Anxiety Disorders: Treatments, Models, and Circuitry Mechanisms.

Anxiety disorders are one of the most prevalent mental health conditions worldwide, imposing a significant burden on individuals affected by them and society in general. Current research endeavors aim to enhance the effectiveness of existing anxiolytic drugs and reduce their side effects through optimization or the development of new treatments. Several anxiolytic novel drugs have been produced as a result of discovery-focused research. However, many drug candidates that show promise in preclinical rodent model studies fail to offer any substantive clinical benefits to patients. This review provides an overview of the diagnosis and classification of anxiety disorders together with a systematic review of anxiolytic drugs with a focus on their targets, therapeutic applications, and side effects. It also provides a concise overview of the constraints and disadvantages associated with frequently administered anxiolytic drugs. Additionally, the study comprehensively reviews animal models used in anxiety studies and their associated molecular mechanisms, while also summarizing the brain circuitry related to anxiety. In conclusion, this article provides a valuable foundation for future anxiolytic drug discovery efforts.

PPARγ-mediated amelioration of lipid metabolism abnormality by kaempferol.

Kaempferol can exert biological functions by regulating various signaling pathways. This study evaluated the ameliorative effect of kaempferol on lipid accumulation using oleic acid and palmitic acid-treated HepG2 cells and high-fat diet mice. In vitro oil red O staining showed that kaempferol treatment improved lipid accumulation (p < 0.001 for TG content and p < 0.05 for TC content). Immunofluorescence, western blot analysis and RT-qPCR showed that kaempferol could promote nuclear translocation of PPARγ and reduce the expression of PPARγ, C/EBPß, and SREBP-1c. Dietary intervention with kaempferol could reduce the lipid accumulation in hepatocytes and inflammatory cell infiltration, as well as attenuated serum levels of IL-6 and TNF-α in HFD-fed mice (p < 0.001 for IL-6 and p < 0.01 for TNF-α at kaempferol 60 mg/kg/d). Meanwhile, histopathological examination revealed that there was no substantial damage or distinct inflammation lesions in organs at the experimental dose, including the heart, lung, kidney, and spleen. The aforementioned research findings can serve as references for further preclinical investigations on the potential of kaempferol to mitigate lipid accumulation.

CDH3 Is an Effective Serum Biomarker of Colorectal Cancer Distant Metastasis Patients.

Few robust biomarkers are available for distant metastatic colorectal cancer (CRC) patients. Aberrant high expression of CDH3 has been reported in advanced CRC patients, but the value of CDH3 as a biomarker for the diagnosis and prognosis of distant metastatic CRC patients remains to be evaluated. In this study, we explored the serum levels of CDH3 in different stages of CRC patients and sought to determine whether serum CDH3 serves as an independent biomarker for distant metastatic CRC patients. We analyzed the serum CDH3 levels by ELISA in a cohort of CRCs (n=96) and normal controls (n=28). We compared the serum CDH3 levels between normal controls and different stages of CRCs. As a potential diagnostic marker of distant metastatic CRC, the specificity and sensitivity of serum CDH3 were evaluated. Multivariate analysis was also performed to determine whether serum CDH3 was an independent risk factor. Moreover, the changes of serum CDH3 levels were monitored and analyzed before and after palliative chemotherapy. Serum levels of CDH3, CA24-2, CA19-9, CA72-4, and CEA were significantly elevated in distant metastatic CRCs. CA24-2 (r=0.24, P=0.01), CA19-9 (r=0.20, P=0.03), CA72-4 (r=0.64, P<0.0001), and CEA (r=0.31, P=0.0012) all had a certain correlation with CDH3. After three cycles of palliative chemotherapy, levels of CDH3, CA24-2, CA19-9, CA72-4, and CEA of partial response CRCs were reduced to 38.8% (95% confidence interval [CI]: 30.95%-53.77%), 57.73% (95% CI: 2.085%-73.83%), 50.33% (95% CI: 9.935%-79.42%), 74.74% (95% CI: 25.21%-88.00%), and 59.16% (95% CI: 12.65%-83.56%) of baseline, respectively. The areas under the receiver operating characteristic curves of CDH3, CA24-2, CA19-9, CA72-4, and CEA with chemotherapy response were 0.900, 0.597, 0.635, 0.608, and 0.507, respectively. Serum CDH3 is an effective serum biomarker for the diagnosis of distant metastatic CRCs and monitoring response to palliative chemotherapy in distant metastatic CRCs.

