A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

Analysis of risk factors for postoperative recurrence of stage I colorectal cancer: a retrospective analysis of a large population.

Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Patients diagnosed with stage I CRC typically do not require postoperative adjuvant treatment. However, postoperative recurrence is present in at least 40% of patients with CRC and often occurs in those with stage I disease. This study aimed to elucidate the current status of recurrence and clinicopathological characteristics in patients with stage I CRC. Methods: Data of indicated patients were obtained from 18 registries in Surveillance, Epidemiology, and End Results (SEER). The multivariable Fine-Gray regression model was used to identify the mortality risk of patients. Disparities in survival were analyzed using Kaplan-Meier curves. Logistic regression was employed to identify factors associated with recurrent risk overestimation. Results: Our study indicated a recurrence rate of 15.04% (1,874/12,452) in stage I CRC cases. Notably, we identified race, age, T stage, and carcinoembryonic antigen (CEA) levels as independent risk factors for tumor recurrence, substantially impacting prognosis. Furthermore, gender, race (Black), age (>65 years), elevated CEA levels, and refusal or unknown status regarding radiotherapy significantly correlated with an adverse prognosis in patients with stage I CRC. Conclusions: We identified certain key clinicopathological features of patients with stage I CRC and demonstrated the survival benefits of radiotherapy, offering a new perspective on stage I CRC follow-up and treatment recommendations.

Rare SMARCA4-deficient thoracic tumor: Insights into molecular characterization and optimal therapeutics methods.

INTRODUCTIONS: The 2021 WHO Classification of Thoracic Tumors recognized SMARCA4-deficient undifferentiated thoracic tumors (SMARCA4-dUT) as a distinct entity that shows a striking overlap in demographic and molecular profiles with SMARCA4-deficient non-small lung cancer (SMARCA4-dNSCLC). The implications of SMARCA4 deficiency based on immunohistochemistry remain unclear. We aimed to investigate molecular characteristics of SMARCA4-deficient thoracic tumors (SDTT) and explore optimal therapeutics. METHODS: From June.15, 2018, to Nov.15, 2023, a large cohort including patients diagnosed with SMARCA4-deficient (N = 196) and SMARCA4-intact (N = 438) thoracic tumors confirmed by immunohistochemistry at SYSUCC were screened. Clinicopathologic and molecular characteristics were identified and compared. External SRRSH cohort (N = 34) was combined into a pooled cohort to compare clinical outcome of first-line therapy efficacy. RESULTS: SDTT is male predominance with smoking history, high tumor burden, and adrenal metastases. The relationship between SMARCA4 mutation and protein expression is not completely parallel. The majority of SMARCA4-deficient patients harbor truncating (Class-I) SMARCA4 mutations, whereas class-II alterations and wild-type also exist. Compared with SMARCA4-intact thoracic tumors, patients with SDTT displayed a higher tumor mutation burden (TMB) and associated with a shorter median OS (16.8 months vs. Not reached; P < 0.001). Notably, SMARCA4 protein deficiency, rather than genetic mutations, played a decisive role in these differences. SDTT is generally resistant to chemotherapy, while sensitive to chemoimmunotherapy (median PFS: 7.5 vs. 3.5 months, P < 0.001). In particular, patients with SMARCA4 deficient thoracic tumors treated with paclitaxel-based chemoimmunotherapy achieved a longer median PFS than those with pemetrexed-based chemoimmunotherapy (10.0 vs. 7.3 months, P = 0.028). CONCLUSIONS: SMARCA4 protein deficiency, rather than genetic mutations, played a decisive role in its characteristics of higher TMB and poor prognosis. Chemoimmunotherapy serves as the optimal option in the current treatment regimen. Paclitaxel-based chemoimmunotherapy performed better than those with pemetrexed-based chemoimmunotherapy.

α-Pyrone mediates quorum sensing through the conservon system in Nocardiopsis sp.

