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Introduction: Non-alcoholic fatty liver disease (NAFLD) is gradually becoming one of the most common chronic liver diseases worldwide. Compared to chemical drugs, traditional Chinese medicine (TCM) has significant advantages in the treatment of NAFLD owing to its long history, remarkable efficacy, and low toxicity. Methods: The scientific databases, including PubMed, Web of Science, and China National Knowledge Infrastructure database (CNKI) were searched using the keywords of NAFLD, TCM, lipid metabolism, high-fat diet, bupleurum decoction, Yinchenhao decoction, Shugan Jiangzhi granules, Shugan Jianpi Jiangzhuo decoction, GanShuang granules, Gegen Qinlian decoction, bupleurum, Yinchen, Jiaogulan, Huangqin, Gegen, Baizhu, flavonoids, baicalein, luteolin, kaempferol, quercetin, apigenin, isorhamnetin, hesperidin, icariin, rutin, soy isoflavones, puerarin, phlorizin, total flavonoids from hawthorn leaves, and total flavonoids from buckwheat flowers and leaves to overview the pathogenesis and treatment of NAFLD. Results: This review explained the causes of NAFLD, including factors like lipotoxicity, insulin resistance, ER stress, mitochondrial dysfunction, oxidative stress, gut dysbiosis, and inflammation. Furthermore, the review provided a thorough overview of the effects and mechanisms of TCM in the treatment of NAFLD. This included an analysis of six TCM formulas, six single herbs, and 14 flavonoids derived from TCM. Discussion: TCM has proven to be highly effective in the treatment of NAFLD, with numerous Chinese medicine formulas and individual herbs being commonly used in clinical practice. The active components in these TCM, flavonoids, have demonstrated significant biological effects in addressing NAFLD. Conclusion: TCM has the potential to greatly enhance the treatment of NAFLD with minimal adverse reactions. Given these results, we are confident that TCM holds promising opportunities for the management of NAFLD and can offer valuable perspectives for future research.

Summary: Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast CSCs self-renewal and prevented their metastasis. Reconstitution of integrin β1 partially rescued USP22-null breast cancer metastasis. USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Immunohistochemistry staining detected a positive correlation among USP22, FoxM1, and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy.

Abstract Background Gene knockout and knock-in have been widely performed in large farm animals based on genome editing systems. However, many types of precise gene editing, including targeted deletion, gene tagging, and large gene fragment replacement, remain a challenge in large farm animals. Results Here, we established versatile self-excising gene-targeting technology in combination with programmable nucleases (SEGCPN) to efficiently generate various types of precise gene editing in bovine. First, we used this versatile method to successfully generate bovine embryos with point mutations and 11-bp deletions at the MSTN locus. Second, we successfully generated bulls with EGFP labeling at the SRY locus. Finally, we successfully generated humanized cows in which the endogenous 18-kb α-casein gene was replaced with a 2.6-kb human α-lactalbumin gene. Conclusions In summary, our new SEGCPN method offers unlimited possibilities for various types of precise gene editing in large animals for application both in agriculture and disease models.

Background: Serum prostate-specific antigen (PSA) is a primary metric for diagnosis and prognosis of prostate cancer (PCa). Exposure to heavy metals, such as lead, cadmium, mercury, and zinc can impact PSA levels in PCa patients. However, it is unclear whether this effect also occurs in men without PCa, which may lead to the overdiagnosis of PCa. Method: Data on a total of 5089 American men who had never been diagnosed with PCa were obtained from the National Health and Nutrition Examination Survey performed from 2003–2010. The relationship between serum PSA levels (dependent variable) and concentrations of lead (μmol/L), cadmium (nmol/L), and mercury (μmol/L) were investigated with dietary zinc intake being used as a potential modifier or covariate in a weighted linear regression model and a generalized additive model. A series of bootstrapping analyses were performed to evaluate sensitivity and specificity using these models. Results: Regression analyses suggested that, in general, lead, cadmium, or mercury did not show an association with PSA levels, which was consistent with the results of the bootstrapping analyses. However, in a subgroup of participants with a high level of dietary zinc intake (≥14.12 mg/day), a significant positive association between cadmium and serum PSA was identified (1.06, 95% CI, P = 0.0268, P for interaction=0.0249). Conclusions: With high-level zinc intake, serum PSA levels may rise in PCa-free men as the exposure to cadmium increases, leading to a potential risk of an overdiagnosis of PCa and unnecessary treatment. Therefore, environmental variables should be factored in the current diagnostic model for PCa that is solely based on PSA measurements. Different criteria for PSA screening are necessary based on geographical variables. Further investigations are needed to uncover the biological and biochemical relationship between zinc, cadmium, and serum PSA levels to more precisely diagnose PCa.

