Mendelian randomization analysis reveals causal associations of serum metabolites with sepsis and 28-day mortality.

Metabolic disorder has been found to be an important factor in the pathogenesis and progression of sepsis. However, the causation of such an association between serum metabolites and sepsis has not been established. We conducted a two-sample Mendelian randomization (MR) study. A genome-wide association study of 486 human serum metabolites was used as the exposure, whereas sepsis and sepsis mortality within 28 days were set as the outcomes. In MR analysis, 6 serum metabolites were identified to be associated with an increased risk of sepsis, and 6 serum metabolites were found to be related to a reduced risk of sepsis. Furthermore, there were 9 metabolites positively associated with sepsis-related mortality, and 8 metabolites were negatively correlated with sepsis mortality. In addition, "glycolysis/gluconeogenesis" (p = 0.001), and "pyruvate metabolism" (p = 0.042) two metabolic pathways were associated with the incidence of sepsis. This MR study suggested that serum metabolites played significant roles in the pathogenesis of sepsis, which may provide helpful biomarkers for early disease diagnosis, therapeutic interventions, and prognostic assessments for sepsis.

The efficacy of using a multiparametric magnetic resonance imaging-based radiomics model to distinguish glioma recurrence from pseudoprogression.

OBJECTIVE: The early differential diagnosis of the postoperative recurrence or pseudoprogression (psPD) of a glioma is of great guiding significance for individualized clinical treatment. This study aimed to evaluate the ability of a multiparametric magnetic resonance imaging (MRI)-based radiomics model to distinguish between the postoperative recurrence and psPD of a glioma early on and in a noninvasive manner. METHODS: A total of 52 patients with gliomas who attended the Hainan Provincial People's Hospital between 2000 and 2021 and met the inclusion criteria were selected for this study. 1137 and 1137 radiomic features were extracted from T1 enhanced and T2WI/FLAIR sequence images, respectively.After clearing some invalid information and LASSO screening, a total of 9 and 10 characteristic radiological features were extracted and randomly divided into the training set and the test set according to 7:3 ratio. Select-Kbest and minimum Absolute contraction and selection operator (LASSO) were used for feature selection. Support vector machine and logistic regression were used to form a multi-parameter model for training and prediction. The optimal sequence and classifier were selected according to the area under the curve (AUC) and accuracy. RESULTS: Radiomic models 1, 2 and 3 based on T1WI, T2FLAIR and T1WI + T2T2FLAIR sequences have better performance in the identification of postoperative recurrence and false progression of T1 glioma. The performance of model 2 is more stable, and the performance of support vector machine classifier is more stable. The multiparameter model based on CE-T1 + T2WI/FLAIR sequence showed the best performance (AUC:0.96, sensitivity: 0.87, specificity: 0.94, accuracy: 0.89,95% CI:0.93-1). CONCLUSION: The use of multiparametric MRI-based radiomics provides a noninvasive, stable, and accurate method for differentiating between the postoperative recurrence and psPD of a glioma, which allows for timely individualized clinical treatment.

Berberine alleviates neuroinflammation by downregulating NFκB/LCN2 pathway in sepsis-associated encephalopathy: network pharmacology, bioinformatics, and experimental validation.

