Physiological and biochemical characteristics of the carbon ion beam irradiation-generated mutant strain Clostridium butyricum FZM 240 in vitro and in vivo.

Clostridium butyricum (C. butyricum) represents a new generation of probiotics, which is beneficial because of its good tolerance and ability to produce beneficial metabolites, such as short-chain fatty acids and enzymes; however, its low enzyme activity limits its probiotic efficacy. In this study, a mutant strain, C. butyricum FZM 240 was obtained using carbon ion beam irradiation, which exhibited greatly improved enzyme production and tolerance. The highest filter paper, endoglucanase, and amylase activities produced by C. butyricum FZM 240 were 125.69 U/mL, 225.82 U/ mL, and 252.28 U/mL, which were 2.58, 1.95, and 2.21-fold higher, respectively, than those of the original strain. The survival rate of the strain increased by 11.40 % and 5.60 % after incubation at 90 °C for 5 min and with simulated gastric fluid at pH 2.5 for 2 h, respectively, compared with that of the original strain. Whole-genome resequencing and quantitative real-time PCR(qRT-PCR) analysis showed that the expression of genes related to enzyme synthesis (GE000348, GE001963 and GE003123) and tolerance (GE001114) was significantly up-regulated, while that of genes related to acid metabolism (GE003450) was significantly down-regulated. On this basis, homology modeling and functional prediction of the proteins encoded by the mutated genes were performed. According to the results, the properties related to the efficacy of C. butyricum as a probiotic were significantly enhanced by carbon ion beam irradiation, which is a novel strategy for the application of Clostridium spp. as feed additives.

[Source and Cause Analysis of High Concentration of Inorganic Aerosol During Two Typical Pollution Processes in Winter over Tianjin].

Inorganic aerosol is the main component of haze days in winter over Tianjin. In this study, two typical high concentrations of secondary inorganic aerosol (SIA) processes, defined as CASE1 and CASE2, were selected during polluted days in January 2020 over Tianjin, and the effects of meteorological factors, regional transport, and chemical processes were comprehensively investigated combined with observations and numerical models (WRF-NAQPMS). The average SIA concentrations in CASE1 and CASE2 were 76.8 µg·m-3 and 66.0 µg·m-3, respectively, and the nitrate concentration was higher than that of sulfate and ammonium, which were typical nitrate-dominated pollution processes. Meteorological conditions played a role in inorganic aerosol formation. The temperature of approximately -6-0℃ and 2-4℃ and the relative humidity of 50%-60% and 80%-100% would be suitable conditions for the high SIA concentration (>80 µg·m-3) in CASE1, whereas the temperature of approximately 2-4℃ and the relative humidity of 60%-70% would be suitable in CASE2. The average contribution rates of external sources to SIA in the CASE1 and CASE2 processes were 62.3% and 22.1%, which were regional transport-dominant processes and local emission-dominant processes, respectively. The contribution of the local emission of CASE1 to nitrate and sulfate was 16.2 µg·m-3 and 8.2 µg·m-3, respectively, higher than that of external sources (31.7 µg·m-3 and 8.8 µg·m-3). the local contribution of CASE2 to nitrate and sulfate was 29.3 µg·m-3 and 25.1 µg·m-3, respectively, whereas the contribution from external sources was 8.1 µg·m-3 and 9.4 µg·m-3, respectively. The quantitative result indicated that local formation and regional transport resulted in higher nitrate concentration than sulfate in CASE1, in contrast to only local sources in CASE2. The gas phase reaction was the main source of inorganic aerosol formation, contributing 48.9% and 57.8% in CASE1 and CASE2, respectively, whereas the heterogeneous reactions were also important processes, with contribution rates of 48.1% and 42.2% to SIA. The effect of aqueous phase reaction was negligible.

Magnetically driven molecular orientational ordering in plastic crystals: The case of d-camphor.

Many solid crystals exhibit a structural phase transition where a subset of its ions or entire molecules become orientationally ordered. As to why such ordering occurs remains mostly unresolved. We consider the extremely weak magnetic elements arising from the reorientations of the molecules experiencing mutual resonance to play the chief role. Two new features are identified in d-camphor: (1) the magnetic susceptibility abruptly changes when crossing the order-disorder phase transition at TII-III = 239.8 K during cooling and at TIII-II = 245.2 K during warming and (2) the complex dielectric constant exhibits two successive discontinuities only 0.2 K apart near the critical temperatures when the sweeping rate is only 0.1 K/min. We discuss how the change in entropy associated with order-disorder transitions in plastic crystals represents temporal changes rather than spatial changes in the system. Our findings may be extended to study why many other crystalline solids exhibit orientational ordering and irreversibility.