Effects of soy protein isolate interaction with brown rice starch on the multiscale structure of brown rice bread.

BACKGROUND: Gluten-free bread (GFB) has technical bottlenecks such as hard texture, rough taste and low nutrition in practical production. In order to solve these problems, this study used germinated brown rice starch as the main raw material, and investigated the effects of soybean isolate protein (SPI) on the multiscale structure of germinated brown rice starch and bread quality. RESULTS: A gluten-free rice bread process simulation system was established, and the interaction between SPI and starch in the simulation system was characterized. The result shows that the interaction forces between SPI and germinated brown rice starch were mainly represented by hydrogen bonds, and with the addition of SPI, the crystallinity of starch showed a downward trend. At the same time, when the amount of SPI was 3%, the appearance quality was the best and the specific volume of bread was 1.08 mL g-1. When the amount of SPI was 6%, the texture quality was the best. Compared with the bread without SPI, the hardness of the bread with 6% SPI was reduced by 0.13 times, the springiness was increased by 0.03 times, the color was the most vibrant, the L* value being 1.02 times the original, and the baking loss was reduced to 0.98 times the original. CONCLUSIONS: The interaction force between SPI and germinated brown rice starch and its effect on bread quality were clarified, and these results inform choices about providing a theoretical basis for the subsequent development of higher-quality GFB. © 2024 Society of Chemical Industry.

Cluster headache: understandings of current knowledge and directions for whole process management.

Cluster headache (CH) is a common primary headache that severely impacts patients' quality of life, characterized by recurrent, severe, unilateral headaches often centered around the eyes, temples, or forehead. Distinguishing CH from other headache disorders is challenging, and its pathogenesis remains unclear. Notably, patients with CH often experience high levels of depression and suicidal tendencies, necessitating increased clinical attention. This comprehensive assessment combines various reports and the latest scientific literature to evaluate the current state of CH research. It covers epidemiology, population characteristics, predisposing factors, and treatment strategies. Additionally, we provide strategic insights into the holistic management of CH, which involves continuous, individualized care throughout the prevention, treatment, and rehabilitation stages. Recent advances in the field have revealed new insights into the pathophysiology of CH. While these findings are still evolving, they offer a more detailed understanding of the neurobiological mechanisms underlying this disorder. This growing body of knowledge, alongside ongoing research efforts, promises to lead to the development of more targeted and effective treatments in the future.

Use of artificial intelligence algorithms to analyse systemic sclerosis-interstitial lung disease imaging features.

The use of artificial intelligence (AI) in high-resolution computed tomography (HRCT) for diagnosing systemic sclerosis-associated interstitial lung disease (SSc-ILD) is relatively limited. This study aimed to analyse lung HRCT images of patients with systemic sclerosis with interstitial lung disease (SSc-ILD) using artificial intelligence (AI), conduct correlation analysis with clinical manifestations and prognosis, and explore the features and prognosis of SSc-ILD. Overall, 72 lung HRCT images and clinical data of 58 patients with SSC-ILD were collected. ILD lesion type, location, and volume on HRCT images were identified and evaluated using AI. The imaging characteristics of diffuse SSC (dSSc)-ILD and limited SSc-ILD (lSSc-ILD) were statistically analysed. Furthermore, the correlations between lesion type, clinical indicators, and prognosis were investigated. dSSc and lSSc were more prevalent in patients with a disease duration of < 1 and ≥ 5 years, respectively. SSc-ILD mainly comprises non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), and unclassifiable idiopathic interstitial pneumonia. HRCT reveals various lesion types in the early stages of the disease, with an increase in the number of lesion types as the disease progresses. Lesions appearing as grid, ground-glass, and nodular shadows were dispersed throughout both lungs, while those appearing as consolidation shadows and honeycomb were distributed across the lungs. Ground-glass opacity lesion type was absent on HRCT images of patients with SSc-ILD and pulmonary hypertension. This study showed that AI can efficiently analyse imaging characteristics of SSc-ILD, demonstrating its potential to learn from complex images with high generalisation ability.

Methionine Improves Boar Sperm Quality by Promoting Mitochondrial Translation during Liquid Storage.