BACKGROUND: Sepsis refers to a systemic inflammatory response caused by infection, involving multiple organs. Sepsis-associated encephalopathy (SAE), as one of the most common complications in patients with severe sepsis, refers to the diffuse brain dysfunction caused by sepsis without central nervous system infection. However, there is no clear diagnostic criteria and lack of specific diagnostic markers. METHODS: The main active ingredients of coptidis rhizoma(CR) were identified from TCMSP and SwissADME databases. SwissTargetPrediction and PharmMapper databases were used to obtain targets of CR. OMIM, DisGeNET and Genecards databases were used to explore targets of SAE. Limma differential analysis was used to identify the differential expressed genes(DEGs) in GSE167610 and GSE198861 datasets. WGCNA was used to identify feature module. GO and KEGG enrichment analysis were performed using Metascape, DAVID and STRING databases. The PPI network was constructed by STRING database and analyzed by Cytoscape software. AutoDock and PyMOL software were used for molecular docking and visualization. Cecal ligation and puncture(CLP) was used to construct a mouse model of SAE, and the core targets were verified in vivo experiments. RESULTS: 277 common targets were identified by taking the intersection of 4730 targets related to SAE and 509 targets of 9 main active ingredients of CR. 52 common DEGs were mined from GSE167610 and GSE198861 datasets. Among the 25,864 DEGs in GSE198861, LCN2 showed the most significant difference (logFC = 6.9). GO and KEGG enrichment analysis showed that these 52 DEGs were closely related to "inflammatory response" and "innate immunity". A network containing 38 genes was obtained by PPI analysis, among which LCN2 ranked the first in Degree value. Molecular docking results showed that berberine had a well binding affinity with LCN2. Animal experiments results showed that berberine could inhibit the high expression of LCN2,S100A9 and TGM2 induced by CLP in the hippocampus of mice, as well as the high expression of inflammatory factors (TNFα, IL-6 and IL-1ß). In addition, berberine might reduce inflammation and neuronal cell death by partially inhibiting NFκB/LCN2 pathway in the hippocampus of CLP models, thereby alleviating SAE. CONCLUSION: Overall, Berberine may exert anti-inflammatory effects through multi-ingredients, multi-targets and multi-pathways to partially rescue neuronal death and alleviate SAE.

Exosomes: efficient macrophage-related immunomodulators in chronic lung diseases.

Macrophages, the predominant immune cells in the lungs, play a pivotal role in maintaining the delicate balance of the pulmonary immune microenvironment. However, in chronic inflammatory lung diseases and lung cancer, macrophage phenotypes undergo distinct transitions, with M1-predominant macrophages promoting inflammatory damage and M2-predominant macrophages fostering cancer progression. Exosomes, as critical mediators of intercellular signaling and substance exchange, participate in pathological reshaping of macrophages during development of pulmonary inflammatory diseases and lung cancer. Specifically, in inflammatory lung diseases, exosomes promote the pro-inflammatory phenotype of macrophages, suppress the anti-inflammatory phenotype, and subsequently, exosomes released by reshaped macrophages further exacerbate inflammatory damage. In cancer, exosomes promote pro-tumor tumor-associated macrophages (TAMs); inhibit anti-tumor TAMs; and exosomes released by TAMs further enhance tumor proliferation, metastasis, and resistance to chemotherapy. Simultaneously, exosomes exhibit a dual role, holding the potential to transmit immune-modulating molecules and load therapeutic agents and offering prospects for restoring immune dysregulation in macrophages during chronic inflammatory lung diseases and lung cancer. In chronic inflammatory lung diseases, this is manifested by exosomes reshaping anti-inflammatory macrophages, inhibiting pro-inflammatory macrophages, and alleviating inflammatory damage post-reshaping. In lung cancer, exosomes reshape anti-tumor macrophages, inhibit pro-tumor macrophages, and reshaped macrophages secrete exosomes that suppress lung cancer development. Looking ahead, efficient and targeted exosome-based therapies may emerge as a promising direction for treatment of pulmonary diseases.

CIRP increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TLR4-IL-2 signaling in the late phase of sepsis.

