Analysis of unsuccessful tests and the effect of prolonged clinical sample preprocessing in the GeneXpert MTB/RIF assay.

BACKGROUND: The GeneXpert MTB/RIF (Xpert) assay is a widely used technology for detecting Mycobacterium tuberculosis (MTB) in clinical samples. However, the study on the failure of the Xpert assay during routine implementation and its potential solutions is limited. METHODS: We retrospectively analyzed the records of unsuccessful tests in the Xpert and the GeneXpert MTB/RIF Ultra (Ultra) assays between April 2017 and April 2021 at the Shanghai Public Health Clinical Center. To further investigate the effect of prolonged preprocessing on clinical sputum, an additional 120 sputum samples were collected for Xpert testing after 15 min, 3 h, and 6 h preprocessing. The analysis was performed by SPSS version 19.0 software. RESULTS: A total of 11,314 test records were analyzed, of which 268 (2.37%) had unsuccessful test results. Among these, 221 (1.95%) were reported as "Error", 43 (0.38%) as "Invalid", and 4 (0.04%) as "No result". The most common clinical specimen for Xpert tests was sputum, accounting for 114 (2.17%) unsuccessful tests. The failure rate of urine specimens was lower than that of sputum (OR = 0.12, 95% CI: 0.02-0.88, χ2 = 6.22, p = 0.021). In contrast, the failure rate of stool specimens was approximately twice as high as that of sputum (OR = 1.93, 95% CI: 1.09-3.40, χ2 = 5.35, p = 0.014). In the prolonged preprocessing experiment, 102 cases (85%) yielded consistent results in Xpert tests. Furthermore, 7 cases (5.83%) detected an increase in MTB load, 8 cases (6.67%) detected a decrease in MTB load, and 3 cases (2.5%) yielded incongruent results in MTB and rifampicin resistance detection. CONCLUSIONS: The primary cause of unsuccessful tests in the Xpert assay was reported as "Error". Despite varying failure rates depending on the samples, the Xpert assay can be applied to extrapulmonary samples. For paucibacillary specimens, retesting the remaining preprocessed mixture should be carefully considered.

A platform to deliver single and bi-specific Cas9/guide RNA to perturb genes in vitro and in vivo.

Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.

Pan-cancer analyses reveal the molecular and clinical characteristics of TET family members and suggests that TET3 maybe a potential therapeutic target.

The Ten-Eleven Translocation (TET) family genes are implicated in a wide array of biological functions across various human cancers. Nonetheless, there is a scarcity of studies that comprehensively analyze the correlation between TET family members and the molecular phenotypes and clinical characteristics of different cancers. Leveraging updated public databases and employing several bioinformatics analysis methods, we assessed the expression levels, somatic variations, methylation levels, and prognostic values of TET family genes. Additionally, we explored the association between the expression of TET family genes and pathway activity, tumor microenvironment (TME), stemness score, immune subtype, clinical staging, and drug sensitivity in pan-cancer. Molecular biology and cytology experiments were conducted to validate the potential role of TET3 in tumor progression. Each TET family gene displayed distinct expression patterns across at least ten detected tumors. The frequency of Single Nucleotide Variant (SNV) in TET genes was found to be 91.24%, primarily comprising missense mutation types, with the main types of copy number variant (CNV) being heterozygous amplifications and deletions. TET1 gene exhibited high methylation levels, whereas TET2 and TET3 genes displayed hypomethylation in most cancers, which correlated closely with patient prognosis. Pathway activity analysis revealed the involvement of TET family genes in multiple signaling pathways, including cell cycle, apoptosis, DNA damage response, hormone AR, PI3K/AKT, and RTK. Furthermore, the expression levels of TET family genes were shown to impact the clinical staging of tumor patients, modulate the sensitivity of chemotherapy drugs, and thereby influence patient prognosis by participating in the regulation of the tumor microenvironment, cellular stemness potential, and immune subtype. Notably, TET3 was identified to promote cancer progression across various tumors, and its silencing was found to inhibit tumor malignancy and enhance chemotherapy sensitivity. These findings shed light on the role of TET family genes in cancer progression and offer insights for further research on TET3 as a potential therapeutic target for pan-cancer.

