCC cells. Knockdown of LUESCC inhibited cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth in vivo. Mechanistic investigation indicated that LUESCC functions as a ceRNA by sponging miR-6785-5p to enhance NRSN2 expression, which is critical for the malignant behaviors of ESCC. Furthermore, ASO targeting LUESCC substantially suppressed ESCC both in vitro and in vivo. Collectively, these data demonstrate that LUESCC may exerts its oncogenic role by sponging miR-6785-5p to promote NRSN2 expression in ESCC, providing a potential diagnostic marker and therapeutic target for ESCC patients.

The marine-derived compound TAG alleviates Parkinson's disease by restoring RUBCN-mediated lipid metabolism homeostasis.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and its prevalence is increasing. Currently, no effective therapies for PD exist. Marine-derived natural compounds are considered important resources for the discovery of new drugs due to their distinctive structures and diverse activities. In this study, tetrahydroauroglaucin (TAG), a polyketide isolated from a marine sponge, was found to have notable neuroprotective effects on MPTP/MPP+-induced neurotoxicity. RNA sequencing analysis and metabolomics revealed that TAG significantly improved lipid metabolism disorder in PD models. Further investigation indicated that TAG markedly decreased the accumulation of lipid droplets (LDs), downregulated the expression of RUBCN, and promoted autophagic flux. Moreover, conditional knockdown of Rubcn notably attenuated PD-like symptoms and the accumulation of LDs, accompanied by blockade of the neuroprotective effect of TAG. Collectively, our results first indicated that TAG, a promising PD therapeutic candidate, could suppress the accumulation of LDs through the RUBCN-autophagy pathway, which highlighted a novel and effective strategy for PD treatment.

Absolute and relative disparity mechanisms revealed by an equivalent noise analysis.

The precision of stereopsis and vergence are ultimately limited by internal binocular disparity noise. Here we propose an equivalent noise model with both global and local internal disparity noises to provide a unified explanation of both absolute and relative disparity thresholds. To test this model, we developed a psychophysical procedure to measure the equivalent internal disparity noise by adding external disparity noise to random-Gabor-patch stereograms. We used the method of constant stimuli to measure the minimum and maximum disparity thresholds (Dmin and Dmax) for both absolute and relative disparity. Consistent with previous studies, we found that Dmin thresholds are substantially worse for absolute disparity than for relative disparity. We tested three relative disparity mechanisms: (1) the difference between the monocular separations of targets projecting to the two eyes; (2) the direct measurement of relative disparity; and (3) the difference of absolute disparities of targets. Computing the difference of absolute disparities when detecting relative disparity, Mechanism 3 cancels global noise, resulting in a much lower relative Dmin threshold, and provides a reasonable fit to the experimental data. We also found that the presence of as much as 2400 arcsec of external disparity noise does not appear to affect the Dmax threshold. This observation suggests that Dmax is implicated in a mechanism that disregards the disparity variance of individual items, relying instead on the average disparity across all items, supporting the depth model proposed in our previous study (Ding & Levi, 2021), which posits distinct mechanisms governing Dmin and Dmax thresholds.

Enhanced sporulation of B. licheniformis BF-002 through automatic co-feeding of carbon and nitrogen sources.

Bacillus licheniformis formulations are effective for environmental remediation, gut microbiota modulation, and soil improvement. An adequate spore quantity is crucial for the activity of B. licheniformis formulations. This study investigated the synergistic effects of carbon/nitrogen source consumption and concentration on B. licheniformis BF-002 cultivation, with the aim of developing an automatic co-feeding strategy to enhance spore production. Initial glucose (10 g/L) and amino nitrogen (1.5 g/L) concentrations promote cell growth, followed by reduced glucose (2.0 g/L) and amino nitrogen (0.5 g/L) concentrations for sustained spore generation. The spore quantity reached 2.59 × 1010 CFU/mL. An automatic co-feeding strategy was developed and implemented in 5 and 50 L cultivations, resulting in spore quantities of 2.35 × 1010 and 2.86 × 1010 CFU/mL, respectively, improving by 6.81% and 30.00% compared to that with a fixed glucose concentration (10.0 g/L). The culture broth obtained at both the 5 and 50 L scales was spray-dried, resulting in bacterial powder with cell viability rates of 85.94% and 82.68%, respectively. Even after exposure to harsh conditions involving high temperature and humidity, cell viability remained at 72.80% and 69.89%, respectively. Employing the automatic co-feeding strategy increased the transcription levels of the spore formation-related genes spo0A, spoIIGA, bofA, and spoIV by 7.42%, 8.46%, 8.87%, and 9.79%, respectively. The proposed strategy effectively promoted Bacillus growth and spore formation, thereby enhancing the quality of B. licheniformis formulations.

One-year outcomes of wide antral cryoballoon ablation guided by high-density mapping vs. conventional cryoballoon ablation for atrial fibrillation: a propensity score-matched study.

Background: Pulmonary vein isolation with wide antral ablation leads to better clinical outcomes for the treatment of atrial fibrillation, but the isolation lesion is invisible in conventional cryoballoon ablation. In this study, we aim to investigate the efficacy of the wide pulmonary vein isolation technique that includes the intervenous carina region, guided by high-density mapping, compared with pulmonary vein isolation alone without the mapping system. Methods: We conducted a propensity score-matched comparison of 74 patients who underwent a wide cryoballoon ablation guided by high-density mapping (mapping group) and 74 controls who underwent conventional cryoballoon ablation in the same period (no-mapping group). The primary outcome was a clinical recurrence of documented atrial arrhythmias for >30 s during the 1-year follow-up. Results: Of 74 patients in the mapping group, residual local potential in the pulmonary vein antrum was found in 30 (40.5%) patients, and additional cryothermal applications were performed to achieve a wide pulmonary vein isolation. Compared with the no-mapping group, the use of the mapping system in the mapping group was associated with a longer fluoroscopic time (26.97 ± 8.07 min vs. 23.76 ± 8.36 min, P = 0.023) and greater fluoroscopic exposure [339 (IQR181-586) mGy vs. 224 (IQR133-409) mGy, P = 0.012]. However, no significant differences between the two groups were found in terms of procedural duration and left atrial dwell time (104.10 ± 18.76 min vs. 102.45 ± 21.01 min, P = 0.619; 83.52 ± 17.01 min vs. 79.59 ± 17.96 min, P = 0.177). The rate of 12-month freedom from clinical atrial arrhythmia recurrence was 85.1% in the mapping group and 70.3% in the no-mapping group (log-rank P = 0.029). Conclusion: Voltage and pulmonary vein potential mapping after cryoballoon pulmonary vein isolation can identify residual potential in the pulmonary vein antrum, and additional cryoablation guided by mapping leads to improved freedom from atrial arrhythmias compared with conventional pulmonary vein isolation without the mapping system. Clinical Trial Registration Number: ChiCTR2200064383.