Low-intensity pulsed ultrasound activated the anti-tumor immunity by irradiating the spleen of mice in 4 T-1 breast cancer.

Tumor immunotherapy is booming around the world. However, strategies to activate the immune system and alleviate the immunosuppression still need to be refined. Here, we demonstrate for the first time that low-intensity pulsed ultrasound (LIPUS, spatial average time average intensity (Isata) is 200 mW/cm2, frequency is 0.3 MHz, repetition frequency is 1 kHz, and duty cycle is 20%) triggers the immune system and further reverses the immunosuppressive state in the mouse models of breast cancer by irradiating the spleen of mice. LIPUS inhibited tumor growth and extended survival in mice with 4 T-1 tumors. Further studies had previously shown that LIPUS enhanced the activation of CD4+ and CD8+ T cells in the spleen and led to significant changes in cytokines, as well as induced upregulation of mRNA levels involved in multiple immune regulatory pathways in the spleen. In addition, LIPUS promoted tumor-infiltrating lymphocyte accumulation and CD8+ T cell activation and improved the dynamics of cytokines/chemokines in the tumor microenvironment, resulting in a reversal of the immunosuppressive state of the tumor microenvironment. These results suggest a novel approach to activate the immune response by irradiating the spleen with LIPUS.

Efficient synthesis of α-amino-vinylphosphine oxides from alkyl nitriles via manganese-catalyzed phosphinoenamination.

A protocol for the synthesis of α-amino-vinylphosphine oxides by phosphinoenamination reaction between alkyl nitriles and phosphine oxides was developed. The combination of Mn(OAc)2 as a Lewis acid and guanidine as a Lewis base was found to be an efficient catalytic system for this reaction. A series of alkyl nitriles and phosphine oxides are compatible with this conversion, furnishing the desired products in up to 95% yield under mild conditions. Furthermore, this method demonstrates the capability of gram-scale synthesis.

Pathogenicity of duck circovirus and novel goose parvovirus co-infection in SPF ducks.

Duck circovirus (DuCV) is one of the most prevalent infectious viruses in the duck industry in China. Although the clinical signs vary, it often causes immunosuppression in the host and leads to secondary infection with other pathogens. Novel goose parvovirus (NGPV) mainly infects ducks and causes short beak and dwarfism syndrome (SBDS) in ducks. However, the incidence of infection in ducks has increased in recent years, and the phenomenon of mixed infection with DuCV is common, resulting in more severe clinical morbidity. However, there are no systematic study evaluating the presence of mixed infections. In order to investigate the synergistic pathogenicity of DuCV and NGPV co-infection in SPF ducks, a comparative experiment between DuCV and NGPV co-infection and mono-infection animal models was established. The results showed that the clinical signs of short beak, dwarfism and immunosuppression were more obvious in DuCV and NGPV co-infected ducks; the tissue damage of target organs was more serious; and the viral titer of organs and cloacal swabs were more significant compared with those of SPF ducks infected with only one virus. The results indicated that co-infection with DuCV and NGPV could promote viral replication and cause more severe tissue damage and immunosuppression than single virus infection. The present study reveals that the co-infection of NGPV and DuCV has a synergistic pathogenic effect from the aspect of pathogenicity, and the conclusions drawn not only clarify the direction of the subsequent research on the mechanism of co-infection of NGPV and DuCV, but also provide a scientific basis for the research on the co-infection of immunosuppressive diseases and other diseases.

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications.

CDK9 is a cyclin-dependent kinase that plays pivotal roles in multiple cellular functions including gene transcription, cell cycle regulation, DNA damage repair, and cellular differentiation. Targeting CDK9 is considered an attractive strategy for antitumor therapy, especially for leukemia and lymphoma. Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials. However, many of them face challenges such as low clinical efficacy and multiple adverse reactions and may necessitate the exploration of novel strategies to lead to success in the clinic. In this perspective, we present a comprehensive overview of the structural characteristics, biological functions, and preclinical status of CDK9 inhibitors. Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

Estimating Efficacy of Conversion Therapy on Patients with Initially Unresectable Colorectal Cancer Liver Metastases by using MRI: Development of a Predictive Score.

