Tetramethylpyrazine nitrone delays the aging process of C. elegans by improving mitochondrial function through the AMPK/mTORC1 signaling pathway.

Aging is characterized as the process of functional decline in an organism from adulthood, often marked by a progressive loss of cellular function and systemic deterioration of multiple tissues. Among the numerous molecular, cellular, and systemic hallmarks associated with aging, mitochondrial dysfunction is considered one of the pivotal factors that initiates the aging process. During aging, mitochondria undergo varying degrees of damage, resulting in impaired energy production and disruption of the homeostatic regulation of mitochondrial quality control systems, which in turn affects cellular energy metabolism and results in cellular dysfunction, accelerating the aging process. AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) are two central kinase complexes responsible for sensing intracellular nutrient levels, regulating metabolic homeostasis, modulating aging and play a crucial role in maintaining the homeostatic balance of mitochondria. Our previous studies found that the novel compound tetramethylpyrazine nitrone (TBN) can protect mitochondria via the AMPK/mTOR pathway in many animal models, extending healthy lifespan through the Nrf2 signaling pathway in nematodes. Building upon this foundation, we have posited a reasonable hypothesis, TBN can improve mitochondrial function to delay aging by regulating the AMPK/mTORC1 signaling pathway. This study focuses on the C. elegans, exploring the impact and underlying mechanisms of TBN on aging and mitochondrial function (especially the mitochondrial quality control system) during the aging process. The present studies demonstrated that TBN extends lifespan of wild-type nematodes and is associated with the AMPK/mTORC1 signaling pathway. TBN elevated ATP and NAD+ levels in aging nematodes while orchestrating mitochondrial biogenesis and mitophagy. Moreover, TBN was observed to significantly enhance normal activities during aging in C. elegans, such as mobility and pharyngeal pumping, concurrently impeding lipofuscin accumulation that were closely associated with AMPK and mTORC1. This study not only highlights the delayed effects of TBN on aging but also underscores its potential application in strategies aimed at improving mitochondrial function via the AMPK/mTOR pathway in C. elegans.

A novel mechanism of resveratrol alleviates Toxoplasma gondii infection-induced pulmonary inflammation via inhibiting inflammasome activation.

BACKGROUND: Infection by Toxoplasma gondii can lead to severe pneumonia, with current treatments being highly inadequate. The NLRP3 inflammasome is one member of the NOD-like receptor family with a pyrin domain, which is crucial in the innate immune defense against T. gondii. Research has shown that resveratrol (RSV) prevents lung damage caused by this infection by inhibiting the T. gondii-derived heat shock protein 70/TLR4/NF-κB pathway, thus reducing the macrophage-driven inflammatory response. However, it should be mentioned that the participation of NLRP3 inflammasome in the immune response to the lung injuries caused by T. gondii infections is not entirely clear. PURPOSE: This study aims to clarify how RSV ameliorates lung damage triggered by Toxoplasma gondii infection, with a particular focus on the pathway involving TLR4, NF-κB, and the NLRP3 inflammasome. METHODS: Both in vitro and in vivo models of infection were developed by employing the RH strain of T. gondii in BALB/c mice and RAW 264.7 macrophage cell lines. The action mechanism of RSV was explored using techniques such as molecular docking, surface plasmon resonance, ELISA, Western blot, co-immunoprecipitation, and immunofluorescence staining. RESULTS: Findings indicate that the suppression of TLR4 or NF-κB impacts the levels of proteins associated with the NLRP3 inflammasome pathway. Additionally, a significant affinity for binding between RSV and NLRP3 was observed. Treatment with RSV led to a marked reduction in the activation and formation of the NLRP3 inflammasome within lung tissues and RAW 264.7 cells, alongside a decrease in IL-1ß concentrations in the bronchoalveolar lavage fluid. These outcomes align with those seen when using the NLRP3 inhibitor CY-09. Moreover, the application of CY-09 prior to RSV negated the latter's anti-inflammatory properties. CONCLUSION: Considering insights from previous research alongside the outcomes of the current investigation, it appears that the TLR4/NF-κB/NLRP3 signaling pathway emerges as a promising target for immunomodulation to alleviate lung injury from T. gondii infection. The evidence gathered in this study lays the groundwork for the continued exploration and potential future clinical deployment of RSV as a therapeutic agent with anti-Toxoplasma properties and the capability to modulate the inflammatory response.

