Systematic investigation of the material basis, effectiveness and safety of Thesium chinense Turcz. and its preparation Bairui Granules against lung inflammation.

BACKGROUND: Thesium chinense Turcz. (Named as Bai Rui Cao in Chinese) and its preparations (e.g., Bairui Granules) have been used to treat inflammatory diseases, such as acute mastitis, lobar pneumonia, tonsillitis, coronavirus disease 2019 (COVID-19), and upper respiratory tract infection. However, the material basis, pharmacological efficiency, and safety have not been illustrated. METHODS: Anti-inflammatory activity-guided isolation of constituents has been performed using multiple column chromatography, and their structures were elucidated by NMR spectroscopy and ECD calculations. The inhibitory effects on lung inflammation and safety of the crude ethanol extract (CE), Bairui Granules (BG), and the purified active constituents were evaluated using lipopolysaccharide (LPS)-stimulated acute lung inflammation (ALI) mice model or normal mice. RESULTS: Seven new compounds (1-7) and fifty-six known compounds (8-63) were isolated from T. chinense, and fifty-four were reported from this plant for the first time. The new flavonoid glycosides 1-2, new fatty acids 4-5, new alkaloid 7 as well as the known constituents including flavonoid aglycones 8-11, lignans 46-54, alkaloids 34 and 45, coumarins 57, phenylpropionic acids 27, and simple aromatic compounds 39, 44 and 58 exhibited anti-inflammatory activity. Network pharmacology analysis indicated that anti-inflammation of T. chinense was attributed to flavonoids and alkaloids by regulating inflammation-related proteins (e.g., TNF, NF-κB, TGF-ß). Furthermore, constituents of T. chinense including kaempferol-3-O-glucorhamnoside (KN, also named as Bairuisu I, 19), astragalin (AG, Bairuisu II, 12), and kaempferol (KF, Bairuisu III, 8), as well as CE and BG could alleviate lung inflammation caused by LPS in mice by preventing neutrophils infiltration and the expression of the genes for pro-inflammatory cytokines NLRP3, caspase-1, IL-1ß, and COX-2. After a 28-day subacute toxicity test, BG at doses of 4.875 g/kg and 9.750 g/kg (equivalent to onefold and twofold the clinically recommended dose) and CE at a dose of 11.138 g/kg (equivalent to fourfold the clinical dose of BG) were found to be safe and non-toxic. CONCLUSIONS: The discovery of sixty-three constituents comprehensively illustrated the material basis of T. chinense. T. chinense and Bairui Granules could alleviate lung inflammation by regulating inflammation-related proteins and no toxicity was observed under the twofold of clinically used doses.

Mechanisms of TREM2 mediated immunosuppression and regulation of cancer progression.

Cancer immunotherapy has recently emerged as a key strategy for cancer treatment. TREM2, a key target for regulating the tumor immune microenvironment, is important in cancer treatment and progression. TREM2 is an immune signaling hub that regulates multiple pathological pathways. It not only suppresses anti-tumor immune responses by inhibiting T cell-mediated immune responses, but it also influences tumorigenesis by affecting NK cell-mediated anti-tumor immunity. Noticeably, TREM2 expression levels also vary significantly among different tumor cells, and it can regulate tumor progression by modulating various signaling pathways. Above all, by summarizing the role of TREM2 in cancer immunotherapy and the mechanism by which TREM2 regulates tumor progression, this paper clarifies TREM2's role in both tumor progression and cancer therapy, identifying a new therapeutic target for oncology diseases.

Isolation of four new monoterpenes from Ailanthus altissima (mill.) Swingle and their enzyme inhibitory effects.