Actinobacteria produce a plethora of bioactive secondary metabolites that are often regulated by quorum-sensing signaling molecules via specific binding to their cognate TetR-type receptors. Here, we identified monocyclic α-pyrone as a new class of actinobacterial signaling molecules influencing quorum sensing process in Nocardiopsis sp. LDBS0036, primarily evidenced by a significant reduction in the production of phenazines in the pyrone-null mutant compared to the wild-type strain. Exogenous addition of the α-pyrone can partially restore the expression of some pathways to the wild strain level. Moreover, a unique multicomponent system referred to as a conservon, which is widespread in actinobacteria and generally contains four or five functionally conserved proteins, may play an important role in detecting and transmitting α-pyrone signals in LDBS0036. We found the biosynthetic gene clusters of α-pyrone and their associated conservon genes are highly conserved in Nocardiopsis, indicating the widespread prevalence and significant function of this regulate mechanism within Nocardiopsis genus. Furthermore, homologous α-pyrones from different actinobacterial species were also found to mediate interspecies communication. Our results thus provide insights into a novel quorum-sensing signaling system and imply that various modes of bacterial communication remain undiscovered.

Family cumulative risk, life satisfaction, and anxiety and depression in adolescents: A developmental cascades model.

INTRODUCTION: Family cumulative risk (FCR) is predominantly regarded as an antecedent for adolescent mental health, as the prevailing perspective continues to emphasize the influential role of parents, despite recognizing the child's influence. To identify the interplay between family adversity (FCR, process-related FCR, and sociodemographic-related FCR), life satisfaction (LS), and anxiety and depression (AD), this study examined the cascade effects among these constructs. METHOD: Participants (N = 707; 52.9% male; grades 10 and 11) from four high schools in Wuhan, China, were recruited to participate, and they completed the measures in October 2018, April 2019, and November 2019. Family sociodemographic risk (e.g., single parenthood) and family process risk (e.g., low family cohesion) were simulated in the models for FCR, sociodemographic-related FCR, and process-related FCR. RESULTS: The random intercept cross-lagged panel models (RI-CLPMs) revealed a lagged effect from LS to FCR; lagged effects from LS and AD to process-related FCR at the within-person level; and significant associations between LS, AD, and family adversity at the between-person level. CONCLUSIONS: The lagged effects provide evidence for the influential child perspective and suggest that FCR and family process risk are sensitive to adolescent well-being and psychopathological symptoms. School mental health prevention and intervention programs that take a complete mental health approach to enhance children's well-being and alleviate symptoms would help prevent increases in family risk.

Discovering Intrinsic Subgoals for Vision-and-Language Navigation via Hierarchical Reinforcement Learning.

Vision-and-language navigation requires an agent to navigate in a photo-realistic environment by following natural language instructions. Mainstream methods employ imitation learning (IL) to let the agent imitate the behavior of the teacher. The trained model will overfit the teacher's biased behavior, resulting in poor model generalization. Recently, researchers have sought to combine IL and reinforcement learning (RL) to overcome overfitting and enhance model generalization. However, these methods still face the problem of expensive trajectory annotation. We propose a hierarchical RL-based method-discovering intrinsic subgoals via hierarchical (DISH) RL-which overcomes the generalization limitations of current methods and gets rid of expensive label annotations. First, the high-level agent (manager) decomposes the complex navigation problem into simple intrinsic subgoals. Then, the low-level agent (worker) uses an intrinsic subgoal-driven attention mechanism for action prediction in a smaller state space. We place no constraints on the semantics that subgoals may convey, allowing the agent to autonomously learn intrinsic, more generalizable subgoals from navigation tasks. Furthermore, we design a novel history-aware discriminator (HAD) for the worker. The discriminator incorporates historical information into subgoal discrimination and provides the worker with additional intrinsic rewards to alleviate the reward sparsity. Without labeled actions, our method provides supervision for the worker in the form of self-supervision by generating subgoals from the manager. The final results of multiple comparison experiments on the Room-to-Room (R2R) dataset show that our DISH can significantly outperform the baseline in accuracy and efficiency.

DDIT3 aggravates TMJOA cartilage degradation via Nrf2/HO-1/NLRP3-mediated autophagy.

