Establishment of a Multiplex Detection Method for Common Bacteria in Blood Based on Human Mannan-Binding Lectin Protein-Conjugated Magnetic Bead Enrichment Combined with Recombinase-Aided PCR Technology.

Objective: Recombinase-aided polymerase chain reaction (RAP) is a sensitive, single-tube, two-stage nucleic acid amplification method. This study aimed to develop an assay that can be used for the early diagnosis of three types of bacteremia caused by Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Acinetobacter baumannii (AB) in the bloodstream based on recombinant human mannan-binding lectin protein (M1 protein)-conjugated magnetic bead (M1 bead) enrichment of pathogens combined with RAP. Methods: Recombinant plasmids were used to evaluate the assay sensitivity. Common blood influenza bacteria were used for the specific detection. Simulated and clinical plasma samples were enriched with M1 beads and then subjected to multiple recombinase-aided PCR (M-RAP) and quantitative PCR (qPCR) assays. Kappa analysis was used to evaluate the consistency between the two assays. Results: The M-RAP method had sensitivity rates of 1, 10, and 1 copies/µL for the detection of SA, PA, and AB plasmids, respectively, without cross-reaction to other bacterial species. The M-RAP assay obtained results for < 10 CFU/mL pathogens in the blood within 4 h, with higher sensitivity than qPCR. M-RAP and qPCR for SA, PA, and AB yielded Kappa values of 0.839, 0.815, and 0.856, respectively ( P < 0.05). Conclusion: An M-RAP assay for SA, PA, and AB in blood samples utilizing M1 bead enrichment has been developed and can be potentially used for the early detection of bacteremia.

Exploring the molecular biology of ischemic cardiomyopathy based on ferroptosis­related genes.

Ischemic cardiomyopathy (ICM) is a serious cardiac disease with a very high mortality rate worldwide, which causes myocardial ischemia and hypoxia as the main damage. Further understanding of the underlying pathological processes of cardiomyocyte injury is key to the development of cardioprotective strategies. Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid hydroperoxides to lethal levels, resulting in oxidative damage to the cell membrane. The current understanding of the role and regulation of ferroptosis in ICM is still limited, especially in the absence of evidence from large-scale transcriptomic data. Through comprehensive bioinformatics analysis of human ICM transcriptome data obtained from the Gene Expression Omnibus database, the present study identified differentially expressed ferroptosis-related genes (DEFRGs) in ICM. Subsequently, their potential biological mechanisms and cross-talk were analyzed, and hub genes were identified by constructing protein-protein interaction networks. Ferroptosis features such as reactive oxygen species generation, changes in ferroptosis marker proteins, iron ion aggregation and lipid oxidation, were identified in the H9c2 anoxic reoxygenation injury model. Finally, the diagnostic ability of Gap junction alpha-1 (GJA1), Solute carrier family 40 member 1 (SLC40A1), Alpha-synuclein (SNCA) were identified through receiver operating characteristic curves and the expression of DEFRGs was verified in an in vitro model. Furthermore, potential drugs (retinoic acid) that could regulate ICM ferroptosis were predicted based on key DEFRGs. The present article presents new insights into the role of ferroptosis in ICM, investigating the regulatory role of ferroptosis in the pathological process of ICM and advocating for ferroptosis as a potential novel therapeutic target for ICM based on evidence from the ICM transcriptome.

Photoinduced Pd-Catalyzed Enantioselective Carboamination of Dienes via Aliphatic C-H Bond Elaboration.