A phytochemical study of the ethanol extract from Ailanthus altissima (Mill.) Swingle leaves resulted in the isolation of four new monoterpenoids (1-3, 5). The structures were elucidated using HRESIMS data, NMR spectroscopic data, quantum chemical calculations for NMR and ECD, and custom DP4+ probability analysis. Additionally, the absolute configuration of sugar was determined by acid hydrolysis. Compounds 1-4 are cyclogeraniane monocyclic monoterpenes, while compound 5 contains an acyclic mycrane monoterpenes skeleton. Anti-tyrosinase, anti-acetylcholinesterase, and anti-butyrylcholinesterase activities were tested. Compound 1 showed notable anti-acetylcholinesterase activity, and compound 3 exhibited significant inhibitory effects on anti-tyrosinase activity. Furthermore, the potential binding sites of compounds 1 and 3 were predicted by molecular docking.

Copper-Catalyzed [2 + 2] Cyclization/Ring Expansion of Ene-Ynamides: Construction of Medium- and Large-Sized Rings.

Catalytic cyclization of enynes is an efficient approach for the preparation of cyclic compounds, and a large variety of four- to six-membered rings could be synthesized using this method. However, it has been rarely employed for the construction of medium- and large-sized rings. Herein, we describe a copper-catalyzed cycloisomerization of ene-ynamides through a [2 + 2] cyclization/electrocyclic ring opening cascade, leading to the atom-economical assembly of indole-fused medium- and large-sized rings in moderate to excellent yields under mild reaction conditions. Importantly, the synthetic utility of this reaction was demonstrated by the convenient synthesis of iprindole.

DDX21 mediates co-transcriptional RNA m6A modification to promote transcription termination and genome stability.

N6-methyladenosine (m6A) is a crucial RNA modification that regulates diverse biological processes in human cells, but its co-transcriptional deposition and functions remain poorly understood. Here, we identified the RNA helicase DDX21 with a previously unrecognized role in directing m6A modification on nascent RNA for co-transcriptional regulation. DDX21 interacts with METTL3 for co-recruitment to chromatin through its recognition of R-loops, which can be formed co-transcriptionally as nascent transcripts hybridize onto the template DNA strand. Moreover, DDX21's helicase activity is needed for METTL3-mediated m6A deposition onto nascent RNA following recruitment. At transcription termination regions, this nexus of actions promotes XRN2-mediated termination of RNAPII transcription. Disruption of any of these steps, including the loss of DDX21, METTL3, or their enzymatic activities, leads to defective termination that can induce DNA damage. Therefore, we propose that the R-loop-DDX21-METTL3 nexus forges the missing link for co-transcriptional modification of m6A, coordinating transcription termination and genome stability.

Antisense oligonucleotide therapeutic approach for Timothy syndrome.

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.

Analysis of Dietary and Nutritional Status of Tuberculosis Patients in Hulunbuir Region.

Objective: Tuberculosis (TB) is a major public health problem that affects millions of people worldwide. Malnutrition is a common complication of TB and can worsen the disease outcome. The purpose of this study was to investigate the dietary and nutritional status, as well as the dietary structure, of TB patients in Hulunbuir City, Inner Mongolia, China. Additionally, the study aimed to analyze the factors that influence the nutritional status in order to provide a theoretical foundation for the prevention and treatment of TB and related issues. Methods: A cross-sectional study was conducted on 334 randomly selected TB patients from Hulunbuir City Second Hospital. A questionnaire survey was administered to collect information on demographic characteristics, dietary habits, and food intake. Nutritional status was assessed by body mass index (BMI). Dietary diversity score (DDS) was calculated based on the number of food groups consumed in the previous 24 hours. Statistical analysis was performed using SPSS 20.0 software. Descriptive statistics employed rates and composition ratios, and categorical data was represented using frequencies and percentages. The chi-square test was used to analyze the association between nutritional status and other variables, with a significance level set at α=0.05. Multivariable ordinal logistic regression analysis was performed to identify the independent factors affecting the nutritional status of TB patients. Results: The univariate analysis revealed statistically significant differences (P < 0.05) in the nutritional status (as measured by BMI) among tuberculosis patients, considering ethnicity, educational level, smoking, meat-based diet, vegetable consumption, and DDS grading. No statistically significant differences were found regarding gender, age, marital status, occupation, sleep duration, alcohol consumption, and consumption of rice and flour dishes. Statistically significant variables from the univariate analysis were included in a multivariable ordinal logistic regression analysis model. The findings highlighted that educational level (high school or below), smoking, meat-based diet, DDS scores of 1-3, and a primarily vegetable-based diet had independent effects on the nutritional status of tuberculosis patients (all P < 0.05). No significant difference was found in nutritional status between the Han ethnic group and other ethnicities. Conclusion: The study revealed that the dietary and nutritional status of TB patients in Hulunbuir City was suboptimal and influenced by several factors. Smoking, meat-based diet, and low dietary diversity score were the primary risk factors for malnutrition among TB patients. The study suggests that nutritional education and intervention programs should be implemented for TB patients to improve their dietary quality and nutritional status.