BACKGROUND: T helper (Th) cell imbalances have been associated with the pathophysiology of sepsis, including the Th1/Th2 and Th17/T regulatory cells (Treg) paradigms. Cold-inducible RNA-binding protein (CIRP), a novel damage-associated molecular pattern (DAMP) was reported that could induce T cell activation, and skew CD4+ T cells towards a Th1 profile. However, the effect and underlying mechanisms of CIRP on Th17/Treg differentiation in sepsis still remains unknown. METHODS: A prospective exploratory study including patients with sepsis was conducted. Blood samples were collected from patients on days 0, 3 and 7 on admission. The serum CIRP and peripheral blood Treg/Th17 percentage was determined by ELISA and flow cytometry. CD4+ T cells from the spleen and lymph nodes of mice with experimental sepsis were collected after treatment with normal saline (NS), recombinant murine CIRP (rmCIRP) and C23 (an antagonist for CIRP-TLR4) at late stage of sepsis. RNA-seq was conducted to reveal the pivotal molecular mechanism of CIRP on Treg/Th17 differentiation. Naïve CD4+ T cell was isolated from the Tlr4 null and wildtype mice in the presence or absence rmCIRP and C23 to confirmed above findings. RESULTS: A total of 19 patients with sepsis finally completed the study. Serum CIRP levels remained high in the majority of patients up to 1 week after admittance was closely associated with high Treg/Th17 ratio of peripheral blood and poor outcome. A univariate logistic analysis demonstrated that higher CIRP concentration at Day 7 is an independent risk factor for Treg/Th17 ratio increasing. CIRP promotes Treg development and suppresses Th17 differentiation was found both in vivo and in vitro. Pretreated with C23 not only alleviated the majority of negative effect of CIRP on Th17 differentiation, but also inhibited Treg differentiation, to some extent. Tlr4 deficiency could abolish almost all downstream effects of rmCIRP. Furthermore, IL-2 is proved a key downstream molecules of the effect CIRP, which also could amplify the activated CD4+ T lymphocytes. CONCLUSIONS: Persistent high circulating CIRP level may lead to Treg/Th17 ratio elevated through TLR4 and subsequent active IL-2 signaling which contribute to immunosuppression during late phases of sepsis.

Endothelium-specific SIRT7 targeting ameliorates pulmonary hypertension through Krüpple-like factor 4 deacetylation.

AIMS: Pulmonary hypertension (PH) is a pulmonary vascular disease characterized by a high mortality rate. Pulmonary arterial endothelium cells (PAECs) serve as a primary sensor of various environmental cues, such as shear stress and hypoxia, but PAEC dysfunction may trigger vascular remodelling during the onset of PH. This study aimed to illustrate the role of Sirtuin 7 (SIRT7) in endothelial dysfunction during PH and explore the potential therapeutic strategy for PH. METHODS AND RESULTS: SIRT7 levels were measured in human and murine experimental PH samples. Bioinformatic analysis, immunoprecipitation, and deacetylation assay were used to identify the association between SIRT7 and Krüpple-like factor 4 (KLF4), a key transcription factor essential for endothelial cell (EC) homeostasis. Sugen5416 + hypoxia (SuHx)-induced PH mouse models and cell cultures were used for the study of the therapeutic effect of SIRT7 for PH. SIRT7 level was significantly reduced in lung tissues and PAECs from PH patients and the SuHx-induced PH mouse model as compared with healthy controls. Pulmonary endothelium-specific depletion of Sirt7 increased right ventricular systolic pressure and exacerbated right ventricular hypertrophy in the SuHx-induced PH model. At the molecular level, we identified KLF4 as a downstream target of SIRT7, which deacetylated KLF4 at K228 and inhibited the ubiquitination-proteasome degradation. Thus, the SIRT7/KLF4 axis maintained PAEC homeostasis by regulating proliferation, migration, and tube formation. PAEC dysfunction was reversed by adeno-associated virus type 1 vector-mediated endothelial overexpression of Sirt7 or supplementation with nicotinamide adenine dinucleotide (NAD)+ intermediate nicotinamide riboside which activated Sirt7; both approaches successfully reversed PH phenotypes. CONCLUSION: The SIRT7/KLF4 axis ensures PAEC homeostasis, and pulmonary endothelium-specific SIRT7 targeting might constitute a PH therapeutic strategy.

Selective Upcycling of Polyethylene Terephthalate towards High-valued Oxygenated Chemical Methyl p-Methyl Benzoate using a Cu/ZrO2 Catalyst.