Three-component diene carboaminations offer a potent means to access synthetically valuable allylic amines with rapid molecular complexity escalation. The existing literature primarily discloses racemic examples, necessitating the use of halides/pseudohalides as substrates. This paper introduces a photoinduced Pd-catalyzed enantioselective three-component carboamination of aryl-substituted 1,3-dienes, leveraging aliphatic C-H bonds for rapid synthesis. The reaction employs 10 mol % of chiral palladium catalyst and an excess aryl bromide as the HAT reagent. This approach yields diverse chiral allylamines with moderate to excellent enantioselectivities. Notably, it stands as the first instance of an asymmetric three-component diene carboamination reaction, directly utilizing abundant C(sp3)-H bearing partners, such as toluene-type substrates, ethers, amines, esters, and ketones. The protocol exhibits versatility across amines, encompassing aliphatic, aromatic, primary, and secondary derivatives. This method could serve as a versatile platform for stereoselective incorporation of various nucleophiles, dienes, and C(sp3)-H bearing partners.

A Multiplex Recombinase-Aided qPCR Assay for Highly Sensitive and Rapid Detection of khe, blaKPC -2, and blaNDM -1 Genes in Klebsiella pneumoniae.

OBJECTIVE: This study aimed to establish a highly sensitive and rapid single-tube, two-stage, multiplex recombinase-aided qPCR (mRAP) assay to specifically detect the khe, blaKPC-2, and blaNDM-1 genes in Klebsiella pneumoniae. METHODS: mRAP was carried out in a qPCR instrument within 1 h. The analytical sensitivities of mRAP for khe, blaKPC-2, and blaNDM-1 genes were tested using recombinant plasmids and dilutions of reference strains. A total of 137 clinical isolates and 86 sputum samples were used to validate the clinical performance of mRAP. RESULTS: mRAP achieved the sensitivities of 10, 8, and 14 copies/reaction for khe, blaKPC-2, and blaNDM-1 genes, respectively, superior to qPCR. The Kappa value of qPCR and mRAP for detecting khe, blaKPC-2, and blaNDM-1 genes was 1, 0.855, and 1, respectively (p < 0.05). CONCLUSION: mRAP is a rapid and highly sensitive assay for potential clinical identification of khe, blaKPC-2, and blaNDM-1 genes in K. pneumoniae.

A multifunctional biomimetic nanoplatform for image-guideded photothermal-ferroptotic synergistic osteosarcoma therapy.

Much effort has been devoted to improving treatment efficiency for osteosarcoma (OS). However, most current approaches result in poor therapeutic responses, thus indicating the need for the development of other therapeutic options. This study developed a multifunctional nanoparticle, PDA-MOF-E-M, an aggregation of OS targeting, programmed death targeting, and near-infrared (NIR)-aided targeting. At the same time, a multifunctional nanoparticle that utilises Fe-MOFs to create a cellular iron-rich environment and erastin as a ferroptosis inducer while ensuring targeted delivery to OS cells through cell membrane encapsulation is presented. The combination of PDA-MOF-E-M and PTT increased intracellular ROS and LPO levels and induced ferroptosis-related protein expression. A PDA-based PTT combined with erastin showed significant synergistic therapeutic improvement in the anti-tumour efficiency of the nanoparticle in vitro and vivo. The multifunctional nanoparticle efficiently prevents the osteoclasia progression of OS xenograft bone tumors in vivo. Finally, this study provides guidance and a point of reference for clinical approaches to treating OS.

The Impacts of Nirmatrelvir-Ritonavir on Myocardial Injury and Long-Term Cardiovascular Outcomes in Hospitalized Patients with COVID-19 amid the Omicron Wave of the Pandemic.

PURPOSE: Even though nirmatrelvir-ritonavir can improve the short-term morbidity and mortality in COVID-19 patients, the effects of this treatment on long-term major adverse cardiovascular events (MACEs), especially myocardial injury, remains undetermined. METHODS: This prospective cohort study identified hospitalized adult patients with COVID-19 between April 19, 2022, and June 9, 2022, amid the omicron wave of the pandemic. Matched nirmatrelvir-ritonavir-treated and non-treated cohorts were formed using the propensity score matching method. The primary outcome of this study was the incidence of MACEs (cardiovascular death, myocardial infarction, stroke, new-onset heart failure or heart failure hospitalization or ventricular arrhythmia) from 30 days to 16 months after the diagnosis of COVID-19. RESULTS: Two 949-patient cohorts with balanced baseline characteristics were formed by propensity score matching. Patients with nirmatrelvir-ritonavir, compared to those untreated, had a lower level of troponin I peak as well as the incidence of troponin I elevation. During the follow-up period, 59 patients in the nirmatrelvir-ritonavir group and 86 patients in the control group developed MACEs (P = 0.020). Regarding specific constituents of MACEs, the differences are mainly reflected in new-onset heart failure or heart failure hospitalization. COVID-19 clinical severity and troponin I peak were the independent predictors, while nirmatrelvir-ritonavir was the independent protective factor for the occurrence of MACEs in this population. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing myocardial injury as well as long-term adverse cardiovascular outcomes among hospitalized patients with COVID-19 amid the omicron wave of the pandemic.

