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Abstract Background Recent years, exosomes have been increasing used to treat diseases, but there is little research on how exosomes affect the metabolism of the body after entering. Therefore, in this study, we discussed the changes of metabolic spectrum and determined the differentially expressed metabolites in the serum of cynomolgus monkeys after injecting exosomes. Six cynomolgus monkeys were divided into control group and exosomes group. After intravenous injection of exosomes, the peripheral blood serum of cynomolgus monkeys was collected at baseline, day 1, day 7 and day 14 respectively. An ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based non-targeted metabolomics platform was used to detect the metabolites. The metabolic spectra of two groups of cynomolgus monkeys were identified and compared, and the time series changes of metabolites in exosomes were described. Results The results showed that there was significant difference in metabolic spectrum between the two groups. 45, 114, 49, 39 differentially expressed metabolites were identified in baseline, day 1, day 7, and day 14, respectively. 6-hydroxydopamine, a metabolite related to the regulation of nerve function, was also found. Tryptophan metabolism, choline metabolism in cancer, porphyrin and chlorophyll metabolism were involved in day 1. Sphingolipid metabolism and histidine metabolism were involved in day 7. Three pathways, including choline metabolism, sphingolipid metabolism and biotin metabolism in cancer were involved in day 14. Through time series analysis, it was found that the level of propionylcarnitine and biliverdin increased on day 1 after inoculation with exosomes, while the level of hippuric acid decreased. These changes of immune-related metabolites suggested that exosomes might participate in the immunoregulation reaction after entering the body of cynomolgus monkeys. Conclusions In our current study, we found that exosomes injected intravenously affect the changes of metabolites and metabolic pathways in cynomolgus monkeys. Intravenous injection of exosomes may affect the metabolite 6-hydroxydopamine, sphingolipid metabolic pathway, and choline metabolic in cancer pathway, which is of some significance for the treatment of Parkinson’s disease. In addition, exosomes may also affect the immune-related metabolites in vivo, such as propionylcarnitine, biliverdin, hippuric acid metabolites, as well as tryptophan metabolism pathway, sphingolipid metabolism pathway involved in immune regulation, which is of great significance for the future study of immune-regulatory mechanisms of exosomes.

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma which possess highly aggressive and heterogeneous. Despite advances in understanding heterogeneity and development of novel targeted agents, the prognosis of DLBCL patients remains unsatisfied. Lipids are crucial components of biological membranes and signal transduction while accumulating evidence has supported the vital roles of abnormal lipid metabolism in tumorigenesis. Furthermore, some related pathways could serve as prognostic biomarkers and potential therapeutic targets. However, the clinical significance of abnormal lipid metabolism reprogramming in DLBCL has not been investigated. In the current study, we developed a prognostic risk model for DLBCL based on the abnormal expressed lipid metabolism genes and moreover based on our risk model we classified patients with DLBCL into novel subtypes and identified potential drugs for DLBCL patients with certain lipid metabolism profiles. Methods We utilized univariate Cox regression analysis to identify the prognosis-related lipid metabolism genes, and then performed LASSO Cox regression to identify prognostic related lipid metabolism related genes. Multivariate cox regression was used to establish the prognostic model. Patients were divided in to high and low risk groups based on the median risk score. Immune cell infiltration and GSEA were used to identify the pathways between high and low risk groups. Oncopredict algorithm was utilized to identify potential drug for high-risk patients. In vitro cell apoptosis and viability analysis were employed to verify the specific tumor inhibition effects of AZD5153. Results Nineteen survival related lipid metabolism genes TMEM176B, LAYN, RAB6B, MMP9, ATAD3B, SLC2A11, CD3E, SLIT2, SLC2A13, SLC43A3, CD6, SIRPG, NEK6, LCP2, CTTN, CXCL2, SNX22, BCL6 and FABP4 were identified and subjected to build the prognostic model which was further verified in four external microarray cohorts and one RNA seq cohorts. Tumor immune microenvironment analysis and GSEA results showed that the activation of MYC targets genes rather than immunosuppression contribute to the poor survival outcome of patients in the high-risk group. AZD5153, a novel bivalent BET bromodomain inhibitor which could inhibit the transcription of MYC and E2F exhibited specific antitumor function for cells with high-risk score. Conclusions Our results provide the first lipid metabolism-based gene signature for predicting the survival of patients with DLBCL. Furthermore, by determining novel subtypes with our lipid metabolism prognostic model we illustrated that drugs that compromising MYC target genes rather than immune checkpoint inhibitors may be beneficial to DLBCL patients with certain lipid metabolism profiles.

