Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile.

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

Efficacy of transcatheter arterial embolization in treating nonvariceal gastric remnant bleeding: a retrospective 5-year study.

BACKGROUND: Gastric remnant bleeding is a special case of upper gastrointestinal bleeding with certain specific disease characteristics, and some matters of transcatheter arterial embolization (TAE) for hemostasis need attention. In this study, we aimed to explore the clinical use of TAE in patients with nonvariceal gastric remnant bleeding and identify the factors influencing the clinical efficacy of these interventions. METHODS: Data were retrospectively analyzed from 42 patients for whom angiography and embolization were performed but could not be treated endoscopically or had failed endoscopic management in our department between January 2018 and January 2023 due to nonvariceal gastric remnant bleeding. We investigated the relationship between the incidence of re-bleeding and the following variables: sex, age, pre-embolization gastroscopy/contrast-enhanced computer tomography, embolization method, aortography performance, use of endoscopic titanium clips, and the presence of collateral gastric-supplying arteries. RESULTS: Forty-two patients underwent 47 interventional embolizations. Of these, 16 were positive for angiographic findings, and 26 were negative. Based on arteriography results, different embolic agents were selected, and the technical success rate was 100%. The incidence of postoperative re-bleeding was 19.1% (9/47), and the overall clinical success rate was 81.0% (34/42). Logistic regression analysis of the relationship between the incidence of early re-bleeding following embolization and the proportion of collateral gastric supply arteries revealed an odds ratio of 10.000 (p = 0.014). CONCLUSIONS: Utilizing TAE for nonvariceal gastric remnant bleeding is safe and effective. The omission of collateral gastric-supplying arteries can lead to early re-bleeding following an intervention.

Single-Cell Analysis Identifies NOTCH3-Mediated Interactions between Stromal Cells That Promote Microenvironment Remodeling and Invasion in Lung Adenocarcinoma.

Cancer immunotherapy has revolutionized the treatment of lung adenocarcinoma (LUAD); however, a significant proportion of patients do not respond. Recent transcriptomic studies to understand determinants of immunotherapy response have pinpointed stromal-mediated resistance mechanisms. To gain a better understanding of stromal biology at the cellular and molecular level in LUAD, we performed single-cell RNA sequencing of 256,379 cells, including 13,857 mesenchymal cells, from 9 treatment-naïve patients. Among the mesenchymal cell subsets, FAP+PDPN+ cancer-associated fibroblasts (CAF) and ACTA2+MCAM+ pericytes were enriched in tumors and differentiated from lung-resident fibroblasts. Imaging mass cytometry revealed that both subsets were topographically adjacent to the perivascular niche and had close spatial interactions with endothelial cells (EC). Modeling of ligand and receptor interactomes between mesenchymal and ECs identified that NOTCH signaling drives these cell-to-cell interactions in tumors, with pericytes and CAFs as the signal receivers and arterial and PLVAPhigh immature neovascular ECs as the signal senders. Either pharmacologically blocking NOTCH signaling or genetically depleting NOTCH3 levels in mesenchymal cells significantly reduced collagen production and suppressed cell invasion. Bulk RNA sequencing data demonstrated that NOTCH3 expression correlated with poor survival in stroma-rich patients and that a T cell-inflamed gene signature only predicted survival in patients with low NOTCH3. Collectively, this study provides valuable insights into the role of NOTCH3 in regulating tumor stroma biology, warranting further studies to elucidate the clinical implications of targeting NOTCH3 signaling. SIGNIFICANCE: NOTCH3 signaling activates tumor-associated mesenchymal cells, increases collagen production, and augments cell invasion in lung adenocarcinoma, suggesting its critical role in remodeling tumor stroma.

Analysis of prognostic factors in patients diagnosed with bladder cancer complicated by hemorrhage treated by drug-eluting bead embolization.