miR-200a-3p inhibits the PDGF-BB-induced proliferation of VSMCs by affecting their phenotype-associated proteins.

Accumulating evidence shows that the abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) can significantly affect the long-term prognosis of coronary artery bypass grafting. This study aimed to explore the factors affecting the proliferation, migration, and phenotypic transformation of VSMCs. First, we stimulated VSMCs with different platelet-derived growth factor-BB (PDGF-BB) concentrations, analyzed the expression of phenotype-associated proteins by Western blotting, and examined cell proliferation by scratch wound healing and the 5-ethynyl-2-deoxyuridine (EdU) assay. VSMC proliferation was induced most by PDGF-BB treatment at 20 ng/mL. miR-200a-3p decreased significantly in A7r5 cells stimulated with PDGF-BB. The overexpression of miR-200a-3p reversed the downregulation of α-SMA (p < 0.001) and the upregulation of vimentin (p < 0.001) caused by PDGF-BB. CCK8 and EdU analyses showed that miR-200a-3p overexpression could inhibit PDGF-BB-induced cell proliferation (p < 0.001). However, flow cytometric analysis showed that it did not significantly increase cell apoptosis. Collectively, the overexpression of miR-200a-3p inhibited the proliferation and migration of VSMCs induced by PDGF-BB, partly by affecting phenotypic transformation-related proteins, providing a new strategy for relieving the restenosis of vein grafts.

A multicenter case-controlled study on laparoscopic hepatectomy versus microwave ablation as first-line therapy for 3-5 cm hepatocellular carcinoma in patients aged 60 and older.

BACKGROUND: There is currently a lack of convincing evidence for microwave ablation (MWA) and laparoscopic liver resection (LLR) for patients ≥60 years old with 3-5 cm hepatocellular carcinoma. MATERIALS AND METHODS: Patients were divided into three cohorts based on restricted cubic spline analysis: 60-64, 65-72, and ≥73 years. Propensity score matching (PSM) was performed to balance the baseline variables in a 1:1 ratio. Overall survival (OS) and disease-free survival (DFS) were assessed, followed by a comparison of complications, hospitalization, and cost. RESULTS: Among 672 patients, the median age was 66 (IQR 62-71) years. After PSM, two groups of 210 patients each were selected. During the 36.0 (20.4-52.4) month follow-up period, the 1-year, 3-year, and 5-year OS rates in the MWA group were 97.6, 80.9, and 65.3% and 95.5, 78.7, and 60.4% in the LLR group (HR 0.98, P =0.900). The corresponding DFS rates were 78.6, 49.6, and 37.5% and 82.8, 67.8, and 52.9% (HR 1.52, P =0.007). The 60-64 age cohort involved 176 patients, with no a significant difference in OS between the MWA and LLR groups (HR 1.25, P =0.370), MWA was associated with a higher recurrence rate (HR 1.94, P =0.004). A total of 146 patients were matched in the 65-72 age cohort, with no significant differences in OS and DFS between the two groups (OS (HR 1.04, P =0.900), DFS (HR 1.56, P =0.110)). In 76 patients aged ≥73 years after PSM, MWA provided better OS for patients (HR 0.27, P =0.015), and there were no significant differences in DFS between the two groups (HR 1.41, P =0.380). Taken together, for patients older than 65 years, the recurrence rate of MWA was comparable with LLR. Safety analysis indicated that LLR was associated with more postoperative bleeding ( P =0.032) and hypoproteinemia ( P =0.024). CONCLUSIONS: MWA was comparable to LLR in patients aged 65 years and older. MWA could be an alternative for the oldest old or the ill patients who cannot afford LLR, while LLR is still the first option of treatments for early-stage 3-5 cm hepatocellular carcinoma in capable elderly's.