OBJECTIVE: DNA damage-inducible transcript 3 (DDIT3), as a downstream transcription factor of endoplasmic reticulum stress, is reported to regulate chondrogenic differentiation under physiological and pathological state. However, the specific involvement of DDIT3 in the degradation of condylar cartilage of temporomandibular joint osteoarthritis (TMJOA) is unclarified. DESIGN: The expression patterns of DDIT3 in condylar cartilage from monosodium iodoacetate-induced TMJOA mice were examined to uncover the potential role of DDIT3 in TMJOA. The Ddit3 knockout (Ddit3-/-) mice and their wildtype littermates (Ddit3+/+) were used to clarify the effect of DDIT3 on cartilage degradation. Primary condylar chondrocytes and ATDC5 cells were applied to explore the mechanisms of DDIT3 on autophagy and extracellular matrix (ECM) degradation in chondrocytes. The autophagy inhibitor chloroquine (CQ) was used to determine the effect of DDIT3-inhibited autophagy in vivo. RESULTS: DDIT3 were highly expressed in condylar cartilage from TMJOA mice. Ddit3 knockout alleviated condylar cartilage degradation and subchondral bone loss, compared with their wildtype littermates. In vitro study demonstrated that DDIT3 exacerbated ECM degradation in chondrocytes induced by TNF-α through inhibiting autophagy. The intraperitoneal injection of CQ further confirmed that Ddit3 knockout alleviated cartilage degradation in TMJOA through activating autophagy in vivo. CONCLUSIONS: Our findings identified the crucial role of DDIT3-inhibited autophagy in condylar cartilage degradation during the development of TMJOA.

Association of dietary nutrient intake with type 2 diabetes: A Mendelian randomization study.

Observational research suggests that the evidence linking dietary nutrient intake (encompassing minerals, vitamins, amino acids, and unsaturated fatty acids) to type 2 diabetes (T2D) is both inconsistent and limited. This study aims to explore the potential causal relationship between dietary nutrients and T2D. Causal estimation utilized Mendelian randomization techniques. Single nucleotide polymorphisms linked to dietary nutrients were identified from existing genome-wide association studies and used as instrumental variables. Genome-wide association studies data pertinent to T2D were sourced from the DIMANTE consortium and the FinnGen database. Techniques including inverse variance weighting (IVW), weighted mode, weighted median, and Mendelian randomization-Egger were employed for causal inference, complemented by sensitivity analysis. Genetically predicted higher phenylalanine (IVW: odds ratio = 1.10 95% confidence interval 1.04-1.17, P = 1.5 × 10-3, q_pval = 3.4 × 10-2) and dihomo-gamma-linolenic acid (IVW: odds ratio = 1.001 95% confidence interval 1.0006-1.003, P = 3.7 × 10-3, q_pval = 4.1 × 10-2) levels were directly associated with T2D risk. Conversely, no causal relationships between other nutrients and T2D were established. We hypothesize that phenylalanine and dihomo-gamma-linolenic acid contribute to the pathogenesis of T2D. Clinically, the use of foods with high phenylalanine content may pose potential risks for patients with a heightened risk of T2D. Our study provides evidence supporting a causal link between dietary nutrient intake and the development of T2D.

Coupled processes involving ammonium inputs, microbial nitrification, and calcite dissolution control riverine nitrate pollution in the piedmont zone (Qingshui River, China).

Rivers in agricultural countries widely suffer from diffuse nitrate (NO3-) pollution. Although pollution sources and fates of riverine NO3- have been reported worldwide, the driving mechanisms of riverine NO3- pollution associated with mineral dissolution in piedmont zones remain unclear. This study combined hydrogeochemical compositions, stable isotopes (δ18O-NO3-, δ15N-NO3-, δ18O-H2O, and δ2H-H2O), and molecular bioinformation to determine the pollution sources, biogeochemical evolution, and natural attenuation of riverine NO3- in a typical piedmont zone (Qingshui River). High NO3- concentration (37.5 ± 9.44 mg/L) was mainly observed in the agricultural reaches of the river, with ~15.38 % of the samples exceeding the acceptable limit for drinking purpose (44 mg/L as NO3-) set by the World Health Organization. Ammonium inputs, microbial nitrification, and HNO3-induced calcite dissolution were the dominant driving factors that control riverine NO3- contamination in the piedmont zone. Approximately 99.4 % of riverine NO3- contents were derived from NH4+-containing pollutants, consisted of manure & domestic sewage (74.0 % ± 13.0 %), NH4+-synthetic fertilizer (16.1 % ± 8.99 %), and soil organic nitrogen (9.35 % ± 4.49 %). These NH4+-containing pollutants were converted to HNO3 (37.2 ± 9.38 mg/L) by nitrifying bacteria, and then the produced HNO3 preferentially participated in the carbonate (mainly calcite) dissolution, which accounted for 40.0 % ± 12.1 % of the total riverine Ca2+ + Mg2+, also resulting in the rapid release of NO3- into the river water. Thus, microbial nitrification could be a new and non-negligible contributor of riverine NO3- pollution, whereas the involvement of HNO3 in calcite dissolution acted as an accelerator of riverine NO3- pollution. However, denitrification had lesser contribution to natural attenuation for high NO3- pollution. The obtained results indicated that the mitigation of riverine NO3- pollution should focus on the management of ammonium discharges, and the HNO3-induced carbonate dissolution needs to be considered in comprehensively understanding riverine NO3- pollution in piedmont zones.