Background: Transcatheter bladder arterial chemoembolization (TACE) is an alternative treatment used to control bladder cancer (BC) with bleeding, especially in older adult patients with comorbidities. This retrospective observational study evaluated the effect and prognostic factors of transcatheter drug-eluting bead (DEB) embolization in patients with advanced BC. Methods: We assessed 39 patients diagnosed with BC with hemorrhage who were either inoperable or unwilling to undergo surgery at our hospital between January 2018 and October 2022. All patients underwent TACE by DEB loaded with epirubicin and imaging scans after 2 months to evaluate the curative effect according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) standard to determine treatment. Re-examination and follow-up were performed every 3-6 months to observe hematuria recurrence and the curative effect. Results: A total of 95 interventional treatments were performed in 39 patients, and all participants achieved complete hemostasis within 5 days after the first intervention. Computed tomography or magnetic resonance imaging showed that the total effective rate [complete response (CR) + partial response (PR)] was 64.1%, and the disease benefit rate (CR +PR + stable disease) was 79.5%. A total of 30 patients (76.9%) had no hematuria recurrence. Logistic regression analysis indicated that the type of blood supply in BC may relate to whether the patients benefited from the intervention. Hematuria recurrence was significantly associated with the total number of tumors and the type of blood supply (P<0.05). Conclusions: Superselective embolization of bladder arteries with DEB can be used to treat BC with hemorrhage. However, hypovascular tumor blood supply may result in poor postoperative efficacy and hematuria recurrence. Additionally, multiple bladder tumors may be a risk factor for hematuria recurrence.

Clinical features of febrile seizures in children with COVID-19: an observational study from a tertiary care hospital in China.

Background: Febrile seizures are a common neurologic manifestation in children with coronavirus disease 2019 (COVID-19). Compared to seasonal respiratory viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a pronounced neurological impact, with the result that febrile seizures with COVID-19 may exhibit unique clinical features. Materials and methods: We conducted a retrospective study in a tertiary care hospital in China. We collected medical record information on febrile seizures with COVID-19, including demographic characteristics, clinical features, laboratory tests, and disease burden. Subsequently, the data were then analyzed descriptively. Results: A total of 103 children diagnosed with febrile seizures and positive COVID-19 PCR results were included in our study. Among them, 81 (78.6%) were males and 22 (21.4%) were females. The age of onset of febrile seizures ranged from 14 to 57 months, with a mean age of 34.9 ± 6.24 months. Complex febrile seizures were observed in 34 (33%) cases. Antiseizure medications were administered to 24 (23.3%) patients. Laboratory tests showed a white blood cell count of (27.05 ± 8.20) × 103/µl, a neutrophil count of (20.09 ± 5.66) × 103/µl and a lymphocyte count of (6.44 ± 1.86) × 103/µl. A creatine kinase level was significantly elevated, with a mean value of (412.00 ± 158.96) U/L. The mean length of stay was 4.36 days. Twelve patients (11.7%) required intensive care services, but there were no deaths or patients remaining on antiseizure medications after discharge. Conclusion: In the post-epidemic era of COVID-19, pediatric clinicians should be aware of the changing clinical features of febrile seizures associated with COVID-19. The average age of onset has increased, with a higher proportion of males. Length of stay and hospitalization costs did not increase significantly. The prognosis remained favorable, although a small number of children required intensive care services during the acute phase.

Practical Real-Time Phase Drift Compensation Scheme for Quantum Communication Systems.

Quantum communication systems are susceptible to various perturbations and drifts arising from the operational environment, with phase drift being a crucial challenge. In this paper, we propose an efficient real-time phase drift compensation scheme in which only existing data from the quantum communication process is used to establish a stable closed-loop control subsystem for phase tracking. This scheme ensures the continuous operation of transmission by tracking and compensating for phase drift in the phase-encoding quantum communication system. The experimental results demonstrate the effectiveness and feasibility of the proposed scheme with an average quantum bit error rate of 1.60% and a standard deviation of 0.0583% for 16 h of continuous operation.

Hypersensitive C-reactive protein as a potential indicator for predicting left ventricular hypertrophy in elderly community-dwelling patients with hypertension.

