Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation.

Fibroblasts, known for their functional diversity, play crucial roles in inflammation and cancer. In this study, we conduct comprehensive single-cell RNA sequencing analyses on fibroblast cells from 517 human samples, spanning 11 tissue types and diverse pathological states. We identify distinct fibroblast subpopulations with universal and tissue-specific characteristics. Pathological conditions lead to significant shifts in fibroblast compositions, including the expansion of immune-modulating fibroblasts during inflammation and tissue-remodeling myofibroblasts in cancer. Within the myofibroblast category, we identify four transcriptionally distinct subpopulations originating from different developmental origins, with LRRC15+ myofibroblasts displaying terminally differentiated features. Both LRRC15+ and MMP1+ myofibroblasts demonstrate pro-tumor potential that contribute to the immune-excluded and immune-suppressive tumor microenvironments (TMEs), whereas PI16+ fibroblasts show potential anti-tumor functions in adjacent non-cancerous regions. Fibroblast-subtype compositions define patient subtypes with distinct clinical outcomes. This study advances our understanding of fibroblast biology and suggests potential therapeutic strategies for targeting specific fibroblast subsets in cancer treatment.

Exploring the potential mechanism of atrazine-induced dopaminergic neurotoxicity based on integration strategy.

BACKGROUND: Atrazine (ATR), a commonly used herbicide, is linked to dopaminergic neurotoxicity, which may cause symptoms resembling Parkinson's disease (PD). This study aims to reveal the molecular regulatory networks responsible for ATR exposure and its effects on dopaminergic neurotoxicity based on an integration strategy. METHODS: Our approach involved network toxicology, construction of protein-protein interaction (PPI) networks, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, as well as molecular docking techniques. Subsequently, we validated the predicted results in PC12 cells in vitro. RESULTS: An integrated analysis strategy indicating that 5 hub targets, including mitogen-activated protein kinase 3 (Mapk3), catalase (Cat), heme oxygenase 1 (Hmox1), tumor protein p53 (Tp53), and prostaglandin-endoperoxide synthase 2 (Ptgs2), may play a crucial role in ATR-induced dopaminergic injury. Molecular docking indicated that the 5 hub targets exhibited certain binding activity with ATR. Cell counting kit-8 (CCK8) results illustrated a dose-response relationship in PC12 cells. Real-time quantitative polymerase chain reaction (RT-qPCR) displayed notable changes in the expression of hub targets mRNA levels, with the exception of Mapk3. Western blotting results suggested that ATR treatment in PC12 cells resulted in an upregulation of the Cat, Hmox1, and p-Mapk3 protein expression levels while causing a downregulation in Tp53, Ptgs2, and Mapk3. CONCLUSION: Our findings indicated that 5 hub targets identified could play a vital role in ATR-induced dopaminergic neurotoxicity in PC12 cells. These results provide preliminary support for further investigation into the molecular mechanism of ATR-induced toxicity.

Si-Ni-San ameliorates cholestatic liver injury by favoring P. goldsteinii colonization.

