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关键词： after surgery   sepsis   sTREM1   diagnosis and prognosis  

摘要： Introduction Sepsis represents a critical response to infection;it is characterized by systemic inflammation, shock, and potential organ failure. Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) has been identified as a crucial marker in sepsis, connecting the activation of innate immunity to systemic inflammation. Methods This prospective nested case control study was carried out in the intensive care unit and surgery department from March 2018 to June 2019. Adults undergoing abdominal surgery, with and without sepsis, were included in the study, and sTREM-1 and cytokine levels were measured. Results A total of 120 patients were included in the study, comprising 31 noninfected individuals, 37 with sepsis, and 52 with septic shock. sTREM-1 levels were statistically significantly elevated in patients with sepsis and septic shock compared with noninfected individuals (P < .001). Receiver operating characteristic curve analysis revealed an area under the curve of 0.722 for sTREM-1 in the prediction of septic shock. Discussion Elevated sTREM-1 levels are associated with the severity of sepsis and may function as a prognostic biomarker. Additional research is required to confirm these findings and investigate therapeutic interventions aimed at the sTREM-1 pathway.

关键词： Pterocarpus soyauxii   Pterocarpus mildbraedii   HIV-1   SARS-CoV-2   molecular docking   network pharmacology  

摘要： This research explored the therapeutic efficacy of bioactive substances derived from Pterocarpus soyauxii and Pterocarpus mildbraedii against HIV-1 and SARS-CoV-2 co-infection. Pharmacokinetic characteristics were evaluated with ADMETlab 3.0. Network pharmacology analyses were conducted using Swiss Target Prediction, GeneCards, STRING, Cytoscape and Metascape, along with pathway mapping in Srplot. The protein structures of EGFR, MMP9 and SARS-CoV-2 polyprotein 1ab were assessed through the SwissModel and ProSA-web databases. Molecular docking and binding sites determination were performed through 1-Click Docking and BC-Dock2 web servers. Inhibitory activity of the compounds on the CDK2 and HIV-1 proteins was carried out in the kinCSM way2drug databases. Results show that Khrinone A and E exhibited positive absorption and distribution profiles. Network pharmacology revealed essential molecular targets and enriched KEGG pathways associated with viral replication. MolProbity scores ranged from 0.77 to 2.28, with over 92% of residues located in Ramachandran preferred regions. Molecular docking revealed significant binding affinities, especially Pterocarpin (-9.9 kcal/mol) with MMP9 and Khrinone A (-8.9 kcal/mol) with NOS2, surpassing reference inhibitors. In comparison to EGFR, the affinities of natural ligands (-7.7 kcal/mol to -7.0 kcal/mol) were similar to Gefitinib, whereas Claussequinone and Khrinone E demonstrated compelling interactions with HIV-1 reverse transcriptase (-7.4 kcal/mol to -7.2 kcal/mol), resembling those of Lawsone (-8.3 kcal/mol). Additionally, Khrinone A and E can serve as potent CDK2 inhibitors (IC50 < 10 mu M), exhibiting pKi values (5.902-5.929) comparable to those of Palbociclib (6.029). These results indicate that compounds derived from Pterocarpus have multitarget antiviral and host-modulating abilities, reinforcing their potential as valuable candidates for therapeutic intervention in HIV/SARS-CoV-2 co-infection.

关键词： Small for gestational age   Short stature   Insulin-like growth factor 1 receptor   Cluster analysis  

摘要： Children born small for gestational age (SGA) who fail to experience catch-up growth often remain short-statured with heterogeneous etiologies, including genetic factors. This study aimed to investigate Insulin-like Growth Factor 1 Receptor (IGF1R) gene alterations and their clinical relevance in 66 Korean children born SGA with persistent short stature. All the subjects underwent detailed phenotyping and molecular analyses. Two patients carried heterozygous deletions encompassing the entire IGF1R gene, as confirmed by chromosomal microarray analysis. Both patients exhibited advanced bone age, with one showing a favorable response to growth hormone therapy. Additionally, 14 variants of uncertain significance were identified, with one rare missense variant (c.158C>T, ***53Met) showing a high predicted pathogenicity. Subgroup analysis showed that severe SGA was associated with lower mid-parental height, and those with an insulin-like growth factor 1 standard deviation score of >= 0 had less bone age delay, but no clear auxological differences were observed between subgroups. These patterns, although not definitive, may help to identify SGA-short children who warrant further evaluation for IGF1R-related growth impairment. Exploratory clustering revealed two subgroups but failed to show distinct phenotypic separation. Although no strong genotype-phenotype correlations were observed, this study highlights the potential clinical value of identifying IGF1R deletions and suggests that molecular and phenotypic profiling may offer hypothesisgenerating insights into SGA-related growth disorders. Our findings underscore the importance of integrating genetic screening into the diagnostic workup for children born SGA with unexplained growth failure, and the need for future studies to functionally characterize rare IGF1R variants.

