[Research progress on pathogenic mechanism of sepsis-induced liver injury and treatment with traditional Chinese medicine and its active components].

Sepsis is a systemic inflammatory response syndrome caused by infection, with high morbidity and mortality. Sepsis-induced liver injury(SILI) is one of the manifestations of sepsis-induced multiple organ syndrome. At present, there is no recommended pharmacological intervention for the treatment of SILI. traditional Chinese medicine(TCM), based on the holism and dialectical treatment concept, shows the therapeutic characteristics of multi-target and multi-pathway and can comprehensively prevent and treat SILI by interfering with inflammatory factors, inflammatory signaling pathways, and anti-oxidative stress and inhibiting apoptosis. This article reviewed the experimental studies on the treatment of SILI with TCM to clarify its pathogenic mechanism and therapeutic characteristics, so as to provide more ideas and directions for the development or preparation of new drugs.

Advancing glioblastoma treatment by targeting metabolism.

Alterations in cellular metabolism are important hallmarks of glioblastoma(GBM). Metabolic reprogramming is a critical feature as it meets the higher nutritional demand of tumor cells, including proliferation, growth, and survival. Many genes, proteins, and metabolites associated with GBM metabolism reprogramming have been found to be aberrantly expressed, which may provide potential targets for cancer treatment. Therefore, it is becoming increasingly important to explore the role of internal and external factors in metabolic regulation in order to identify more precise therapeutic targets and diagnostic markers for GBM. In this review, we define the metabolic characteristics of GBM, investigate metabolic specificities such as targetable vulnerabilities and therapeutic resistance, as well as present current efforts to target GBM metabolism to improve the standard of care.

Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1.

Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

Sex difference in cardiac performance in individuals with irregular shift work.

Background: sex differences existed in animal behavioral adaption and activity rhythms when exposed to chronic disruption of the circadian rhythm. Whether these differences extend to cardiac performance has not been fully investigated by cardiac imaging technology. Methods: One hundred and thirty patients enrolled in this study. Patients were divided into the day shift (DS) group and the irregular shift (IRS) group based on whether involved in the night shift and the frequency of the night shift. Comparisons of clinical data and cardiac imaging parameters were performed to identify the sex difference in cardiac function in the participants with day shift work or irregular shifts. Results: The absolute value of GLS was significantly lower in male IRS group than in male DS group. In females, no significant difference was tested in left ventricular function between the two groups. In male participants, Weekly work hours (WWH) was positively correlated with HR (r = 0.51, p = 0.02) and QTc duration (r = 0.68, p < 0.00), and weakly negatively correlated with the GLS (r = -0.38, p = 0.05). Amongst patients, there was a 2.67-fold higher relative risk (RR) for impaired GLS in males than in females, with a 95 % confidence interval (CI) of 1.20-5.61. Moreover, there was an increased risk in the male IRS group compared to the female IRS group to develop impaired GLS (RR:3.14, 95 % CI 1.20-7.84). Conclusions: The present study suggests that chronic circadian disruption brings cardiac dysfunction in people with night-shift work. Gender differences exist in the impact of circadian rhythmicity on cardiac function and may help to guide the work schedule and breaks in shift workers and bring forward prevention strategies in response to chronic circadian disruption.

Analysis of changes in the spatiotemporal characteristics of impervious surfaces and their influencing factors in the Central Plains Urban Agglomeration of China from 2000 to 2018.

The change of the impervious surface area (ISA) is an important feature of urban spatial expansion. Understanding the spatial and temporal change characteristics of urban impervious surfaces and their influencing factors is of great significance to the planning, management, and urbanization development of cities. This paper adopts a global artificial impervious surface dataset, with a resolution of 30 m, calculates and processes the data based on the ArcGIS platform, adopts the MK trend test method, introduces the dynamic degree, qualitatively and quantitatively analyses the changing characteristics of the ISA in the Central Plains Urban Agglomeration (CPUA), and analyzes the influencing factors of ISA changes using GeoDetector. The results show that the ISA dynamic degree was significantly enhanced from 2000 to 2018, which increased 1.86 times, indicating the accelerated outward expansion of the CPUA and the rapid level of urban development during that period. The explanatory power of the greenery coverage area on the change of the ISA in the CPUA during 2000-2018 was the strongest; the same factor has different explanatory powers for the ISA in different periods. The influencing factors have an enhanced relationship between two and two, including two-factor enhancement and nonlinear enhancement, in 2000-2009, during which the interaction level of the greenery coverage area and the GDP per capita was strong, while from 2009 to 2018, the interaction between transportation and other factors was significantly strong.