ETHNOPHARMACOLOGICAL RELEVANCE: Current treatment options for cholestatic liver diseases are limited, and addressing impaired intestinal barrier has emerged as a promising therapeutic approach. Si-Ni-San (SNS) is a Traditional Chinese Medicine (TCM) formula commonly utilized in the management of chronic liver diseases. Our previous studies have indicated that SNS effectively enhanced intestinal barrier function through the modulation of gut microbiota. AIM OF THE STUDY: This study aims to verify the therapeutic effects of SNS on cholestatic liver injury, focusing on elucidating the underlying mechanism involving the gut-liver axis. MATERIALS AND METHODS: The 16s RNA gene sequencing, non-targeted metabolomics were used to investigate the effects of SNS on the gut microbiota dysbiosis. Fecal microbiota transplantation (FMT) was conducted to identify potential beneficial probiotics underlying the therapeutic effects of SNS. RESULTS: Our results demonstrated that SNS significantly ameliorated cholestatic liver injury induced by partial bile duct ligation (pBDL). Additionally, SNS effectively suppressed cholestasis-induced inflammation and barrier dysfunction in both the small intestine and colon. While SNS did not impact the intestinal FXR-FGF15-hepatic CYP7A1 axis, it notably improved gut microbiota dysbiosis and modulated the profile of microbial metabolites, including beneficial secondary bile acids and tryptophan derivatives. Furthermore, gut microbiota depletion experiments and FMT confirmed that the therapeutic benefits of SNS in cholestatic liver disease are dependent on gut microbiota modulation, particularly through the promotion of the growth of potential probiotic P. goldsteinii. Moreover, a synergistic improvement in cholestatic liver injury was observed with the co-administration of P. goldsteinii and SNS. CONCLUSION: Our study underscores that SNS effectively alleviates cholestatic liver injury by addressing gut microbiota dysbiosis and enhancing intestinal barrier function, supporting its rational clinical utilization. Furthermore, we highlight P. goldsteinii as a promising probiotic candidate for the management of cholestatic liver diseases.

Exploring molecular mechanisms of diazinon toxicity in HT22 hippocampal neurons through integrated miRNA and mRNA profiling.

Diazinon (DZN), a persistent organophosphate insecticide, has been associated with neurotoxic effects, particularly in the hippocampus. However, the specific molecular mechanisms of DZN-induced hippocampal toxicity remain unknown. In this study, we analyzed the mRNA and miRNA expression patterns of HT22 cells following exposure to DZN (125 µM), and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted subsequently. The integration of miRNA sequencing (miRNA-seq) and mRNA sequencing (mRNA-seq) data identified 33 differentially expressed miRNAs (DEMIs, 15 up-regulated and 18 down-regulated) and 271 differentially expressed mRNAs (DEMs, 69 up-regulated and 202 down-regulated) targeted by the DEMIs. Moreover, the 3 most central mRNAs (ITGAV, FN1, and EGFR) and 7 associated miRNAs (mmu-miR-700-5p, mmu-miR-26a-2-3p, mmu-miR-452-3p, mmu-miR-25-3p, mmu-miR-582-5p, mmu-miR-467a-5p, and mmu-miR-467b-5p) were screened and validated using quantitative real-time PCR. Furthermore, the GO analysis revealed that the identified DEMs were enriched in biological adhesion extracellular matrix, and growth factor binding, while the KEGG analysis suggested that the enriched DEMs were involved in ECM-receptor interaction, mTOR signaling pathway, MAPK signaling pathway, and AMPK signaling pathway. Our results may aid in elucidating the underlying mechanisms associated with DZN-induced hippocampal toxicity and provide valuable insights into the pathogenesis of neurotoxicity triggered by other organophosphorus pesticides.

Effects of Maternal SARS-CoV-2 Infection During Pregnancy on Fetal Development.

BACKGROUND: The severe acute respiratory syndrome coronavirus (SARS-CoV-2) outbreak in 2019 has necessitated investigating its potential adverse effects on pregnancy outcomes and fetal development. OBJECTIVE: This study aimed to review the evidence on the impact of SARS-CoV-2 infection during pregnancy on fetal outcomes. METHOD OF STUDY: Literatures since the outbreak of COVID-19 from PubMed and Web of Science were summarized in this narrative review, to show the effects of maternal SARS-CoV-2 infection during pregnancy on fetal development. RESULTS: SARS-CoV-2 infection during pregnancy can be transmitted vertically through the placenta, both in utero and perinatally, affecting the maternal-fetal immune interface and placental function. Viral infections during pregnancy have been linked to central nervous system development impairments and disorders such as autism. Changes in the structure and function of the respiratory, immune, and visceral systems have also been reported. SARS-CoV-2 infection during pregnancy has been linked with increased risks of stillbirth and preterm birth. However, the mechanisms involved remain unclear and may include cytokine storms, macrophage mediation, genetic mutations, methylation, and other epigenetic changes. Exploring the protective effects of antiviral treatment and other interventions in animal and clinical studies may help improve outcomes. CONCLUSION: SARS-CoV-2 infection during pregnancy activates the maternal-fetal immune interface through vertical transmission, and has short- and long-term effects on fetal development, including the central nervous system. Future long-term studies may help provide evidence that can inform interventions to reduce the risk of adverse outcomes.