Evaluating the efficacy of MEANGS for mitochondrial genome assembly of cartilaginous and ray-finned fish species.

The assembly of complete and circularized mitochondrial genomes (mitogenomes) is essential for population genetics, phylogenetics and evolution studies. Recently, Song et al. developed a seed-free tool called MEANGS for de novo mitochondrial assembly from whole genome sequencing (WGS) data in animals, achieving highly accurate and intact assemblies. However, the suitability of this tool for marine fish remains unexplored. Additionally, we have concerns regarding the overlap sequences in their original results, which may impact downstream analyses. In this Letter to the Editor, the effectiveness of MEANGS in assembling mitogenomes of cartilaginous and ray-finned fish species was assessed. Moreover, we also discussed the appropriate utilization of MEANGS in mitogenome assembly, including the implementation of the data-cut function and circular detection module. Our observations indicated that with the utilization of these modules, MEANGS efficiently assembled complete and circularized mitogenomes, even when handling large WGS datasets. Therefore, we strongly recommend users employ the data-cut function and circular detection module when using MEANGS, as the former significantly reduces runtime and the latter aids in the removal of overlapped sequences for improved circularization. Furthermore, our findings suggested that approximately 2× coverage of clean WGS data was sufficient for MEANGS to assemble mitogenomes in marine fish species. Moreover, due to its seed-free nature, MEANGS can be deemed one of the most efficient software tools for assembling mitogenomes from animal WGS data, particularly in studies with limited species or genetic background information.

Dendritic cell-cytokine killer combined with microwave ablation reduced recurrence for hepatocellular carcinoma compared to ablation alone.

BACKGROUND: Several international practice guidelines have recommended local ablation as the first-line treatment for early-stage hepatocellular carcinoma (HCC). OBJECTIVE: This study aims to investigate the synergetic anti-tumor impact of dendritic cell-cytokine killer (DC-CIK) combined with microwave ablation (MWA) for HCC. METHODS: This retrospective study included 1,141 patients from the American Joint Committee on Cancer stage I-II HCC, who were treated with therapeutic MWA. The immunotherapy group encompassing 40 patients received additional immunotherapy with DC-CIK, whereas the control group consisting of 1,101 patients was treated with MWA alone. Propensity score matching (PSM) with ratio of 1:3 was employed to balance selection bias. The oncological outcome and immune status were measured after combination therapy. RESULTS: The immunotherapy group patients exhibited significant longer disease-free survival (DFS, primary HCC: p= 0.036; recurrent HCC: p= 0.026). For patients with primary HCC, the recurrence frequency was reduced (p= 0.002), and recurrence interval (19 months vs. 9 months, p< 0.001) was prolonged in the immunotherapy group. Subgroup analysis revealed that patients ⩽ 60 years old, moderately-differentiated HCC, or co-infected with Hepatitis B Virus (HBV) had a significant benefit over DFS in the immunotherapy group. After combination therapy, the serum CD3+ (p= 0.049), CD8/CD28+ (p= 0.045) were elevated. CONCLUSION: Combination therapy with DC-CIK and MWA can significantly reduce the recurrence and prolong DFS, especially for patients ⩽ 60 years old or with moderately-differentiated HCC or co-infected with HBV.

Global metabolomics revealed deviations from the metabolic aging clock in colorectal cancer patients.