BACKGROUND: The aim of this study was to investigate the relationship between Hypersensitive C-reactive protein (hs-CRP) and left ventricular hypertrophy (LVH) in elderly community-dwelling patients with hypertension. METHODS: A cross-sectional study was conducted, involving the recruitment of 365 elderly hypertensive residents ≥ 65 years of age from five communities. The participants were divided into two groups: an LVH group (n = 134) and a non-LVH group (n = 231), based on the left ventricular mass index (LVMI) determined by echocardiography. Spearman correlation analysis was used to assess the relationship between hs-CRP and LVH. Univariate and Multivariate analysis was performed to detect variables associated with LVH. The diagnostic value of hs-CRP for LVH was expressed as the area under the receiver operating characteristic (ROC) curve. RESULTS: The incidence of LVH in elderly hypertension patients in the community was 36.7%. The hs-CRP levels were significantly higher in subjects with LVH compared to those without LVH (1.9 [0.8, 2.9] vs. 0.7 [0.4, 1.4], P = 0.002). Spearman correlation analysis demonstrated a positive correlation between hs-CRP and LVMI (r = 0.246, P < 0.001), as well as with IVST (r = 0.225, P < 0.001) and LVPWT (r = 0.172, P = 0.001). Among elderly hypertensive residents in the community, the cut-off value of hs-CRP for diagnosing LVH was 1.25 mg/L (sensitivity: 57.5%; specificity: 78.4%), and the area under the ROC curve for hs-CRP to predict LVH was 0.710 (95%CI: 0.654-0.766; P < 0.001). In the final model, hs-CRP ≥ 1.25 mg/L (OR = 3.569; 95%CI, 2.153-5.916; P<0.001) emerged as an independent risk factor for LVH. This association remained significant even after adjusting for various confounding factors (adjusted OR = 3.964; 95%CI, 2.323-6.765; P < 0.001). CONCLUSIONS: This community-based cohort of elderly hypertensive individuals demonstrates a strong association between hs-CRP levels and the presence of LVH. The hs-CRP ≥ 1.25 mg/L may serve as an independent predictor for LVH in hypertensive subjects and exhibit good diagnostic efficacy for LVH.

Genetically Determined Rheumatoid Arthritis May Not Affect Heart Failure: Insights from Mendelian Randomization Study.

Background: Evidence from observational epidemiological studies indicated that rheumatoid arthritis (RA) increased the risk of heart failure (HF). However, there is a possibility that the correlation is not explained as a causative role for RA in the pathogenesis of HF. A two-sample Mendelian randomization (MR) framework was designed to explore the potential etiological role of RA in HF to identify the target to improve the burden of HF disease. Methods: To assess the causal association between RA and HF, we analyzed summary statistics from genome-wide association studies (GWASs) for individuals of European descent. Genetic instruments for RA were identified at a genome-wide significance threshold (p < 5 × 10-8). Corresponding data were obtained from a GWAS meta-analysis (95,524 cases and 1,270,968 controls) to identify genetic variants underlying HF. MR estimates were pooled using the inverse variance weighted method. Complementary analyses were conducted to assess the robustness of the results. Results: There was no evidence of a causal association between genetically predicted RA and HF [odds ratio (OR), 1.00; 95% confidence interval (CI), 0.99-1.02; P = 0.60]. Various sensitivity analyses suggested no pleiotropy detected (all p > 0.05). Conclusion: Our findings did not support the causal role of RA in the etiology of HF. As such, therapeutics targeted at the control of RA may have a lower likelihood of effectively controlling the occurrence of HF.

Effects of Solid Fermentation on Polygonatum cyrtonema Polysaccharides: Isolation, Characterization and Bioactivities.

Polygonati Rhizoma is a widely used traditional Chinese medicine (TCM) with complex pre-processing steps. Fermentation is a common method for processing TCM to reduce herb toxicity and enhance their properties and/or produce new effects. Here, in this study, using Bacillus subtilis and Saccharomyces cerevisiae, we aimed to evaluate the potential application of solid fermentation in isolating different functional polysaccharides from Polygonatum cyrtonema Hua. With hot water extraction, ethanol precipitation, DEAE anion exchange chromatography and gel filtration, multiple neutral and acidic polysaccharides were obtained, showing different yields, content, compositions and functional groups after fermentation. Combining in vitro experiments and in vivo aging and immunosuppressed mouse models, we further compared the antioxidant and immunomodulating bioactivities of these polysaccharides and found a prominent role of a natural polysaccharide (BNP) from fermented P. cyrtonema via Bacillus subtilis in regulating intestinal antioxidant defense and immune function, which may be a consequence of the ability of BNP to modulate the homeostasis of gut microbiota. Thus, this work provides evidence for the further development and utilization of P. cyrtonema with fermentation, and reveals the potential values of BNP in the treatment of intestinal disorders.