Abstract This case report presents a notable instance of subcutaneous implantable cardioverter defibrillator (S-ICD) implantation in a 9-year-old patient diagnosed with Timothy syndrome (TS), which is a rare condition characterized by mutations in the CACNA1c gene. Conventional therapies often have limited efficacy in managing TS. This case is significant, as it represents the youngest age for S-ICD implantation recorded in mainland China. While the absence of ventricular arrhythmias during hospitalization and follow-up is encouraging, it is not sufficient to conclusively establish the safety and feasibility of this intervention in young TS patients. Further research is needed to evaluate the long-term outcomes and to consider S-ICD as a potential standard treatment option for TS. Additionally, there is a need for a more detailed exploration of the molecular mechanisms underlying gene therapy and personalized interventions.

Abstract Background Approximately 90% of intracardial thrombi originate from the left atrial appendage in non-valvular atrial fibrillation patients. Even with anticoagulant therapy, left atrial appendage thrombus (LAAT) still occurs in 8% of patients. While left atrial appendage closure (LAAC) could be a promising alternative, the current consensus considers LAAT a contraindication to LAAC. However, the feasibility and safety of LAAC in patients with LAAT have yet to be determined. Methods This systematic review synthesizes published data to explore the feasibility and safety of LAAC for patients with LAAT. Results This study included a total of 136 patients with LAATs who underwent successful LAAC. The Amulet Amplatzer device was the most frequently utilized device (48.5%). Among these patients, 77 (56.6%) had absolute contraindications to anticoagulation therapy. Cerebral protection devices were utilized by 47 patients (34.6%). Transesophageal echocardiography (TEE) is the primary imaging technique used during the procedure. Warfarin and novel oral anticoagulants were the main anticoagulant medications used prior to the procedure, while dual antiplatelet therapy was primarily used post-procedure. During a mean follow-up period of 13.2 ± 11.5 months, there was 1 case of fatality, 1 case of stroke, 3 major bleeding events, 3 instances of device-related thrombus, and 8 cases of peri-device leakage. Conclusions This review highlights the preliminary effectiveness and safety of the LAAC procedure in patients with persistent LAAT. Future large-scale RCTs with varied LAAT characteristics and LAAC device types are essential for evidence-based decision-making in clinical practice.

In allusion to solve the issue of fault diagnosis for bearing and other rotatory machinery, a technique based on fined-grained multi-scale Kolmogorov entropy and whale optimized multi-class support vector machine (abbreviated as FGMKE-WOA-MSVM) is proposed. Firstly, vibration signals are decomposed by fine-grained multi-scale decomposition, and the Kolmogorov entropy of the sub-signals at different analysis scales is calculated as the multi-dimension feature vector, which quantitatively characterize the complexity of the signal at multi-scales. Aiming at the problem of sensitive parameters selection for multi-class support vector machine model (abbreviated as MSVM), the whale optimization algorithm (abbreviated as WOA) is introduced to optimize the penalty factor and kernel function parameter, and constructing optimal WOA-MSVM model. Finally, an instance analysis is carried out with Jiangnan University bearing datasets to verify the effectiveness and superiority of this technique. The results show that compared with different feature vectors and models such as K nearest neighbors (abbreviated as KNN) and Decision Tree (abbreviated as RF), the proposed technique is superior with fast computation speed and high diagnostic efficiency.

Introduction: Intrauterine adhesions (IUA), also known as Asherman's syndrome, is caused by trauma to the pregnant or non-pregnant uterus, which leads to damaged endometrial basal lining and partial or total occlusion of the uterine chambers, resulting in abnormal menstruation, infertility, or recurrent miscarriage. The essence of this syndrome is endometrial fibrosis. And there is no effective treatment for IUA to stimulate endometrial regeneration currently. Recently, menstrual blood-derived stem cells (MenSCs) have been proved to hold therapeutic promise in various diseases, such as myocardial infarction, stroke, diabetes, and liver cirrhosis.Methods: In this study, we examined the effects of MenSCs on the repair of uterine adhesions in a rat model, and more importantly, promoted such therapeutic effects via a xeno-free VitroGel MMP carrier.Results: This combined treatment reduced the expression of inflammatory factors, increased the expression of anti-inflammatory factors, restricted the area of endometrial fibrosis, diminished uterine adhesions, and partially restored fertility, showing stronger effectiveness than each component alone and almost resembling the sham group.Discussion: Our findings suggest a highly promising strategy for IUA treatment.