The First Infant Anaerobic Meningitis Infected by Prevotella bivia: A Case Report and Literature Review.

Anaerobic bacterial meningitis is a serious infection of the central nervous system (CNS) that leads to severe neurological complications, resulting in high levels of disability and mortality worldwide. However, accurately diagnosing and isolating the responsible pathogens remains challenging due to the difficulty in culturing anaerobic bacteria, as they require harsh anaerobic culture conditions. Anaerobic bacteria have rarely been reported in meningitis, especially in children. This report details the first infant with anaerobic meningitis caused by Prevotella bivia. Additionally, we present a case of infant anaerobic meningitis caused by P. bivia, detected using metagenomics next-generation sequencing (mNGS). Our clinical experience highlights the importance of early identification of Prevotella spp. through mNGS and anaerobic culture, the effectiveness of antimicrobial medications, and the timely implementation of carefully planned precision therapeutic regimens. Furthermore, we have conducted a comprehensive review of 10 cases of Prevotella spp. infection, summarized their clinical and laboratory examination characteristics, and identified their commonalities.

Performance evaluation of influenza a rapid antigen test and PCR among nasopharyngeal and oropharyngeal samples.

Objectives: Rapid antigen test (RAT) and polymerase chain reaction (PCR) using nasopharyngeal (NP) or oropharyngeal (OP) swab specimens are the two main testing techniques used for laboratory diagnosis of influenza in clinical practice. However, performance variations have been observed not only between techniques, but also between different specimens. This study evaluated the differences in performance between specimens and testing techniques to identify the best combination in clinical practice. Methods: Both NP and OP samples from suspected influenza patients collected in the 2023/4-2023/5 Flu-season in Xiamen, China, were tested for RAT and quantitative PCR. The testing performance of the different specimens and testing techniques were recorded and evaluated. Results: Compared to PCR, RAT showed 58.9 % and 10.3 % sensitivity for NP and OP swabs, respectively. The Limit of Detection (LoD) was 28.71 the Median Tissue Culture Infectious Dose (TCID50)/mL. Compared with PCR using NP swabs, PCR with OP swabs showed 89.5 % sensitivity and 95.4 % specificity. Conclusions: There were no significant differences in performance between the specimens when PCR was used to test for influenza. However, a decrease in sensitivity was observed when the RAT was used, regardless of the specimen type. Therefore, to avoid false-negative results, PCR may be a better choice when OP swabs are used as specimens. In contrast, NP swabs should be the recommended specimens for RAT.

SENP1-Mediated HSP90ab1 DeSUMOylation in Cardiomyocytes Prevents Myocardial Fibrosis by Paracrine Signaling.

Myocardial infarction (MI) triggers a poor ventricular remodeling response, but the underlying mechanisms remain unclear. Here, the authors show that sentrin-specific protease 1 (SENP1) is downregulated in post-MI mice and in patients with severe heart failure. By generating cardiomyocyte-specific SENP1 knockout and overexpression mice to assess cardiac function and ventricular remodeling responses under physiological and pathological conditions. Increased cardiac fibrosis in the cardiomyocyte-specific SENP1 deletion mice, associated with increased fibronectin (Fn) expression and secretion in cardiomyocytes, promotes fibroblast activation in response to myocardial injury. Mechanistically, SENP1 deletion in mouse cardiomyocytes increases heat shock protein 90 alpha family class B member 1 (HSP90ab1) SUMOylation with (STAT3) activation and Fn secretion after ventricular remodeling initiated. Overexpression of SENP1 or mutation of the HSP90ab1 Lys72 ameliorates adverse ventricular remodeling and dysfunction after MI. Taken together, this study identifies SENP1 as a positive regulator of cardiac repair and a potential drug target for the treatment of MI. Inhibition of HSP90ab1 SUMOylation stabilizes STAT3 to inhibit the adverse ventricular remodeling response.

Causal associations between the gut microbiota and multiple myeloma: a two-sample Mendelian randomization study.