Lactate secreted by esophageal cancer cells induces M2 macrophage polarization via the AKT/ERK pathway.

BACKGROUND: Elevated lactate results in an acidic tumor microenvironment (TME), which stimulates the progression of esophageal cancer (EC). Tumor-associated macrophages (TAMs) are an essential component of the TME. However, the regulatory mechanisms of lactate secreted by EC on TAMs and the effects of EC advancement are unclear. METHODS: Proteins and mRNA expression were determined by western blot and RT-qPCR. Cell metastasis and growth were assessed by scratch assay, transwell and BrdU assays. Lactate in cells was quantified using a lactate kit. A mouse model was constructed for validation in vivo. RESULTS: First, we determined that lactate upgraded the M2-type polarization marker levels of macrophages. Cell function assays confirmed that lactate-activated M2 macrophages accelerated EC cell migration and proliferation in vitro. However, the lactate inhibitor - oxamate hampered the level of lactate in TE-1 cells. Oxamate abolished the facilitation of macrophage polarization by lactate. In addition, we discovered that phosphorylated AKT and phosphorylated ERK was obviously raised in lactate-stimulated macrophages, and oxamate addition reversed this change, implying that AKT and ERK signaling pathways were involved in macrophage polarization. Response experiments proved that attenuation of AKT/ERK signaling markedly returned the lactate-induced promotion of EC migration and proliferation by macrophages. Finally, mouse tumor models demonstrated that lactate enhanced EC growth by inducing M2 macrophage polarization. CONCLUSION: EC-secreted lactate stimulated macrophage M2 polarization via the AKT/ERK pathway thereby boosting the growth of EC.

Why do employees actively work overtime? The motivation of employees' active overtime in China.

Introduction: Previous studies have defined "workaholic" effort as "bad effort" while work engagement is defined as "good effort." Active overtime is a mapping of work effort, but at this stage there is still relatively little exploration of the motivation behind "good effort" in the Chinese context. Methods: This study explores the reasons that promote employees' initiative to perform overtime work in Chinese enterprises based on the two-factor theory. The study mainly used data empirical research approaches, including exploratory factor analysis, validation factor analysis, and data modeling. The questionnaire scale was developed based on factors that have been proven to be of high reliability and validity. The data are mainly for employees who are currently employed in Chinese companies. Results and discussion: We received a total of 1741 valid questionnaires, which provided a good database for this study. The results of the study show that both motivational and hygiene factors can positively promote employees' motivation to intentionally work overtime to a certain extent. Among them, overtime culture, institutional agreement, good physical office environment, career growth, financial rewards, and work challenges can positively promote motivation to work overtime. Work stress can increase the frequency and intensity of overtime work, but negatively promote motivation to work overtime. The study helps to improve enterprise management, optimize work design, and enhance psychological satisfaction.

Reappraising the role of chronic inflammatory burden in heart failure.

BACKGROUND: Heart failure (HF) is a clinical syndrome associated with poor quality of life, substantial utilization of health care resources, and premature mortality. It is now considered to be the most urgent unmet medical need in the field of cardiovascular disease. Accumulated evidence suggested that comorbidity-driven inflammation has emerged as a critical component of HF pathogenesis. Although anti-inflammatory therapies have increased in popularity, very few effective treatments are still available. A comprehensive understanding of the interplay between chronic inflammation and its impact on HF will facilitate the identification of future therapeutic targets. METHODS: A two-sample Mendelian randomization study was conducted to assess the association between genetic liability for chronic inflammation and HF. By analyzing functional annotations and enrichment data, we were able to identify common pathophysiological mechanisms. RESULTS: The present study did not provide evidence for chronic inflammation as the cause of HF and the reliability of the results was enhanced by the other three Mendelian randomization analysis methods. Functional annotations of genes and pathway enrichment analyses have indicated that chronic inflammation and HF share a common pathophysiology. CONCLUSIONS: The associations between chronic inflammation and cardiovascular disease from observational studies may be explained by shared risk factors and comorbidities rather than direct effects.