Boar sperm quality serves as an important indicator of reproductive efficiency, playing a direct role in enhancing the output of livestock production. It has been demonstrated that mitochondrial protein translation is present in sperm and plays a crucial role in regulating sperm motility, capacitation and in vitro fertilization rate. The present study aimed to determine whether methionine supplementation enhances mitochondrial translation in boar sperm, thereby improving sperm quality. The results showed a significant elevation in the abundance of mitochondrial methionyl-tRNA formyltransferase (MTFMT), a crucial enzyme for mitochondrial protein translation, and mitochondrial DNA-encoded cytochrome c oxidase subunit 1 (COX1) in boar sperm exhibiting high motility. Both amino acids and methionine supplementation significantly enhanced boar sperm motility during storage. Moreover, methionine supplementation mitigates the loss of acrosomal integrity, enhances the expression of COX1, and boosts mitochondrial activity. Furthermore, the positive impact of methionine was negated in the presence of the mitochondrial translation inhibitor chloramphenicol. Together, these findings suggest that boar sperm may utilize methionine as a protein translation substrate to enhance sperm motility by stimulating mitochondrial protein translation. The supplementation of methionine may enhance the quality of boar sperm, thereby providing guidance for the optimization of diluent formulations for liquid storage and the identification of physiological regulators that regulate sperm motility.

Primary intraspinal neuroendocrine tumor: A case report and literature review.

RATIONALE: Neuroendocrine tumors (NET) refer to a group of uncommon tumors arising in the neuroendocrine system. Most NETs occur in the digestive tract and bronchi but are rare in the central nervous system, especially in the spinal canal. NET in the central nervous system mainly metastasize from other systems, with non-specific clinical symptoms. In this study, we report the diagnosis and treatment of intraspinal NET to provide clinical guidance as well as to avoid misdiagnosis and missed diagnosis. PATIENT CONCERNS: A 59-year-old male patient, presented with recurrent right lower limb pain for half a year, accompanied by numbness and weakness for 4 months and aggravation for 2 months. Lumbar spine magnetic resonance imaging (MRI) revealed a space-occupying lesion in the spinal canal. The diagnosis of primary intraspinal NET was confirmed by topathological examination. DIAGNOSIS: Primary intraspinal NET tumor. INTERVENTIONS: Surgical resection. OUTCOMES: Significant improvements in right lower limb pain, numbness, and weakness were observed, and lumbar spine MRI was performed again to dynamically observe the changes in intraspinal NET. CONCLUSIONS: Surgical resection may be an effective treatment for intraspinal NETs. LESSONS: Intraspinal NETs are relatively rare and mostly manifest as limb numbness, weakness, and pain. Due to its nonspecific clinical symptoms, intraspinal NETs are easily misdiagnosed as lumbar disc herniation with radiculopathy and lumbar spondylolisthesis. Therefore, in patients with long-term symptoms, in addition to common lumbar neuromuscular diseases, lumbar MRI should be performed promptly to exclude the possibility of lumbar NETs.

A novel model based on serum N-glycan markers for evaluating stage of liver necroinflammation in treatment-naïve chronic hepatitis B patients.

This study aimed to establish a novel noninvasive model based on the serum N-glycan spectrum for providing an objective value for determining the stage of liver necroinflammation related to chronic hepatitis B (CHB) patients. N-glycan profiles of the sera of 295 treatment-naïve CHB patients were analyzed. N-glycan profiles were tested for different liver necroinflammation stages using DNA sequence-assisted fluorophore-assisted carbohydrate electrophoresis. A serum N-glycan model named N-glycan-LI (NGLI) using support vector machine was selected to evaluate the classification of liver necroinflammation (G < 2 and G ≥ 2). The area under the receiver operating characteristic curves (AUROCs) was 0.898 (training set, n = 236) and 0.911 (validation set, n = 59) regardless of the stage of liver fibrosis (AUROC = 0.886 and 0.926, respectively, in S < 2 and S ≥ 2 group). The NGLI correspondingly had the highest specificity (SP) of 90.79% and negative predictive value of 92.00% in an inactive stage (including immune-tolerant [IT] and inactive-carrier [IC] stage), had the highest positive predictive value of 95.18% in stage immune-active, and had the highest SP of 93.94% in grey zone IT + IC. N-glycan profiles appear to correlate well with hepatic necroinflammation in CHB when compared with liver biopsy. The newly developed model appears to reliably predict liver damage in naïve-treatment patients with CHB.

DNAJA1 regulates protein ubiquitination and is essential for spermatogenesis in the testes of mice and rats.