Pro-CRISPR PcrIIC1-associated Cas9 system for enhanced bacterial immunity.

The CRISPR system is an adaptive immune system found in prokaryotes that defends host cells against the invasion of foreign DNA1. As part of the ongoing struggle between phages and the bacterial immune system, the CRISPR system has evolved into various types, each with distinct functionalities2. Type II Cas9 is the most extensively studied of these systems and has diverse subtypes. It remains uncertain whether members of this family can evolve additional mechanisms to counter viral invasions3,4. Here we identify 2,062 complete Cas9 loci, predict the structures of their associated proteins and reveal three structural growth trajectories for type II-C Cas9. We found that novel associated genes (NAGs) tended to be present within the loci of larger II-C Cas9s. Further investigation revealed that CbCas9 from Chryseobacterium species contains a novel ß-REC2 domain, and forms a heterotetrameric complex with an NAG-encoded CRISPR-Cas-system-promoting (pro-CRISPR) protein of II-C Cas9 (PcrIIC1). The CbCas9-PcrIIC1 complex exhibits enhanced DNA binding and cleavage activity, broader compatibility for protospacer adjacent motif sequences, increased tolerance for mismatches and improved anti-phage immunity, compared with stand-alone CbCas9. Overall, our work sheds light on the diversity and 'growth evolutionary' trajectories of II-C Cas9 proteins at the structural level, and identifies many NAGs-such as PcrIIC1, which serves as a pro-CRISPR factor to enhance CRISPR-mediated immunity.

Tetramethylpyrazine Nitrone alleviates D-galactose-induced murine skeletal muscle aging and motor deficits by activating the AMPK signaling pathway.

Tetramethylpyrazine nitrone (TBN), a novel derivative of tetramethylpyrazine (TMP) designed and synthesized by our group, possesses multi-functional mechanisms of action and displays broad protective effects in vitro and in animal models of age-related brain disorders such as stroke, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD). In the present report, we investigated the effects of TBN on aging, specifically on muscle aging and the associated decline of motor functions. Using a D-galactose-induced aging mouse model, we found that TBN could reverse the levels of several senescence and aging markers including p16, p21, ceramides, and telomere length and increase the wet-weight ratio of gastrocnemius muscle tissue, demonstrating its efficacy in ameliorating muscle aging. Additionally, the pharmacological effects of TBN on motor deficits (gait analysis, pole-climbing test and grip strength test), muscle fibrosis (hematoxylin & eosin (HE), Masson staining, and αSMA staining), inflammatory response (IL-1ß, IL-6, and TNF-α), and mitochondrial function (ATP, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also confirmed in the D-galactose-induced aging models. Further experiments demonstrated that TBN alleviated muscle aging and improved the decline of age-related motor deficits through an AMPK-dependent mechanism. These findings highlight the significance of TBN as a potential anti-aging agent to combat the occurrence and development of aging and age-related diseases.

Improved Diagnostic Accuracy of Multi-Slice Spiral CT Combined with MRI in Colon Cancer Patients with Ileus: A Comparative Study.