关键词： metabolic myopathy   mouse model   purine metabolism   adenylosuccinate synthetase   ADSS1  

摘要： ADSS1 myopathy is an ultrarare congenital myopathy characterized by progressive cardiac and skeletal muscle degeneration with childhood to adolescent onset. This autosomal recessive disease is caused by mutations in the ADSS1 gene, encoding the enzyme adenylosuccinate synthetase (AdSS1). AdSS1 plays a critical role in the adenine nucleotide cycle, which is important for energy metabolism in muscle cells. Enzymatic defects, engendered by loss-of-function mutations in ADSS1, lead to a bottleneck in the adenine nucleotide cycle, causing metabolic dysfunction that ultimately results in progressive muscle weakness, mobility impairment, and respiratory and cardiac dysfunction, often requiring the use of a ventilator. Despite its debilitating nature, there are currently no cures or targeted treatments available, and little research into possible therapeutic strategies has been done. With a limited patient profile encompassing fewer than 200 known patients worldwide, establishing a mouse model for ADSS1 myopathy is critical to understanding its pathogenesis and for developing future therapies. Here, we present and characterize the first mouse model of ADSS1 myopathy-a constitutive Adss1 knockout model-by (1) defining its natural history, (2) exploring its metabolic pathomechanisms, and (3) characterizing its histopathological features. We find that Adss1KO/KO mice have subtle motor deficits and present with histopathological features consistent with patient phenotypes. Overall, we show that despite a relatively mild phenotype, this novel mouse model has quantifiable pathological features that can be used to develop therapies for, and further probe pathophysiology of, ADSS1 myopathy.

关键词： HIV integrase   LEDGF/p75   LEDGINs   natural products   molecular dynamics simulation   thermodynamics profile  

摘要： HIV integrase is an essential enzyme responsible for incorporating viral DNA into the host's genome, a vital phase in the HIV replication process. The host protein, Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75), connects with the HIV Integrase (IN) Catalytic Core Domain (CCD) via its Integrase Binding Domain (IBD) and anchors the pre-integration complex, aiding in the integration of HIV into regions of chromatin that are transcriptionally active. This interaction underscores the importance of the integrase-LEDGF/p75 complex as a target for therapeutic intervention. Interrupting this interaction with allosteric inhibitors of the LEDGF/p75-IN interaction, known as LEDGINs, has become a promising method to curb HIV replication. Although LEDGINs are still being studied for clinical application, they may be too costly for developing countries if approved, emphasizing the necessity for ongoing research into alternative methods. Natural substances like terpenes and flavonoids show antiviral properties. Consequently, utilizing natural compound libraries to target the HIV integrase-LEDGF/p75 interaction offers a new strategy for creating effective antiviral medications. This research assessed a collection of compounds derived from natural sources. To refine a library of over 76,000 compounds, Lipinski's rule of five was applied. Molecular docking and 300 ns Molecular Dynamics (MD) simulations were conducted to pinpoint compounds with strong binding affinity and stability to the CCD-IBD interface, using LEDGIN6 as a benchmark inhibitor. Through molecular docking studies, Guanipiperazine B, CHEBI:211233 and Okaramine T were identified as promising inhibitors of the HIV-1 integrase-LEDGF/p75 complex, showing stronger binding affinities compared to the reference drug LEDGIN6. Among these, Guanipiperazine B exhibited the most stable binding, as evidenced by the lowest Root Mean Square Deviation (RMSD) and RMSF values in MD simulations, indicating robust and stable interac

关键词： Immune response   Large yellow croaker   PAAR-1   Pathogenicity   Pseudomonas plecoglossicida  

摘要： Pseudomonas plecoglossicida is a pathogen bacterium responsible for visceral white spot disease (VWND) in Large Yellow Croakers (Larimichthys crocea), causing significant economic losses in commercial fish farms. The proline-alanine-alanine-arginine repeats protein (PAAR) is a core component of the spike structure in the type VI secretion system (T6SS), which injects toxic effectors into host and contributes to bacterial virulence. However, the role of the PAAR gene in P. plecoglossicida and its impact on bacterial infection and host immune responses remain unexplored. In this study, PAAR-1 was identified for the first time in P. plecoglossicida as an effector gene within the T6SS-1 gene cluster, which is regulated and secreted by T6SS-1. The P. plecoglossicida mutant strain (ΔPAAR-1) and its complementary strain (C-ΔPAAR-1) were constructed for subsequent investigation. Compared to the wild-type strain, ΔPAAR-1 exhibited reduced biofilm formation, adhesion, total antioxidant capacity, and secretion of T6SS core protein Hcp-1. In vitro, ΔPAAR-1 showed decreased survival rates in Large Yellow Croaker macrophage cell line (LYC-FM) due to impaired oxidative stress tolerance. In vivo, infection with ΔPAAR-1 led to a significant reduction in mortality, bacterial colonization, and the formation of spleen nodules in Large Yellow Croakers. Comparative transcriptome analysis revealed that PAAR-1 predominantly influences the host Toll-like receptor (TLR) signaling pathway and apoptosis by upregulating the expression of plasma membrane-associated TLRs, including TLR1, TLR2, and TLR5, while downregulating the expression of endosomal TLRs like TLR3, TLR7, TLR8, and TLR9, along with its downstream molecules such as MyD88 and TRAF3. Additionally, knockout PAAR-1 downregulates a