DNAJA1 is a member of type I DnaJ proteins, which is essential for spermatogenesis and male fertility. However, its expression pattern in the testes and its impact on spermatogenesis remains unclear. Our study aimed to elucidate the mechanism of action of DNAJA1. We employed DNAJA1 knockout mice in this study. Western blotting and immunofluorescence analysis were conducted to determine the protein abundance of DNAJA1 in testes at various developmental stages. Our results revealed that DNAJA1 is predominantly expressed in the testes, and its knockout leads to complete infertility in male mice. We observed that DNAJA1 protein levels increased on postnatal days 14, 21, and 28, peaking on postnatal day 35 in mice. Immunofluorescence staining indicated that DNAJA1 expression varies across different stages of the spermatogenesis cycle. Additionally, DNAJA1 was absent in epididymal sperm. In early- and mid-stage tubules, DNAJA1 protein distribution was co-localized with residual bodies in elongating spermatids. Furthermore, we found that DNAJA1 knockout significantly reduced protein polyubiquitination in the testis. Analysis of the GEO database showed that DNAJA1 levels were significantly decreased in semen samples from subjects with teratozoospermia, asthenozoospermia, and impaired spermatogenesis. Our findings suggest that DNAJA1 is an essential protein for spermatogenesis, and its deletion reduces protein polyubiquitination in the testis, ultimately resulting in infertility and spermatogenesis defects.

Functional hyaluronic acid microneedles for skin photoaging based on collagen induction and oxidative stress regulation strategies.

Photoaging holds remarkable importance for skin health and senescence. Ultraviolet (UV) irradiation results in the disruption of the extracellular matrix (ECM) microenvironment, the degradation of collagen, and the generation of oxidative stress. Traditional hyaluronic acid (HA) exhibits a diminished capacity to stimulate collagen regeneration, and hampered by its poor permeability as a macromolecule, ultimately resulting in constrained therapeutic outcomes for the treatment of photoaging. In this study, HA/PX was prepared by functional modification of HA with sulfonate-rich or phosphatidylcholine-rich polymers, which could complement the loss of ECM and ameliorate the senescence of human fibroblasts (HDFs) and hairless mouse models subjected to UVB-induced photoaging. The results indicate that HA/PX exhibits superior abilities in delaying cellular aging, promoting collagen regeneration, and resisting reactive oxygen species (ROS) compared to HA. Furthermore, HA/PX shows good biocompatibility both in vivo and in vitro, without causing allergic reactions or other adverse effects. We also demonstrated that the transdermal delivery of HA/PX via microneedle arrays (MNs) can significantly mitigate wrinkles and skin damage in photoaged nude mice, and achieve the treatment of skin photoaging by enhancing epidermal thickness, promoting collagen deposition, and reducing oxidative stress. Therefore, our research offers a novel possibility for future anti-aging therapeutic strategies.

Delimiting species, revealing cryptic diversity, and population divergence in Qinghai-Tibet Plateau weevils through DNA barcoding.

The Leptomias group represents one of the most diverse taxonomic group of weevils in the Qinghai-Tibet Plateau and its adjacent areas. Despite the potential of hidden diversity, relatively few comprehensive studies have been conducted on species diversity in this taxonomic group. In this study, we performed DNA barcoding analysis for species of the Leptomias group using a comprehensive DNA barcode dataset that included 476 sequences representing 54 morphospecies. Within the dataset, our laboratory contributed 474 sequences, and 390 sequences were newly generated for this study. The average Kimura 2-parameter distances among morphospecies and genera were 0.76% and 19.15%, respectively. In 94.4% of the species, the minimum interspecific distances exceeded the maximum intraspecific distances, indicating the presence of barcode gaps in most species of Leptomias group. The application of Automatic Barcode Gap Discovery, Assemble Species by Automatic Partitioning, Barcode Index Number, Bayesian Poisson tree processes, jMOTU, and Neighbor-joining tree methods revealed 45, 45, 63, 54, and 55 distinct clusters representing single species, respectively. Additionally, a total of four morphospecies, Leptomias kangmarensis, L. midlineatus, L. siahus, and L. sp.9RL, were found to be assigned to multiple subclade each, indicating the geographical divergences and the presence of cryptic diversity. Our findings of this study demonstrate that Qinghai-Tibet Plateau exhibits a higher species diversity of the Leptomias group, and it is imperative to investigate cryptic species within certain morphospecies using integrative taxonomic approaches in future studies. Moreover, the construction of a DNA barcode reference library presented herein establishes a robust foundational dataset to support forthcoming research on weevil taxonomy, phylogenetics, ecology, and evolution.