RATIONALE AND OBJECTIVES: The conversion success rate (CSR) has crucial implication for clinical outcomes of initially unresectable colorectal liver metastases (CRLM) following conversion therapy. This study aimed to develop a simple predictive scoring model for identifying CSR according to baseline magnetic resonance imaging (MRI) features, and confirm its performance and prognostic significance in a validation cohort. METHODS: A total of 155 consecutive patients with initially unresectable CRLM were retrospectively reviewed in the study. A simple MRI-based predictive scoring model for identifying CSR was developed in the development cohort (n = 104) by using multivariable logistic regression analyzes. The diagnostic performance was evaluated for the predictive score. Thereafter, patients in the validation cohort (n = 51) were stratified into groups with predicted high CSR or low CSR according to the score. The progression-free survival (PFS) and overall survival (OS) were compared between two groups using the log-rank test. RESULTS: The predictive score of CSR, named mrNISE, incorporated the number of CRLM ≥ 10, the largest size ≥ 50 mm, poorly defined tumor-liver interface, and peritumoral enhancement. The AUC of the mrNISE score was 0.845 for the development cohort and 0.776 for the validation cohort. According to the score, patients with predicted high CSR had better PFS and OS than those with low CSR in both development and validation cohorts. CONCLUSION: The predictive score demonstrated great performance for identifying CSR of initially unresectable CRLM. Stratifying patients by the score, personalized treatment goals can be formulated before conversion therapy to improve clinical prognosis and reduce adverse events caused by ineffective treatment.

Disentangling microbial niche balance and intermediates' trade-offs for anaerobic digestion stability and regulation.

Anaerobic digestion (AD) is a key technology for converting organic matters to methane-rich biogas. However, nutrient imbalance can destabilize the whole digestion. To realize stable operation of AD and improve its efficiency, this work considers a new strategy to control the intermediate concentrations of poor AD under nutrient stress. For this purpose, long-term digestion under different nutrient conditions was investigated. Results showed that the feedstock with a low C/N ratio (= 6) caused VFA accumulation (2072 ± 632 mg/L), leading to the inhibition of methane production. Employing a substrate with a higher C/N ratio (= 11) and/or adding NH4HCO3 (200 mg NH4+-N/Ladd) could alleviate the VFA inhibition, but excessive dosage of NH4HCO3 would induce ammonia inhibition. Through the established digestion balance between free ammonia nitrogen (FAN) between 0 and 25 mg/L, volatile fatty acid (VFA) 510-2100 mg/L, and alkalinity (ALK) 3300-7800 mg/L, an efficient methane yield of 150-250 mL/g VS was achieved and stable operation of AD under nutrient stress (low C/N ratio) was realized. Metabolic reconstruction between Euryarchaeota sp. MAG162, Methanosarcina mazei MAG53 and Mesotoga infera MAG119 highlighted that microbial niche balance was developed as a result of digestion balance, which is beneficial for stable operation of AD. These findings improved our understanding of the interaction mechanism between intermediates and microbial niches for stability control in AD.

Moiré effect enables versatile design of topological defects in nematic liquid crystals.

Recent advances in surface-patterning techniques of liquid crystals have enabled the precise creation of topological defects, which promise a variety of emergent applications. However, the manipulation and application of these defects remain limited. Here, we harness the moiré effect to engineer topological defects in patterned nematic liquid crystal cells. Specifically, we combine simulation and experiment to examine a nematic cell confined between two substrates of periodic surface anchoring patterns; by rotating one surface against the other, we observe a rich variety of highly tunable, novel topological defects. These defects are shown to guide the three-dimensional self-assembly of colloids, which can conversely impact defects by preventing the self-annihilation of loop-defects through jamming. Finally, we demonstrate that certain nematic moiré cells can engender arbitrary shapes represented by defect regions. As such, the proposed simple twist method enables the design and tuning of mesoscopic structures in liquid crystals, facilitating applications including defect-directed self-assembly, material transport, micro-reactors, photonic devices, and anti-counterfeiting materials.

Association between serum galectin-3 and chronic obstructive pulmonary disease: A meta-analysis.

Chronic obstructive pulmonary disease (COPD) is a significant public health issue characterized by progressive and irreversible airflow limitation. The aim of this meta-analysis was to determine the association between changes in serum galectin-3 levels and COPD and to assess the relationship between serum galectin-3 levels and acute exacerbations of COPD (AECOPD). Relevant observational studies were retrieved from electronic databases, including PubMed, Web of Science, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI). A random-effects model was used to combine the data, incorporating the influence of between-study heterogeneity. Twelve case-control studies were included. The pooled results showed a significantly higher serum level of galectin-3 in patients with COPD compared to controls (standardized mean difference [SMD] 0.60; 95% confidence interval [CI] 0.40 - 0.80; P < 0.001; I2 = 68%). Further meta-analysis suggested higher levels of serum galectin-3 in patients with AECOPD compared to those with stable COPD (SMD 0.33; 95% CI 0.20 - 0.46; P < 0.001; I2 = 0%). Subgroup analyses according to the mean age of the participants, the proportion of males, and study quality scores did not significantly change the results (P for subgroup differences all > 0.05). In conclusion, patients with COPD were found to have higher serum levels of galectin-3, with levels further elevated in patients with AECOPD compared to those with stable COPD.