Light-Quality-Adapted Carotenoid Photoprotection in the Photosystem of Roseiflexus castenholzii.

The photosystem of filamentous anoxygenic phototroph Roseiflexus (Rfl.) castenholzii comprises a light-harvesting (LH) complex encircling a reaction center (RC), which intensely absorbs blue-green light by carotenoid (Car) and near-infrared light by bacteriochlorophyll (BChl). To explore the influence of light quality (color) on the photosynthetic activity, we compared the pigment compositions and triplet excitation dynamics of the LH-RCs from Rfl. castenholzii was adapted to blue-green light (bg-LH-RC) and to near-infrared light (nir-LH-RC). Both LH-RCs bind γ-carotene derivatives; however, compared to that of nir-LH-RC (12%), bg-LH-RC contains substantially higher keto-γ-carotene content (43%) and shows considerably faster BChl-to-Car triplet excitation transfer (10.9 ns vs 15.0 ns). For bg-LH-RC, but not nir-LH-RC, selective photoexcitation of Car and the 800 nm-absorbing BChl led to Car-to-Car triplet transfer and BChl-Car singlet fission reactions, respectively. The unique excitation dynamics of bg-LH-RC enhances its photoprotection, which is crucial for the survival of aquatic anoxygenic phototrophs from photooxidative stress.

Isolation and characterization of seven neovibsane-type diterpenoids from Viburnum odoratissimum and their neuroblastoma cell protective effects.

Seven undescribed neovibsane-type diterpenoids (1-7) were isolated from the leaves of Viburnum odoratissimum. Their planar structures and relative configurations were elucidated based on a combination of 1D and 2D NMR analysis. The absolute configurations were confirmed by Rh2(OCOCF3)4-induced ECD analysis and comparison of experimental and TDDFT-calculated ECD spectrum. Based on the empirical results of the ECD of in situ formed Rh-complexes, rapid determination of the absolute configuration of C-14 within vibsane-type diterpenoids was proposed. In addition, 3 exhibited a high neuroblastoma cell protective effect of 81.8 % at 50 µM (the control group showed a neuroblastoma cell protective effect of 56.2 % at 50 µM).

[Spatial and Temporal Evolution and Prediction of Carbon Storage in Kunming City Based on InVEST and CA-Markov Model].