The objective of this study was to construct a recombinant adenovirus expressing the foot-and-mouth disease virus (FMDV) capsid protein of types O and A for future FMDV vaccines to be used in the livestock industry for the reduction in losses caused by FMD outbreaks. Three recombinant adenoviruses, rAdv-P12A3B3C-OZK93, rAdv-P12A3B3C-OA58, and rAdv-P12A3C-AF72, were packaged, characterized, and amplified using the AdMaxTM adenovirus packaging system, and the humoral and cellular immunity levels were further evaluated in guinea pigs with monovalent or bivalent forms. The results showed that the three recombinant adenoviruses could elicit high levels of humoral and cellular immune responses against FMDV types O and A when immunizing monovalent or bivalent forms, and the immune effect changes with the change in the proportion of recombinant adenovirus types O and A, laying an important foundation for the future development of a new FMD live-carrier vaccine. These results implied that the recombinant adenovirus expressing the FMDV capsid protein of types O and A could be used to prevent FMDV in livestock.

Traditional isolation methods often lead to the rediscovery of known natural products. In contrast, genome mining strategies are considered effective for the continual discovery of new natural products. In this study, we discovered a unique prenyltransferase (PT) through genome mining, capable of catalyzing the transfer of a prenyl group to an aromatic nucleus to form C-C or C-O bonds. A pair of new hydroxyphenylacetic acid derivative enantiomers with prenyl units, (±)-peniprenydiol A (1), along with 16 known compounds (2–17), were isolated from a marine fungus, Penicillium sp. W21C371. The separation of 1 using chiral HPLC led to the isolation of the enantiomers 1a and 1b. Their structures were established on the basis of extensive spectroscopic analysis, including 1D, 2D NMR and HRESIMS. The absolute configurations of the new compounds were determined by a modified Mosher method. A plausible biosynthetic pathway for 1 was deduced, facilitated by PT catalysis. In the in vitro assay, 2 and 3 showed promising inhibitory activity against Escherichia coli β-glucuronidase (EcGUS), with IC50 values of 44.60 ± 0.84 μM and 21.60 ± 0.76 μM, respectively, compared to the positive control, D-saccharic acid 1,4-lactone hydrate (DSL). This study demonstrates the advantages of genome mining in the rational acquisition of new natural products.

Eectrochemical glucose sensors is crucial for both environmental and human health, requiring rational nanoarchitectures with high electrochemical performance for glucose oxidation. Ni(OH)2/Ni(DMG)2 composite nanotubes were synthesized by etching nickel-dimethylglyoxime (DMG) nanorods with OH−, using Ni(DMG)2 as a partially sacrificial template. The optimal Ni(OH)2/Ni(DMG)2 nonenzymatic glucose sensor was evaluated on both conventional and portable electrochemical workstations, showing high sensitivity and a low detection limit. The optimal Ni(OH)2/Ni(DMG)2 glucose sensors integrated into smartphones demonstrated a low detection limit of 3.3 µM (M = mol L−1), a wide linear range (10 µM–8 mM), and a sensitivity of 262.80 µA mM−1 cm−2 for glucose detection. The sensors also exhibited favorable stability and reproducibility, along with preferable resistance to interference in the presence of uric acid, gluconate, proline, NaCl, valine, and lysine. Moreover, the portable sensor also demonstrated satisfactory glucose recovery (97.25–104 %) in serum samples, indicating its potential for future applications in real samples analysis.