Upgrading of polyethylene terephthalate (PET) waste into valuable oxygenated molecules is a fascinating process, yet it remains challenging. Herein, we developed a two-step strategy involving methanolysis of PET to dimethyl terephthalate (DMT), followed by hydrogenation of DMT to produce the high-valued chemical methyl p-methyl benzoate (MMB) using a fixed-bed reactor and a Cu/ZrO2 catalyst. Interestingly, we discovered the phase structure of ZrO2 significantly regulates the selectivity of products. Cu supported on monoclinic ZrO2 (5 %Cu/m-ZrO2 ) exhibits an exceptional selectivity of 86 % for conversion of DMT to MMB, while Cu supported on tetragonal ZrO2 (5 %Cu/t-ZrO2 ) predominantly produces p-xylene (PX) with selectivity of 75 %. The superior selectivity of MMB over Cu/m-ZrO2 can be attributed to the weaker acid sites present on m-ZrO2 compared to t-ZrO2 . This weak acidity of m-ZrO2 leads to a moderate adsorption capability of MMB, and facilitating its desorption. Furthermore, DFT calculations reveal Cu/m-ZrO2 catalyst shows a higher effective energy barrier for cleavage of second C-O bond compared to Cu/t-ZrO2 catalyst; this distinction ensures the high selectivity of MMB. This catalyst not only presents an approach for upgrading of PET waste into fine chemicals but also offers a strategy for controlling the primary product in a multistep hydrogenation reaction.

A newly characterized dense granule protein (GRA76) is important for the growth and virulence of Toxoplasma gondii.

Pathogenicity of the zoonotic pathogen Toxoplasma gondii largely depends on the secretion of effector proteins into the extracellular milieu and host cell cytosol, including the dense granule proteins (GRAs). The protein-encoding gene TGME49_299780 was previously identified as a contributor to parasite fitness. However, its involvement in parasite growth, virulence and infectivity in vitro and in vivo remains unknown. Here, we comprehensively examined the role of this new protein, termed GRA76, in parasite pathogenicity. Subcellular localization revealed high expression of GRA76 in tachyzoites inside the parasitophorous vacuole (PV). However, its expression was significantly decreased in bradyzoites. A CRISPR-Cas9 approach was used to knock out the gra76 gene in the T. gondii type I RH strain and type II Pru strain. The in vitro plaque assays and intracellular replication showed the involvement of GRA76 in replication of RH and Pru strains. Deletion of the gra76 gene significantly decreased parasite virulence, and reduced the brain cyst burden in mice. Using RNA sequencing, we detected a significant increase in the expression of bradyzoite-associated genes such as BAG1 and LDH2 in the PruΔgra76 strain compared with the wild-type Pru strain. Using an in vitro bradyzoite differentiation assay, we showed that loss of GRA76 significantly increased the propensity for parasites to form bradyzoites. Immunization with PruΔgra76 conferred partial protection against acute and chronic infection in mice. These findings show the important role of GRA76 in the pathogenesis of T. gondii and highlight the potential of PruΔgra76 as a candidate for a live-attenuated vaccine.

A pilot study on Paxlovid therapy for hemodialysis patients with severe acute respiratory syndrome coronavirus 2 infections.

We aimed to investigate the safety and efficacy of nirmatrelvir/ritonavir (Paxlovid) therapy for hemodialysis-dependent patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Thirteen hemodialysis patients infected with the Omicron variant of SARS-CoV-2 from April 3 to May 30, 2022, were recruited. Laboratory parameters and chest CT (computed tomography) imaging were analyzed. The treatment group included six patients who received 150 mg/100 mg of Paxlovid orally once daily for 5 days, whereas the control group included seven patients who received basic treatment. No serious adverse reactions or safety events were recorded. Four control patients progressed to moderate disease, and none in the treatment group showed progression of chest CT findings (P < 0.05). Paxlovid therapy tended toward early viral clearance and low viral load on Day 8. Moreover, 83.3% of the patients in the treatment group and 57.1% of the patients in the control group turned negative within 22 days. In the Paxlovid treatment group, we found significantly increased levels of lymphocytes (P=0.03) and eosinophils (P=0.02) and decreased levels of D-dimer on Day 8 compared with those on Day 1. Paxlovid therapy showed a potential therapeutic effect with good tolerance in hemodialysis patients. The optimal dose and effectiveness evaluation must be further investigated in a largeer cohort.

The splicing factor SR2 is an important virulence factor of Toxoplasma gondii.