In Situ Sprayed Exosome-Cross-Linked Gel as Artificial Lymph Nodes for Postoperative Glioblastoma Immunotherapy.

One key challenge in postoperative glioblastoma immunotherapy is to guarantee a potent and durable T-cell response, which is restricted by the immunosuppressive microenvironment within the lymph nodes (LNs). Here, we develop an in situ sprayed exosome-cross-linked gel that acts as an artificial LN structure to directly activate the tumor-infiltrating T cells for prevention of glioma recurrence. Briefly, this gel is generated by a bio-orthogonal reaction between azide-modified chimeric exosomes and alkyne-modified alginate polymers. Particularly, these chimeric exosomes are generated from dendritic cell (DC)-tumor hybrid cells, allowing for direct and robust T-cell activation. The gel structure with chimeric exosomes as cross-linking points avoids the quick clearance by the immune system and thus prolongs the durability of antitumor T-cell immunity. Importantly, this exosome-containing immunotherapeutic gel provides chances for ameliorating functions of antigen-presenting cells (APCs) through accommodating different intracellular-acting adjuvants, such as stimulator of interferon genes (STING) agonists. This further enhances the antitumor T-cell response, resulting in the almost complete elimination of residual lesions after surgery. Our findings provide a promising strategy for postsurgical glioma immunotherapy that warrants further exploration in the clinical arena.

Urbanization promotes carbon storage or not? The evidence during the rapid process of China.

China's commitment to attaining carbon neutrality by 2060 has galvanized research into carbon sequestration, a critical approach for mitigating climate change. Despite the rapid urbanization observed since the turn of the millennium, a comprehensive analysis of how urbanization influences urban carbon storage throughout China remains elusive. Our investigation delves into the nuanced effects of urbanization on carbon storage, dissecting both the direct and indirect influences by considering urban-suburban gradients and varying degrees of urban intensity. We particularly scrutinize the roles of climatic and anthropogenic factors in mediating the indirect effects of urbanization on carbon storage. Our findings reveal that urbanization in China has precipitated a direct reduction in carbon storage by approximately 13.89 Tg of carbon (Tg C). Remarkably, urban sprawl has led to a diminution of vegetation carbon storage by 8.65 Tg C and a decrease in soil carbon storage by 5.24 Tg C, the latter resulting from the sequestration of impervious surfaces and the elimination of organic matter inputs following vegetation removal. Meanwhile, carbon storage in urban greenspaces has exhibited an increase of 6.90 Tg C and offsetting 49.70% of the carbon loss induced by direct urbanization effects. However, the indirect effects of urbanization predominantly diminish carbon storage in urban greenspaces by an average of 5.40%. The degree of urban vegetation management emerges as a pivotal factor influencing the indirect effects of urbanization on carbon storage. To bolster urban carbon storage, curbing urban sprawl and augmenting urban green spaces are imperative strategies. Insights from this study are instrumental in steering sustainable urban planning and advancing towards the goal of carbon neutrality.

A Vision/Inertial Navigation/Global Navigation Satellite Integrated System for Relative and Absolute Localization in Land Vehicles.