Regulating epileptiform discharges by heterogeneous interneurons in thalamocortical model.

Inhibitory interneurons in the cortex are abundant and have diverse roles, classified as parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal polypeptide (VIP) according to chemically defined categories. Currently, their involvement with seizures has been partially uncovered in physiological terms. Here, we propose a corticothalamic model containing heterogeneous interneurons to study the effects of various interneurons on absence seizure dynamics by means of optogenetic stimulation. First, the important role of feedforward inhibition caused by SRN→PV→PN projections on seizures is verified. Then, we demonstrate that light activation targeting either PV or SOM INs can control seizures. Finally, with different inhibition contributions from PV INs and SOM INs, the possible disinhibitory effect of blue light acting on VIP INs is mainly discussed. The results suggest that depending on the inhibition degree of both types, the disinhibition brought about by the VIP INs will trigger seizures, will control seizures, and will not work or cause the PNs to tend toward a high saturation state with high excitability. The circuit mechanism and the related bifurcation characteristics in various cases are emphatically revealed. In the model presented, in addition to Hopf and saddle-node bifurcations, the system may also undergo period-doubling and torus bifurcations under stimulus action, with more complex dynamics. Our work may provide a theoretical basis for understanding and further exploring the role of heterogeneous interneurons, in particular, the VIP INs, a novel target, in absence seizures.

Natural arginine-based deep eutectic solvents for rapid microwave-assisted pretreatment on crystalline bamboo cellulose with boosting enzymatic conversion performance.

Development of amino acid-based natural deep eutectic solvents (DESs) pretreatment technology on lignocellulosic biomass is a promising approach to biorefinery. In this study, for arginine-based DESs with different molar ratios, the viscosity and Kamlet-Taft solvation parameters were quantified to evaluate the pretreatment performance on bamboo biomass. Further, microwave assisted DES pretreatment was eminent, evidenced by 84.8% lignin removal and increased saccharification yield (from 6.3% to 81.9%) in moso bamboo at 120 °C and ratio of 1:7 (arginine: lactic acid). Results showed degradation of lignin molecules together with release of phenolic hydroxyl units after DESs pretreatment, which is conducive to subsequent utilization. Meanwhile, DES-pretreated cellulose exhibited unique structural characteristics including destroyed crystalline region of cellulose (Crystallinity Index from 67.2% to 53.0%), decreased crystallite size (from 3.41 nm to 3.14 nm) and roughened fiber surface. Thus, arginine-based DES pretreatment has excellent potential in bamboo lignocellulose pretreatment.

ARID1A mutations in cancer development: mechanism and therapy.

AT-Rich Interaction Domain 1A (ARID1A) is an important SWItch/Sucrose Non-Fermentation (SWI/SNF) chromatin remodeling complex subunit, and its coding gene has a high mutation frequency in many cancers. Current studies have reported that ARID1A mutational status is correlated to cancer development, including cell proliferation, invasiveness, metastasis, and morphological alterations. ARID1A acts as a tumor suppressor, regulating gene transcription, participating in DNA damage response, and influencing tumor immune microenvironment and signaling pathways. The absence of ARID1A in cancer can lead to widespread dysregulation of gene expression in cancer initiation, promotion, and progression. For patients with ARID1A mutations, effective individualized treatment can improve the prognosis of patients. In this review, we aim to discuss the mechanism of ARID1A mutations in cancer development and explore the significance of discoveries for treatment.

Study of gray matter atrophy pattern with subcortical ischemic vascular disease-vascular cognitive impairment no dementia based on structural magnetic resonance imaging.