Characteristics of molecular subtypes and cinical outcomes in the immunotherapy Queue of extensive-stage small cell lung cancer patients.

BACKGROUND: With a series of clinical trials confirming the sensitivity of small cell lung cancer (SCLC) to immunotherapy, research on personalized treatment for SCLC has gained increasing attention. Currently, the most widely accepted subtype of SCLC is based on the expression levels of Achaete-Scute Family BHLH Transcription Factor 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), and POU class 2 homeobox 3 (POU2F3). However, real-world studies on this classification remain limited. METHODS: We retrospectively collected biopsy specimens from patients who received immunotherapy at Shandong Provincial Hospital between January 2019 and July 2021. After determining the patient subtypes using immunohistochemistry, we analyzed the relationships between each subtype and survival as well as some clinical characteristics. RESULTS: In our study, we found that the subtype I achieved a significant survival advantage compared to the other groups. Additionally, the subtype A demonstrated a significant survival disadvantage. Among patients in the subtype I, there was a higher proportion of early brain metastasis and patients with a family history of tumors, while the subtype A had a lower proportion. Furthermore, the subtype A exhibited relatively poor immune infiltration. CONCLUSION: In a diverse cohort of SCLC patients receiving immunotherapy, the subtype-I showed significant survival advantages while the subtype-A experienced a worse survival.

CycPeptMP: enhancing membrane permeability prediction of cyclic peptides with multi-level molecular features and data augmentation.

Cyclic peptides are versatile therapeutic agents that boast high binding affinity, minimal toxicity, and the potential to engage challenging protein targets. However, the pharmaceutical utility of cyclic peptides is limited by their low membrane permeability-an essential indicator of oral bioavailability and intracellular targeting. Current machine learning-based models of cyclic peptide permeability show variable performance owing to the limitations of experimental data. Furthermore, these methods use features derived from the whole molecule that have traditionally been used to predict small molecules and ignore the unique structural properties of cyclic peptides. This study presents CycPeptMP: an accurate and efficient method to predict cyclic peptide membrane permeability. We designed features for cyclic peptides at the atom-, monomer-, and peptide-levels and seamlessly integrated these into a fusion model using deep learning technology. Additionally, we applied various data augmentation techniques to enhance model training efficiency using the latest data. The fusion model exhibited excellent prediction performance for the logarithm of permeability, with a mean absolute error of $0.355$ and correlation coefficient of $0.883$. Ablation studies demonstrated that all feature levels contributed and were relatively essential to predicting membrane permeability, confirming the effectiveness of augmentation to improve prediction accuracy. A comparison with a molecular dynamics-based method showed that CycPeptMP accurately predicted peptide permeability, which is otherwise difficult to predict using simulations.

Radix rehmanniae praeparata extracts ameliorate hepatic ischemia-reperfusion injury by reversing LRP1-NOTCH1-C/EBPß axis-mediated senescence fate of LSECs.

BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) is commonly observed in cases of extensive hepatic resection and involves complex mechanisms. Cell senescence has been recognized as a factor in liver injury including HIRI, where it presents as a pro-inflammatory phenotype called senescence-associated secretory phenotype (SASP). Radix Rehmanniae Praeparata (RRP) is a commonly utilized traditional Chinese medicine known for its hepatoprotective, anti-aging and antioxidant qualities. Despite its recognized benefits, the specific mechanisms by which RRP may impede the progression of HIRI through the regulation of cell senescence and the identification of the most potent anti-aging extracts from RRP remain unclear. MATERIALS AND METHODS: Here, we first applied different chemical analysis methods to identify the RRP aqueous extract (RRPAE) and active fractions of RRP. Next, we constructed a surgically established mouse model and a hypoxia-reoxygenation (HR)-stimulated liver sinusoidal endothelial cells (LSECs) model to explore the underlying mechanism of RRP against HIRI through transcriptomics and multiple molecular biology experiments. RESULTS: After identifying active ingredients in RRP, we observed that RRP and its factions effectively restored LSECs fenestration and improved inflammation, cellular swelling and vascular continuity in the hepatic sinusoidal region during HIRI. Transcriptomic results revealed that RRP might reverse HIRI-induced senescence through the NOTCH signaling pathway and cell categorization further showed that the senescent cell population in HIRI liver was primarily LSECs rather than other cell types. Different RRPAE, especially RRP glucoside (RRPGLY), improved LSECs senescence and suppressed the expression of pro-inflammatory SASP genes either induced by HR insult or NOTCH1 activator, which was accompanied with the inhibition of LRP1-NOTCH1-C/EBPß pathways. Additionally, the specific inhibition of NOTCH1 by siRNA synergistically enhanced the hepatoprotective effect of RRPGLY. The ChIP-qPCR results further showed that C/EBPß was enriched at the promoter of a representative SASP, Il-1ß, in hypoxic LSECs but was significantly inhibited by RRPGLY. CONCLUSION: Our study not only clarified the potential mechanism of RRP active extractions in alleviating HIRI, but also highlighted RRPGLY was the main component of RRP that exerted anti-aging and anti-HIRI effects, providing a fresh perspective on the use of RRP to improve HIRI.

Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies.

Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.

Synthesis and Performance Study of Self-Degradable Gel Plugging Agents Suitable for Medium- and Low-Temperature Reservoirs.

Aiming at the problems of current similar hydrogel plugging agents, such as poor breaking performance, nonspontaneous degradation, and reservoir pollution which have been plaguing their application in temporary plugging operations, this study has synthesized a cross-linking agent for hydrogels with dimethylaminoethyl acrylate and dibromo-p-xylene as raw materials. With Fourier transform infrared, 1H nuclear magnetic resonance, and thermogravimetric analyses as representations of the structure and thermal stability of the cross-linking agent, a set of self-degrading hydrogel systems has been developed with the cross-linking agent as the core so as to make evaluations on the temperature resistance, plugging performance, and core damage performance of the hydrogel and conduct a study on its gelation kinetics. The research results show that the cross-linking agent shows good thermal stability. When applied in the hydrogel system, the hydrogel has shown high temperature resistance, maintaining gel strength for 5-10 days at 50-90 °C, with viscosity after complete degradation lower than 10 mPa·s. The excellent bearing strength of the hydrogel system has led to a core damage rate below 5%. The study on gelation kinetics of the hydrogel system shows that, with the increase in the concentration of the cross-linking agent, the gelation time of the hydrogel system is shortened, with the reaction order between the cross-linker concentration and the gelation time at about 0.6 under the condition of 50-90 °C.

Genomic Language Models: Opportunities and Challenges.

Large language models (LLMs) are having transformative impacts across a wide range of scientific fields, particularly in the biomedical sciences. Just as the goal of Natural Language Processing is to understand sequences of words, a major objective in biology is to understand biological sequences. Genomic Language Models (gLMs), which are LLMs trained on DNA sequences, have the potential to significantly advance our understanding of genomes and how DNA elements at various scales interact to give rise to complex functions. In this review, we showcase this potential by highlighting key applications of gLMs, including fitness prediction, sequence design, and transfer learning. Despite notable recent progress, however, developing effective and efficient gLMs presents numerous challenges, especially for species with large, complex genomes. We discuss major considerations for developing and evaluating gLMs.

Picroside II promotes HSC apoptosis and inhibits the cholestatic liver fibrosis in Mdr2-/- mice by polarizing M1 macrophages and balancing immune responses.