[Mongolian medicine Naru-3 reduces neuroinflammation in maintenance stage of neuropathic pain by inhibiting astrocyte activation].

Neuropathic pain(NP) is difficult to be treated since it has similar phenotypes but different pathogenesis in different pathological stages. Targeted intervention of the core regulatory elements at different pathological stages of NP has become a new direction of drug research and development in recent years and provides the possibility for the treatment of NP. The Mongolian medicine Naru-3(NR-3) is effective in the treatment of sciatica and trigeminal neuralgia, the mechanisms of which remain unknown. On the basis of the previous study of the priming stage, this study established the mouse model of spinal nerve ligation(SNL) and measured the changes of pain thresholds by behavioral tests. The network analysis, Western blot, immunofluorescence assay, ELISA, and agonist/antagonist were employed to decipher the mechanism of NR-3 in the treatment of NP in the maintenance stage. The results showed that NR-3 increased the mechanical and thermal pain thresholds of SNL mice, while it had no significant effect on the basal pain threshold of normal mice. NR-3 may relieve the pain in the maintenance stage of NP by blocking the matrix metalloproteinase 2(MMP2)/interleukin-1ß(IL-1ß) pathway in the astrocytes of the dorsal root ganglion(DRG) and spinal cord. The findings have enriched the biological connotation of NR-3 in the treatment of the maintenance stage of NP and provide reference for the rational use of this medicine in clinical practice.

Variation and Interaction of Distinct Subgenomes Contribute to Growth Diversity in Intergeneric Hybrid Fish.

Intergeneric hybridization greatly reshapes regulatory interactions among allelic and non-allelic genes. However, their effects on growth diversity remain poorly understood in animals. In this study, we conducted whole-genome sequencing and RNA sequencing (RNA-seq) analyses in diverse hybrid varieties resulting from the intergeneric hybridization of goldfish (Carassius auratus red var.) and common carp (Cyprinus carpio). These hybrid individuals were characterized by distinct mitochondrial genomes and copy number variations. Through a weighted gene correlation network analysis, we identified 3693 genes as candidate growth-regulated genes. Among them, the expression of 3672 genes in subgenome R (originating from goldfish) displayed negative correlations with growth rate, whereas 20 genes in subgenome C (originating from common carp) exhibited positive correlations. Notably, we observed intriguing patterns in the expression of slc2a12 in subgenome C, showing opposite correlations with body weight that changed with water temperatures, suggesting differential interactions between feeding activity and weight gain in response to seasonal changes for hybrid animals. In 40.31% of alleles, we observed dominant trans-regulatory effects in the regulatory interaction between distinct alleles from subgenomes R and C. Integrating analyses of allelic-specific expression and DNA methylation data revealed that the influence of DNA methylation on both subgenomes shapes the relative contribution of allelic expression to the growth rate. These findings provide novel insights into the interaction of distinct subgenomes that underlie heterosis in growth traits and contribute to a better understanding of multiple allele traits in animals.

Intranuclear Irradiation Inhibits Solid Tumor Growth by Upregulating Caspase8 and Activating Apoptosis.

Radioimmunotherapy (RIT) is a novel and promising cancer treatment method, with ongoing research focusing on RIT antibody selection, radionuclides, treatment options, and benefited patient groups. As we dive into the mechanisms of tumor biology, a deeper exploration of how RIT affects tumor tissue is needed to provide new ways to improve clinical treatment outcome and patient prognosis. We labeled the anti-PD-L1 monoclonal antibody atezolizumab with iodine-131 (131I), separated and purified the labeled mAb with Sephadex G-25 medium gel filtration resin, and tested product stability. We detected the in vivo activity of 131I-PD-L1 mAb by analyzing its in vivo biodistribution and performing SPECT imaging and then set different treatment groups to study the effect of 131I-atezolizumab on the survival of tumor-bearing mice. Western blot, real-time quantitative PCR, and immunohistochemistry were used to detect the expression level of Caspase8 and Nlrp3 in tumor. TUNEL fluorescence staining was used to detect the apoptosis in the tumor. The radiopharmaceutical molecular probe 131I-atezolizumab showed high stability and in vivo biological activity. The treatment regimen adopted had a positive effect on the survival of tumor-bearing mice. 131I internal irradiation upregulated Caspase8 in tumor and ultimately inhibited solid tumor growth by activating apoptosis pathways. We also found a significant increase in the expression of NLRP3, which plays an important role in the pyroptosis pathway, in tumor. In summary, our data demonstrated that radiopharmaceuticals combined with immunotherapy affected tumor tissue by modulating relevant biological pathways, thereby achieving better antitumor effects compared with single therapy and providing new insights for promoting better patient prognosis and combination treatment strategies.