Abstract Background Endogenous neural stem cells (NSCs) are critical for the remyelination of axons following spinal cord injury (SCI). Cell–cell communication plays a key role in the regulation of the differentiation of NSCs. Astrocytes act as immune cells that encounter early inflammation, forming a glial barrier to prevent the spread of destructive inflammation following SCI. In addition, the cytokines released from astrocytes participate in the regulation of the differentiation of NSCs. The aim of this study was to investigate the effects of cytokines released from inflammation-stimulated astrocytes on the differentiation of NSCs following SCI and to explore the influence of these cytokines on NSC–NSC communication. Results Lipopolysaccharide stimulation of astrocytes increased bone morphogenetic protein 2 (BMP2) release, which not only promoted the differentiation of NSCs into astrocytes and inhibited axon remyelination in SCI lesions but also enriched miRNA-22-3p within extracellular vesicles derived from NSCs. These miRNA-22 molecules function as a feedback loop to promote NSC differentiation into oligodendrocytes and the remyelination of axons following SCI by targeting KDM3A. Conclusions This study revealed that by releasing BMP2, astrocytes were able to regulate the differentiation of NSCs and NSC–NSC communication by enriching miRNA-22 within NSC-EVs, which in turn promoted the regeneration and remyelination of axons by targeting the KDM3A/TGF-beta axis and the recovery of neurological outcomes following SCI.

Particle swarm optimization (PSO) is a type of swarm intelligence algorithm that is frequently used to resolve specific global optimization problems due to its rapid convergence and ease of operation. However, PSO still has certain deficiencies, such as a poor trade-off between exploration and exploitation and premature convergence. Hence, this paper proposes a dual-stage hybrid learning particle swarm optimization (DHLPSO). In the algorithm, the iterative process is partitioned into two stages. The learning strategy used at each stage emphasizes exploration and exploitation, respectively. In the first stage, to increase population variety, a Manhattan distance based learning strategy is proposed. In this strategy, each particle chooses the furthest Manhattan distance particle and a better particle for learning. In the second stage, an excellent example learning strategy is adopted to perform local optimization operations on the population, in which each particle learns from the global optimal particle and a better particle. Utilizing the Gaussian mutation strategy, the algorithm’s searchability in particular multimodal functions is significantly enhanced. On benchmark functions from CEC 2013, DHLPSO is evaluated alongside other PSO variants already in existence. The comparison results clearly demonstrate that, compared to other cutting-edge PSO variations, DHLPSO implements highly competitive performance in handling global optimization problems.

Williams-Beuren syndrome (WBS) is an autosomal dominant genetic disorder closely associated with cardiovascular malformations, distinctive facial features, impaired cognitive ability, abnormal growth and development, endocrine dysfunction, and other related systems. In patients with WBS, the presence of cardiovascular malformations often necessitates genetic testing. This testing not only confirms the diagnosis but also facilitates the identification of associated syndromic features. Early and accurate diagnosis through genetic testing is instrumental for guiding further investigations, and initiating targeted therapies and support services. Such proactive management can substantially improve prognosis and quality of life for patients with WBS. Although surgery remains the most effective approach for repairing cardiovascular malformations, its implementation entails notable surgical risks. Clinicians should prioritize the identification and diagnosis of WBS, and strive to develop an effective management model involving collaboration among hospitals, families, and society. Here, we presented a case report of a patient with WBS and congenital heart disease, to contribute to a deeper understanding of this condition.

Colorectal adenocarcinoma (CRC) is the third most common malignancy worldwide. Metastatic CRC has a poor prognosis because of chemotherapy resistance. Our previous study demonstrated that semaphorin 3F (SEMA3F) signaling may contribute to reversing chemotherapy resistance in CRC cells by reducing E-cadherin and integrin αvβ3 expression levels. Another study showed that upregulation of p27 significantly increase the expression of E-cadherin and integrin. This study aimed to evaluate the effect of SEMA3F on P27 and whether it can reverse resistance in CRC cells. We compared the chemosensitivity of human colorectal cancer cell lines with different SEMA3F expression levels to 5-Fu through cell experiment and animal experiment. Then the interaction between SEMA3F and p27 and its possible mechanism were explored by Western Blot, immunofluorescence and immunocoprecipitation. We also compared the disease-free survival of 118 CRC patients with high or low expression of SEMA3F.The results showed that overexpresstion of SEMA3F enhanced the chemotherapy sensitivity and apoptosis of CRC cells in vitro and in vivo. Among 118 postoperative CRC specimens, the disease-free survival of patients with positive SEMA3F expression was significantly longer than that with negative SEMA3F expression after adjuvant treatment. Upregulation of SEMA3F in multicellular spheroid culture (MSC) could increase p27 phosphorylation at serine 10 (Ser10), subsequently promote the cytosolic translocation of P27. Overall, our results reveal a novel molecular mechanism: SEMA3F mediates the degradation of p27 and regulates its subcellular localization to enhance chemosensitivity to 5-Fu in CRC cells, rather than inhibits p27 expression.