Objective: This study explored the structural imaging changes in patients with subcortical ischemic vascular disease (SIVD)-vascular cognitive impairment no dementia (VCIND) and the correlation between the changes in gray matter volume and the field of cognitive impairment to provide new targets for early diagnosis and treatment. Methods: Our study included 15 patients with SIVD-normal cognitive impairment (SIVD-NCI), 63 with SIVD-VCIND, 26 with SIVD-vascular dementia (SIVD-VD), and 14 normal controls (NC). T1-weighted images of all participants were collected, and DPABI and SPM12 software were used to process the gray matter of the four groups based on voxels. Fisher's exact test, one-way ANOVA and Kruskal-Wallis H test were used to evaluate all clinical and demographic data and compare the characteristics of diencephalic gray matter atrophy in each group. Finally, the region of interest (ROI) of the SIVD-VCIND was extracted, and Pearson correlation analysis was performed between the ROI and the results of the neuropsychological scale. Results: Compared to the NC, changes in gray matter atrophy were observed in the bilateral orbitofrontal gyrus, right middle temporal gyrus, superior temporal gyrus, and precuneus in the SIVD-VCIND. Gray matter atrophy was observed in the left cerebellar region 6, cerebellar crural region 1, bilateral thalamus, right precuneus, and calcarine in the SIVD-VD. Compared with the SIVD-VCIND, gray matter atrophy changes were observed in the bilateral thalamus in the SIVD-VD (p < 0.05, family-wise error corrected). In the SIVD-VCIND, the total gray matter volume, bilateral medial orbital superior frontal gyrus, right superior temporal gyrus, middle temporal gyrus, and precuneus were positively correlated with Boston Naming Test score, whereas the total gray matter volume, right superior temporal gyrus, and middle temporal gyrus were positively correlated with overall cognition. Conclusion: Structural magnetic resonance imaging can detect extensive and subtle structural changes in the gray matter of patients with SIVD-VCIND and SIVD-VD, providing valuable evidences to explain the pathogenesis of subcortical vascular cognitive impairment and contributing to the early diagnosis of SIVD-VCIND and early warning of SIVD-VD.

Insights into key factors affecting bioconversion efficiency of rattan biomass: The supramolecular structural variations of cellulose.

Global energy concerns urged us to search for sufficient utilization of biomass to renewable energy. Herein, rattan biomass displaying herbaceous species-like anatomy and hardwood-like chemical composition was used as model of lignocellulose to determine its recalcitrance inhibiting efficient bioconversion. Delignification and continuous mild alkaline treatments were applied for deconstruction of rattan cane (Calamus simplicifolius) followed by cellulase enzymatic hydrolysis. Cellulose supramolecular structural variations were proved to be the major reason for the enhanced hydrolysis in addition to the removal of lignin and hemicelluloses matrix. Lowered crystallinity (50-65 %) as well as swelled crystallite sizes (4.8-5.0 nm) during allomorphic transformation favored the enhanced hydrolysis, rather than the crystalline cellulose II. Moreover, well-distributed separation and fibrillation of cellulose elementary fibrils also contributed to glucose yield promotion. The study will provide new insights to the strategy to efficient bioconversion of lignocellulosic biomass.

Analysis of a machine learning-based risk stratification scheme for acute kidney injury in vancomycin.

Vancomycin-associated acute kidney injury (AKI) continues to pose a major challenge to both patients and healthcare providers. The purpose of this study is to construct a machine learning framework for stratified predicting and interpreting vancomycin-associated AKI. Our study is a retrospective analysis of medical records of 724 patients who have received vancomycin therapy from 1 January 2015 through 30 September 2020. The basic clinical information, vancomycin dosage and days, comorbidities and medication, laboratory indicators of the patients were recorded. Machine learning algorithm of XGBoost was used to construct a series risk prediction model for vancomycin-associated AKI in different underlying diseases. The vast majority of sub-model performed best on the corresponding sub-dataset. Additionally, the aim of this study was to explain each model and to explore the influence of clinical variables on prediction. As the results of the analysis showed that in addition to the common indicators (serum creatinine and creatinine clearance rate), some other underappreciated indicators such as serum cystatin and cumulative days of vancomycin administration, weight and age, neutrophils and hemoglobin were the risk factors for cancer, diabetes mellitus, heptic insufficiency respectively. Stratified analysis of the comorbidities in patients with vancomycin-associated AKI further confirmed the necessity for different patient populations to be studied.

Allomorphic regulation of bamboo cellulose by mild alkaline peroxide for holocellulose nanofibrils production.

The exploration of sustainable lignocellulosic nanomaterials with unique properties and applicable functions is receiving growing interest. In this work, holocellulose nanofibrils (HCNFs) were prepared from moso bamboo using mild alkaline peroxide bleaching method (MAPB) followed by mechanical nanofibrillation. MAPB was proved to effectively remove lignin and retain hemicellulose. Meanwhile, partial allomorphic changes from cellulose I to cellulose II were revealed together with varying degrees of crystallinity. Thermogravimetric analysis (TGA) experiment showed an increasing thermal stability trend due to more allomorphic changes into anti-parallel cellulose II. Well-dispersed HCNFs suspensions were successfully prepared by homogenization and HCNFs films with high transparency and flexibility were fabricated. The films reached the maximum tensile strength of 55.8 MPa and tensile strain of 1.55 % along with a calculated toughness of 25 MJ/m3. Moreover, the prepared materials are biocompatible and completely non-toxic, which will theoretically support the application of HCNFs materials in fields of biology, medicine and food industry.

Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2.

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key enzyme, which extensively digests CoV replicase polyproteins essential for viral replication and transcription, making it an attractive target for antiviral drug development. However, the molecular mechanism of how Mpro of SARS-CoV-2 digests replicase polyproteins, releasing the nonstructural proteins (nsps), and its substrate specificity remain largely unknown. Here, we determine the high-resolution structures of SARS-CoV-2 Mpro in its resting state, precleavage state, and postcleavage state, constituting a full cycle of substrate cleavage. The structures show the delicate conformational changes that occur during polyprotein processing. Further, we solve the structures of the SARS-CoV-2 Mpro mutant (H41A) in complex with six native cleavage substrates from replicase polyproteins, and demonstrate that SARS-CoV-2 Mpro can recognize sequences as long as 10 residues but only have special selectivity for four subsites. These structural data provide a basis to develop potent new inhibitors against SARS-CoV-2.

Mutation breeding of Aspergillus niger by atmospheric room temperature plasma to enhance phosphorus solubilization ability.

Background: Phosphorus (P) is abundant in soils, including organic and inorganic forms. Nevertheless, most of P compounds cannot be absorbed and used by plants. Aspergillus niger v. Tiegh is a strain that can efficiently degrade P compounds in soils. Methods: In this study, A. niger xj strain was mutated using Atmospheric Room Temperature Plasma (ARTP) technology and the strains were screened by Mo-Sb Colorimetry with strong P-solubilizing abilities. Results: Compared with the A. niger xj strain, setting the treatment time of mutagenesis to 120 s, four positive mutant strains marked as xj 90-32, xj120-12, xj120-31, and xj180-22 had higher P-solubilizing rates by 50.3%, 57.5%, 55.9%, and 61.4%, respectively. Among them, the xj120-12 is a highly efficient P solubilizing and growth-promoting strain with good application prospects. The growth characteristics such as plant height, root length, and dry and fresh biomass of peanut (Arachis hypogaea L.) increased by 33.5%, 43.8%, 43.4%, and 33.6%, respectively. Besides available P, the chlorophyll and soluble protein contents also vary degrees of increase in the P-solubilizing mutant strains. Conclusions: The results showed that the ARTP mutagenesis technology can improve the P solubilization abilities of the A. niger mutant strains and make the biomass of peanut plants was enhanced of mutant strains.

Research frontiers and trends in the application of artificial intelligence to sepsis: A bibliometric analysis.

Background: With the increasing interest of academics in the application of artificial intelligence to sepsis, thousands of papers on this field had been published in the past few decades. It is difficult for researchers to understand the themes and latest research frontiers in this field from a multi-dimensional perspective. Consequently, the purpose of this study is to analyze the relevant literature in the application of artificial intelligence to sepsis through bibliometrics software, so as to better understand the development status, study the core hotspots and future development trends of this field. Methods: We collected relevant publications in the application of artificial intelligence to sepsis from the Web of Science Core Collection in 2000 to 2021. The type of publication was limited to articles and reviews, and language was limited to English. Research cooperation network, journals, cited references, keywords in this field were visually analyzed by using CiteSpace, VOSviewer, and COOC software. Results: A total of 8,481 publications in the application of artificial intelligence to sepsis between 2000 and 2021 were included, involving 8,132 articles and 349 reviews. Over the past 22 years, the annual number of publications had gradually increased exponentially. The USA was the most productive country, followed by China. Harvard University, Schuetz, Philipp, and Intensive Care Medicine were the most productive institution, author, and journal, respectively. Vincent, Jl and Critical Care Medicine were the most cited author and cited journal, respectively. Several conclusions can be drawn from the analysis of the cited references, including the following: screening and identification of sepsis biomarkers, treatment and related complications of sepsis, and precise treatment of sepsis. Moreover, there were a spike in searches relating to machine learning, antibiotic resistance and accuracy based on burst detection analysis. Conclusion: This study conducted a comprehensive and objective analysis of the publications on the application of artificial intelligence in sepsis. It can be predicted that precise treatment of sepsis through machine learning technology is still research hotspot in this field.

Isolation and Identification of Antibacterial Bioactive Compounds From Bacillus megaterium L2.