Discovery of a Potent Dual Son of Sevenless 1 (SOS1) and Epidermal Growth Factor Receptor (EGFR) Inhibitor for the Treatment of Prostate Cancer.

Multitarget medications represent an appealing therapy against the disease with multifactorial abnormalities─cancer. Therefore, simultaneously targeting son of sevenless 1 (SOS1) and epidermal growth factor receptor (EGFR), two aberrantly expressed proteins crucial for the oncogenesis and progression of prostate cancer, may achieve active antitumor effects. Here, we discovered dual SOS1/EGFR-targeting compounds via pharmacophore-based docking screening. The most prominent compound SE-9 exhibited nanomolar inhibition activity against both SOS1 and EGFR and efficiently suppressed the phosphorylation of ERK and AKT in prostate cancer cells PC-3. Cellular assays also revealed that SE-9 displayed strong antiproliferative activities through diverse mechanisms, such as induction of cell apoptosis and G1 phase cell cycle arrest, as well as reduction of angiogenesis and migration. Further in vivo findings showed that SE-9 potently inhibited tumor growth in PC-3 xenografts without obvious toxicity. Overall, SE-9 is a novel dual-targeting SOS1/EGFR inhibitor that represents a promising treatment strategy for prostate cancer.

Intrauterine infusion of platelet-rich plasma improves fibrosis by transforming growth factor beta 1/Smad pathway in a rat intrauterine adhesion model.

This study aims to elucidate the effects of Platelet-rich plasma (PRP) in fibrosis development in intrauterine adhesion (IUA), and the associated underlying mechanisms are also explored, which are expected to be a potential therapeutic scheme for IUA. In this research, PRP was obtained and prepared from the peripheral venous blood of rats. A rat model was induced by mechanical injury. Further, PRP was directly injected into the uterus for treatment. The appearance and shape of the uterus were assessed based on the tissues harvested. The fibrosis biomarker levels were analyzed. The transforming growth factor beta 1 (TGF-ß1) and Mothers against decapentaplegic homolog 7 (Smad7) levels, the phosphorylation of Smad2 (p-Smad2), and the phosphorylation of Smad3 (p-Smad3) were analyzed, and the molecular mechanism was investigated by rescue experiments. It was found that PRP improved the appearance and shape of the uterus in IUA and increased endometrial thickness and gland numbers. The administration of PRP resulted in a decrease in the expressions of fibrosis markers including collagen I, α-SMA, and fibronectin. Furthermore, PRP increased Smad7 levels and decreased TGF-ß1 levels, p-Smad2, and p-Smad3. Meanwhile, administration of TGF-ß1 activator reversed the therapeutic effects of PRP in IUA. Collectively, the intrauterine infusion of PRP can promote endometrial damage recovery and improve endometrial fibrosis via the TGF-ß1/Smad pathway. Hence, PRP can be a potential therapeutic strategy for IUA.

Multifunctional Lipidated Protein Carrier with a Built-In Adjuvant as a Universal Vaccine Platform Potently Elevates Immunogenicity of Weak Antigens.

Weak antigens represented by MUC1 are poorly immunogenic, which greatly constrains the development of relevant vaccines. Herein, we developed a multifunctional lipidated protein as a carrier, in which the TLR1/2 agonist Pam3CSK4 was conjugated to the N-terminus of MUC1-loaded carrier protein BSA through pyridoxal 5'-phosphate-mediated transamination reaction. The resulting Pam3CSK4-BSA-MUC1 conjugate was subsequently incorporated into liposomes, which biomimics the membrane structure of tumor cells. The results indicated that this lipidated protein carrier significantly enhanced antigen uptake by APCs and obviously augmented the retention of the vaccine at the injection site. Compared with the BSA-MUC1 and BSA-MUC1 + Pam3CSK4 groups, Pam3CSK4-BSA-MUC1 evoked 22- and 11-fold increases in MUC1-specific IgG titers. Importantly, Pam3CSK4-BSA-MUC1 elicited robust cellular immunity and significantly inhibited tumor growth. This is the first time that lipidated protein was constructed to enhance antigen immunogenicity, and this universal carrier platform exhibits promise for utilization in various vaccines, holding the potential for further clinical application.