Background: Previous observational studies have indicated a potential association between the gut microbiota and multiple myeloma (MM). However, the relationship between the gut microbiota and MM remains unclear. This study aimed to ascertain the existence of a causal link between the gut microbiota and MM. Methods: To investigate the potential causal relationship between gut microbiota and MM, a two-sample Mendelian randomization (MR) analysis was conducted. Exposure data was obtained from the MiBioGen consortium, which provided genetic variants associated with 211 bacterial traits. MM outcome data was obtained from the FinnGen consortium. The selection of Single nucleotide polymorphisms estimates was performed through meta-analysis using inverse-variance weighting, and sensitivity analyses were conducted using weighted median, MR Egger, Simple mode, and MR-PRESSO. Results: The results of the study demonstrated a significant positive correlation between the genus Eubacterium ruminantium group and the risk of MM (OR 1.71, 95% CI 1.21 to 2.39). Conversely, the genus: Dorea (OR 0.46, 95% CI 0.24 to 0.86), Coprococcus1 (OR 0.47, 95% CI 0.22 to 1.00), RuminococcaceaeUCG014 (OR 0.57, 95% CI 0.33 to 0.99), Eubacterium rectale group (OR 0.37, 95% CI 0.18 to 0.77), and order: Victivallales (OR 0.62, 95% CI 0.41-0.94), class: Lentisphaeria (OR 0.62, 95% CI 0.41 to 0.94), exhibited a negative association with MM. The inverse variance weighting analysis provided additional support for these findings. Conclusion: This study represents an inaugural exploration of MR to investigate the connections between gut microbiota and MM, thereby suggesting potential significance for the prevention and treatment of MM.

Central serous chorioretinopathy secondary to drugs: a real-world pharmacovigilance study of the FDA adverse event reporting system (FAERS).

BACKGROUND: The objective of this study was to evaluate the reporting associations between Central serous chorioretinopathy (CSCR) and many available drugs using FAERS. RESEARCH DESIGN AND METHODS: FAERS reports from 2004 to 2023 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify CSCR cases. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the reporting associations between available drugs and CSCR were calculated. A reporting association was considered statistically significant when the lower limit of the 95% CI was > 1.0. RESULTS: There were 1002 reports of 110 drugs with suspected drug-associated CSCR based on the 'primary suspects' role code in the FAERS database found to have statistically significant signals. Among the top 20 ROR drugs, the most frequently reported drugs were dermatological drugs (ATC:D, 210 cases, 64.41%), followed by antitumor agents and immunological agents (ATC:L,77 cases, 23.62%), Systemic Hormonal Preparations, Excl. Sex hormones and Insulins (ATC:H, 19 cases, 5.80%) and sensory organ drugs (ATC:S, 9 cases, 2.76%). The top 3 drugs associated with CSCR were Prednisolone (144 cases, 44.17%), Fluticasone (29 cases, 8.90%), and Methylprednisolone (27 cases, 8.28%). CONCLUSIONS: This is the first real-world study using FAERS database to investigate drug-induced CSCR. Clinicians and pharmacist must keep in mind CSCR is a serious ocular complication associated with glucocorticoids, tyrosine kinase receptor inhibitor, and other drugs that can cause CSCR.

Optimizing of a suitable protocol for isolating tissue-derived extracellular vesicles and profiling small RNA patterns in hepatocellular carcinoma.