Bacterial metabolites exhibit a variety of biologically active compounds including antibacterial and antifungal activities. It is well known that Bacillus is considered to be a promising source of bioactive secondary metabolites. Most plant pathogens have an incredible ability to mutate and acquire resistance, causing major economic losses in the agricultural field. Therefore, it is necessary to use the natural antibacterial compounds in microbes to control plant pathogens. This study was conducted to investigate the bio-active compounds of Bacillus megaterium L2. According to the activity guidance of Agrobacterium tumefaciens T-37, Erwinia carotovora EC-1 and Ralstonia solanacearum RS-2, five monomeric compounds, including erucamide (1), behenic acid (2), palmitic acid (3), phenylacetic acid (4), and ß-sitosterol (5), were fractionated and purified from the crude ethyl acetate extract of B. megaterium. To our knowledge, all compounds were isolated from the bacterium for the first time. To understand the antimicrobial activity of these compounds, and their minimum inhibitory concentrations (MICs) (range: 0.98∼500 µg/mL) were determined by the broth microdilution method. For the three tested pathogens, palmitic acid exhibited almost no antibacterial activity (>500 µg/mL), while erucamide had moderate antibacterial activity (MIC = 500 µg/mL). Behenic acid showed MICs of 250 µg/mL against T-37 and RS-2 strains with an antibacterial activity. ß-sitosterol showed significant antimicrobial activity against RS-2. ß-sitosterol showed remarkable antimicrobial activity against RS-2 with an MIC of 15.6 µg/mL. In addition, with the antimicrobial activity, against T-37 (62.5 µg/mL) and against EC-1 (125 µg/mL) and RS-2 (15.6 µg/mL) strains notably, phenylacetic acid may be interesting for the prevention and control of phytopathogenic bacteria. Our findings suggest that isolated compounds such as behenic acid, ß-sitosterol, and phenylacetic acid may be promising candidates for natural antimicrobial agents.

Rhein protects 5/6 nephrectomized rat against renal injury by reducing inflammation via NF-κB signaling.

BACKGROUND/AIMS: Inflammation is well known to play a pivotal role in renal injury. Rhein is a major component of the medicinal Rhubarb. The aim of this study was to investigate whether Rhein protects against renal injury and explore its underlying mechanism. METHODS: 5/6 nephrectomization (5/6 Nx) was operated on Sprague-Dawley rats. Human kidney tubular epithelial (HK-2) cells were treated with lipopolysaccharide (LPS). The level of blood urea nitrogen (BUN) and serum creatinine (SCr) was examined. Kidney tissues were stained with hematoxylin and eosin to check the morphology. The cell viability was examined. The levels of cytokines and chemokines were measured by ELISA kit. The protein expression was determined by western blot. RESULTS: Rhein significantly decreased SCr and BUN levels in 5/6 Nx rat. The morphologic findings indicated noteworthy amelioration of the damaged renal tissue in Rhein-treated rats. Rhein significantly protects HK-2 cells from LPS-mediated apoptosis. The productions of inflammatory signaling molecules (TNF-α, IL-6 and MCP-1) were inhibited by Rhein. LPS-induced NF-κB activation was also attenuated by Rhein via blocking its nuclear translocation by inhibiting phosphorylation of IκBα. CONCLUSION: These findings provide evidence that Rhein protect against renal injury, and NF-κB signaling pathway is involved in this protective effect.

Lyciumamide A, a dimer of phenolic amide, protects against NMDA-induced neurotoxicity and potential mechanisms in vitro.

Currently, the excessive activation of N-methyl-D-aspartate receptors (NMDARs) is considered to be a crucial mechanism of brain injury. Lycium barbarum A (LyA) is a dimer of phenol amides isolated from the fruit of Lycium barbarum. Our previous studies have shown that LyA has potential antioxidant activity. This study aimed to explore the neuroprotective effect of LyA and its potential mechanism. Firstly, the molecular docking was used to preliminarily explore the potential function of LyA to block NMDAR. Then, the ability of LyA was further verified by NMDA-induced human neuroblastoma SH-SY5Y cells in vivo. Treatment with LyA significantly attenuated NMDA-induced neuronal insults by increasing cell viability, reducing lactate dehydrogenase (LDH) release, and increasing cell survival. Meanwhile, LyA significantly reversed the increase in intracellular calcium and in ROS production induced by NMDA. Finally, the western blot indicated that LyA could suppress the Ca2+ influx and increase the p-NR2B, p-CaMKII, p-JNK, and p-p38 level induced by NMDA. These above findings provide evidence that LyA protect against brain injury, and restraining NMDARs and suppressing mitochondrial oxidative stress and inhibiting cell apoptosis may be involved in the protective mechanism.