α-Glucosidase (AGS) inhibitors have been regarded as an ideal target for the management of type 2 diabetes mellitus (T2DM) since they can maintain an acceptable blood glucose level by delaying the digestion of carbohydrates and diminishing the absorption of monosaccharides. In the process of our endeavor in mining AGS inhibitors from natural sources, the culture broth of two mangrove-derived actinomycetes Streptomyces sp. WHUA03267 and Streptomyces sp. WHUA03072 exhibited an apparent inhibitory activity against AGS. A subsequent chemical investigation into the two extracts furnished 28 secondary metabolites that were identified by spectroscopic methods as two previously undescribed linear polyketides 1–2, four benzenoid ansamycins 3–6, fourteen cyclodipeptides 7–18, one prenylated indole derivative 19, two fusicoccane-type diterpenoids 20–21, two hydroxamate siderophore 22–23, and five others 24–28. Among all of the isolates, 11 and 24 were obtained from actinomycetes for the first time, while 20–21 had never been reported to occur in a marine-derived microorganism previously. In the in vitro AGS inhibitory assay, compounds 3, 8, 9, 11, 14, 16, and 17 exhibited potent to moderate activity with IC50 values ranging from 35.76 ± 0.40 to 164.5 ± 15.5 μM, as compared with acarbose (IC50 = 422.3 ± 8.4 μM). The AGS inhibitory activity of 3, 9, 14, 16, and 17 was reported for the first time. In particular, autolytimycin (3) represented the first ansamycin derivative reported to possess the AGS inhibitory activity. Kinetics analysis and molecular docking were performed to determine the inhibition types and binding modes of these inhibitors, respectively. In the MTT assay, 3, 8, 9, 11, 14, 16, and 17 exhibited no apparent cytotoxicity to the human normal hepatocyte (LO2) cells, suggesting satisfactory safety of these AGS inhibitors.

Patients with idiopathic pulmonary fibrosis (IPF) have a high risk of developing lung cancer compared with the general population. The morbidity of lung cancer in IPF patient ranges from 3% to 22%, and in some cases exceeds 50%, and these patients have a reduced survival time. However, the mechanisms through which IPF increases the morbidity and mortality in lung cancer remain unclear.By carefully analyzing the pathological features of these two diseases, we uncovered that, first, similar to IPF, lung carcinomas are more frequently found in the peripheral area of the lungs and, second, lung cancers tend to develop from the honeycomb areas in IPF. In accordance with the above pathological features, due to the spatial location, the peripheral areas of the lung experience a high stretch force because the average distance between adjacent alveolar cells in this area tends to be larger than that at the central lung when inflated; furthermore, the honeycomb areas, comprised of condensed fibrous tissue, are characterized by increased stiffness. Both of these pathological features of lung cancer and IPF are coincidentally related to abnormal mechanical forces (stretch and tissue stiffness). Therefore, we believe that the aberrant mechanical forces that are generated in the lung with IPF may contribute to the onset and progression of lung cancer.In this review, we discuss the possible effects of mechanical forces that are generated in IPF on the initiation and progression of lung cancer from the perspective of the hallmarks of cancer, including proliferation, metastasis, angiogenesis, cancer stem cells, immunology, epigenetics, and metabolism, so as to advance our understanding of the pathogenesis of IPF-related lung cancer and to harness these concepts for lung cancer mechanotherapies.