Abstract Background Microbial residues are significant contributors to stable soil organic carbon (SOC). Soil aggregates effectively protect microbial residues against decomposition; thus, microbial residue accumulation and distribution among soil aggregates determine long-term SOC stability. However, how tree species influence accumulation and distribution of soil microbial residues remains largely unknown, hindering the chances to develop policies for SOC management. Here, we investigated microbial residue accumulation and distribution in soil aggregates under four subtropical tree species (Cunninghamia lanceolata, Pinus massoniana, Michelia macclurei, and Schima superba) after 29 years of afforestation. Results Accumulation of microbial residues in the 0–10 cm soil layer was 13.8–26.7% higher under S. superba than that under the other tree species. A structural equation model revealed that tree species affected the accumulation of microbial residues directly by altering fungal biomass. Additionally, tree species significantly affected microbial residue distribution and contribution to SOC in the top 20 cm soil. In particular, microbial residue distribution was 17.2–33.4% lower in large macro-aggregates (LMA) but 60.1–140.7% higher in micro-aggregates (MA) under S. superba than that under the other species in the 0–10 cm soil layer, and 14.3–19.0% lower in LMA but 43–52.1% higher in MA under S. superba than that under C. lanceolata and M. macclurei in the 10–20 cm soil layer. Moreover, the contribution of microbial residues to SOC was 44.4–47.5% higher under S. superba than under the other tree species. These findings suggest a higher stability of microbial residues under S. superba than that under the other studied tree species. Conclusions Our results demonstrate that tree species influence long-term microbial persistence in forest soils by affecting accumulation and stabilization of microbial residues.

Abstract. Integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.

Background: The most common disease caused by biallelic AFG3L2 mutations is spastic ataxia type 5 (SPAX5). Identification of complex phenotypes resulting from biallelic AFG3L2 mutations has been increasing in recent years. Methods: A retrospective analysis was performed on a child with microcephaly and recurrent seizures. The child underwent physical and neurological examinations, laboratory tests, electroencephalography (EEG), and brain magnetic resonance imaging (MRI). Trio-whole-exome sequencing (trio-WES) was performed to identify possible causative mutations. Results: We described a child who exhibited early-onset and intractable epilepsy, developmental regression, microcephaly, and premature death. Neuroimaging revealed global cerebral atrophy (GCA) involving the cerebrum, cerebellum, corpus callosum, brainstem, cerebellar vermis, and basal ganglia. On trio-WES, two novel compound heterozygous mutations, c.1834G > T (p.E612*) and c.2176-6T > A in the AFG3L2 gene, were identified in this patient. Conclusions: Our findings have expanded the mutation spectrum of the AFG3L2 gene and identified a severe neurodegenerative phenotype of global cerebral atrophy caused by biallelic AFG3L2 mutations.

Abstract Background Currently, there are relatively few studies on the effects of changes in oestrogen and androgen levels on prostatic microvessel density (MVD). This article aimed to study the changes in prostatic MVD in Sprague-Dawley (SD) rats after castration under the effect of oestrogen/androgen at different concentrations. Methods Male SD rats aged 3–4 months were randomly divided into a control group, a castration group, and groups with different concentrations of oestrogen/androgen treatment after castration. Dihydrotestosterone (DHT) and oestradiol (E) were administered daily by subcutaneous injection for one month. All the rats were killed by cervical dislocation after one month, and the serum DHT and E concentrations of the rats in each group were measured by ELISA. Prostate tissue specimens were immunohistochemically stained with monoclonal antibodies against CD34 and factor VIII for MVD. Results Compared with the control group, the MVD decreased significantly in the castration group (P

Temperature and precipitation patterns during the Last Glacial Maximum are better predictors of global-scale variations in the temperature sensitivity of soil respiration in response to nitrogen enrichment than contemporary climate, according to a global meta-analysis and structural equation model.

Abstract Background The correlation between modified bladder outlet obstruction index (MBOOI) and surgical efficacy still remains unknown. The purpose of the study was to investigate the clinical value of the MBOOI and its use in predicting surgical efficacy in men receiving transurethral resection of the prostate (TURP). Methods A total of 403 patients with benign prostate hyperplasia (BPH) were included in this study. The International Prostate Symptom Score (IPSS), quality of life (QoL) index, transrectal ultrasonography, and pressure flow study were conducted for all patients. The bladder outlet obstruction index (BOOI) (PdetQmax–2Qmax) and MBOOI (Pves–2Qmax) were calculated. All patients underwent TURP, and surgical efficacy was accessed by the improvements in IPSS, QoL, and Qmax 6 months after surgery. The association between surgical efficacy and baseline factors was statistically analyzed. Results A comparison of effective and ineffective groups based on the overall efficacy showed that significant differences were observed in PSA, Pves, PdetQmax, Pabd, BOOI, MBOOI, TZV, TZI, IPSS-t, IPSS-v, IPSS-s, Qmax, and PVR at baseline (p