Land use/cover change is an important driving factor for carbon stock changes in terrestrial ecosystems and affects the carbon cycle of the whole ecosystem. Taking Kunming City as a case study, based on the modified carbon density coefficient, this study analyzed the spatio-temporal characteristics of carbon storage changes in the terrestrial ecosystem under different land use scenarios from 2000 to 2020 and "three-line" constraints by coupling the carbon storage module of the InVEST model and CA-Markov model. The results showed that:① cultivated land, forest land, and grassland were the main types of land use in Kunming City, and land use transfer also occurred among the three types. ② From 2000 to 2020, the overall carbon storage in Kunming City was low in the south and high in the north, and the carbon storage decreased yearly with a cumulative loss of 5.27×106 t. The degradation of forest land and grassland was the main reason for the decrease in carbon storage. ③ From 2020 to 2030, the carbon storage of the four scenarios should decrease, and the decline in carbon storage in the inertia development scenario was the most obvious, which was mainly caused by the rapid expansion of construction land. The cultivated land protection scenario effectively slowed down the reduction in carbon storage compared with the inertia development scenario. The ecological protection scenario could enhance the carbon sequestration capacity of the study area, with carbon storage reaching 262.49×106 t, but could not effectively control the reduction in cultivated land area. The scenario of preventing urban expansion effectively inhibited the disorderly expansion of construction land and indirectly prevented further reduction in carbon storage. Therefore, the cultivated land protection scenario, ecological protection scenario, and urban expansion prevention scenario can be considered comprehensively in the study area, which could not only increase the carbon sink space of the study area but also ensure food and ecological security.

Identification of Burkholderia gladioli pv. cocovenenans in Black Fungus and Efficient Recognition of Bongkrekic Acid and Toxoflavin Producing Phenotype by Back Propagation Neural Network.

Burkholderia gladioli pv. cocovenenans is a serious safety issue in black fungus due to the deadly toxin, bongkrekic acid. This has triggered the demand for an efficient toxigenic phenotype recognition method. The objective of this study is to develop an efficient method for the recognition of toxin-producing B. gladioli strains. The potential of multilocus sequence typing and a back propagation neural network for the recognition of toxigenic B. cocovenenans was explored for the first time. The virulent strains were isolated from a black fungus cultivation environment in Qinba Mountain area, Shaanxi, China. A comprehensive evaluation of toxigenic capability of 26 isolates were conducted using Ultra Performance Liquid Chromatography for determination of bongkrekic acid and toxoflavin production in different culturing conditions and foods. The isolates produced bongkrekic acid in the range of 0.05-6.24 mg/L in black fungus and a highly toxin-producing strain generated 201.86 mg/L bongkrekic acid and 45.26 mg/L toxoflavin in co-cultivation with Rhizopus oryzae on PDA medium. Multilocus sequence typing phylogeny (MLST) analysis showed that housekeeping gene sequences have a certain relationship with a strain toxigenic phenotype. We developed a well-trained, back-propagation neutral network for prediction of toxigenic phenotype in B. gladioli based on MLST sequences with an accuracy of 100% in the training set and an accuracy of 86.7% in external test set strains. The BP neutral network offers a highly efficient approach to predict toxigenic phenotype of strains and contributes to hazard detection and safety surveillance.

Increased formation of neutrophil extracellular traps induced by autophagy and identification of autophagy-related biomarkers in systemic lupus erythematosus.

Abnormal death of neutrophils and the subsequent ineffective clearance of cell fragments result in production of autoantigens that can lead to systemic lupus erythematosus (SLE). Excessive formation of neutrophil extracellular traps (NETs) can trigger the synthesis of pro-inflammatory cytokines such as type I interferons, leading to tissue damage and immune dysfunction in SLE patients. In this study, we found that a decrease in neutrophil counts in the peripheral blood was correlated with clinical parameters in SLE patients. Patients with low neutrophil counts had high renal activity index and chronicity index scores. NET formation and neutrophil autophagy in SLE patients were increased. The autophagy inhibitor hydroxychloroquine was shown to restrict NET formation. Using comprehensive bioinformatics analysis, we found that the expression of the autophagy-related gene, hypoxia-inducible factor 1A (HIF1A), was enhanced in peripheral neutrophils and in the renal glomeruli in SLE patients. Targeting HIF1A could be a potential therapeutic approach for SLE.

Four pairs of neolignan enantiomers with distinctive isochroman moiety from the fruits of Crataegus pinnatifida and their protective activities against H2O2-induced SH-SY5Y cells.