Inflammation-associated chronic pain is a global clinical problem, affecting millions of people worldwide. However, the underlying mechanisms that mediate inflammation-associated chronic pain remain unclear. A rat model of cutaneous inflammation induced by Complete Freund’s Adjuvant (CFA) has been widely used as an inflammation-induced pain hypersensitivity model. We present the transcriptomics profile of CFA-induced inflammation in the rat dorsal root ganglion (DRG) via an approach that targets gene expression, DNA methylation, and post-transcriptional regulation. We identified 418 differentially expressed mRNAs, 120 differentially expressed microRNAs (miRNAs), and 2,670 differentially methylated regions (DMRs), which were all highly associated with multiple inflammation-related pathways, including nuclear factor kappa B (NF-κB) and interferon (IFN) signaling pathways. An integrated analysis further demonstrated that the activator protein 1 (AP-1) network, which may act as a regulator of the inflammatory response, is regulated at both the transcriptomic and epigenetic levels. We believe our data will not only provide drug screening targets for the treatment of chronic pain and inflammation but will also shed light on the molecular network associated with inflammation-induced hyperalgesia.

As open public data initiatives have become prevalent among local and national governments across the globe with promises of benefits such as increased accountability, challenges, especially the governments’ lack of willingness to open public data, have also begun to emerge. Existing governance research on open public data primarily focuses on how open public data can increase the accountability of public bodies. The important steps in achieving accountability are, however, ignored. In this paper, we view the perceived risk of liability as a barrier for the public bodies to disclose their data in the first place, and hence to achieve accountability as a desired outcome. We explore the link between perceived risk of liability and accountability by looking into the recently announced Interim Measures for the Opening of Public Data in Shanghai as an example of a local regulatory initiative of open public data. Our findings show that by identifying the specific data entities and outlining their corresponding duties, the interim measures clarify the roles of different public bodies and under what conditions they can incur liability. By introducing an exemption clause, they also provide public bodies with legal flexibility to cope with uncertain consequences of data utilization. In this way, we argue that the interim measures, outlining duties for specific entities in data opening in accounting for the consequences of data utilization while remaining flexible due to their temporality, constitute a novel regulatory approach towards reducing the legal uncertainty around perceived risks of liability in the area of open public data, hence potentially contributing to increased accountability.

The root-knot nematode (Meloidogyne spp.) is one of the major challenges in eggplant (Solanum melongena L.) production. Fluopyram, known to be an effective fungicide, is also used for controlling root-knot nematode. However, in China, little information is currently available regarding the efficacy of fluopyram via chemigation against root-knot nematode and its effects on soil properties. For this, the objective of this work was to test mortality of root-knot nematode, functional diversity of soil microbial community, activity of soil enzyme after fluopyram applicated by chemigation. The results of two field experiments revealed that concentration of 60 g·ha-1 fluopyram applied with 200 L·ha-1 irrigation water at 2 L·h-1 flow velocity was the most effective chemigation parameters for controlling eggplant against root-knot nematode. The functional diversity of the soil microbial community was significantly affected by fluopyram. The activities of soil urease and β-glucosidase decreased during the initial stages but recovered at later stages. In brief, fluopyram has advantageous for the efficient control of root-knot nematode with no deleterious effects on soil properties as well as chemigation is positive for application in karst landscape in Guangxi.

Background: In recent years, the phenomenon of coexisting systemic autoimmune diseases (ADs) in patients with autoimmune encephalitis (AE) has been increasingly found, while its clinical significance remains unexplored. This study aimed to investigate the types and potential clinical associations of autoimmune comorbidities in patients with antibody-positive AE.Methods: A retrospective cohort study of patients with antibody-positive AE was conducted from 2011 to 2018. The demographics, clinical characteristics, and follow-up data were reviewed.Results: We enrolled 517 patients, among whom 45 were affected by one or more types of ADs, including Hashimoto's thyroiditis (HT) (n = 28), systemic lupus erythematosus (SLE) (n = 3), anaphylactoid purpura (n = 3), vitiligo (n = 3), Sjögren's syndrome (SS) (n = 2), chronic urticaria (n = 2), bullous pemphigoid (n = 1), uveitis (n = 1), myasthenia gravis (MG) (n = 1), and the coexistence of SLE and anaphylactoid purpura (n = 1). The proportion of patients with coexisting ADs was higher in those with anti–leucine-rich glioma-inactivated 1 (LGI1) encephalitis than in those with anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis (13/111 vs. 16/307) (P = 0.021). In anti-NMDAR and anti-LGI1 encephalitis patients, there were no significant differences in the age at onset, sex ratio, proportion of patients with tumors, disease severity, or recurrence between the groups with and without ADs.Conclusions: One or more types of ADs developed in AE patients, and patients with anti-LGI1 encephalitis had a higher frequency of autoimmune comorbidities than those with anti-NMDAR encephalitis. And we found that autoimmune comorbidities did not affect the clinical course of AE.