关键词： Chinese soft-shelled turtles Pelodiscus sinensis   Hibernation   Intestine   Proline  

摘要： The object of this study was to assess the impact of proline (Pro) supplementation on mediating hibernation induced intestinal barrier dysfunction in turtle and to explore the underling mechanisms. Pelodiscus sinensis were given a simulated hibernation experiment for 4 weeks, followed by feeding the control (Con) diet and Pro diet for 4 weeks. Results showed that the turtles fed of Pro diet significantly enhanced the feed intake and intestinal Pro deposition, while increased the villus height, crypt depth and the ratio of villus height to crypt depth in intestine of turtles. Pro significantly facilitated the conversion of intestinal type II and III goblet cells to type I goblet cells, and markedly upregulated the expression of muc-2, zo-1, claudin-1, claudin-3, the key gene associated with the intestinal barrier, as well as restrained the expression of mlck. Moreover, Tunel-immunohistochemical analysis showed that Pro diet significantly reduced the number of intestinal late apoptotic cell, and levels of pro-apoptosis and pro-inflammation related genes in Pro treatment were significantly lowered than those in Con treatment. Furthermore, Nf-κB p65 serves as a pivotal transcription factor in activating apoptosis and inflammation, and its expression can be regulated by Nrf2/HO-1. Pro significantly upregulated the protein levels of total-Nrf2, nuclear-Nrf2, and HO-1, while simultaneously suppressing the phosphorylation of NF-κB p65 in the intestine of turtles. These findings revealed the underling mechanism of action of Pro in hibernation stress of P. sinensis, confirming that Pro increased Nrf2 and HO-1 that, which subsequently suppresses the Nf-κB p65 in intestine thereby reducing inflammation and apoptosis, and thus alleviated intestinal tight junction dysfunction and barrier damage of P. sinensis caused by hibernation.

关键词： Aeromonas hydrophila   Colonization   Fibroblast-like cells   Green fluorescent protein   Pelodiscus sinensis  

摘要： The Chinese soft-shelled turtle (Pelodiscus sinensis) is a crucial economically significant aquatic species, yet its aquaculture is severely impacted by disease-related challenges. Among these, Aeromonas hydrophila stands out as one of the most prevalent pathogenic bacteria, responsible for the highest diversity of disease manifestations and detection rates in farmed P. sinensis. In this study, a pathogenic strain A. hydrophila PS-1 from diseased P. sinensis was isolated and identified. A green fluorescent protein (GFP) labeled PS-1 (PS-1/GFP) was constructed with the pAPR-EGFP plasmid. The growth, motility, and pathogenicity of PS-1/GFP showed no difference from that of the wild type strain. After artificial infection, green fluorescence was only observed in the intestine and liver in a paraffin section at 72 h of infection, which indicated that PS-1 infection exhibited tissue specificity. Accordingly, the colonization sites of PS-1 in P. sinensis were intestine and liver, with bacterial loads reaching as high as 5 × 10⁹ CFU/g and 7 × 10⁸ CFU/g, respectively. Moreover, PS-1 could internalize into intestinal fibroblast-like cells and induce similar cell morphological changes akin to pyroptosis. This work established methodological tools and fundamental insights for investigating diseases in P. sinensis, and laid the groundwork for further elucidation of the pathogen-host interaction mechanisms between A. hydrophila and P. sinensis.

摘要： The L_1/2 regularization plays a crucial role in promoting sparsity of the solution in the optimization models. The half thresholding algorithm, which is derived based on the threshold representation theorem, serves as an efficient solver for the non-convex L_1/2 regularization problem. However, an excessively large matrix norm leads to an excessively small threshold, thereby impeding the convergence rate of half thresholding algorithm. In this study, we introduce two preconditioning matrices in the L_1/2 regularization model. One matrix enhances convergence by improving the algebraic properties of the matrix, while another adjusts the threshold and value of the regularization parameter automatically in every iteration. In particular, when the sparsity of the solution is unknown, the exact number of nonzero components can be approached iteratively. Furthermore, we expedite the half thresholding iterative algorithm using the Nesterov acceleration technique and provide the corresponding convergence results. We validate both the effectiveness and efficiency of our proposed algorithm through the examples in computational spectrometer reconstruction.

关键词： nonlinear acoustics   thermoviscoelasticity   small-data solution   decay rate 2020 MSC35B40 (primary)   35L05   35B35 (secondary)  

摘要： In bounded n-dimensional domains with n ≥ 1, this manuscript examines an initial-boundary value problem for the system