Influence of different magnetic forces on the effect of colonic anastomosis in rats.

BACKGROUND: Despite much work having been conducted on magnetic compression anastomosis (MCA) in the digestive tract, there are no reports on the influence of magnetic force on the anastomosis. AIM: To investigate the effect of different magnetic force magnets on the MCA of the digestive tract. METHODS: Two groups of magnets of the same sizes but different magnetic forces were designed and produced. A total of 24 Sprague-Dawley rats were randomly assigned into two groups (powerful magnet group and common magnet group), with 12 rats in each group. Two types of magnets were used to complete the colonic side-to-side anastomosis of the rats. The operation time and magnet discharge time were recorded. The anastomotic specimens were obtained 4 wk after the operation and then the burst pressure and diameter of the anastomosis were measured, and the anastomosis was observed via the naked eye and subjected to histological examination. RESULTS: The magnetic forces of the powerful and common magnet groups at zero distance were 8.26 N and 4.10 N, respectively. The colonic side-to-side anastomosis was completed in all 24 rats, and the operation success rate and postoperative survival rate were 100%. No significant difference was noted in the operation time between the two groups. The magnet discharge time of the powerful magnet group was slightly longer than that of the common magnet group, but the difference was not statistically significant (P = 0.513). Furthermore, there was no statistical difference in the burst pressure (P = 0.266) or diameter of magnetic anastomosis (P = 0.095) between the two groups. The gross specimens of the two groups showed good anastomotic healing, and histological observation indicated good mucosal continuity without differences on healing. CONCLUSION: In the rat colonic side-to-side MCA model, both the powerful magnet with 8.26 N and the common magnet with 4.10 N showed no significant impact on the anastomosis establishment process or its effect.

Continuous flow biocatalysis: synthesis of purine nucleoside esters catalyzed by lipase TL IM from Thermomyces lanuginosus.

Purine nucleoside ester is one of the derivatives of purine nucleoside, which has antiviral and anticancer activities. In this work, a continuous flow synthesis of purine nucleoside esters catalyzed by lipase TL IM from Thermomyces lanuginosus was successfully achieved. Various parameters including solvent, reaction temperature, reaction time/flow rate and substrate ratio were investigated. The best yields were obtained with a continuous flow microreactor for 35 min at 50 °C with the substrate ratio of 1 : 5 (nucleosides to vinyl esters) in the solvent of tert-amyl alcohol. 12 products were efficiently synthesized with yields of 78-93%. Here we reported for the first time the use of lipase TL IM from Thermomyces lanuginosus in the synthesis of purine nucleoside esters. The significant advantages of this methodology are a green solvent and mild conditions, a simple work-up procedure and the highly reusable biocatalyst. This research provides a new technique for rapid synthesis of anticancer and antiviral nucleoside drugs and is helpful for further screening of drug activity.

Design, synthesis, and biological evaluation of novel benzimidazole derivatives as anti-cervical cancer agents through PI3K/Akt/mTOR pathway and tubulin inhibition.

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 µM and 23.96 µM respectively). Its IC50 value was at 3.38 µM to the SiHa cells. Further mechanistic studies revealed that 4r induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.

Characterization of SIPs-type aquaporins and their roles in response to environmental cues in rice (Oryza sativa L.).

BACKGROUND: Aquaporins (AQPs) facilitate water diffusion across biological membranes and are involved in all phases of growth and development. Small and basic intrinsic proteins (SIPs) belong to the fourth subfamily of the plant AQPs. Although SIPs are widely present in higher plants, reports on SIPs are limited. Rice is one of the major food crops in the world, and water use is an important factor affecting rice growth and development; therefore, this study aimed to provide information relevant to the function and environmental response of the rice SIP gene family. RESULTS: The rice (Oryza sativa L. japonica) genome encodes two SIP-like genes, OsSIP1 and OsSIP2, whose products are predominantly located in the endoplasmic reticulum (ER) membrane but transient localization to the plasma membrane is not excluded. Heterologous expression in a yeast aquaglyceroporin-mutant fps1Δ showed that both OsSIP1 and OsSIP2 made the cell more sensitive to KCl, sorbitol and H2O2, indicating facilitated permeation of water and hydrogen peroxide. In addition, the yeast cells expressing OsSIP2 were unable to efflux the toxic methylamine taken up by the endogenous MEP permeases, but OsSIP1 showed subtle permeability to methylamine, suggesting that OsSIP1 may have a wider conducting pore than OsSIP2. Expression profiling in different rice tissues or organs revealed that OsSIP1 was expressed in all tissues tested, whereas OsSIP2 was preferentially expressed in anthers and weakly expressed in other tissues. Consistent with this, histochemical staining of tissues expressing the promoter-ß-glucuronidase fusion genes revealed their tissue-specific expression profile. In rice seedlings, both OsSIPs were upregulated to varied levels under different stress conditions, including osmotic shock, high salinity, unfavorable temperature, redox challenge and pathogen attack, as well as by hormonal treatments such as GA, ABA, MeJA, SA. However, a reduced expression of both OsSIPs was observed under dehydration treatment. CONCLUSIONS: Our results suggest that SIP-like aquaporins are not restricted to the ER membrane and are likely to be involved in unique membrane functions in substrate transport, growth and development, and environmental response.