Cancer vaccines have gradually attracted attention for their tremendous preclinical and clinical performance. With the development of next-generation sequencing technologies and related algorithms, pipelines based on sequencing and machine learning methods have become mainstream in cancer antigen prediction; of particular focus are neoantigens, mutation peptides that only exist in tumor cells that lack central tolerance and have fewer side effects. The rapid prediction and filtering of neoantigen peptides are crucial to the development of neoantigen-based cancer vaccines. However, due to the lack of verified neoantigen datasets and insufficient research on the properties of neoantigens, neoantigen prediction algorithms still need to be improved. Here, we recruited verified cancer antigen peptides and collected as much relevant peptide information as possible. Then, we discussed the role of each dataset for algorithm improvement in cancer antigen research, especially neoantigen prediction. A platform, Cancer Antigens Database (CAD, http://cad.bio-it.cn/), was designed to facilitate users to perform a complete exploration of cancer antigens online.

Reactivation of fetal hemoglobin (HbF, α2γ2) alleviates clinical symptoms in patients with β-thalassemia and sickle cell disease, although the regulatory mechanisms of γ-globin expression have not yet been fully elucidated. Recent studies found that interfering with the expression of the membrane protein ANTXR1 gene upregulated γ-globin levels. However, the exact mechanism by which ANTXR1 regulates γ-globin levels remains unclear. Our study showed that overexpression and knockdown of ANTXR1 in K562, cord blood CD34+, and HUDEP-2 cells decreased and increased γ-globin expression, respectively. ANTXR1 regulates the reactivation of fetal hemoglobin (HbF, α2γ2) in K562, cord blood CD34+, and adult peripheral blood CD34+ cells through interaction with LRP6 to promote the nuclear entry of β-catenin and activate the Wnt/β-catenin signaling pathway. The overexpression or knockdown of ANTXR1 on γ-globin and Wnt/β-catenin signaling in K562 cells was reversed by the inhibitor XAV939 and the activator LiCl, respectively, where XAV939 inhibits the transcription of β-catenin in the Wnt pathway, but LiCl inhibits GSK3-β. We also showed that the binding ability of the rank4 site in the transcriptional regulatory region of the SOX6 gene to c-Jun was significantly increased after overexpression of ANTXR1 in K562 cells. SOX6 protein expression was increased significantly after overexpression of the c-Jun gene, indicating that the transcription factor c-Jun initiated the transcription of SOX6, thereby silencing γ-globin. Our findings may provide a new intervention target for the treatment of β-hemoglobinopathies.

The replenishment and priming effect (PE) are two decisive processes that determine the carbon (C) sequestration potential of biochar. However, how increased nitrogen (N) availability affect these two processes and the consequent net C balance remains poorly understood. By collecting soils from three forest ecosystems (deciduous broad-leaf forest (DBF), evergreen coniferous forest (ECF), and evergreen broad-leaf forest (EBF)), we conducted a 365-day incubation experiment by adding 13C-labelled biochar plus five rates of inorganic N (0 to 15% N of soil total N). The -results showed that N addition significantly stimulated the early period (0–48 days) but did not affect the late period (49–365 days) of biochar decomposition. The effect of N addition on PE varied largely with the forest type and decomposition period; N addition significantly enhanced the negative PE -in both periods in DBF and at the late period in EBF, whereas it stimulated positive PE in the early period in EBF and ECF. At the end of incubation, the addition of biochar caused net C accumulation across all treatments due to the huge proportion of biochar (98.1%–98.9% of added biochar) retained in soils and the negative or neutral cumulative PE (−11.25–0.35 g C kg−1 SOC), and the magnitude of net C balance increased linearly with the N addition rate in DBF and EBF. Collectively, the results of this study indicate that biochar input can contribute to soil C sequestration and that N addition can enhance the C sequestration potential of biochar.