BACKGROUND: Extracellular vesicles (EVs) facilitate cell-cell interactions in the tumour microenvironment. However, standard and efficient methods to isolate tumour tissue-derived EVs are lacking, and their biological functions remain elusive. METHODS: To determine the optimal method for isolating tissue-derived EVs, we compared the characterization and concentration of EVs obtained by three previously reported methods using transmission electron microscopy, nanoparticle tracking analysis, and nanoflow analysis (Nanoflow). Additionally, the differential content of small RNAs, especially tsRNAs, between hepatocellular carcinoma (HCC) and adjacent normal liver tissues (ANLTs)-derived EVs was identified using Arraystar small RNA microarray. The targets of miRNAs and tsRNAs were predicted, and downstream functional analysis was conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, non-negative matrix factorization and survival prediction analysis. RESULTS: A differential centrifugation-based protocol without cell cultivation (NC protocol) yielded higher EV particles and higher levels of CD9+ and CD63+ EVs compared with other isolation protocols. Interestingly, the NC protocol was also effective for isolating frozen tissue-derived EVs that were indistinguishable from fresh tissue. HCC tissues showed significantly higher EV numbers compared with ANLTs. Furthermore, we identified different types of small RNAs in HCC tissue-derived EVs, forming a unique multidimensional intercellular communication landscape that can differentiate between HCC and ANLTs. ROC analysis further showed that the combination of the top 10 upregulated small RNAs achieved better diagnostic performance (AUC = .950 [.895-1.000]). Importantly, most tsRNAs in HCC tissue-derived EVs were downregulated and mitochondria-derived, mainly involving in lipid-related metabolic reprogramming. CONCLUSION: The NC protocol was optimal for isolating EVs from HCC, especially from frozen tissues. Our study emphasized the different roles of small-RNA in regulating the HCC ecosystem, providing insights into HCC progression and potential therapeutic targets.

Alleviation effects of dexmedetomidine on myocardial ischemia/reperfusion injury through fatty acid metabolism pathway via Elovl6.

Dexmedetomidine (Dex) is widely used in the sedation in intensive care units and as an anesthetic adjunct. Considering the anti-inflammatory and antioxidant properties of Dex, we applied in vivo rat model as well as in vitro cardiomyocyte models (embryonic rat cardiomyocytes H9c2 cells and neonatal rat cardiomyocytes, NRCMs) to evaluate the effects of Dex against myocardial ischemia reperfusion (I/R) injury. Transcriptomic sequencing for gene expression in heart tissues from control rats and Dex-treated rats identified that genes related to fatty acid metabolism were significantly regulated by Dex. Among these genes, the elongation of long-chain fatty acids (ELOVL) family member 6 (Elovl6) was most increased upon Dex-treatment. By comparing the effects of Dex on both wild type and Elovl6-knockdown H9c2 cells and NRCMs under oxygen-glucose deprivation/reoxygenation (OGD/R) challenge, we found that Elovl6 knockdown attenuated the protection efficiency of Dex, which was supported by the cytotoxicity endpoints (cell viability and lactate dehydrogenase release) and apoptosis as well as key gene expressions. These results indicate that Dex exhibited the protective function against myocardial I/R injury via fatty acid metabolism pathways and Elovl6 plays a key role in the process, which was further confirmed using palmitate exposure in both cells, as well as in an in vivo rat model. Overall, this study systematically evaluates the protective effects of Dex on the myocardial I/R injury and provides better understanding on the fatty acid metabolism underlying the beneficial effects of Dex.

Multi-layered heterogeneous interfaces created in Co0.85Se@Ni3S4/NF to enhance supercapacitor performances by multi-step alternating electrodeposition.

Heterogeneous interface construction is of far-reaching significance to optimize the electrochemical performance of electrodes. Herein, a multi-step alternating electrochemical deposition (MAED) method is proposed to alternately deposit Co0.85Se and Ni3S4 nanosheets on a nickel foam (NF), forming a special alternate layer-by-layer structure with multi-layered heterogeneous interfaces. The creation of the multi-layered heterogeneous interfaces provides a large interfacial area for redox reactions with optimum interstitials facilitating ion diffusion, thus greatly improving the electrochemical energy storage efficiency. With the increase in the layer number, the material exhibits increasingly better energy storage performance, and 8L-Co0.85Se@Ni3S4/NF exhibits the highest specific capacitances of 2508 F g-1 and 1558 F g-1 at a scan rate of 2 mV s-1 and a current density of 1 A g-1. The 8L-Co0.85Se@Ni3S4/NF//polypyrrole (PPy)/NF asymmetric supercapacitor provides a maximum operation potential window of 1.55 V and energy densities of 76.98 and 35.74 W h kg-1 when the power densities are 775.0 and 15 500 W kg-1, respectively, superior to most of the related materials reported. Through MAED, the deposited phase and the layer number can be accurately controlled, thus providing an efficient strategy for interface construction so as to increase the electrochemical activity of the energy storage materials.

