Ursodeoxycholic acid and COVID-19 outcomes: a cohort study and data synthesis of state-of-art evidence.

BACKGROUND: The potential of ursodeoxycholic acid (UDCA) in inhibiting angiotensin-converting enzyme 2 was demonstrated. However, conflicting evidence emerged regarding the association between UDCA and COVID-19 outcomes, prompting the need for a comprehensive investigation. RESEARCH DESIGN AND METHODS: Patients diagnosed with COVID-19 infection were retrospectively analyzed and divided into two groups: the UDCA-treated group and the control group. Kaplan-Meier recovery analysis and Cox proportional hazards models were used to evaluate the recovery time and hazard ratios. Additionally, study-level pooled analyses for multiple clinical outcomes were performed. RESULTS: In the 115-patient cohort, UDCA treatment was significantly associated with a reduced recovery time. The subgroup analysis suggests that the 300 mg subgroup had a significant (adjusted hazard ratio: 1.63 [95% CI, 1.01 to 2.60]) benefit with a shorter duration of fever. The results of pooled analyses also show that UDCA treatment can significantly reduce the incidence of severe/critical diseases in COVID-19 (adjusted odds ratio: 0.68 [95% CI, 0.50 to 0.94]). CONCLUSIONS: UDCA treatment notably improves the recovery time following an Omicron strain infection without observed safety concerns. These promising results advocate for UDCA as a viable treatment for COVID-19, paving the way for further large-scale and prospective research to explore the full potential of UDCA.

Study on the Permeability Enhancement of Propped Fractures under the Action of a Coal Fine Plugging Removal Agent.

The retention of coal fines in propped fractures impedes the efficient flow of gas and water, leading to a substantial decrease in coal seam permeability and gas production efficiency. In this article, a coal fine plugging removal agent with good dispersion stability and powerful powder-carrying capacity was developed to study the coal fine plugging removal and permeability enhancement in the propped fracture. The results show that 0.8% SDS + 0.4% NaCl + 0.8% BS-12 was the most effective coal fine plugging removal agent compounding system. Increasing the injection rate of the plugging removal agent and performing recycles of intermittent unblocking when it was used as a plugging agent will effectively enhance the gas-liquid two-phase effective permeability of propped fractures and improve the release of retained coal fines. After three recycles of intermittent unblocking, the coal fine discharging rate can be increased to more than 90%, resulting in a 3.88 times increase of the gas-liquid two-phase permeability compared to that with the single unblocking cycle. This method has important practical significance and theoretical value for solving the problem of coal fine plugging in fractures and ensuring the stable and efficient discharge of coalbed gas-water-coal fines.

Effects of Mechanical Properties on Gas-Water Flow Characteristics around Boreholes: Implementation of Damage-Based Coupling Models.

Neglecting the coal damage effect around a borehole could result in low accuracy of gas extraction seepage analysis. A fluid-solid coupling model incorporating coal stress and damage, gas diffusion, and seepage was established. Reliability of the proposed model was validated using field data. Variation characteristics of gas-water phase parameters in the borehole damage zone during gas drainage were analyzed. Meanwhile, effects of equivalent plastic strain, lateral pressure coefficient, internal friction angle, cohesion, Young's modulus, and Poisson's ratio on the damage state and spatiotemporal change properties of gas extraction flow were investigated. Results indicate that due to coal damage, permeability shows a three-zone distribution around the borehole, among which the fracture zone has the highest permeability, approximately 40 times of the original value. Permeability in the plastic zone decreases rapidly, while permeability is the smallest in the elastic zone. Coal permeability within the damage zone increases with continuous gas extraction. A smooth and low-value zone occurs for both fracture and matrix gas pressures. With the increase in equivalent plastic strain, the damage zone decreases, while peak permeability in the damage zone rises, and gas pressure in the smooth low-pressure zone continues to drop. The damage zone becomes smaller with an increasing lateral pressure coefficient, while those plastic and elastic zones become larger. The damage zone area corresponding to the lateral pressure coefficient of 0.89 is 82.3% smaller compared with that of 0.56. As internal friction angle and cohesion rise, the damage zone gradually decreases and shifts from a butterfly shape to elliptical shape. When Young's modulus is heterogeneously distributed, except for concentrated shear damage zones around the borehole, punctate microdamage zones are also found at positions far from the borehole. Those damage zones gradually become smaller as shape parameters of the Weibull distribution get larger. The above findings are expected to offer theoretical support and practical guidance for borehole drilling and efficient extraction of clean methane resources.

Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2.