Gene variants and clinical characteristics of children with sitosterolemia.

OBJECTIVE: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients. METHODS: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected. RESULTS: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment. CONCLUSION: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids.

A decentralized and security-enhanced professional title evaluation system in universities under mobile Internet of Things.

Digital online application is a commonly used method for professional title evaluation in colleges and universities. With the rapid development of the mobile Internet of Things, the fastest way for users to access the evaluation system is through mobile devices. However, this also poses security challenges to the traditional professional title evaluation system. Therefore, this paper proposes a decentralized and security-enhanced digital title evaluation system in mobile IoT. Since the system uses blockchain to implement a decentralized review process, the transparency and fairness of the review process are guaranteed. At the same time, the review data and reviewer information in the system are encrypted and stored in the distributed network to ensure the security and non-tamperability of the data. All review records are recorded on the blockchain, and anyone can view and verify the legitimacy of the review results. Additionally, the system incorporates security enhancement mechanisms such as identity verification, smart contracts, and auditing functions to improve the credibility of the evaluation process and prevent cheating under mobile IoT. Experiments have shown that this system has important application value in the field of professional title review in universities, which can improve review efficiency, reduce human intervention, and provide strong support for the credibility of review results.

Novel metabolic biomarker for early detection and diagnosis to the patients with gastric cardia adenocarcinoma.

BACKGROUND: Gastric cardia adenocarcinoma (GCA) is classified as Siewert type II adenocarcinoma at the esophagogastric junction in Western countries. The majority of GCA patients do not exhibit early warning symptoms, leading to over 90% of diagnoses at an advanced stage, resulting in a grim prognosis, with less than a 20% 5-year survival rate. METHOD: Metabolic features of 276 GCA and 588 healthy controls were characterized through a widely-targeted metabolomics by UPLC-MS/MS analysis. This study encompasses a joint pathway analysis utilizing identified metabolites, survival analysis in both early and advanced stages, as well as high and negative and low expression of HER2 immunohistochemistry staining. Machine learning techniques and Cox regression models were employed to construct a diagnostic panel. RESULTS: A total of 25 differential metabolites were consistently identified in both discovery and validation sets based on criteria of p < 0.05, (VIP) ≥ 1, and FC ≥ 2 or FC ≤ 0.5. Early-stage GCA patients exhibited a more favorable prognosis compared to those in advanced stages. HER2 overexpression was associated with a more positive outcome compared to the negative and low expression groups. Metabolite panel demonstrated a robust diagnostic performance with AUC of 0.869 in discovery set and 0.900 in validation set. CONCLUSIONS: A total of 25 common and stable differential metabolites may hold promise as liquid non-invasive indicators for GCA diagnosis. HER2 may function as a tumor suppressor gene in GCA, as its overexpression is associated with improved survival. The downregulation of bile acid metabolism in GCA may offer valuable theoretical insights and innovative approaches for precision-targeted treatments in GCA patients.

Reduced-dose chemotherapy followed by blinatumomab in induction therapy for newly diagnosed B-cell acute lymphoblastic leukemia.