Diagnostic performance of the quantitative flow ratio and CT-FFR for coronary lesion-specific ischemia.

Fractional flow reserve (FFR) has become the gold standard for evaluating coronary lesion-specific ischemia. However, FFR is an invasive method that may cause possible complications in the coronary artery and requires expensive equipment, which limits its use. Promising noninvasive diagnostic methods, such as computed tomography angiography-derived FFR (CT-FFR) and the quantitative flow ratio (QFR), have been proposed. In this study, we evaluated the diagnostic performance of the QFR and CT-FFR in predicting coronary lesion-specific ischemia, with the FFR serving as the reference standard. Patients with suspected or known coronary artery disease who underwent coronary CT angiography revealing 30-90% diameter stenosis in the main coronary artery (≥ 2.0 mm reference diameter) were enrolled. The FFR was measured during invasive coronary angiography (within 15 days after coronary CT angiography). An FFR ≤ 0.8 was the reference standard for coronary lesion-specific ischemia. A total of 103 vessels from 92 consecutive patients (aged 59.8 ± 9.2 years; 60.9% were men) were evaluated. The diagnostic performance of a QFR ≤ 0.80 for predicting coronary lesion-specific ischemia demonstrated good diagnostic accuracy, sensitivity, and specificity (92.2%, 87.2%, and 96.4%, respectively), with an area under the receiver operating characteristic curve (AUC) of 0.987 (P < 0.0001). The diagnostic performance of a CT-FFR ≤ 0.80 for predicting coronary lesion-specific ischemia also demonstrated good diagnostic accuracy, sensitivity, and specificity (96.1%, 95.7%, and 96.4%, respectively), with an AUC of 0.967 (P < 0.0001). However, there was no significant difference in the AUC between a QFR ≤ 0.80 and a CT-FFR ≤ 0.80 for predicting coronary lesion-specific ischemia (P = 0.319). There was an excellent correlation between the QFR and FFR (r = 0.856, P < 0.0001). The CT-FFR and FFR also showed a good direct correlation (r = 0.816, P < 0.0001). The QFR and CT-FFR are strongly correlated with the FFR and can provide excellent clinical diagnostic performance for coronary lesion-specific ischemia detection.

Self-Sustained-Release Strategy Realizes Colloid Oriented Assembly to Fabricate Prussian Blue with Hierarchical Structure.

The controlled self-assembly of nanomaterials has been a great challenge in nanosynthesis, especially for hierarchical architectures with high complexity. Particularly, the structural design of Prussian blue (PB) series materials with robustness and fast nucleation is even more difficult. Herein, a self-sustained-release strategy based on the slow release of metal ions from coordination ions is proposed to guide the assembly of PB crystals. The key to this strategy is the slow release by ligand, which can create ultra-low concentrations of metal ions so as to provide the possibility to realize the surface charge manipulation of PB primary colloids. By adding electrolyte or changing the polarity of the solution, the surface charge regulation of PB colloid is realized, and the PB hierarchical structures with branch fractal structure (PB-BS), octahedral fractal structure, and spherical fractal structure are effectively constructed. This work not only achieves the designability of the PB structure, but also synchronizes the functionalization during the PB assembly growth process by in situ encapsulation of the effective catalytic active component L-Ascorbic acid. As a result, the assembled PB-BS exhibits greatly enhanced catalytic activity and selectivity in styrene oxidation with the selectivity of oxidized styrene increasing from 35.6% (PB) to 80.5% (PB-BS).

The Association of Cerebral Oxygen Desaturation with Postoperative Cognitive Dysfunction in Older Patients: A Review.

Postoperative cognitive dysfunction (POCD) is a neurological complication associated with surgery and anesthesia that is commonly observed in older patients, and it can significantly affect patient prognosis and survival. Therefore, predicting and preventing POCD is important. Regional cerebral oxygen saturation (rSO2) reflects cerebral perfusion and oxygenation, and decreased intraoperative cerebral oxygen saturation has been reported to increase the risk of POCD. In this review, we elucidated the important relationship between the decline in rSO2 and risk of POCD in older patients. We also emphasized the importance of monitoring rSO2 during surgery to predict and prevent adverse perioperative cognitive outcomes. The findings reveal that incorporating intraoperative rSO2 monitoring into clinical practice has potential benefits, such as protecting cognitive function, reducing perioperative adverse outcomes, and ultimately improving the overall quality of life of older adults.