PACAP/VIP in the prefrontal cortex mediates the rapid antidepressant effects of zhizichi decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhizichi decoction (ZZCD) is a traditional Chinese medicine formula that consists of Gardenia jasminoides J.Ellis (GJ) and Semen Sojae Praeparatum. It is used to treat insomnia and emotion-related disorders, such as irritability. Previous studies have found that GJ has a rapid antidepressant effect. The study found that ZZCD is safer than GJ at the same dosage. Consequently, ZZCD is a superior drug with quicker antidepressant effects than GJ. The rapid antidepressant effects of ZZCD were examined in this study, along with the components that make up this effect. It was determined that the activation of prefrontal Pituitary Adenylate Cyclase Activating Polypeptide (PACAP)/Vasoactive Intestinal Polypeptide (VIP) is essential for ZZCD's rapid antidepressant effects. AIM: This study identified and discussed the rapid antidepressant effects and biological mechanisms of ZZCD. MATERIALS AND METHODS: The tail suspension test (TST) and the forced swimming test (FST) were used to screen the effective dosage of ZZCD (0.67 g/kg, 1 g/kg, 4 g/kg). The effective dosage of ZZCD (1 g/kg) was tested in the TST conducted on Institute of Cancer Research (ICR) mice that were treated with lipopolysaccharide (LPS) at a concentration of 0.1 mg/mL. To confirm the expression of c-Fos, PACAP, and VIP in the prefrontal cortex (PFC), immunohistochemistry tests were conducted on mice following intragastric injection of ZZCD. Chemical characterization analysis and HPLC quality control analysis were conducted using UHPLC-Q-Obitrap-HRMS and chromatographic analysis. RESULTS: The results showed that an acute administration of ZZCD (1 g/kg) decreased the immobility time of Kunming (KM) mice in TST and FST. Depressive behaviors in TST-induced ICR mice treated with LPS (0.1 mg/mL) were reversed by ZZCD (1 g/kg). The results of immunohistochemical experiments showed that ZZCD (1 g/kg) activated neurons in the PFC and PACAP/VIP in the PFC. In this study, 22 substances in ZZCD were identified. Five primary distinctive fingerprint peaks-geniposide, genistin, genipin-1-ß-D-gentiobioside, glycitin, and daidzin-were found among the ten common peaks. CONCLUSION: ZZCD (1 g/kg) had significant rapid antidepressant effects. PACAP/VIP in the PFC was found to mediate the rapid antidepressant effects of ZZCD.

The AaBBX21-AaHY5 module mediates light-regulated artemisinin biosynthesis in Artemisia annua L.

The sesquiterpene lactone artemisinin is an important anti-malarial component produced by the glandular secretory trichomes of sweet wormwood (Artemisia annua L.). Light was previously shown to promote artemisinin production, but the underlying regulatory mechanism remains elusive. In this study, we demonstrate that ELONGATED HYPOCOTYL 5 (HY5), a central transcription factor in the light signaling pathway, cannot promote artemisinin biosynthesis on its own, as the binding of AaHY5 to the promoters of artemisinin biosynthetic genes failed to activate their transcription. Transcriptome analysis and yeast two-hybrid screening revealed the B-box transcription factor AaBBX21 as a potential interactor with AaHY5. AaBBX21 showed a trichome-specific expression pattern. Additionally, the AaBBX21-AaHY5 complex cooperatively activated transcription from the promoters of the downstream genes AaGSW1, AaMYB108, and AaORA, encoding positive regulators of artemisinin biosynthesis. Moreover, AaHY5 and AaBBX21 physically interacted with the A. annua E3 ubiquitin ligase CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1). In the dark, AaCOP1 decreased the accumulation of AaHY5 and AaBBX21 and repressed the activation of genes downstream of the AaHY5-AaBBX21 complex, explaining the enhanced production of artemisinin upon light exposure. Our study provides insights into the central regulatory mechanism by which light governs terpenoid biosynthesis in the plant kingdom.