Background: Markers of aging hold promise in the context of colorectal cancer (CRC) care. Utilizing high-resolution metabolomic profiling, we can unveil distinctive age-related patterns that have the potential to predict early CRC development. Our study aims to unearth a panel of aging markers and delve into the metabolomic alterations associated with aging and CRC. Methods: We assembled a serum cohort comprising 5,649 individuals, consisting of 3,002 healthy volunteers, 715 patients diagnosed with colorectal advanced precancerous lesions (APL), and 1,932 CRC patients, to perform a comprehensive metabolomic analysis. Results: We successfully identified unique age-associated patterns across 42 metabolic pathways. Moreover, we established a metabolic aging clock, comprising 9 key metabolites, using an elastic net regularized regression model that accurately estimates chronological age. Notably, we observed significant chronological disparities among the healthy population, APL patients, and CRC patients. By combining the analysis of circulative carcinoembryonic antigen levels with the categorization of individuals into the "hypo" metabolic aging subgroup, our blood test demonstrates the ability to detect APL and CRC with positive predictive values of 68.4% (64.3%, 72.2%) and 21.4% (17.8%, 25.9%), respectively. Conclusions: This innovative approach utilizing our metabolic aging clock holds significant promise for accurately assessing biological age and enhancing our capacity to detect APL and CRC.

Percutaneous microwave ablation versus sclerotherapy for large hepatic hemangioma: a multi-center cohort study.

OBJECTIVE: The study aimed to compare the effectiveness and safety of ultrasound-guided microwave ablation (MWA) and percutaneous sclerotherapy (PS) for the treatment of large hepatic hemangioma (LHH). METHODS: This retrospective study included 96 patients who underwent MWA (n = 54) and PS (n = 42) as first-line treatment for LHH in three tertiary hospitals from January 2016 to December 2021. Primary outcomes were technique efficacy rate (volume reduction rate [VRR] > 50% at 12 months), symptom relief rate at 12 months and local tumor progression (LTP). Secondary outcomes included procedure time, major complications, treatment sessions, cost and one-, two-, three-year VRR. RESULTS: During a median follow-up of 36 months, the MWA group showed a higher technique efficacy rate (100% vs. 90.4%, p = .018) and symptom relief rate (100% vs. 80%, p = .123) than the PS group. The MWA group had fewer treatment sessions, higher one-, two- and three-year VRR, lower LTP rate (all p < .05), longer procedure time and higher treatment costs than the PS group (both p < .001). MWA shared a comparable major complications rate (1.8% vs. 2.4%, p = .432) with PS. After multivariate analysis, the lesion's heterogeneity and maximum diameter >8.1 cm were independent risk factors for LTP (all p < .05). In the PS group, lesions with a cumulative dose of bleomycin > 0.115 mg/cm3 had a lower risk of LTP (p = .006). CONCLUSIONS: Both MWA and PS treatments for large hepatic hemangioma are safe and effective, with MWA being superior in terms of efficacy.

Age-Dependent Female Survival Advantage in Hepatocellular Carcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a higher incidence in males, but the association of sex with survival remains controversial. This study aimed to examine the effect of sex on HCC survival and its association with age. METHODS: Among 33,238 patients with HCC from 12 Chinese tertiary hospitals, 4175 patients who underwent curative-intent hepatectomy or ablation were analyzed. Cancer-specific survival (CSS) was analyzed using Cox regression and Kaplan-Meier methods. Two propensity score methods and multiple mediation analysis were applied to mitigate confounding. To explore the effect of estrogen, a candidate sex-specific factor that changes with age, female participants' history of estrogen use, and survival were analyzed. RESULTS: There were 3321 males and 854 females included. A sex-related disparity of CSS was present and showed a typical age-dependent pattern: a female survival advantage over males appeared at the perimenopausal age of 45 to 54 years (hazard risk [HR], 0.77; 5-year CSS, 85.7% vs 70.6%; P = .018), peaked at the early postmenopausal age of 55 to 59 years (HR, 0.57; 5-year CSS, 89.8% vs 73.5%; P = .015), and was not present in the premenopausal (<45 y) and late postmenopausal groups (≥60 y). Consistent patterns were observed in patients after either ablation or hepatectomy. These results were sustained with propensity score analyses. Confounding or mediation effects accounted for only 19.5% of sex survival disparity. Female estrogen users had significantly longer CSS than nonusers (HR, 0.74; 5-year CSS, 79.6% vs 72.5%; P = .038). CONCLUSIONS: A female survival advantage in HCC depends on age, and this may be associated with age-dependent, sex-specific factors.