BACKGROUND: Blinatumomab early-line treatment in B-cell precursor acute lymphoblastic leukemia (B-ALL) might improve clinical outcomes. METHODS: We conducted a retrospective real-world cohort analysis in 20 newly diagnosed B-ALL patients who received reduced-dose chemotherapy (idarubicin, vindesine, and dexamethasone) for 1-3 weeks, followed by blinatumomab for 1-4 weeks as an induction therapy. RESULTS: At the end of the induction therapy, a complete remission rate of 100% was achieved; 17 (85%) patients were minimal residual disease (MRD) negative (<1 × 10-4 ). Adverse events (AEs) were reported in 12 (60%) patients-43.8% were grade 1-2 and 56.2% were grade 3-4. No incidence of neurotoxicity or grade ≥3 cytokine release syndrome was reported. CONCLUSIONS: Blinatumomab demonstrated a significant improvement in clinical outcomes in patients with newly diagnosed B-ALL irrespective of their poor-risk factor status and the pretreatment blast burden.

GFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice.

In 2017, four independent publications described the glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as receptor for the growth differentiation factor 15 (GDF15, also MIC-1, NAG-1) with an expression exclusively in the mice brainstem area postrema (AP) and nucleus tractus solitarii (NTS) where it mediates effects of GDF15 on reduction of food intake and body weight. GDF15 is a cell stress cytokine with a widespread expression and pleiotropic effects, which both seem to be in contrast to the reported highly specialized localization of its receptor. This discrepancy prompts us to re-evaluate the expression pattern of GFRAL in the brain and peripheral tissues of mice. In this detailed immunohistochemical study, we provide evidence for a more widespread distribution of this receptor. Apart from the AP/NTS region, GFRAL-immunoreactivity was found in the prefrontal cortex, hippocampus, nucleus arcuatus and peripheral tissues including liver, small intestine, fat, kidney and muscle tissues. This widespread receptor expression, not taken into consideration so far, may explain the multiple effects of GDF-15 that are not yet assigned to GFRAL. Furthermore, our results could be relevant for the development of novel pharmacological therapies for physical and mental disorders related to body image and food intake, such as eating disorders, cachexia and obesity.

Antibacterial conductive polyacrylamide/quaternary ammonium chitosan hydrogel for electromagnetic interference shielding and strain sensing.

The utilization of biomass-based conductive polymer hydrogels in wearable electronics holds great promise for advancing performance and sustainability. An interpenetrating network of polyacrylamide/2-hydroxypropyltrimethyl ammonium chloride chitosan (PAM/HACC) was firstly obtained through thermal-initiation polymerization of AM monomers in the presence of HACC. The positively charged groups on HACC provide strong electrostatic interactions and hydrogen bonding with the PAM polymer chains, leading to improved mechanical strength and stability of the hydrogel network. Subsequently, the PAM/HACC networks served as the skeletons for the in-situ polymerization of polypyrrole (PPy), and then the resulting conductive hydrogel demonstrated stable electromagnetic shielding performance (40 dB), high sensitivity for strain sensing (gauge factor = 2.56). Moreover, the incorporation of quaternary ammonium chitosan into PAM hydrogels enhances their antimicrobial activity, making them more suitable for applications in bacterial contamination or low-temperature environments. This conductive hydrogel, with its versatility and excellent mechanical properties, shows great potential in applications such as electronic skin and flexible/wearable electronics.

Coinfection with hepatic cystic and alveolar echinococcosis with abdominal wall abscess and sinus tract formation: A case report.

BACKGROUND: Hepatic cystic and alveolar echinococcosis coinfections, particularly with concurrent abscesses and sinus tract formation, are extremely rare. This article presents a case of a patient diagnosed with this unique presentation, discussing the typical imaging manifestations of both echinococcosis types and detailing the diagnosis and surgical treatment experience thereof. CASE SUMMARY: A 39-year-old Tibetan woman presented with concurrent hepatic cystic and alveolar echinococcosis, accompanied by abdominal wall abscesses and sinus tract formation. Initial conventional imaging examinations suggested only hepatic cystic echinococcosis, but intraoperative and postoperative pathological examination revealed the coinfection. Following radical resection of the lesions, the patient's condition improved, and she was discharged soon thereafter. Subsequent outpatient follow-ups confirmed no recurrence of the hydatid lesion and normal surgical wound healing. Though mixed hepatic cystic and alveolar echinococcosis with abdominal wall abscesses and sinus tract formations are rare, the general treatment approach remains consistent with that of simpler infections of alveolar echinococcosis. CONCLUSION: Lesions involving the abdominal wall and sinus tract formation, may require radical resection. Long-term prognosis includes albendazole and follow-up examinations.