Mongolian medicine Wenguanmu ointment treats eczema by inhibiting the CKLF-1/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The main clinical manifestations of eczema include itching, erythema, swelling and pain. Currently, allergies and TH1/TH2 cytokine imbalances are significant causes of eczema. TCM believes that eczema is mainly caused by incongruity between dry and wet. Wenguanmu ointment is a classic Mongolian medicine, which mainly composed of Xanthoceras sorbifolia Bunge, Coptis chinensis Franch and Bezoar. These ingredients can clear heat and dampness, dispel wind and dehumidification, anti-inflammatoryad analgesic. In this study, it was found that Wenguanmu ointment can treat eczema with anti-inflammatory, analgesic and antipruritic. AIM OF THE STUDY: In this study, the content of main components in Wenguanmu ointment was tested. Moreover, the therapeutic effect and mechanism of Wenguanmu ointment on eczema model mice were studied. MATERIALS AND METHODS: Kunming mice (25 ± 2 g) were randomly divided into 6 groups: Control group; Model group; Vehicle group; Wenguanmu ointment group; Compound dexamethasone acetate cream group; Chushizhiyang ointment group. The eczema mouse model was established by DNCB. HPLC and TLC tests were used to determine the content of the main components in Wenguanmu ointment. HE staining was used to assess skin damage in mice. In order to detect the anti-inflammatory effect of Wenguanmu ointment on eczema, The levels of IgE, TNF-α, IFN-γ, COX-2 and IL-4 in serum was measured by ELISA. Genecards and Online Mendelian Inheritance in Man databases were used to analyze potential target gene predictions, and it was speculated that Wenguanmu ointment was associated with NF-κB signaling pathway and chemokine signaling pathway. To detect this inference, RT-qPCR and western blotting were used to detect protein and mRNA levels of CKLF-1, IκB-α, and NF-κB. RESULTS: Wenguanmu ointment can repress the symptoms of eczema caused by 2, 4-dinitrochlorobenzene, and inhibit the level of serum immunoglobulin E. Simultaneously it restrain the elevation of miscellaneous pro-inflammatory cytokines and chemokines, as well as reducing the expression of CKLF-1 and NF-κB protein in the nucleus, and increasing the protein expression of IκB to improve eczema. CONCLUSIONS: The ameliorating effect of Wenguanmu ointment on eczema lesions can play a importment role by inhibiting the CKLF-1/NF-κB pathway.

Revelation for the Influence Mechanism of Long-Chain Fatty Acid Ethyl Esters on the Baijiu Quality by Multicomponent Chemometrics Combined with Modern Flavor Sensomics.

Long-chain fatty acid ethyl ester (LCFAEEs) is colorless and has a weak wax and cream aroma. It can be used as an intermediate for the synthesis of emulsifiers, and stabilizers and be applied in the production of flavor essence. It is also an important trace component in Baijiu and is attributed to making a contribution to the quality of Baijiu, but its distribution in Baijiu has not been clear, and its influence mechanisms on Baijiu quality have not been systematically studied. Therefore, the distribution of LCFAEEs for Baijiu in different years (2014, 2015, 2018, and 2022), different grades (premium, excellent, and level 1; note: here Baijiu grade classification was based on Chinese standard (GB/T 10781) and enterprise classification standard), and different sun exposure times (0, 6, 12, 20, 30, and 50 days) was uncovered. Thus, in this study, the effect of LCFAEEs on the quality of Baijiu was comprehensively and objectively proven by combining modern flavor sensomics and multicomponent chemometrics. The results showed that with the increase in Baijiu storage time, the concentration of LCFAEEs increased significantly in Baijiu (4.38-196.95 mg/L, p < 0.05). The concentration of LCFAEEs in level 1 Baijiu was significantly higher than that in excellent and premium Baijiu (the concentration ranges of ET, EP, EO, E9, E912, and E91215 were: 0.27-2.31 mg/L, 0.75-47.41 mg/L, 0.93-1.80 mg/L, 0.98-12.87 mg/L, 1.01-27.08 mg/L, and 1.00-1.75 mg/L, respectively, p < 0.05). With the increase in sun exposure time, the concentration of LCFAEEs in the Baijiu first increased significantly and then decreased significantly (4.38-5.95 mg/L, p < 0.05). As the flavor sensomics showed, the concentrations of LCFAEEs in Baijiu bodies were significantly correlated with the Baijiu taste sense (inlet taste, aroma sensation in the mouth), as well as with the evaluation after drinking (maintaining taste) (p < 0.05, r > 0.7). Based on the above, LCFAEEs are critical factors for Baijiu flavor thus, it is essential to explore a suitable concentration of LCFAEEs in Baijiu to make Baijiu's quality more ideal.