This paper presents an enhanced ground vehicle localization method designed to address the challenges associated with state estimation for autonomous vehicles operating in diverse environments. The focus is specifically on the precise localization of position and orientation in both local and global coordinate systems. The proposed approach integrates local estimates generated by existing visual-inertial odometry (VIO) methods into global position information obtained from the Global Navigation Satellite System (GNSS). This integration is achieved through optimizing fusion in a pose graph, ensuring precise local estimation and drift-free global position estimation. Considering the inherent complexities in autonomous driving scenarios, such as the potential failures of a visual-inertial navigation system (VINS) and restrictions on GNSS signals in urban canyons, leading to disruptions in localization outcomes, we introduce an adaptive fusion mechanism. This mechanism allows seamless switching between three modes: utilizing only VINS, using only GNSS, and normal fusion. The effectiveness of the proposed algorithm is demonstrated through rigorous testing in the Carla simulation environment and challenging UrbanNav scenarios. The evaluation includes both qualitative and quantitative analyses, revealing that the method exhibits robustness and accuracy.

Development and Evaluation of a Water-Free In Situ Depot Gel Formulation for Long-Acting and Stable Delivery of Peptide Drug ACTY116.

In situ depot gel is a type of polymeric long-acting injectable (pLAI) drug delivery system; compared to microsphere technology, its preparation process is simpler and more conducive to industrialization. To ensure the chemical stability of peptide ACTY116, we avoided the use of harsh conditions such as high temperatures, high shear mixing, or homogenization; maintaining a water-free and oxygen-free environment was also critical to prevent hydrolysis and oxidation. Molecular dynamics (MDs) simulations were employed to assess the stability mechanism between ACTY116 and the pLAI system. The initial structure of ACTY116 with an alpha helix conformation was constructed using SYBYL-X, and the copolymer PLGA was generated by AMBER 16; results showed that PLGA-based in situ depot gel improved conformational stability of ACTY116 through hydrogen bonds formed between peptide ACTY116 and the components of the pLAI formulation, while PLGA (Poly(DL-lactide-co-glycolide)) also created steric hindrance and shielding effects to prevent conformational changes. As a result, the chemical and conformational stability and in vivo long-acting characteristics of ACTY116 ensure its enhanced efficacy. In summary, we successfully achieved our objective of developing a highly stable peptide-loaded long-acting injectable (LAI) in situ depot gel formulation that is stable for at least 3 months under harsh conditions (40 °C, above body temperature), elucidating the underlying stabilisation mechanism, and the high stability of the ACTY116 pLAI formulation creates favourable conditions for its in vivo pharmacological activity lasting for weeks or even months.

Enhanced immunosuppressive capability of mesenchymal stem cell-derived small extracellular vesicles with high expression of CD73 in experimental autoimmune uveitis.

BACKGROUND: Autoimmune uveitis is an inflammatory disease triggered by an aberrant immune response. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) are emerging as potential therapeutic agents for this condition. CD73, an ectoenzyme present on MSC-sEVs, is involved in mitigating inflammation by converting extracellular adenosine monophosphate into adenosine. We hypothesize that the inhibitory effect of MSC-sEVs on experimental autoimmune uveitis (EAU) could be partially attributed to the surface expression of CD73. METHODS: To investigate novel therapeutic approaches for autoimmune uveitis, we performed lentiviral transduction to overexpress CD73 on the surface of MSC-sEVs, yielding CD73-enriched MSC-sEVs (sEVs-CD73). Mice with interphotoreceptor retinoid-binding protein (IRBP)-induced EAU were grouped randomly and treated with 50 µg MSC-sEVs, vector infected MSC-sEVs, sEVs-CD73 or PBS via single tail vein injection. We evaluated the clinical and histological features of the induced mice and analyzed the proportion and functional capabilities of T helper cells. Furthermore, T-cells were co-cultured with various MSC-sEVs in vitro, and we quantified the resulting inflammatory response to assess the potential therapeutic benefits of sEVs-CD73. RESULTS: Compared to MSC-sEVs, sEVs-CD73 significantly alleviates EAU, leading to reduced inflammation and diminished tissue damage. Treatment with sEVs-CD73 results in a decreased proportion of Th1 cells in the spleen, draining lymph nodes, and eyes, accompanied by an increased proportion of regulatory T-cells (Treg cells). In vitro assays further reveal that sEVs-CD73 inhibits T-cell proliferation, suppresses Th1 cells differentiation, and enhances Treg cells proportion. CONCLUSION: Over-expression of CD73 on MSC-sEVs enhances their immunosuppressive effects in EAU, indicating that sEVs-CD73 has the potential as an efficient immunotherapeutic agent for autoimmune uveitis.