A Comparative Study of the Effects of Electronic Cigarette and Traditional Cigarette on the Pulmonary Functions of C57BL/6 Male Mice.

INTRODUCTION: Electronic cigarettes (E-cigs) are in a controversial state. Although E-cig aerosol generally contains fewer harmful substances than smoke from burned traditional cigarettes, aerosol along with other compounds of the E-cigs may also affect lung functions and promote the development of lung-related diseases. We investigated the effects of E-cig on the pulmonary functions of male C57BL/6 mice and reveal the potential underlying mechanisms. METHODS: A total of 60 male C57BL/6 mice were randomly divided into four groups. They were exposed to fresh-air, traditional cigarette smoke, E-cig vapor with 12 mg/mL of nicotine, and E-cig with no nicotine for 8 weeks. Lung functions were evaluated by using quantitative analysis of the whole body plethysmograph, FlexiVent system, lung tissue histological and morphometric analysis, and RT-PCR analysis of mRNA expression of inflammation-related genes. In addition, the effects of nicotine and acrolein on the survival rate and DNA damage were investigated using cultured human alveolar basal epithelial cells. RESULTS: Exposure to E-cig vapor led to significant changes in lung functions and structures including the rupture of the alveolar cavity and enlarged alveolar space. The pathological changes were also accompanied by increased expression of interleukin-6 and tumor necrosis factor-α. CONCLUSIONS: The findings of the present study indicate that the safety of E-cig should be further evaluated. IMPLICATIONS: Some people currently believe that using nicotine-free E-cigs is a safe way to smoke. However, our research shows that E-cigs can cause lung damage regardless of whether they contain nicotine.

Ultrasound-guided microwave ablation versus surgery for solitary T1bN0M0 papillary thyroid carcinoma: a prospective multicenter study.

OBJECTIVE: Microwave ablation (MWA) has emerged as a minimally invasive technology for papillary thyroid microcarcinoma (PTMC), but it has not been widely applied to treat T1bN0M0 PTC with high-level evidence. This study was designed to compare the real-world efficacy and safety of MWA or surgery for treating T1bN0M0 PTC. METHODS: From December 2019 to April 2021, 123 continuous unifocal T1bN0M0 PTC patients without lymph node metastasis (LNM) or distant metastasis (DM) were included from 10 hospitals. Patients were allocated into the MWA or surgery group based on their willingness. The main outcomes were local tumour progression (LTP), new thyroid cancer, LNM, and DM. The secondary outcomes included changes in tumour size and volume, complications, and cosmetic results. Subgroup analyses were conducted to identify influencing factors. RESULTS: Fifty-two patients chose MWA, and 71 patients chose surgery. Patients had similar demographic information and tumour characteristics in the two groups. The follow-up durations after MWA and surgery were 10.6 ± 4.2 and 10.4 ± 3.4 months, respectively. The LNM rate was 5.8% in the MWA group and 1.4% in the surgery group (p = 0.177). No LTP, new thyroid cancer, or distant metastasis (DM) occurred in either group. Five (9.6%) of the 52 patients in the MWA group and 8 (11.3%) of the 71 patients in the surgery group had complications (p = 0.27). Better cosmetic results were found in the MWA group (p < 0.01). CONCLUSION: MWA achieved comparable short-term treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC but concerns about LNM need to be studied further. CLINICAL RELEVANCE STATEMENT: MWA achieved comparable short-time treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC. KEY POINTS: • MWA achieved comparable short-term treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC but concerns about LNM need to be studied further. • The complication rate in the surgery group was higher than that in the MWA group without a significant difference. • There was no statistically significant difference in the LNM rate between the MWA and surgery groups.