"Key Factor" for Baijiu Quality: Research Progress on Acid Substances in Baijiu.

Baijiu is the national liquor of China, which has lasted in China for more than 2000 years. Abundant raw materials, multi-strain co-fermentation, and complex processes make the secrets of baijiu flavor and taste still not fully explored. Acid substances not only have a great influence on the flavor and taste of baijiu, but also have certain functions. Therefore, this paper provides a systematic review for the reported acid substances, especially for their contribution to the flavor and functional quality of baijiu. Based on previous studies, this paper puts forward a conjecture, a suggestion, and a point of view, namely: the conjecture of "whether acid substances can be used as 'key factor' for baijiu quality "; the suggestion of "the focus of research on acid substances in baijiu should be transferred to evaluating their contribution to the taste of baijiu"; and the view of "acid substances are 'regulators' in the fermentation process of baijiu". It is worth thinking about whether acid substances can be used as the key factors of baijiu to be studied and confirmed by practice in the future. It is hoped that the systematic review of acid substances in baijiu in this paper can contribute to further in-depth and systematic research on baijiu by researchers in the future.

Long-term continuous mono-cropping of Macadamia integrifolia greatly affects soil physicochemical properties, rhizospheric bacterial diversity, and metabolite contents.

Macadamia integrifolia is the most economically important Proteaceae crop known for its edible nuts. The present study was conducted to examine the effect of continuous cultivation (for 1, 5, and 20 years) of M. integrifolia on soil quality, bacterial diversity, and metabolites. Soil rhizospheres from three different Macadamia rhizosphere orchards, 1-year monoculture orchard (CK), 5-year monoculture orchard (Y5), and 20-year monoculture orchard (Y20), were analyzed through metagenomic and metabolomic profiling. The soil physicochemical properties, including organic matter, and available nutrients (P, N, and K) were first increased significantly (p < 0.05) from the CK to the Y5 group and then decreased (p < 0.05) from the Y5 to the Y20 group. The soil pH continuously decreased (p < 0.05) over time from CK to Y20. Metagenomic profiling revealed that Actinobacteria, Acidobacteria, and Proteobacteria were the top three abundant phyla with their inconsistent relative abundance patterns from CK to Y20 (CK: 23.76%, Y5: 34. 06%, and Y20: 31.55%), (CK: 13.59%, Y5: 18.59%, and Y20: 21.35%), and (CK: 27.59%, Y5: 15.98%, and Y20: 17.08%), respectively. Furthermore, the Y5 rhizospheres had a higher number of beneficial bacterial genera belonging to Proteobacteria and Actinobacteria than the Y20 rhizospheres. The KEGG annotation analysis revealed that cellular processes, organism systems, metabolism, and genetic information were the most enriched functional categories. CAZy database screening indicated the highest enrichment of glycoside hydrolases following the glycoside transferases and carbohydrate-binding modules. Differential metabolite analysis revealed the highest number of metabolites (11) in the Y5 group than in the Y20 group (6). It is concluded that continuous monoculture of M. integrifolia improves the soil physicochemical properties, bacterial diversity, and metabolite contents in short-term planted orchards which, however, are deteriorated in long-term planted orchards.