The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients.

Since variants of uncertain significance (VUS) reported in genetic testing cannot be acted upon clinically, this classification may delay or prohibit precise diagnosis and genetic counseling in adult genetic disorders patients. Large-scale analyses about qualitatively distinct lines of evidence used for VUS can make them re-classification more accurately. We analyzed 458 Chinese adult patients WES data, within 15 pathogenic evidence PS1, PS2, PM1, PM6 and PP4 were not used for VUS pathogenic classification, meanwhile the PP3, BP4, PP2 were used much more frequently. The PM2_Supporting was used most widely for all reported variants. There were also 31 null variants (nonsense, frameshift, canonical ±1 or 2 splice sites) which were probably the disease-causing variants of the patients were classified as VUS. By analyzed the evidence used for all VUS we recommend that appropriate genetic counseling, reliable releasing of in-house data, allele frequency comparison between case and control, expanded verification in patient family, co-segregation analysis and functional assays were urgent need to gather more evidence to reclassify VUS. We also found adult patients with nervous system disease were reported the most phenotype-associated VUS and the lower the phenotypic specificity, the more reported VUS. This result emphasized the importance of pretest genetic counseling which would make less reporting of VUS. Our result revealed the characteristics of the pathogenic classification evidence used for VUS in adult genetic disorders patients for the first time, recommend a rules-based process to evaluate the pathogenicity of VUS which could provide a strong basis for accurately evaluating the pathogenicity and clinical grade information of VUS. Meanwhile, we further expanded the genetic spectrum and improve the diagnostic rate of adult genetic disorders.

Enabling Modular Click Chemistry Library through Sequential Ligations of Carboxylic Acids and Amines.

High-throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new click able building blocks remain exceedingly challenging. Here in , we describe a double-click strategy that enables the sequential ligation of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO 2 NCO) via a modular amidation/SuFEx process. This method provides facile access to chemical libraries of N-fluorosulfonyl amides (RCONHSO 2 F) and N-acylsulfamides (RCONHSO 2 NR ´ R ´´ ) in near-quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96-well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compound s  exhibit high antimicrobial activities against Gram-positive bacterium  S. aureus and drug-resistant MRSA (MIC up to 6.25·µg mL-1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high-throughput medicinal chemistry.

Spatial metabolomics reveals key features of hippocampal lipid changes in rats with postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a common complication after cardiac surgery. Numerous evidence suggest that dysregulation of lipid metabolism is associated with cognitive impairment; however, its precise role in the development of POCD is still obscure. In this study, we established a cardiopulmonary bypass (CPB) model in rats and employed the Barnes maze to assess cognitive function, selecting POCD rats for subsequent experimentation. Utilizing mass spectrometry imaging, we detected plenty of lipids accumulates within the hippocampal CA1in the POCD group. Immunofluorescence staining revealed a significant reduction in the fluorescence intensity of calcium-independent phospholipases A2 (iPLA2) in the POCD group compared to the control, while serine palmitoyl transferase (SPT) was markedly increased in the POCD group. Transmission electron microscopy revealed that the number of synapses in hippocampal CA1decreased significantly and postsynaptic density became thinner in POCD group. Furthermore, after reversing the metabolic disorders of iPLA2 and SPT in the rat brain with docosahexaenoic acid and myriocin, the incidence of POCD after CPB was significantly reduced and the disrupted lipid metabolism in the hippocampus was also normalized. These findings may offer a novel perspective for exploring the etiology and prevention strategies of POCD after CPB.

Rogersonins C-F, 9H-Imidazo[2,1-i]purine-Incorporating Adenine-Polyketide Hybrids from an Ophiocordyceps-Associated Clonostachys rogersoniana.