OBJECTIVE: Glioma, a malignant primary brain tumor, is notorious for its high incidence rate. However, the clinical application of temozolomide (TMZ) as a treatment option for glioma is often limited due to resistance, which has been linked to hypoxic glioma cell-released exosomes. In light of this, the present study aimed to investigate the role of exosomal pyruvate kinase M2 (PKM2) in glioma cells that exhibit resistance to TMZ. METHODS: Sensitive and TMZ-resistant glioma cells were subjected to either a normoxic or hypoxic environment, and the growth patterns and enzymatic activity of glycolysis enzymes were subsequently measured. From these cells, exosomal PKM2 was isolated and the subsequent effect on TMZ resistance was examined and characterized, with a particular focus on understanding the relevant mechanisms. Furthermore, the intercellular communication between hypoxic resistant cells and tumor-associated macrophages (TAMs) via exosomal PKM2 was also assessed. RESULTS: The adverse impact of hypoxic microenvironments on TMZ resistance in glioma cells was identified and characterized. Among the three glycolysis enzymes that were examined, PKM2 was found to be a critical mediator in hypoxia-triggered TMZ resistance. Upregulation of PKM2 was found to exacerbate the hypoxia-mediated TMZ resistance. Exosomal PKM2 were identified and isolated from hypoxic TMZ-resistant glioma cells, and were found to be responsible for transmitting TMZ resistance to sensitive glioma cells. The exosomal PKM2 also contributed towards mitigating TMZ-induced apoptosis in sensitive glioma cells, while also causing intracellular ROS accumulation. Additionally, hypoxic resistant cells also released exosomal PKM2, which facilitated TMZ resistance in tumor-associated macrophages. CONCLUSION: In the hypoxic microenvironment, glioma cells become resistant to TMZ due to the delivery of PKM2 by exosomes. Targeted modulation of exosomal PKM2 may be a promising strategy for overcoming TMZ resistance in glioma.

Improved Formation of Biomethane by Enriched Microorganisms from Different Rank Coal Seams.

The influence of enrichment of culturable microorganisms in in situ coal seams on biomethane production potential of other coal seams has been rarely studied. In this study, we enriched culturable microorganisms from three in situ coal seams with three coal ranks and conducted indoor anaerobic biomethane production experiments. Microbial community composition, gene functions, and metabolites in different culture units by 16S rRNA high-throughput sequencing combined with liquid chromatography-mass spectrometry-time-of-flight (LC-MS-TOF). The results showed that biomethane production in the bituminous coal group (BC)cc resulted in the highest methane yield of 243.3 µmol/g, which was 12.3 times higher than that in the control group (CK). Meanwhile, Methanosarcina was the dominant archaeal genus in the three experimental groups (37.42 ± 11.16-52.62 ± 2.10%), while its share in the CK was only 2.91 ± 0.48%. Based on the functional annotation, the relative abundance of functional genes in the three experimental groups was mainly related to the metabolism of nitrogen-containing heterocyclic compounds such as purines and pyrimidines. Metabolite analysis showed that enriched microorganisms promoted the degradation of a total of 778 organic substances in bituminous coal, including 55 significantly different metabolites (e.g., purines and pyrimidines). Based on genomic and metabolomic analyses, this paper reconstructed the heterocyclic compounds degradation coupled methane metabolism pathway and thereby preliminarily elucidated that enriched culturable bacteria from different coal-rank seams could promote the degradation of bituminous coal and intensify biogenic methane yields.

A method of genetic transformation and gene editing of succulents without tissue culture.

Succulents, valued for their drought tolerance and ornamental appeal, are important in the floriculture market. However, only a handful of succulent species can be genetically transformed, making it difficult to improve these plants through genetic engineering. In this study, we adapted the recently developed cut-dip-budding (CDB) gene delivery system to transform three previously recalcitrant succulent varieties - the dicotyledonous Kalanchoe blossfeldiana and Crassula arborescens and the monocotyledonous Sansevieria trifasciata. Capitalizing on the robust ability of cut leaves to regenerate shoots, these plants were successfully transformed by directly infecting cut leaf segments with the Agrobacterium rhizogenes strain K599. The transformation efficiencies were approximately 74%, 5% and 3.9%-7.8%, respectively, for K. blossfeldiana and C. arborescens and S. trifasciata. Using this modified CDB method to deliver the CRISPR/Cas9 construct, gene editing efficiency in K. blossfeldiana at the PDS locus was approximately 70%. Our findings suggest that succulents with shoot regeneration ability from cut leaves can be genetically transformed using the CDB method, thus opening up an avenue for genetic engineering of these plants.

Cell-permeable PI3 kinase competitive peptide inhibits KIT mutant mediated tumorigenesis of gastrointestinal stromal tumor (GIST).