Background: Colon cancer is a common malignant tumor that often leads to intestinal obstruction, resulting in significant morbidity and mortality. Early and accurate diagnosis of colon cancer and associated ileus is crucial for timely treatment and improved patient outcomes. Various diagnostic methods, including MSCT and MRI, are currently used in clinical practice. However, the optimal imaging approach for accurate diagnosis remains uncertain. Objective: To study the value and accuracy of multi-slice spiral CT (MSCT) combined with magnetic resonance imaging (MRI) in diagnosing colon cancer obstruction. Methods: A retrospective analysis was performed on 100 cases of colon cancer and ileus patients admitted to the Hai'an Hospital of Chinese Medicine from January 2019 to July 2020. The cases were randomly divided into control and experimental groups, with 50 cases in each. The control group was diagnosed with MSCT, and the experimental group was diagnosed with MRI based on the control group. The positive and negative detection rates, test accuracy, sensitivity, and specificity were compared between the 2 groups. The area under the curve (AUC), quality of life (QOL) score, and mental status scale in non-psychiatric settings (MSSNS) score were calculated with the receiver operator characteristic curve (ROC) and compared between the 2 groups. Results: The test accuracy, positive detection rate, negative detection rate, test specificity, sensitivity, and AUC of the experimental group were significantly higher than those of the control group, and the results were statistically significant (P < .05). There was no significant difference in the QOL and the MSSNS scores between the 2 groups (P > .05). Conclusion: MSCT combined with MRI has a high application value in diagnosing colon cancer obstruction patients, and can significantly improve the test's accuracy, specificity and sensitivity.

The Stress of Fungicides Changes the Expression of Clock Protein CmFRQ and the Morphology of Fruiting Bodies of Cordyceps militaris.

The physiological, biochemical, and morphological changes brought about by fungi in response to fungicides can undoubtedly bring diversity to fungi. Cordyceps militaris strains TN (mating type genes MAT1-1-1, MAT1-1-2, and MAT1-2-1) and CmFRQ-454 (mating type genes MAT1-1-1 and MAT1-1-2) were treated with non-lethal doses of fungicides amphotericin B, L-cysteine, terbinafine, and 5-fluorocytosine. The results showed that the treatment with amphotericin B, terbinafine, and 5-fluorocytosine promoted an increase in the relative content of clock protein CmFRQ (C. militaris FREQUENCY) in the mycelium of strain TN, while the high concentration of L-cysteine inhibited the expression of CmFRQ in strain TN. These four fungicides could reduce the relative contents of CmFRQ in the mycelium of strain CmFRQ454. The relative contents of CmFRQ in the mycelium of strain TN were increased after removing the four fungicides, but the relative contents of CmFRQ in the mycelium of strain CmFRQ454 were decreased after removing the four fungicides. This indicates that the effect of fungicides on CmFRQ on mycelium was still sustained after removing the stress of fungicides, and the operation of the circadian clock was changed. The fruiting bodies of C. militaris strain TN and CmFRQ-454 were still degenerated to varying degrees after removing amphotericin B, L-cysteine, and terbinafine. However, the fruiting bodies of strain TN after removing 5-fluorocytosine did not show significant degeneration; the fruiting bodies of strain CmFRQ-454 after removing 5-fluorocytosine obtained rejuvenation. These results indicate that the stress of fungicides could lead to the degeneration of fruiting bodies as well as the rejuvenation of fruiting bodies, resulting in the morphological diversity of C. militaris. The increase or decrease of the CmFRQ-454, the main component of the circadian clock, caused by the stress of fungicants, might lead to the differential degeneration of different mating-type strains of C. militaris.

Explainable Machine Learning-Based Prediction Model for Diabetic Nephropathy.

The aim of this study is to analyze the effect of serum metabolites on diabetic nephropathy (DN) and predict the prevalence of DN through a machine learning approach. The dataset consists of 548 patients from April 2018 to April 2019 in the Second Affiliated Hospital of Dalian Medical University (SAHDMU). We select the optimal 38 features through a least absolute shrinkage and selection operator (LASSO) regression model and a 10-fold cross-validation. We compare four machine learning algorithms, including extreme gradient boosting (XGB), random forest, decision tree, and logistic regression, by AUC-ROC curves, decision curves, and calibration curves. We quantify feature importance and interaction effects in the optimal predictive model by Shapley additive explanation (SHAP) method. The XGB model has the best performance to screen for DN with the highest AUC value of 0.966. The XGB model also gains more clinical net benefits than others, and the fitting degree is better. In addition, there are significant interactions between serum metabolites and duration of diabetes. We develop a predictive model by XGB algorithm to screen for DN. C2, C5DC, Tyr, Ser, Met, C24, C4DC, and Cys have great contribution in the model and can possibly be biomarkers for DN.

GestaltMatcher Database - A global reference for the facial phenotypic variability of rare human diseases.