Liver fibrosis is characterized by chronic inflammatory responses and progressive fibrous scar formation. Macrophages play a central role in the pathogenesis of hepatic fibrosis by reconstructing the immune microenvironment. Picroside II (PIC II), extracted from Picrorhizae Rhizoma, has demonstrated therapeutic potential for various liver damage. However, the mechanisms by which macrophage polarization initiates immune cascades and contributes to the development of liver fibrosis, and whether this process can be influenced by PIC II, remain unclear. In the current study, RNA sequencing and multiple molecular approaches were utilized to explore the underlying mechanisms of PIC II against liver fibrosis in multidrug-resistance protein 2 knockout (Mdr2-/-) mice. Our findings indicate that PIC II activates M1-polarized macrophages to recruit natural killer cells (NK cells), potentially via the CXCL16-CXCR6 axis. Additionally, PIC II promotes the apoptosis of activated hepatic stellate cells (aHSCs) and enhances the cytotoxic effects of NK cells, while also reducing the formation of neutrophil extracellular traps (NETs). Notably, the anti-hepatic fibrosis effects associated with PIC II were largely reversed by macrophage depletion in Mdr2-/- mice. Collectively, our research suggests that PIC II is a potential candidate for halting the progression of liver fibrosis.

Targeted reprogramming of tumor-associated macrophages for overcoming glioblastoma resistance to chemotherapy and immunotherapy.

The resistance of glioblastoma multiforme (GBM) to standard chemotherapy is primarily attributed to the existence of tumor-associated macrophages (TAMs) in the GBM microenvironment, particularly the anti-inflammatory M2 phenotype. Targeted modulation of M2-TAMs is emerging as a promising strategy to enhance chemotherapeutic efficacy. However, combination TAM-targeted therapy with chemotherapy faces substantial challenges, notably in terms of delivery efficiency and targeting specificity. In this study, we designed a pH-responsive hierarchical brain-targeting micelleplex loaded with temozolomide (TMZ) and resiquimod (R848) for combination chemo-immunotherapy against GBM. This delivery system, termed PCPA&PPM@TR, features a primary Angiopep-2 decoration on the outer layer via a pH-cleavable linker and a secondary mannose analogue (MAN) on the middle layer. This pH-responsive hierarchical targeting strategy enables effective BBB permeability while simultaneous GBM- and TAMs-targeting delivery. GBM-targeted delivery of TMZ induces alkylation and triggers an anti-GBM immune response. Concurrently, TAM-targeted delivery of R848 reprograms their phenotype from M2 to pro-inflammatory M1, thereby diminishing GBM resistance to TMZ and amplifying the immune response. In vivo studies demonstrated that targeted modulation of TAMs using PCPA&PPM@TR significantly enhanced anti-GBM efficacy. In summary, this study proposes a promising brain-targeting delivery system for the targeted modulation of TAMs to combat GBM.

Association between sleep quality and living environment among Chinese older persons: a cross-sectional study.

Sleep quality significantly affects the quality of life of older persons. Therefore, this study explored the relationship between sleep quality and living environment of older persons in China to provide a theoretical basis for therapies to alleviate sleep disorders in older persons. A total of 6211 subjects > 60 years of age in Anhui Province, China, were evaluated using the Pittsburgh Sleep Quality Index and a self-reported questionnaire. Multivariate logistic regression analysis revealed that living alone (OR = 1.26, 95% CI 1.09-1.46) and living in a rural area (OR = 1.19, 95% CI 1.06-1.34) were significantly associated with a high incidence of sleep disorders in older persons. Living near a park or foot paths suitable for exercise or walking was significantly associated with a lower incidence of sleep disorders in older persons (OR = 0.87, 95% CI 0.77-0.96). Individual factors such as female sex (OR = 1.30, 95% CI 1.14-1.48) and depression (OR = 2.80, 95% CI 2.47-3.19) were also associated with sleep quality in older persons. These data indicate a correlation exists between living environment and sleep quality.