Soil heterotrophic respiration (Rh) is an important pathway of carbon (C) dioxide release from terrestrial soils to the atmosphere. It is often measured using sieved soil in a laboratory, but the uncertainty of how it is influenced by soil sieving persists, which limits the accuracy of predicting soil organic C dynamics in C models. To address how soil sieving during laboratory incubation affects Rh and its response to increased carbon availability, we investigated Rh in sieved and intact soil cores and its response to 13C-glucose addition. This was conducted through a 27-day laboratory incubation in four forests, including two ectomycorrhizal-dominated (ECM) forests and two arbuscular mycorrhizal-dominated forests. The significant influence of soil sieving on Rh in all forests was not observed during incubation when glucose was not added. After adding glucose, the Rh in the sieved soils on the 5th day of incubation was averaged 27.2% lower than that in intact soils in ECM forests. On the 27th day it was 22.1% lower in the Pinus massoniana forest, but 78.0% higher in the Castanea mollissima forest. Strong relationships were detected between Rh in sieved and intact soils (r2 = 0.888), and in soils both with and without the addition of glucose (r2 = 0.827). The measured soil variables explained 74.7% and 49.7% of the variation in Rh on the 5th and 27th day of incubation, and the role of soil nutrients and microbial PLFA groups in regulating Rh varied temporally. Our findings suggest that plant mycorrhizal types influenced the role of increased C availability to microbes in regulating the response of Rh to sieving in forest ecosystems.

Soil microbial residues contribute to the majority of stable soil organic carbon (SOC) pools, and their distribution among aggregate fractions determines long-term soil carbon (C) stability and, consequently, soil productivity. However, how microbial residue accumulation and distribution respond to stand age remains unexplored. To fill this knowledge gap, we investigated microbial residues in bulk soil and soil aggregate fractions under a chronosequence of Chinese fir (Cunninghamia lanceolata [Lamb.] Hook) plantations with stands aged 3, 17, 27, and 36 years. The results showed that microbial residues in topsoil did not change across the different stand ages, but the residues in the subsoil increased from 3 to 17 years of age and then remained constant. Moreover, microbial residue distribution in microaggregates decreased with stand age, and the residue distribution in small macroaggregates was lower at age 17 years than at other stand ages. The effect of stand age on microbial residue distribution was due to the fact of their effect on aggregate distribution but not microbial residue concentrations in aggregate fractions. Collectively, our results indicate that microbial residue stability decreased with stand age, which has significant implications for the management of SOC in subtropical plantations.

Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies. Herein, we describe a CRISPR-based screening platform and identified ATXN3 as a positive regulator for PD-L1 transcription. TCGA database analysis revealed a positive correlation between ATXN3 and CD274 in more than 80% of human cancers. ATXN3-induced Pd-l1 transcription was promoted by tumor microenvironmental factors, including the inflammatory cytokine IFN-γ and hypoxia, through protection of their downstream transcription factors IRF1, STAT3, and HIF-2α. Moreover, ATXN3 functioned as a deubiquitinase of the AP-1 transcription factor JunB, indicating that ATNX3 promotes PD-L1 expression through multiple pathways. Targeted deletion of ATXN3 in cancer cells largely abolished IFN-γ– and hypoxia-induced PD-L1 expression and consequently enhanced antitumor immunity in mice, and these effects were partially reversed by PD-L1 reconstitution. Furthermore, tumoral ATXN3 suppression improved the preclinical efficacy of checkpoint blockade antitumor immunotherapy. Importantly, ATXN3 expression was increased in human lung adenocarcinoma and melanoma, and its levels were positively correlated with PD-L1 as well as its transcription factors IRF1 and HIF-2α. Collectively, our study identifies what we believe to be a previously unknown deubiquitinase, ATXN3, as a positive regulator for PD-L1 transcription and provides a rationale for targeting ATXN3 to sensitize checkpoint blockade antitumor immunotherapy [ABSTRACT FROM AUTHOR]

In the modern multishaft gas turbine engines, orifice is an important throttling element, and the discharge coefficient of rotating orifices may vary considerably depending on the operating conditions, the geometry, and surrounding environment. The influences of the rotating number and the pressure ratio on the rotating orifices' flow characteristics are investigated in this study. Besides, the effects of confined space, wall inclination angle (α), and the angle between the axis of orifice and the disk wall normal (β) are also analyzed statistically. It is found that the rotating number has a significant effect on the discharge coefficient. As the rotating number increases from 0 to 0.6, the discharge coefficient reduces by about 47.88%. When rotating number is 0.74 and pressure ratio is 1.10, the discharge coefficient can be improved by 16.88% with α changes from 90 deg to 180 deg. The parameter, β, affects discharge coefficient slightly in rotating condition. However, the maximum discharge coefficient is achieved with β = 0 deg in the static condition. The results also show that a confined space weakens the effect of rotation and changes the air flow direction in the inlet chamber, which also has a positive impact on the discharge coefficient. In the current research, it is found that there is a significant difference between the traditional empirical formulas used in the literature and the fitting result. By modifying the incidence angle and taking account of the influence of the angle of inclination, the maximum error was reduced from 56.79% to 3.16%. [ABSTRACT FROM AUTHOR]