Dysmorphologists sometimes encounter challenges in recognizing disorders due to phenotypic variability influenced by factors such as age and ethnicity. Moreover, the performance of Next Generation Phenotyping Tools such as GestaltMatcher is dependent on the diversity of the training set. Therefore, we developed GestaltMatcher Database (GMDB) - a global reference for the phenotypic variability of rare diseases that complies with the FAIR-principles. We curated dysmorphic patient images and metadata from 2,224 publications, transforming GMDB into an online dynamic case report journal. To encourage clinicians worldwide to contribute, each case can receive a Digital Object Identifier (DOI), making it a citable micro-publication. This resulted in a collection of 2,312 unpublished images, partly with longitudinal data. We have compiled a collection of 10,189 frontal images from 7,695 patients representing 683 disorders. The web interface enables gene- and phenotype-centered queries for registered users (https://db.gestaltmatcher.org/). Despite the predominant European ancestry of most patients (59%), our global collaborations have facilitated the inclusion of data from frequently underrepresented ethnicities, with 17% Asian, 4% African, and 6% with other ethnic backgrounds. The analysis has revealed a significant enhancement in GestaltMatcher performance across all ethnic groups, incorporating non-European ethnicities, showcasing a remarkable increase in Top-1-Accuracy by 31.56% and Top-5-Accuracy by 12.64%. Importantly, this improvement was achieved without altering the performance metrics for European patients. GMDB addresses dysmorphology challenges by representing phenotypic variability and including underrepresented groups, enhancing global diagnostic rates and serving as a vital clinician reference database.

Protective effect of arctiin against Toxoplasma gondii HSP70-induced allergic acute liver injury by disrupting the TLR4-mediated activation of cytosolic phospholipase A2 and platelet-activating factor.

Toxoplasma gondii (T. gondii)-derived heat shock protein 70 (T.g.HSP70) is a toxic protein that downregulates host defense responses against T. gondii infection. T.g.HSP70 was proven to induce fatal anaphylaxis in T. gondii infected mice through cytosolic phospholipase A2 (cPLA2) activated-platelet-activating factor (PAF) production via Toll-like receptor 4 (TLR4)-mediated signaling. In this study, we investigated the effect of arctiin (ARC; a major lignan compound of Fructus arctii) on allergic liver injury using T.g.HSP70-stimulated murine liver cell line (NCTC 1469) and a mouse model of T. gondii infection. Localized surface plasmon resonance, ELISA, western blotting, co-immunoprecipitation, and immunofluorescence were used to investigate the underlying mechanisms of action of ARC on T. gondii-induced allergic acute liver injury. The results showed that ARC suppressed the T.g.HSP70-induced allergic liver injury in a dose-dependent manner. ARC could directly bind to T.g.HSP70 or TLR4, interfering with the interaction between these two factors, and inhibiting activation of the TLR4/mitogen-activated protein kinase/nuclear factor-kappa B signaling, thereby inhibiting the overproduction of cPLA2, PAF, and interferon-γ. This result suggested that ARC ameliorates T.g.HSP70-induced allergic acute liver injury by disrupting the TLR4-mediated activation of inflammatory mediators, providing a theoretical basis for ARC therapy to improve T.g.HSP70-induced allergic liver injury.

Detection of 14 sulfonate esters impurities of active pharmaceutical ingredients based on GC-MS/MS and LC-MS/MS / 药学学报