BACKGROUND: Mutations in the receptor tyrosine kinase KIT are the main cause of gastrointestinal stromal tumor (GIST), and the KIT mutants mediated PI3 kinase activation plays a key role in the tumorigenesis of GIST. In this study, we aimed to block PI3 kinase activation by cell-permeable peptide and investigate its possible application in the treatment of GIST. METHODS AND RESULTS: We designed cell-permeable peptides based on the binding domain of PI3 kinase subunit p85 to KIT or PI3 kinase subunit p110, respectively, in order to compete for the binding between p85 and KIT or p110 and therefore inhibit the activation of PI3 kinases mediated by KIT. The results showed that the peptide can penetrate the cells, and inhibit the activation of PI3 kinases, leading to reduced cell survival and cell proliferation mediated by KIT mutants in vitro. Treatment of mice carrying germline KIT/V558A mutation, which can develop GIST, with the peptide that can compete for the binding between p85 and p110, led to reduced tumorigenesis of GIST. The peptide can further enhance the inhibition of the tumor growth by imatinib which is used as the first line targeted therapy of GIST. CONCLUSIONS: Our results showed that cell-permeable PI3 kinase competitive peptide can inhibit KIT-mediated PI3 kinase activation and tumorigenesis of GIST, providing a rationale to further test the peptide in the treatment of GIST and even other tumors with over-activation of PI3 kinases.

Simple method for transformation and gene editing in medicinal plants.

A sample delivery method, modified from cut-dip-budding, uses explants with robust shoot regeneration ability, enabling transformation and gene editing in medicinal plants, bypassing tissue culture and hairy root formation. This method has potential for applications across a wide range of plant species.

Effect of Clostridium butyricum on the formation of primary choledocholithiasis based on intestinal microbiome and metabolome analysis.

AIMS: To investigate the function and probable mechanism of Clostridium butyricum in the development of choledocholithiasis. METHODS AND RESULTS: The lithogenic diet group and the lithogenic diet + C. butyricum group were used to develop the choledocholithiasis model. During the experiment, C. butyricum suspension was administered to the rats in the lithogenic diet + C. butyricum group. The findings demonstrated that the C. butyricum intervention decreased the Firmicutes/Bacteroidetes ratio in the colon of experimental animals given a lithogenic diet. The relative levels of Desulfovibrio (0.93%) and Streptococcus (0.38%) fell, whereas Lactobacillus (22.36%), Prevotella (14.09%), and bacteria that produce short-chain fatty acids increased. Finally, 68 distinct metabolic products were found based on nontargeted metabonomics, and 42 metabolic pathways associated to the various metabolites were enriched. CONCLUSIONS: We found that C. butyricum decreased the development of choledocholithiasis. It keeps the equilibrium of the rat's gut microbiome intact and lowers the danger of bacterial infections of the gastrointestinal and biliary systems. It is hypothesized that by controlling lipid metabolism, it may also have an impact on the development of cholelithiasis.

Genesis of Low CBM Production in Mid-Deep Reservoirs and Methods to Increase Regional Production: A Case Study in the Zhengzhuang Minefield, Qinshui Basin, China.

With the increase of the burial depth of the no. 3 coal seam in the Zhengzhuang minefield of Qinshui Basin, the production of surface coal bed methane (CBM) vertical wells was low. By means of theoretical analysis and numerical calculation, the causes of low production of CBM vertical wells were studied from the aspects of reservoir physical properties, development technology, stress conditions, and desorption characteristics. It was found that the high in situ stress conditions and stress state changes were the main controlling factors of the low production in the field. On this basis, the mechanism of increasing production and reservoir stimulation was explored. An L-type horizontal well was constructed alternately among the existing vertical wells on the surface to initiate a method to increase the regional production of fish-bone-shaped well groups. This method has the advantages of a large fracture extension range and a wide pressure relief area. It could also effectively connect the pre-existing fracture extension area of surface vertical wells, realizing the overall stimulation of the low-yield area and increasing the regional production. Through the optimization of the favorable stimulation area in the minefield, 8 L-type horizontal wells that adopted this method were constructed in the area with high gas content (greater than 18 m3/t), a thick coal seam (thicker than 5 m), and relatively rich groundwater in the north of the minefield. The average production of a single L-type horizontal well reached 6000 m3/d, which was about 30 times that of the surrounding vertical wells. The length of the horizontal section and the original gas content of the coal seam had a significant influence on the production of the L-type horizontal wells. This method for increasing the regional production of fish-bone-shaped well groups was an effective and feasible low-yield well stimulation technology, which provided a reference for increasing the production and efficiently developing CBM under the high-stress conditions in mid-deep high-rank coal seams.