Serine/arginine-rich (SR) proteins are key factors with important roles in constitutive and alternative splicing (AS) of pre-mRNAs. However, the role of SR splicing factors in the pathogenicity of T. gondii remains largely unexplored. Here, we investigated the role of splicing factor SR2, a homolog of Plasmodium falciparum SR1, in the pathogenicity of T. gondii. We functionally characterized the predicted SR2 in T. gondii by gene knockout and studied its subcellular localization by endogenous protein HA tagging using CRISPR-Cas9 gene editing. The results showed that SR2 was localized in the nucleus and expressed in the tachyzoite and bradyzoite stages. In vitro studies including plaque formation, invasion, intracellular replication, egress and bradyzoite differentiation assays showed that deletion of SR2 in type I RH strain and type II Pru strains had no significant effect on the parasite growth and bradyzoite differentiation (p > 0.05). Interestingly, the disruption of SR2 in RH type I (p < 0.0001) and Pru type II (p < 0.05) strains resulted in varying degrees of attenuated virulence. In addition, disruption of SR2 in type II Pru strain significantly reduced brain cyst burden by ~80% (p < 0.0001). Collectively, these results suggest that splicing factor SR2 is important for the pathogenicity of T. gondii, providing a new target for the control and treatment of toxoplasmosis.

Risk factors and the value of microbiological examinations of COVID-19 associated pulmonary aspergillosis in critically ill patients in intensive care unit: the appropriate microbiological examinations are crucial for the timely diagnosis of CAPA.

Introduction: During the Omicron pandemic in China, a significant proportion of patients with Coronavirus Disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA) necessitated admission to intensive care unit (ICU) and experienced a high mortality. To explore the clinical risk factors and the application/indication of microbiological examinations of CAPA in ICU for timely diagnosis are very important. Methods: This prospective study included patients with COVID-19 admitted to ICU between December 1, 2022, and February 28, 2023. The clinical data of influenza-associated pulmonary aspergillosis (IAPA) patients from the past five consecutive influenza seasons (November 1, 2017, to March 31, 2022) were collected for comparison. The types of specimens and methods used for microbiological examinations were also recorded to explore the efficacy in early diagnosis. Results: Among 123 COVID-19 patients, 36 (29.3%) were diagnosed with probable CAPA. CAPA patients were more immunosuppressed, in more serious condition, required more advanced respiratory support and had more other organ comorbidities. Solid organ transplantation, APACHEII score ≥20 points, 5 points ≤SOFA score <10 points were independent risk factors for CAPA. Qualified lower respiratory tract specimens were obtained from all patients, and 84/123 (68.3%) patients underwent bronchoscopy to obtain bronchoalveolar lavage fluid (BALF) specimens. All patients' lower respiratory tract specimens underwent fungal smear and culture; 79/123 (64.2%) and 69/123 (56.1%) patients underwent BALF galactomannan (GM) and serum GM detection, respectively; metagenomic next-generation sequencing (mNGS) of the BALF was performed in 62/123 (50.4%) patients. BALF GM had the highest diagnostic sensitivity (84.9%), the area under the curve of the mNGS were the highest (0.812). Conclusion: The incidence of CAPA was extremely high in patients admitted to the ICU. CAPA diagnosis mainly depends on microbiological evidence owing to non-specific clinical manifestations, routine laboratory examinations, and CT findings. The bronchoscopy should be performed and the BALF should be obtained as soon as possible. BALF GM are the most suitable microbiological examinations for the diagnosis of CAPA. Due to the timely and accuracy result of mNGS, it could assist in early diagnosis and might be an option in critically ill CAPA patients.

Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries.

Mounting attention has been focused on defects of the autophagy-lysosomal pathway in sepsis, however, the precise mechanisms governing the autophagy-lysosomal process in sepsis are poorly known. We have previously reported that Erbin deficiency aggravated the inflammatory response and organ injuries caused by sepsis. In the present study, we found that Erbin knockout impaired the autophagy process in both muramyl dipeptide (MDP)-induced bone marrow-derived macrophages (BMDMs) and sepsis mouse liver and lung, as detected by the accumulation of LC3-II and SQSTM1/p62, and autophagosomes. Pretreatment with autophagy inhibitor chloroquine (CQ) further aggravated inflammatory response and organ injuries in vivo and in vitro sepsis model. We also observed that the impaired lysosomal function mediated autophagic blockade, as detected by the decreased expression of ATP6V, cathepsin B (CTSB) and LAMP2 protein. Immunoprecipitation revealed that the C-terminal of Erbin (aa 391-964) interacts with the N-terminal of transcription factor EB (TFEB) (aa 1-247), and affects the stability of TFEB-14-3-3 and TFEB-PPP3CB complexes and the phosphorylation status of TFEB, thereby promote the nucleus translocation of TFEB and the TFEB target genes transcription. Thus, our study suggested that Erbin alleviated sepsis-induced inflammatory responses and organ injuries by rescuing dysfunction of the autophagy-lysosomal pathway through TFEB-14-3-3 and TFEB-PPP3CB pathway.