Two methods including gas chromatography tandem mass spectrometry (GC-MS/MS) and high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) were established to detect common alkyl sulfonates and aryl sulfonates genotoxic impurities. Four alkyl sulfonates and methyl benzenesulfonate were determined by GC-MS/MS using butyl methanesulfonate as the internal standard, the chromatographic column was HP-5MS UI (30 mm × 0.25 mm, 0.25 µm), the carrier gas was helium, the flow rate was 1.0 mL·min-1 in a constant flow mode, the sample inlet temperature was set to 250 ℃, the split ratio was 10∶1, and the initial temperature of the heating program was 80 ℃, maintained for 1 minute, and then increased to 240 ℃ at a heating rate of 30 ℃·min-1 for 2 minutes. The mass spectrometry detector was an electron bombardment ion source (EI source), the data collection condition was multi reaction monitoring mode (MRM), and method validation using the raw material of clinical drug citalopram hydrobromide as a sample. The results showed that the linear range of four alkyl sulfonates and methyl benzenesulfonate were good at 3-50 ng·mL-1 and 9-150 ng·mL-1, with a correlation coefficient of r > 0.999, The spiked recovery was 80%-120%. The detection limits were 1 and 3 ng·mL-1; Ten aryl sulfonates determined by LC-MS/MS, the chromatographic column was CSH Fluoro phenyl (100 mm × 2.1 mm, 1.7 µm), the mobile phase was methanol (B)-5 mmol·L-1 ammonium formate (D), with a flow rate of 0.2 mL·min-1, and gradient elution was performed. The gradient program (T/% B) was set as 0/20, 25/90, 35/90, 42/20. The mass spectrometer detector was electro spray ionization with positive ionization mode (ESI+), the data collection was in dynamic multi reaction monitoring mode (dMRM), and the method was validated using the raw material of the clinical drug citalopram hydrobromide as a sample. The results showed that the linear range of aryl sulfonates were good at 9-2 000 ng·mL-1, 3-100 ng·mL-1 and 0.9-30 ng·mL-1, respectively. The correlation coefficient r > 0.999, the spiked recovery was 80%-120%. The detection limits were 30, 1 and 0.3 ng·mL-1. Two detection methods did not detect potential sulfonate genotoxicity impurities in the above APIs. The established analytical methods are reliable and effective, which can provide reference for drug quality control and detection.

Effects of microplastics on seed germination and seedling physiological characteristics of Spinacia oleracea under alkali stress.

Microplastics, a type of new environmental pollutant, have received much attention for their negative effects on organisms and environment. We examined the effects of microplastics on seed germination and seedling physiological characteristics of spinach (Spinacia oleracea) under alkali stress, taking polystyrene microspheres with a diameter of 100 nm (200, 400, 800, 1600 mg·L-1) as the microplastic treatment, and mixed NaHCO3 and Na2CO3 as alkaline salt solution (5, 10, 20, 40 mmol·L-1) according to the molar ratio of 1:1. The results showed that the presence of MPs (≥400 mg·L-1) inhibited seed germination, and that the length of roots and shoots increased at low while decreased at high concentration of MPs. Different concentrations of alkali alone could inhibit seed germination, root and bud elongation. With the increases of MPs concentration, SOD activity of spinach seedlings gradually decreased, while POD activity firstly increased and then decreased, and chlorophyll content increased at low concentration (200 mg·L-1) and decreased significantly at medium and high concentration (≥400 mg·L-1). Different alkali stresses reduced chlorophyll content of spinach seedlings, and the effects on SOD and POD were 'promotion at low concentration and inhibition at high'. In the treatments of microplastics (200, 800 mg·L-1) and alkali (5, 20 mmol·L-1) combined exposure, germination of spinach seeds was inhibited, and chlorophyll content decreased. The activities of SOD and POD in spinach seedlings were reduced under the combined exposure except the treatment of 200 mg·L-1 MPs and 5 mmol·L-1 alkali. Compared to the alkali stress, the combination of low concentration of MPs (200 mg·L-1) and alkali could improve germination rate, germination index, germination vigor and vigor index of seeds, and significantly promoted the elongation of roots and shoots, while the addition of high concentration of MPs (800 mg·L-1) reduced the germination rate, germination index, germination vigor and vigor index of seeds and inhibited the growth of roots and buds. The different concentrations of combined exposure inhibited the activities of SOD and POD and decreased the content of chlorophyll in spinach seedlings.

[Surgical Safety of Elderly Hospitalized Patients Stratified by Age in General Surgery].