Alterations of mouse gut microbiome in alveolar echinococcosis.

Alveolar echinococcosis (AE) may affect the composition of the host's gut microbiota, potentially disrupting the balance between the gut microbiota and metabolites. Metagenomics and untargeted metabolomics were employed to characterize changes in the gut microbiota and metabolites in mouse models infected with E. multilocularis. Pearson correlation coefficients were calculated to compare the distribution of microbiota and metabolites, revealing synergistic or mutually exclusive relationships. Functional outputs of the gut microbiota were explored using the CAZy database and six enzymes involved in carbohydrate metabolism were identified with statistically significant differential expression between infected and control groups. The resistome was characterized by identifying antibiotic resistance genes annotated in the Comprehensive Antibiotic Resistance Database from the metagenomes of the groups. Firmicutes are the main carrier of ARGs in the host gut with tetQ being most prevalent. Antibiotic efflux, inactivation and target modification were the principal mechanisms of resistance. Comparison and analysis of two sets of antibiotic metabolic pathways allowed the identification of enzyme reactions unique to infected mice. KEGG pathway overview shows phenazine biosynthesis involving phzG to be one of them. In conclusion, infection with AE in mice leads to an overall disruption of gut microbiota and metabolites with the involvement of enzymes related to carbohydrate metabolism. Furthermore, antibiotic-resistance genes may play a role in disease progression, offering potential insights into the relationship between antibiotic use in AE and treatment outcomes.

An Integrated Multi-omics prediction model for stroke recurrence based on Lnet transformer layer and dynamic weighting mechanism.

BACKGROUND AND OBJECTIVE: Stroke is a disease with high mortality and disability. Importantly, the fatality rate demonstrates a significant increase among patients afflicted by recurrent strokes compared to those experiencing their initial stroke episode. Currently, the existing research encounters three primary challenges. The first is the lack of a reliable, multi-omics image dataset related to stroke recurrence. The second is how to establish a high-performance feature extraction model and eliminate noise from continuous magnetic resonance imaging (MRI) data. The third is how to integration multi-omics data and dynamically weighted for different omics data. METHODS: We systematically compiled MRI and conventional detection data from a cohort comprising 737 stroke patients and established PSTSZC, a multi-omics dataset for predicting stroke recurrence. We introduced the first-ever Integrated Multi-omics Prediction Model for Stroke Recurrence, MPSR, which is based on ResNet, Lnet-transformer, LSTM and dynamically weighted DNN. The MPSR model comprises two principal modules, the Feature Extraction Module, and the Integrated Multi-Omics Prediction Module. In the Feature Extraction module, we proposed a novel Lnet regularization layer, which effectively addresses noise issues in MRI data. In the Integrated Multi-omics Prediction Module, we propose a dynamic weighted mechanism based on evaluators, which mitigates the noise impact brought about by low-performance omics. RESULTS: We compared seven single-omics models and six state-of-the-art multi-omics stroke recurrence models. The experimental results demonstrate that the MPSR model exhibited superior performance. The accuracy, AUROC, specificity, and sensitivity of the MPSR model can reach 0.96, 0.97, 1, and 0.94, respectively, which is higher than the results of contrast model. CONCLUSION: MPSR is the first available high-performance multi-omics prediction model for stroke recurrence. We assert that the MPSR model holds the potential to function as a valuable tool in assisting clinicians in accurately diagnosing individuals with a predisposition to stroke recurrence.

Identification of the Clinical Candidate PF-07284890 (ARRY-461), a Highly Potent and Brain Penetrant BRAF Inhibitor for the Treatment of Cancer.

Mutant BRAFV600E is one of the most common oncogenic drivers in metastatic melanoma. While first generation BRAFV600E inhibitors are capable of controlling tumors systemically, they are unable to adequately treat tumors that have metastasized to the brain due to insufficient penetration across the blood-brain barrier (BBB). Through a combination of structure-based drug design (SBDD) and the optimization of physiochemical properties to enhance BBB penetration, we herein report the discovery of the brain-penetrant BRAFV600E inhibitor PF-07284890 (ARRY-461). In mice studies, ARRY-461 proved to be highly brain-penetrant and was able to drive regressions of A375 BRAFV600E tumors implanted both subcutaneously and intracranially. Based on compelling preclinical safety and efficacy studies, ARRY-461 was progressed into a Phase 1 A/B clinical trial (NCT04543188).