Photothermal-Ionic-Pharmacotherapy of Myocardial Infarction with Enhanced Angiogenesis and Antiapoptosis.

Promoting angiogenesis is an effective therapeutic strategy to repair damaged hearts after myocardial infarction (MI). Copper ions and mild heat (41-42 °C) have been shown to promote angiogenesis, but their efficacy in MI is unknown. Here, a multicomponent hydrogel (EDR@PHCuS HG) is developed by encapsulating edaravone (EDR, a free radical scavenger) loaded porous hollow copper sulfide nanoparticles (PHCuS NPs) in a hyaluronic acid hydrogel (HG). Exposed to 808 nm near-infrared (NIR) light irradiation, the EDR@PHCuS HG exhibits controlled copper-ion release and mild photothermal effect to synergistically promote angiogenesis. In addition, released EDR inhibits cardiomyocyte apoptosis to further repair hearts. In the mouse model of MI, treatment with the EDR@PHCuS HG under an 808 nm laser significantly recovers the cardiac function and inhibits ventricular remodeling. This platform elucidates the cardioprotective effects of copper ions and mild heat and will provide a highly efficient treatment for MI.

COMMO: a web server for the identification and analysis of consensus gene modules across multiple methods.

SUMMARY: A variety of computational methods have been developed to identify functionally related gene modules from genome-wide gene expression profiles. Integrating the results of these methods to identify consensus modules is a promising approach to produce more accurate and robust results. In this application note, we introduce COMMO, the first web server to identify and analyze consensus gene functionally related gene modules from different module detection methods. First, COMMO implements eight state-of-the-art module detection methods and two consensus clustering algorithms. Second, COMMO provides users with mRNA and protein expression data for 33 cancer types from three public databases. Users can also upload their own data for module detection. Third, users can perform functional enrichment and two types of survival analyses on the observed gene modules. Finally, COMMO provides interactive, customizable visualizations and exportable results. With its extensive analysis and interactive capabilities, COMMO offers a user-friendly solution for conducting module-based precision medicine research. AVAILABILITY AND IMPLEMENTATION: COMMO web is available at https://commo.ncpsb.org.cn/, with the source code available on GitHub: https://github.com/Song-xinyu/COMMO/tree/master.

Research progress and challenges of preimplantation genetic testing for polygenic diseases. / å¤šåŸºå› ç–¾ç— èƒšèƒŽæ¤å ¥å‰é—ä¼ å­¦æ£€æµ‹çš„ç ”ç©¶è¿›å±•åŠæŒ‘æˆ˜.

Preimplantation genetic testing is an important part in assisted reproductive technology, which can block the intergenerational inheritance of single gene or chromosomal diseases. Preimplantation genetic testing for polygenic disease risk (PGT-P) is the latest development in the field. It is known that polygenic diseases usually have the characteristics of high incidence, late onset, affecting the quality of life and mental health of patients. On the basis of the development of artificial intelligence and genetic detection technology, PGT-P can analyze genetic material, calculate polygenic risk score turning into incidence probability. Embryos with relatively low incidence probability can be screened for transfer, so as to reduce the possibility of offspring suffering from the disease in the future, which has significant clinical and social significance. At present, PGT-P has been applied clinically and made phased progress at home and abroad. At the same time, as a developing technology, PGT-P still has some technical defects, unstable results, environmental influences and racial differences cannot be ruled out. From the perspective of ethics, if the screening indications are not strictly regulated, it is likely to cause new social problems. In this paper, we review the technical composition and recent progress of PGT-P, and put forward the prospect of its future development, especially how to establish a complete and suitable screening model for Chinese population.

Clinical and Temporal Radiological Findings from Critical Patients with COVID-19 Pneumonia: A Descriptive Study.