Objective To compare the surgical safety of elderly hospitalized patients in different age groups undergoing general surgery,and provide references for preoperative evaluation and treatment decision-making.Methods The inpatients ≥ 60 years old in the department of general surgery were selected from a national multi-center survey conducted from January to June in 2015 and from January to June in 2016.The patient characteristics and postoperative outcomes were described,and the risk factors for adverse postoperative outcomes of patients in different age groups were explored.Results The elderly patients (≥75 years old) accounted for 17.33%.The non-elderly patient (< 75 years old) group and the elderly patient (≥75 years old) group had significant differences in the proportions of patients with three or more chronical diseases (13.18% vs.5.36%,P<0.001),emergency surgery (16.64% vs.7.62%,P<0.001),American Society of Anesthesiologists score≥3 (48.68% vs.27.28%,P<0.001),and postoperative return to the intensive care unit(33.64% vs.12.00%,P<0.001).The occurrence of postoperative infectious complications showed no significant difference between the two age groups (7.29% vs.6.40%,P=0.410),while severe complications differed between the two groups (6.51% vs.2.60%,P<0.001).Besides,emergency surgery was a common independent risk factor for the two age groups.Conclusions Advanced age is not a contraindication to surgery of elderly patients.With consideration to patient's physical conditions and available surgical resources,elderly patients can still benefit from surgery.

Electrochemical Trifluoromethylation and Sulfonylation of N-Allylamides: Synthesis of Oxazoline Derivatives.

We report a new method for the synthesis of trifluoromethylated and sulfonylated oxazolines by electrochemical radical cascade cyclizations of N-allylamides with sodium trifluoromethanesulfinate or sulfonylhydrazines. This protocol provides a green and useful strategy to synthesize trifluoromethylated and sulfonylated oxazolines with a broad substrate scope under ambient conditions.

Three new species of Entomobryidae (Collembola, Entomobryoidea) from China.

Three new species of entomobryid springtails (Collembola) from China are described here. Homidiapseudozhangisp. nov. is characterised by a narrow irregular longitudinal stripe on the body, smooth chaetae e and l1 of the labial base, and the relative position of the specialized microchaeta on Abd. I; H.qianensissp. nov. by its colour pattern on the antennae and nine sutural macrochaetae on the head; and Entomobryashaanxiensissp. nov. by its colour pattern, labral papillae and the lateral process of labial papilla E. Specimens of Akabosiamatsudoensis Kinoshita, 1919 from China are redescribed, including description of some characters for the first time.

Electrochemical Decarboxylative Silylation of α,ß-Unsaturated Carboxylic Acids.

An electrochemical method for the decarboxylative silylation of α,ß-unsaturated carboxylic acids was developed. A variety of alkenylsilanes could be obtained in satisfactory yields and excellent selectivities under external oxidant- and metal-free conditions. Mechanistic studies showed that the formation of the silyl radical was mediated by NHPI, which produces the hydrogen atom transfer (HAT) reagent phthalimide N-oxyl (PINO) via multiple-site concerted proton-electron transfer (MS-CPET).

On-Site Cross-Linking of Polyacrylamide to Efficiently Bind the Silicon Anode of Lithium-Ion Batteries.

Silicon anode suffers from rapid capacity decay because of its irreversible volume changes during charging and discharging. As one of the important components of the electrode structure, the binder plays an irreplaceable role in buffering the volume changes of the silicon anode and ensuring close contact between various components of the electrode. Traditional PVDF binder is based on weak van der Waals forces and cannot effectively buffer the stress coming from silicon volume expansion, resulting in rapid decay of silicon anode capacity. In addition, most natural polysaccharide binders with a single force face the same problem due to poor toughness. Therefore, it is extremely important to develop a binder with good force and toughness between the silicon particles. Herein, polyacrylamide (PAM) polymer chains that are premixed homogeneously with various components are cross-linked on-site on the current collector via the condensation reaction with citric acid, forming a polar three-dimensional (3D) network with improved tensile properties and adhesion for both silicon particles and current collector. The silicon anode with the cross-linked PAM binder exhibits higher reversible capacity and enhanced long-term cycling stability; the capacity remains at 1280 mA h g-1 after 600 cycles at 2.1 A g-1 and 770.9 mA h g-1 after being subjected to 700 cycles at 4.2 A g-1. It also exhibits excellent cycle stability in silicon-carbon composite materials. This study provides a cost-effective binder engineering strategy, which significantly enhances the long-term cycle performance and stability of silicon anodes, paving the way for large-scale practical applications.