Exoskeleton rehabilitation robot training for balance and lower limb function in sub-acute stroke patients: a pilot, randomized controlled trial.

PURPOSE: This pilot study aimed to investigate the effects of REX exoskeleton rehabilitation robot training on the balance and lower limb function in patients with sub-acute stroke. METHODS: This was a pilot, single-blind, randomized controlled trial. Twenty-four patients with sub-acute stroke (with the course of disease ranging from 3 weeks to 3 months) were randomized into two groups, including a robot group and a control group. Patients in control group received upright bed rehabilitation (n = 12) and those in robot group received exoskeleton rehabilitation robot training (n = 12). The frequency of training in both groups was once a day (60 min each) for 5 days a week for a total of 4 weeks. Besides, the two groups were evaluated before, 2 weeks after and 4 weeks after the intervention, respectively. The primary assessment index was the Berg Balance Scale (BBS), whereas the secondary assessment indexes included the Fugl-Meyer Lower Extremity Motor Function Scale (FMA-LE), the Posture Assessment Scale for Stroke Patients (PASS), the Activities of Daily Living Scale (Modified Barthel Index, MBI), the Tecnobody Balance Tester, and lower extremity muscle surface electromyography (sEMG). RESULTS: The robot group showed significant improvements (P < 0.05) in the primary efficacy index BBS, as well as the secondary efficacy indexes PASS, FMA-LE, MBI, Tecnobody Balance Tester, and sEMG of the lower limb muscles. Besides, there were a significant differences in BBS, PASS, static eye-opening area or dynamic stability limit evaluation indexes between the robotic and control groups (P < 0.05). CONCLUSIONS: This is the first study to investigate the effectiveness of the REX exoskeleton rehabilitation robot in the rehabilitation of patients with stroke. According to our results, the REX exoskeleton rehabilitation robot demonstrated superior potential efficacy in promoting the early recovery of balance and motor functions in patients with sub-acute stroke. Future large-scale randomized controlled studies and follow-up assessments are needed to validate the current findings. CLINICAL TRIALS REGISTRATION: URL: https://www.chictr.org.cn/index.html.Unique identifier: ChiCTR2300068398.

Predicting potential and quality distribution of Anisodus tanguticus (Maxim.) Pascher under different climatic conditions in the Qinghai-Tibet plateau.

Anisodus tanguticus (Maxim.) Pascher, a distinctive medicinal plant native to the Qinghai-Tibet Plateau, China, has garnered attention due to increasing market demand. This study explores the impact of environmental factors on the distribution and levels of active compounds namely anisodamine, anisodine, and atropine within A. tanguticus. Our goal was to identify suitable cultivation areas for this plant. This study employs the maximum entropy model to simulate the suitable area of A. tanguticus under current conditions and three climate change scenarios during the 2050s and 2070s. The finding revealed that altitude, precipitation in the warmest season (Bio 18), the average annual temperature (Bio 1) exerted significant influences on the distribution of A. tanguticus. Among the environmental factors considered, temperature difference between day and night (Bio 2) had the most substantial impact on the distribution of anisodamine, temperature seasonal variation variance (Bio 4) predominantly influenced anisodine distribution, and Bio 1 had the greatest effected on the distribution of atropine. The suitable areas primarily exist in the eastern Qinghai-Tibet Plateau in China, encompassing a total area of 30.78 × 104 km2. Under the climate scenarios for the future, the suitable areas exhibit increasing trends of approximately 30.2%, 30.3%, and 39.8% by the 2050s, and 25.1%, 48.8%, and 60.1% by the 2070s. This research would provide theoretical suggestions for the protection, and cultivation management of A. tanguticus resources to face the challenge of global climate change.

A 10-year in-depth follow-up of post-lingual hearing loss patients with Chinese domestic cochlear implants.