Amygdalin ameliorates alopecia areata on C3H/HeJ mice by inhibiting inflammation through JAK2/STAT3 pathway.

BACKGROUND: Evidence has demonstrated that Chinese medicine formula Xuefu Zhuyu decoction can markedly promote the formation of new hair in patients and mice with alopecia areata (AA). Amygdalin is one of the active components of Xuefu Zhuyu decoction, but its therapeutic effects and the underlying mechanisms on AA remains largely unrevealed. PURPOSE: Therefore, this study aims to investigate the therapeutic effects and to probe its molecular mechanisms of inflammation and immune regulation on AA model of C3H/HeJ mice. STUDY DESIGN: The C3H/HeJ female mice were divided into control, AA, rusolitinib (60 mg/kg), and amygdalin groups (60, 90, and 120 mg/kg, 0.2 ml/10 g, i.g.). METHODS: The optical microscope was used to observe the feature of the local skin, and the number of lanugo and terminal hair. H&E staining was performed to determine the degree of pathological damage to the skin. ELISA was performed to detect levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in mice serum. Flow cytometry was carried out to analyze the CD4+CD25+FOXP3+, CD4+ and CD8+ of skin tissue. And the levels of CD4+ and CD8+, p-JAK/JAK2, p-STAT3/STAT, and SOCS3 were detected by immunohistochemistry. Western blot and qRT-PCR were employed to examine the expression levels of IL-6, TNF-α, IFN-γ, JAK2, p-JAK, STAT, p-STAT3 and SOCS3 proteins and genes in skin tissues. RESULTS: Compared with AA group, amygdalin immensely increased the number of vellus hairs and decreased the number of terminal hairs determined by skin microscopy and H&E staining. ELISA, Western blot and qRT-PCR data showed that the levels of IL-6, TNF-α and IFN-γ in serum and skin tissues of AA mice were significantly increased, while amygdalin administration dramatically restrained the contents of the three pro-inflammatory factors. Flow cytometry and immunohistochemistry hinted that amygdalin observably enhanced the number of CD4+CD25+FOXP3+ and CD4+ cells, while inhibited the number of CD8+ positive cells in mice with AA. Moreover, amygdalin signally reduced JAK2/STAT3 pathway-related protein and gene levels in AA mice. CONCLUSION: Amygdalin could inhibit inflammatory response and improve immune function in the treatment of AA. The underlying molecular mechanism may be related to inhibition of JAK2/STAT3 pathway.

Characteristics of advanced anaerobic digestion sludge-based biochar and its application for sewage sludge conditioning.

The utilization of sludge-based biochar, characterized by abundant pore structures, proves advantageous in enhancing sludge dewatering performance. In this study, advanced anaerobic digestion sludge underwent pyrolysis to produce biochar, subsequently employed for sludge conditioning. Results revealed that biochar, obtained at 800 °C, exhibited the highest specific surface area (105.3 m2/g) and pore volume (0.17 cm3/g). As the pyrolysis temperature increased, the sludge's functional groups tended to aromatize. When used to condition sludge, particularly at a 20 % (dry solid) dosage, biochar significantly reduced sludge capillary suction time and floc size. The addition of biochar enhanced the conditioning effect of cationic polyacrylamide by absorbing extracellular polymeric substances, creating water molecule channels, and forming skeletons for sludge flocs. These findings introduce a novel approach to sludge reuse and provide valuable data supporting the use of biochar as a sludge conditioner.

CircZFR promotes colorectal cancer progression via stabilizing BCLAF1 and regulating the miR-3127-5p/RTKN2 axis.