Coixol ameliorates Toxoplasma gondii infection-induced lung injury by interfering with T. gondii HSP70/TLR4/NF-κB signaling pathway.

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that causes pulmonary toxoplasmosis, although its pathogenesis is incompletely understood. There is no cure for toxoplasmosis. Coixol, a plant polyphenol extracted from coix seeds, has a variety of biological activities. However, the effects of coixol on T. gondii infection have not been clarified. In this study, we infected a mouse macrophage cell line (RAW 264.7) and BALB/c mice with the T. gondii RH strain to establish infection models in vitro and in vivo, respectively, to explore protective effects and potential mechanisms of coixol on lung injury caused by T. gondii infection. Anti-T. gondii effects and underlying anti-inflammatory mechanisms of coixol were investigated by real-time quantitative PCR, molecular docking, localized surface plasmon resonance, co-immunoprecipitation, enzyme-linked immunosorbent assay, western blotting, and immunofluorescence microscopy. The results show that coixol inhibits T. gondii loads and T. gondii-derived heat shock protein 70 (T.g.HSP70) expression. Moreover, coixol reduced inflammatory cell recruitment and infiltration, and ameliorated pathological lung injury induced by T. gondii infection. Coixol can directly bind T.g.HSP70 or Toll-like receptor 4 (TLR4) to disrupt their interaction. Coixol prevented overexpression of inducible nitric oxide synthase, tumor necrosis factor-α, and high mobility group box 1 by inhibiting activation of the TLR4/nuclear factor (NF)-κB signaling pathway, consistent with effects of the TLR4 inhibitor CLI-095. These results indicate that coixol improves T. gondii infection-induced lung injury by interfering with T.g.HSP70-mediated TLR4/NF-κB signaling. Altogether, these findings suggest that coixol is a promising effective lead compound for the treatment of toxoplasmosis.

Screening Chest CT Prior to Allogenic Hematopoietic Stem Cell Transplantation.

Pulmonary complications constitute a major cause of morbidity and mortality in the post-allogenic hematopoietic stem cell transplantation (alloHSCT) period. Although chest X-ray (CXR) is customarily used for screening, we have used chest computed tomography (CT) scans. To characterize the prevalence of abnormalities and explore their impact on alloHSCT eligibility and outcomes post-transplantation, we conducted a retrospective analysis using real-world data collected at our center for adult patients who were evaluated for alloHSCT between January 2013 and December 2020 and identified 511 eligible patients. The most common primary disease was acute myeloid leukemia, in 49% of patients, followed by myelodysplastic syndrome (23%), lymphoma (11%), and acute lymphocytic leukemia (10%). Abnormal screening chest CT results were found in 199 patients (39%). The most frequent detected abnormality was pulmonary nodule, in 78 patients (35%), followed by consolidation in 42 (19%), ground-glass opacification in 33 (15%), bronchitis and bronchiolitis in 25 (11%), pleural effusions in 14 (6%), and new primary cancer in 7 (2%). CXR detected abnormalities in only approximately one-half of the patients (48%) with an abnormal chest CT scan. Among the 199 patients with an abnormal chest CT scan, 98 (49%) underwent further assessment and/or intervention before transplantation. The most common workup was pulmonary consultation in 32%, followed by infectious diseases consultation in 24%. Lung biopsy was obtained in 20%, and antimicrobial therapy was initiated after confirming an infection diagnosis in 20%. Patients with an abnormal chest CT scan demonstrated worse overall survival (P = .032), nonrelapse mortality (P = .015), and pulmonary-related mortality (P < .001) compared to those with a normal chest CT scan. Our study suggests that pretransplantation screening chest CT is beneficial in uncovering invasive infections and underlying malignancies and allows for appropriate interventions before alloHSCT to prevent potentially serious post-transplantation complications without causing a delay in alloHSCT. Nevertheless, abnormal CT findings prior to transplantation may be associated with overall worse prognosis.