BACKGROUND: Follow-up of cochlear implant effectiveness is mainly focused on 3 years postoperatively, and studies with more than 5 years of observation are rare, especially for local Chinese brands. OBJECTIVES: Nurotron (Chinese domestic cochlear implant brand) CI recipients who participated in the clinical trial in 2009 were followed-up for 10 years prospectively, providing data to guide doctors and patients. MATERIAL AND METHODS: From December 2009 to April 2010, 57 subjects underwent Nurotron Venus CI surgery at multiple-centers, and were continued to be followed up and assessed at 1, 2, 3, 4, 5, and 10 years after switch on. RESULTS: All recipients were successfully implanted with CIs with no difficulty in subsequent use with one reported case of re-implantation at 9 years after implantation. The aided hearing thresholds were significantly improved at one month after switch on (p < 0.0001) and remained stable afterwards for 10 years. Speech recognition scores were significantly higher than pre-operative results (p < 0.05) and continued to improve till 3 years after switch on. At 10 years post-operation, most subjects had improved QOL scores in most sub-items. CONCLUSIONS AND SIGNIFICANCE: Nurotron Venus CI System provides long-term, stable results in hearing speech assistance capabilities and can improve the quality of life of CI recipients.

Whole-genome DNA methylation profiling revealed epigenetic regulation of NF-κB signaling pathway involved in response to Vibrio alginolyticus infection in the Pacific oyster, Crassostrea gigas.

DNA methylation, an essential epigenetic alteration, is tightly linked to a variety of biological processes, such as immune response. To identify the epigenetic regulatory mechanism in Pacific oyster (Crassostrea gigas), whole-genome bisulfite sequencing (WGBS) was conducted on C. gigas at 0 h, 6 h, and 48 h after infection with Vibrio alginolyticus. At 6 h and 48 h, a total of 11,502 and 14,196 differentially methylated regions (DMRs) were identified (p<0.05, FDR<0.001) compared to 0 h, respectively. Gene ontology (GO) analysis showed that differentially methylated genes (DMGs) were significantly enriched in various biological pathways including immunity, cytoskeleton, epigenetic modification, and metabolic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that transcription machinery (ko03021) is one of the most important pathways. Integrated transcriptome and methylome analyses allowed the identification of 167 and 379 DMG-related DEGs at 6 h and 48 h, respectively. These genes were significantly enriched in immune-related pathways, including nuclear factor kappa B (NF-κB) signaling pathway (ko04064) and tumor necrosis factor (TNF) signaling pathway (ko04668). Interestingly, it's observed that the NF-κB pathway could be activated jointly by TNF Receptor Associated Factor 2 (TRAF2) and Baculoviral IAP Repeat Containing 3 (BIRC3, the homolog of human BIRC2) which were regulated by DNA methylation in response to the challenge posed by V. alginolyticus infection. Through this study, we provided insightful information about the epigenetic regulation of immunity-related genes in the C. gigas, which will be valuable for the understanding of the innate immune system modulation and defense mechanism against bacterial infection in invertebrates.

Insight into selectivity of photocatalytic methane oxidation to formaldehyde on tungsten trioxide.

Tungsten trioxide (WO3) has been recognized as the most promising photocatalyst for highly selective oxidation of methane (CH4) to formaldehyde (HCHO), but the origin of catalytic activity and the reaction manner remain controversial. Here, we take {001} and {110} facets dominated WO3 as the model photocatalysts. Distinctly, {001} facet can readily achieve 100% selectivity of HCHO via the active site mechanism whereas {110} facet hardly guarantees a high selectivity of HCHO along with many intermediate products via the radical way. In situ diffuse reflectance infrared Fourier transform spectroscopy, electron paramagnetic resonance and theoretical calculations confirm that the competitive chemical adsorption between CH4 and H2O and the different CH4 activation routes on WO3 surface are responsible for diverse CH4 oxidation pathways. The microscopic mechanism elucidation provides the guidance for designing high performance photocatalysts for selective CH4 oxidation.

The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism.

Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.