Pathogenicity studies and molecular characterization of DPV infection in ducklings.

In the spring of 2023, 10 to 21-day-old chicks in a broiler duck farm in Shandong Province, China, developed swelling of the head and neck, moist eyes with mucous discharge, difficulty in walking, shrinking of the neck, and loose and disorganized coat. Anatomical observation revealed hemorrhages in the esophageal mucosa, myocardium, and liver, and severe hemorrhages in the trachea with copious inflammatory secretions. Soon after, similar symptoms appeared in a large number of ducks in the flock, which eventually led to the elimination of all the 20,000-odd newly introduced ducklings on the farm, resulting in huge economic losses. We detected duck plague virus in the tissues of liver, spleen and lungs of diseased and dead ducks, and successfully isolated the pathogenic strain, named SD423, by inoculating duck embryos and inoculating duck embryo fibroblasts. We successfully conducted animal regression experiments with the isolated strain, and the experimental animals in the 1 d of age group showed symptoms of swollen eyes and tearing, shrinking of the neck, crouching, and hemorrhage in organs such as the liver and intestines successively from the 3rd d. We sequenced the whole genome of the isolated duck plague strain, and by comparing the homology with the published duck plague virus whole sequences in Genbank, the virus strain obtained in this study had the highest homology with the Chinese virulent strain SD (MN518864.1), with nucleotide (nt) homology of about 99.90% and amino acid (aa) homology of about 99.75%, which indicated that the isolate is a virulent strain. Previously, it was reported that the natural infection of duck plague virus mainly occurs above 30 d of age, but the duck plague virus found in this study can naturally infect ducklings up to 20 d of age, and the mortality rate is as high as 100%. In this study, the pathogenicity test and whole genome sequence analysis of this isolate provided data support and theoretical basis for further research on pathogenicity and virulence-related gene analysis of duck plague virus.

A Highly Selective Implantable Electrochemical Fiber Sensor for Real-Time Monitoring of Blood Homovanillic Acid.

Homovanillic acid (HVA) is a major dopamine metabolite, and blood HVA is considered as central nervous system (CNS) dopamine biomarker, which reflects the progression of dopamine-associated CNS diseases and the behavioral response to therapeutic drugs. However, facing blood various active substances interference, particularly structurally similar catecholamines and their metabolites, real-time and accurate monitoring of blood HVA remains a challenge. Herein, a highly selective implantable electrochemical fiber sensor based on a molecularly imprinted polymer is reported to accurately monitor HVA in vivo. The sensor exhibits high selectivity, with a response intensity to HVA 12.6 times greater than that of catecholamines and their metabolites, achieving 97.8% accuracy in vivo. The sensor injected into the rat caudal vein tracked the real-time changes of blood HVA, which paralleled the brain dopamine fluctuations and indicated the behavioral response to dopamine increase. This study provides a universal design strategy for improving the selectivity of implantable electrochemical sensors.

Diet-Wide Association Study for the Incidence of Type 2 Diabetes Mellitus in Community-Dwelling Adults Using the UK Biobank Data.

This longitudinal study used diet-wide association studies (DWAS) to investigate the association between diverse dietary food and nutrient intakes and the onset of type 2 diabetes mellitus (T2DM). Out of 502,505 participants from the UK Biobank, 119,040 with dietary data free of T2DM at the baseline were included, and 3241 developed T2DM during a median follow-up of 11.7 years. The DWAS analysis, which is based on Cox regression models, was used to analyse the associations between dietary food or nutrient intake factors and T2DM risk. The study found that 10 out of 225 dietary factors were significantly associated with the T2DM risk. Total alcohol (HR = 0.86, 0.85-0.92, p = 1.26 × 10-32), red wine (HR = 0.89, 0.88-0.94, p = 7.95 × 10-19), and fresh tomatoes (HR = 0.92, 0.89-0.94, p = 2.3 × 10-11) showed a negative association with T2DM risk, whereas sliced buttered bread exhibited a positive association. Additionally, 5 out of 21 nutrient intake variables revealed significant associations with the T2DM risk, with iron having the highest protective effect and starch as a risk factor. In conclusion, DWAS is an effective method for discovering novel associations when exploring numerous dietary variables simultaneously and could provide valuable insight into future dietary guidance for T2DM.