Rogersonins C-F (1-4), four unprecedented adenine-polyketide hybrids featuring a rare 9H-imidazo[2,1-i]purine (1,N6-ethenoadenine) moiety, were isolated from an Ophiocordyceps-associated fungus, Clonostachys rogersoniana. Their structures were elucidated primarily by NMR experiments. The absolute configurations of 1-4 were assigned by a combination of the modified Mosher method, chemical degradation, electronic circular dichroism (ECD) calculations, and X-ray crystallography using Cu Kα radiation. Compound 3 downregulated the expression of PD-L1 protein in MDA-MB-231 and A549 cells, but did not show detectable effect on mRNA transcription of the PD-L1-encoding gene CD274.

Tracking emergence and outbreak of Klebsiella pneumoniae co-producing NDM-1 and KPC-2 after sulfamethoxazole-trimethoprim treatment: Insights from genetic analysis.

The co-production of KPC and NDM carbapenemases in carbapenem-resistant Klebsiella pneumoniae (CRKP) complicates clinical treatment and increases mortality rates. The emergence of KPC-NDM CRKP is believed to result from the acquisition of an NDM plasmid by KPC CRKP, especially under the selective pressure of ceftazidime-avibactam (CZA). In this study, a CRKP-producing KPC-2 (JNP990) was isolated from a patient at a tertiary hospital in Shandong Province, China. Following sulfamethoxazole-trimethoprim (SXT) treatment, the isolate evolved into a strain that co-produces KPC and NDM (JNP989), accompanied by resistance to SXT (minimum inhibitory concentration >2/38 µg/mL) and CZA (dd ≤14 mm). Whole-genome sequencing and S1 nuclease pulsed-field gel electrophoresis revealed that JNP989 acquired an IncC plasmid (NDM plasmid) spanning 197 kb carrying sul1 and blaNDM-1 genes. The NDM plasmid could be transferred successfully into Escherichia coli J53 at a conjugation frequency of (8.70±2.47) × 10-4. The IncFⅡ/IncR plasmid carrying the blaKPC-2 gene in JNP990 could only be transferred in the presence of the NDM plasmid at a conjugation frequency of (1.93±0.41) × 10-5. Five CRKP strains with the same resistance pattern as JNP989, belonging to the same clone as JNP989, with sequence type 11 were isolated from other patients in the same hospital. Two strains lost resistance to CZA due to the loss of the blaNDM-1-carrying fragment mediated by insertion sequence 26. Plasmid stability testing indicated that the IncC plasmid was more stable than the blaNDM-1 genes in the hosts. This study describes the evolution of KPC-NDM CRKP and its spread in hospitalized patients following antibiotic treatment, highlighting the severity of the spread of resistance.

I2U-Net: A dual-path U-Net with rich information interaction for medical image segmentation.

Although the U-shape networks have achieved remarkable performances in many medical image segmentation tasks, they rarely model the sequential relationship of hierarchical layers. This weakness makes it difficult for the current layer to effectively utilize the historical information of the previous layer, leading to unsatisfactory segmentation results for lesions with blurred boundaries and irregular shapes. To solve this problem, we propose a novel dual-path U-Net, dubbed I2U-Net. The newly proposed network encourages historical information re-usage and re-exploration through rich information interaction among the dual paths, allowing deep layers to learn more comprehensive features that contain both low-level detail description and high-level semantic abstraction. Specifically, we introduce a multi-functional information interaction module (MFII), which can model cross-path, cross-layer, and cross-path-and-layer information interactions via a unified design, making the proposed I2U-Net behave similarly to an unfolded RNN and enjoying its advantage of modeling time sequence information. Besides, to further selectively and sensitively integrate the information extracted by the encoder of the dual paths, we propose a holistic information fusion and augmentation module (HIFA), which can efficiently bridge the encoder and the decoder. Extensive experiments on four challenging tasks, including skin lesion, polyp, brain tumor, and abdominal multi-organ segmentation, consistently show that the proposed I2U-Net has superior performance and generalization ability over other state-of-the-art methods. The code is available at https://github.com/duweidai/I2U-Net.