Four pairs of neolignan enantiomers (±)-1- (±)-4 with a distinctive isochroman moiety, including seven undescribed compounds, were isolated and identified from the fruits of Crataegus pinnatifida. Structural characterization of these compounds was established through comprehensive spectroscopic analyses, as well as quantum chemical calculations of ECD and NMR data. The preliminary bioassay displayed that compounds (+)-2 and (±)-3 exerted protective activities against H2O2-induced human neuroblastoma SH-SY5Y cells compared with the positive control. These bioactive compounds could be potential candidates for further pharmaceutical applications.

Photocatalytic Conversion of Diluted CO2 into Tunable Syngas via Modulating Transition Metal Hydroxides.

The conversion of diluted CO2 into tunable syngas via photocatalysis is critical for implementing CO2 reduction practically, although the efficiency remains low. Herein, we report the use of graphene-modified transition metal hydroxides, namely, NiXCo1-X-GR, for the conversion of diluted CO2 into syngas with adjustable CO/H2 ratios, utilizing Ru dyes as photosensitizers. The Ni(OH)2-GR cocatalyst can generate 12526 µmol g-1 h-1 of CO and 844 µmol g-1 h-1 of H2, while the Co(OH)2-GR sample presents a generation rate of 2953 µmol g-1 h-1 for CO and 10027 µmol g-1 h-1 for H2. Notably, by simply altering the addition amounts of nickel and cobalt in the transition metal composite, the CO/H2 ratios in syngas can be easily regulated from 18:1 to 1:4. Experimental characterization of composites and DFT calculations suggest that the differing adsorption affinities of CO2 and H2O over Ni(OH)2-GR and Co(OH)2-GR play a significant role in determining the selectivity of CO and H2 products, ultimately affecting the CO/H2 ratios in syngas. Overall, these findings demonstrate the potential of graphene-modified transition metal hydroxides as efficient photocatalysts for CO2 reduction and syngas production.

A Comparison of the Preclinical Performance of the Echelon™+ Stapler with Thunderbird Reloads to Two Commercial Endoscopic Surgical Staplers.

Background: Design of surgical staplers continues to advance with more consistent staple formation that can lead to higher leak pressures and lower rates of leak along the staple line. This study was performed to compare the Ethicon Echelon™+ Stapler with Thunderbird reloads to two other currently available commercial staplers, Reach Anzhi and Fulbright Lunar with corresponding reloads. Methods: The rate of malformed staples for three staplers was determined in porcine stomach (3.0-3.3 mm thickness) via CT scanning. Staple line air leak pressures in bronchial tissue (3.0-3.3 mm) and fluid leak pressures in colon (1.3-1.7 mm) were measured and compared to a standard success criterion for both tissues. Results: The rate of malformed staples in gastric tissue for Echelon+ was more than 90% lower than for the two other commercial staplers (p < 0.001). In bronchus, Echelon+ had 56% higher air leak pressures than Reach Anzhi (p < 0.001) and was not significantly different from Fulbright Lunar. In colon, Echelon+ had over twice the fluid leak pressures of the comparators (p < 0.001). Conclusion: The Echelon+ Stapler with Thunderbird reloads exhibited a low rate of malformed staples, and its staple lines withstood high leak pressures in both thick and thin tissues. Clinical studies are needed to confirm that these observed benefits carry over into actual practice.

Copper-catalyzed atroposelective formal [4+1] annulation of 1,2-diketones with vinyl cations.

The enantioselective transformation of easily accessible 1,2-diketones represents a quick pathway towards enantioenriched molecules. Herein, we disclose a copper-catalyzed atroposelective formal [4+1] annulation of 1,2-diketones with vinyl cations, enabling the efficient and atom-economical construction of axially chiral arylpyrroles bearing 1,3-dioxole moieties with good to excellent enantioselectivities under mild reaction conditions. Importantly, this methodology constitutes the first enantioselective formal [4+1] annulation of 1,2-diketones.