BACKGROUND: In late December 2019, Wuhan, the capital of Hubei Province, China, became the center of an outbreak of pneumonia caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). INTRODUCTION: The radiological changes in the lungs of critical people with coronavirus disease 2019 (COVID-19) pneumonia at different times have not been fully characterized. We aim to describe the computed tomography findings of patients with critical COVID-19 pneumonia at different disease stages. METHODS: Clinical and laboratory features of critical patients were assessed. CT scans were assigned to groups 1, 2, 3, or 4 based on the interval from symptom onset (within 2 weeks; ≥ 2-4 weeks; ≥ 4-6 weeks; or ≥ 6 weeks, respectively). Imaging features were analyzed and compared across the four groups. Total CT scores, corresponding periods of laboratory findings, and glucocorticoid dosages during the imaging intervals were longitudinally observed in five patients with complete data. RESULTS: All 11 critical patients (median age: 60 years [42-69]) underwent a total of 40 CT examinations, and the acquisition times ranged from 1-59 days after symptom onset. Median total CT scores were 18 (9-25.25); 44.5 (42.88-47.62); 43.75 (38.62-49.38); and 42 (32.25-53.25) in groups 1, 2, 3, and 4, respectively. The observed lesions were mainly bilateral (37 [92.5%]). The median values of involved lung segments were 10.5 (4.5-13.5); 17 (16-18.5); 18 (18-19.5); and 18 (18-19) in groups 1-4, respectively. The predominant patterns of observed abnormalities were ground-glass opacities (GGO) (9 [90%]); GGO with reticulation and mixed patterns (3 [37.5%] for both); GGO with consolidation (3 [30%]); and GGO with reticulation (8 [66.7%]) in groups 1-4, respectively. Patients developed fibrotic manifestations at later stages. CONCLUSION: Critical patients with COVID-19 infection generally presented with temporally changing abnormal CT features from focal unilateral to diffuse bilateral GGO and consolidation that progressed to or coexisted with reticulation in the long term after symptom onset. Low-dose glucocorticoids may be effective in patients with interstitial changes on CT findings.

Functional Characterization of Eight Zinc Finger Motif-Containing Proteins in Toxoplasma gondii Type I RH Strain Using the CRISPR-Cas9 System.

The Zinc finger protein (ZFP) family is widely distributed in eukaryotes and interacts with DNA, RNA, and various proteins to participate in many molecular processes. In the present study, the biological functions of eight ZFP genes in the lytic cycle and the pathogenicity of Toxoplasma gondii were examined using the CRISPR-Cas9 system. Immunofluorescence showed that four ZFPs (RH248270-HA, RH255310-HA, RH309200-HA, and RH236640-HA) were localized in the cytoplasm, and one ZFP (RH273150-HA) was located in the nucleus, while the expression level of RH285190-HA, RH260870-HA, and RH248450-HA was undetectable. No significant differences were detected between seven RHΔzfp strains (RHΔ285190, RHΔ248270, RHΔ260870, RHΔ255310, RHΔ309200, RHΔ248450, and RHΔ236640) and the wild-type (WT) strain in the T. gondii lytic cycle, including plaque formation, invasion, intracellular replication, and egress, as well as in vitro virulence (p > 0.05). However, the RHΔ273150 strain exhibited significantly lower replication efficiency compared to the other seven RHΔzfp strains and the WT strain, while in vivo virulence in mice was not significantly affected. Comparative expression analysis of the eight zfp genes indicates that certain genes may have essential functions in the sexual reproductive stage of T. gondii. Taken together, these findings expand our current understanding of the roles of ZFPs in T. gondii.

Design-driven regional industry transformation and upgrading under the perspective of sustainable development.