TW-37 is a novel, potent and non-peptide Bcl-2 small-molecule inhibitor. Its activity in colorectal cancer (CRC) cells is studied. In both HCT-116 cells and primary human colon cancer cells, treatment with TW-37 at only nM concentration efficiently inhibited cell survival and proliferation. TW-37 also induced caspase-3/9 and apoptosis activation in CRC cells. Feedback autophagy activation was observed in TW-37-treated CRC cells. Reversely pharmacological autophagy inhibition or Beclin-1 knockdown by targeted-shRNA potentiated TW-37-induced apoptosis and killing of CRC cells. In vivo, intravenous injection of TW-37 inhibited HCT-116 tumor growth in mice. TW-37's anti-tumor activity was further potentiated against Beclin-1-silenced HCT-116 tumors. Together, targeting Bcl-2 family protein by TW-37 efficiently inhibits CRC cell growth in vitro and in vivo. Inhibition of feedback autophagy activation could further sensitize TW-37.

Leta Hong Fincher: Leftover Women: The Resurgence of Gender Inequality in China. Zed Books Ldt, 2014Engebretsen, Elisabeth L.: Queer Women in Urban China: An Ethnography. New York and London: Routledge, 2014Jung Chang: Empress Dowager Cixi. The concubine who launched modern China. Alfred A. Knops. New York, 2013Nancy Fraser: Fortunes of Feminism. From State-Managed Capitalism to Neoliberal Crisis, Verso. London – New York. 2013

Fungi generate a diverse array of bioactive compounds with significant pharmaceutical applications. However, the chemical diversity of natural products in fungi remains largely unexplored. Here, we present a paradigm for specifically discovering diverse and bioactive compounds from fungi by integrating genome mining with building block molecular network and coculture analysis. Through pangenome and sequence similarity network analysis, we identified a rare type I polyketide enzyme from Penicillium sp. ZJUT-34. Subsequent building block molecular network and coculture strategy led to the identification and isolation of a pair of novel polyketides, (±)-peniphenone E [(±)−1], three known polyketides (2–4), and three precursor compounds (5–7) from a combined culture of Penicillium sp. ZJUT-34 and Penicillium sp. ZJUT23. Their structures were established through extensive spectroscopic analysis, including NMR and HRESIMS. Chiral HPLC separation of compound 1 yielded a pair of enantiomers (+)−1 and (−)−1, with their absolute configurations determined using calculated ECD methods. Compound (±)−1 is notable for its unprecedented structure, featuring a unique 2-methyl-hexenyl-3-one moiety fused with a polyketide clavatol core. We proposed a hypothetical biosynthetic pathway for (±)−1. Furthermore, compounds 2, 5, and 6 exhibited strong antioxidant activity, whereas (−)−1, (+)−1, 3, and four exhibited moderate antioxidant activity compared to the positive control, ascorbic acid. Our research demonstrates a pioneering strategy for uncovering novel polyketides by merging genome mining, metabolomics, and cocultivation methods. This approach addresses the challenge of discovering natural compounds produced by rare biosynthetic enzymes that are often silent under conventional conditions due to gene regulation. IMPORTANCE Polyketides, particularly those with complex structures, are crucial in drug development and synthesis. This study introduces a novel approach to discover new polyketides by integrating genomics, metabolomics, and cocultivation strategies. By combining genome mining, building block molecular networks, and coculturing techniques, we identified and isolated a unique polyketide, (±)-peniphenone E, along with three known polyketides and three precursor compounds from Penicillium sp. ZJUT-34 and Penicillium sp. ZJUT23. This approach highlights the potential of using combined strategies to explore fungal chemical diversity and discover novel bioactive compounds. The successful identification of (±)-peniphenone E, with its distinctive structure, demonstrates the effectiveness of this integrated method in enhancing natural product discovery and underscores the value of innovative approaches in natural product research. [ABSTRACT FROM AUTHOR]