STUB1 is an intracellular checkpoint for interferon gamma sensing.

Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFNγ) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFNγ response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models-with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFNγ sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.

Clostridium btbubcensis BJN0001, a potentially new species isolated from the cellar mud of Chinese strong-flavor baijiu, produces ethanol, acetic acid and butyric acid from glucose.

A novel strain, designated BJN0001, was isolated from the cellar mud of Chinese strong-flavor baijiu. The complete genome of strain BJN0001 was 2,688,791 bp and annotated with 2610 genes. Whole-genome similarity metrics such as average nucleotide identity (ANI) of BJN0001 with reference genomes reveals clear species boundaries of < 95% ANI value for species. The DNA-DNA hybridization (DDH) values of BJN0001 with the type species were all lower than 70% DDH value for species. Based on these results, the strain BJN0001 was considered a potentially new species of the genus Clostridium. Meanwhile, the fermentation characteristics indicated that the strain had the capability to convert glucose to ethanol, acetic acid and butyric acid, which could provide basic data for revealing its function in baijiu fermentation. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03271-7.

Risk Factors for Benign Convulsions With Mild Gastroenteritis.

Objective: To investigate the risk factors for benign convulsions with mild gastroenteritis (CwG) and provide a basis for the early identification and diagnosis. Method: We selected children with CwG and acute gastroenteritis in the same period who attended the pediatric department of the Liyang People's Hospital from June 2018 to June 2021. A retrospective analysis of the general data, clinical characteristics, and laboratory test results of the two groups was performed. Finally, we conducted a multifactorial logistic regression analysis to derive the risk factors for CwG. Results: A total of 82 children were included in the CwG and 93 children were included in the acute gastroenteritis group. Univariate analysis showed no significant differences in gender, age, vomiting, diarrhea, neutrophil, lymphocyte, hemoglobin, platelets, and serum calcium. Statistically significant differences were found in onset season, rotavirus, white blood cells, aspartate aminotransferase, alanine transaminase, serum sodium, and uric acid. Finally, multifactorial logistic regression analysis showed rotavirus (OR, 3.042, 95% CI, 1.116-8.289, p = 0.030), serum sodium (OR, 0.811, 95% CI, 0.684-0.962, p = 0.016) and uric acid (OR, 1.018, 95% CI, 1.012-1.024, p = 0.000) to be independent risk factors. Conclusion: Characteristics of gastroenteritis symptoms such as vomiting and diarrhea cannot be used to predict the onset of CwG. Rotavirus is an independent risk factor for CwG, and decreased serum sodium and increased uric acid can be used as early warning indicators for CwG.

Investigating the Association between COMMD3 Expression and the Prognosis of Hepatocellular Carcinoma.

The Copper Metabolism MURR1 Domain (COMMD) family proteins are known to play roles in promoting or inhibiting the proliferation, migration and invasion of tumor cells. However, the role of COMMD3 in hepatocellular carcinoma are still unclear. By investigating the TCGA datasets, we found that the mRNA expression of COMMD3 was significantly upregulated in hepatocellular carcinoma tissue compared with normal liver tissue, which was further supported by Oncomine dataset, Western blot, qRT-PCR, and IHC analysis. Moreover, Kaplan-Meier survival analysis showed that the high expression of COMMD3 was associated with poor overall survival (OS) and disease-free survival (DFS). Consistently, the clinic-pathological analysis found that the overexpression of COMMD3 was correlated with advanced TNM stage, advanced T stage and vascular invasion. By performing multivariate analysis, we found that the expression of COMMD3 was an independent influencing factor on OS and DFS. Furthermore, we knocked down COMMD3 in HCC cells via RNA interference. The results showed that silencing COMMD3 could inhibit the migration, invasion, and angiogenesis of HCC cells. Finally, we established xenograft tumor model in nude mice, and the knockdown of COMMD3 suppressed tumor growth and angiogenesis. In summary, our study showed that the high expression of COMMD3 was correlated with poor prognosis in HCC patients and contributed to migration, invasion and angiogenesis of HCC cells.