Aberrant expression of circular RNAs (circRNAs) is frequently linked to colorectal cancer (CRC). Here, we identified circZFR as a promising biomarker for CRC diagnosis and prognosis. CircZFR was upregulated in CRC tissues and serum exosomes and its level was linked to cancer incidence, advanced-stages, and metastasis. In both in vitro and in vivo settings, circZFR promoted the growth and spread while suppressing apoptosis of CRC. Exosomes with circZFR overexpression promoted the proliferation and migration of cocultured CRC cells. Mechanistically, epithelial splicing regulatory protein 1 (ESRP1) in CRC cells may enhance the production of circZFR. BCL2-associated transcription factor 1 (BCLAF1) bound to circZFR, which prevented its ubiquitinated degradation. Additionally, circZFR sponged miR-3127-5p to boost rhotekin 2 (RTKN2) expression. Our TCP1-CD-QDs nanocarrier was able to carry and deliver circZFR siRNA (si-circZFR) to the vasculature of CRC tissues and cells, which inhibited the growth of tumors in patient-derived xenograft (PDX) models. Taken together, our results show that circZFR is an oncogenic circRNA, which promotes the development and spread of CRC in a BCLAF1 and miR-3127-5p-dependent manner. CircZFR is a possible serum biopsy marker for the diagnosis and a desirable target for further treatment of CRC.

Abietane diterpenoids from Caryopteris incana (Thunb.) Miq. And their HIF-2α inhibitory activities in vitro.

Eleven previously undescribed abietane-type diterpenoids, named caryopincanoids A-K (1-11), together with five known compounds, were isolated from the EtOH extract of the aerial parts of Caryopteris incana (Thunb.) Miq. Their structures were elucidated on the basis of comprehensive spectroscopic data, NMR calculations, and ECD calculations. The inhibitory activities of all compounds against HIF-2α gene expression in 786-O cells were tested by luciferase assay. Compounds 7, 9, 15, and 16 showed significant inhibitory effects with IC50 values ranging from 12.73 to 23.80 µM. The preliminary structure-activity relationship of these compounds was also discussed.

Structural mechanism of bacteriophage lambda tail's interaction with the bacterial receptor.

Bacteriophage infection, a pivotal process in microbiology, initiates with the phage's tail recognizing and binding to the bacterial cell surface, which then mediates the injection of viral DNA. Although comprehensive studies on the interaction between bacteriophage lambda and its outer membrane receptor, LamB, have provided rich information about the system's biochemical properties, the precise molecular mechanism remains undetermined. This study revealed the high-resolution cryo-electron microscopy (cryo-EM) structures of the bacteriophage lambda tail complexed with its irreversible Shigella sonnei 3070 LamB receptor and the closed central tail fiber. These structures reveal the complex processes that trigger infection and demonstrate a substantial conformational change in the phage lambda tail tip upon LamB binding. Providing detailed structures of bacteriophage lambda infection initiation, this study contributes to the expanding knowledge of lambda-bacterial interaction, which holds significance in the fields of microbiology and therapeutic development.

Effect of Dl-3-n-Butylphthalide on olfaction in rotenone-induced Parkinson's rats.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Olfactory dysfunction (OD) is an important nonmotor feature of PD. Dl-3-n-Butylphthalide (NBP) is a synthetic compound isolated from Apium graveolens seeds. The present study was conducted to investigate the effect of NBP on olfaction in rotenone-induced Parkinson's rats to explore the mechanism and pathway of OD in PD. Methods: The PD model was established using rotenone-induced SD rats, divided into blank control, model, and treatment groups. A sham group was also established, with 10 rats in each group. The treatment group was given NBP (1 mg/kg, 10 mg/kg, and 100 mg/kg, dissolved in soybean oil) intragastrically for 28 days. Meanwhile, the control group rats were given intra-gastrically soybean oil. After behavioral testing, all rats were executed, and brain tissue was obtained. Proteomics and Proteomic quantification techniques (prm) quantification were used to detect proteomic changes in rat brain tissues. Results: Compared with the control group, the model group showed significant differences in behavioral tests, and this difference was reduced after treatment. Proteomics results showed that after treatment with high-dose NBP, there were 42 differentially expressed proteins compared with the model group. Additionally, the olfactory marker (P08523) showed a significant upregulation difference. We then selected 22 target proteins for PRM quantification and quantified 17 of them. Among them, the olfactory marker protein was at least twofold upregulated in the RTH group compared to the model group.