Carotenoid-Mediated Long-Range Energy Transfer in the Light Harvesting-Reaction Center Complex from Photosynthetic Bacterium Roseiflexus castenholzii.

The light harvesting-reaction center complex (LH-RC) of Roseiflexus castenholzii binds bacteriochlorophylls a (BChls a), B800 and B880, absorbing around 800 and 880 nm, respectively. We comparatively investigated the interband excitation energy transfer (EET) dynamics of the wild-type LH-RC (wt-LH-RC) of Rfl. castenholzii and its carotenoid (Car)-less mutant (m-LH-RC) and found that Car can boost the B800 → B880 EET rate from (2.43 ps)-1 to (1.75 ps)-1, accounting for 38% acceleration of the EET process. Interestingly, photoexcitation of wt-LH-RC at 800 nm induced pronounced excitation dynamics of Car despite the insufficient photon energy for direct Car excitation, a phenomenon which is attributed to the BChl-Car exciplex 1[B800(↑↑)···Car(↓↓)]*. Such an exciplex is suggested to play an essential role in promoting the B800 → B880 EET process, as corroborated by the recently reported cryo-EM structures of wt-LH-RC and m-LH-RC. The mechanism of Car-mediated EET will be helpful to deepen the understanding of the role of Car in bacterial photosynthesis.

A double-decomposition based parallel exact algorithm for the feedback length minimization problem.

Product development projects usually contain many interrelated activities with complex information dependences, which induce activity rework, project delay and cost overrun. To reduce negative impacts, scheduling interrelated activities in an appropriate sequence is an important issue for project managers. This study develops a double-decomposition based parallel branch-and-prune algorithm, to determine the optimal activity sequence that minimizes the total feedback length (FLMP). This algorithm decomposes FLMP from two perspectives, which enables the use of all available computing resources to solve subproblems concurrently. In addition, we propose a result-compression strategy and a hash-address strategy to enhance this algorithm. Experimental results indicate that our algorithm can find the optimal sequence for FLMP up to 27 activities within 1 h, and outperforms state of the art exact algorithms.

Structurally diverse terpenoids from Elephantopus scaber L. and their acetylcholinesterase inhibitory activities.

Three undescribed compounds elephantopuscabers A-C, along with one previously reported compound spirowallichiione, were isolated from Elephantopus scaber L. Their structures were determined via extensive NMR spectroscopic analysis, quantum chemical calculations, and single-crystal X-ray diffraction crystallography. A plausible biosynthetic pathway for spirowallichiione was proposed. All the isolated compounds were tested for their acetylcholinesterase inhibitory activities. Among them, elephantopuscaber B and C displayed promising inhibitory activities against AChE, and the binding sites were predicted by molecular docking.

Integrating Co(OH)2 nanosheet arrays on graphene for efficient noble-metal-free EY-sensitized photocatalytic H2 evolution.

The development of an efficient noble-metal-free cocatalyst is the key to photocatalytic hydrogen production technology. In this study, hierarchical Co(OH)2 nanosheet array-graphene (GR) composite cocatalysts are developed. With Eosin Y (EY) as a photosensitizer, the optimal Co(OH)2-10%GR hybrid cocatalyst presents excellent photocatalytic activity with an H2 production rate of 17 539 µmol g-1 h-1, and the apparent quantum yield for hydrogen production can reach 12.8% at 520 nm, which remarkably surpasses that of pure Co(OH)2 and most similar hybrid cocatalyst systems. Experimental investigations demonstrate that the excellent photocatalytic activity of Co(OH)2-GR arises from its unique nanosheet array architecture, which can collaboratively expose rich active sites for photocatalytic hydrogen evolution and facilitate the migration and separation of photogenerated charge carriers. It is desired that this study would supply a meaningful direction for the rational optimization of the constitute and structure of cocatalysts to achieve efficient photocatalytic hydrogen generation.