This study combines relevant theories and methods from economics and ecology to investigate design-driven transformation and upgrade paths for the long-term success of regional industries in the context of sustainable transformation, drawing on the design research literature's emphasis on sustainability, synergy, and a systemic approach. This evaluation may be thought of as a precondition for transformation. The regional industrial base dictates the upgrading route for sustainable transformation. Huaihua, a prefecture-level city in Hunan Province, China, serves as a case study for this investigation. Huaihua City's ecological footprints, human development index, and ecological welfare performance are used to evaluate the region's industrial base. A system based on quantitative data criteria and hierarchical analysis was built to choose top regional industries. The design study has promising implications for the sustainable transformation of major regional industries since it is an interdisciplinary, collaborative, and methodical type of research. Huaihua City, as a representative region of the less developed southwest region in China, designs a sustainable industrial transformation and upgrading path by providing a theoretical basis and quantitative measurement criteria for the sustainable transformation of regional industries.

Gaussian attractive potential for carboxylate/cobalt surface interactions.

Ligand-decorated metal surfaces play a pivotal role in various areas of chemistry, particularly in selective catalysis. Molecular dynamics simulations at the molecular mechanics level of theory are best adapted to gain complementary insights to experiments regarding the structure and dynamics of such organic films. However, standard force fields tend to capture only weak physisorption interactions. This is inadequate for ligands that are strongly adsorbed such as carboxylates on metal surfaces. To address this limitation, we employ the Gaussian Lennard-Jones (GLJ) potential, which incorporates an attractive Gaussian potential between the surface and ligand atoms. Here, we develop this approach for the interaction between cobalt surfaces and carboxylate ligands. The accuracy of the GLJ approach is validated through the analysis of the interaction of oxygen with two distinct cobalt surfaces. The accuracy of this method reaches a root mean square deviation (RMSD) of about 3 kcal/mol across all probed configurations, which corresponds to a percentage error of roughly 4%. Application of the GLJ force field to the dynamics of the organic layer on these surfaces reveals how the ligand concentration influences the film order, and highlights differing mobility in the x and y directions, attributable to surface corrugation on Co(112̄0). GLJ is versatile, suitable for a broad range of metal/ligand systems, and can, subsequently, be utilized to study the organic film on the adsorption/desorption of reactants and products during a catalytic process.

Clinical characteristics and prognosis of pneumonia-related bloodstream infections in the intensive care unit: a single-center retrospective study.

Background: Bloodstream infections (BSI) are one of the most severe healthcare-associated infections in intensive care units (ICU). However, there are few studies on pneumonia-related BSI (PRBSI) in the ICU. This study aimed to investigate the clinical and prognostic characteristics of patients with PRBSI in the ICU and to provide a clinical basis for early clinical identification. Methods: We retrospectively collected data from patients with bacterial BSI in a single-center ICU between January 1, 2017, and August 31, 2020. Clinical diagnosis combined with whole-genome sequencing (WGS) was used to clarify the diagnosis of PRBSI, and patients with PRBSI and non-PRBSI were analyzed for clinical features, prognosis, imaging presentation, and distribution of pathogenic microorganisms. Results: Of the 2,240 patients admitted to the MICU, 120 with bacterial BSI were included in this study. Thirty-two (26.7%) patients were identified as having PRBSI based on the clinical diagnosis combined with WGS. Compared to patients without PRBSI, those with PRBSI had higher 28-day mortality (81.3 vs.51.1%, p = 0.003), a higher total mortality rate (93.8 vs. 64.8%, p = 0.002), longer duration of invasive mechanical ventilation (median 16 vs. 6 days, p = 0.037), and prolonged duration of ICU stay (median 21 vs. 10 days, p = 0.004). There were no differences in other baseline data between the two groups, but patients with PRBSI had extensive consolidation on chest radiographs and significantly higher Radiographic Assessment of Lung Edema scores (mean 35 vs. 24, p < 0.001). The most common causative organisms isolated in the PRBSI group were gram-negative bacteria (n = 31, 96.9%), with carbapenem-resistant gram-negative bacteria accounting for 68.8% (n = 22) and multidrug-resistant bacteria accounting for 81.3% (n = 26). Conclusion: Pneumonia-related BSI is an important component of ICU-BSI and has a poor prognosis. Compared to non-PRBSI, patients with PRBSI do not have typical clinical features but have more severe lung consolidation lesions, and should be alerted to the possibility of their occurrence when combined with pulmonary gram-negative bacterial infections, especially carbapenem-resistant bacteria. Further multicenter, large-sample studies are needed to identify the risk factors for the development of PRBSI and prevention and treatment strategies.