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice.

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study.

BACKGROUND: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear. METHODS: Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined. RESULTS: In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A, TET2, RUNX1, and ASXL1. During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively (P<0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257-3.816]; P=0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1ß and interleukin-6 and lower interleukin-4 and IgG galactosylation levels. CONCLUSIONS: This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.

Efficacy of prednisone combined with mycophenolate mofetil for immunoglobulin A nephropathy with moderate-to-severe renal dysfunction.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a common form of chronic glomerulonephritis. Currently, IgAN is one of the main causes of chronic renal failure in China; its prognosis varies greatly between patients, with renal function at the time of diagnosis and prognosis being strongly correlated. Mycophenolate mofetil (MMF) is a drug with a good immunomodulatory effect and is commonly used clinically. However, its effects in IgAN have not yet been clearly demonstrated. Therefore, herein, we retrospectively compared the effectiveness and safety of prednisone alone or combined with MMF for the treatment of primary IgAN with moderate-to-severe renal impairment. AIM: To evaluate the effectiveness and safety of prednisone and MMF in treating IgAN with moderate-to-severe renal dysfunction. METHODS: Between January 2011 and December 2020, 200 patients with moderate-to-severe IgAN were included in this study, all of whom were admitted to Wuxi People's Hospital affiliated with Nanjing Medical University. All patients underwent a renal puncture biopsy, which revealed primary IgAN with a glomerular filtration rate (GFR) of 30-60 mL/min. The patients were divided into a glucocorticoid therapy group (GTG) and an immunosuppressive therapy group (ITG) according to the different treatment regimens, with 100 patients in each group. Based on general treatments, such as angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers, patients in the GTG were administered prednisone 0.5-0.8 mg/ (kg·d-1) for 4-8 wk, which was reduced by 5 mg every two weeks until the maintenance(30 mg/d) dose was reached and maintained for 12 mo. In the ITG, MMF was administered at 1.0 g/d for 6-12 mo, followed by a maintenance dosage of 0.5 g/d for 12 mo. Age, sex, blood pressure, 24-h urinary egg white measurement, serum creatinine (Scr), blood uric acid, blood albumin, blood potassium (K), hemoglobin, GFR, alanine aminotransferase, total cholesterol (T-CHO), fasting blood glucose, and body mass index were recorded. The 24-h urinary protein, Scr, and GFR levels were recorded 3, 6, 9, and 12 mo after treatment. Follow-up data were also collected. RESULTS: No discernible differences existed between the two groups in terms of age, sex, blood pressure, creatinine, 24-h urinary protein level, GFR, or other biochemical indicators at the time of enrollment. Both regimens significantly reduced the 24-h urinary protein quantitation and stabilized renal function. Nine months after treatment, the 24-h urinary protein and Scr of the ITG decreased more significantly than those of the GTG. By the 12th month of treatment, the 24-h urinary protein and Scr in both groups continued to decrease compared to those by the 9th month. In addition, the overall response rate in the ITG was significantly higher than that in the GTG. The occurrence of side effects did not vary significantly between the two regimens; however, endpoint events were significantly more common in the GTG than in the ITG. The follow-up time for the GTG was noticeably lower than that for the ITG. CONCLUSION: Prednisone combined with MMF was effective for the treatment of IgAN with moderate-to-severe renal dysfunction.

High-throughput quantitation of amino acids and acylcarnitine in cerebrospinal fluid: identification of PCNSL biomarkers and potential metabolic messengers.

Background: Due to the poor prognosis and rising occurrence, there is a crucial need to improve the diagnosis of Primary Central Nervous System Lymphoma (PCNSL), which is a rare type of non-Hodgkin's lymphoma. This study utilized targeted metabolomics of cerebrospinal fluid (CSF) to identify biomarker panels for the improved diagnosis or differential diagnosis of primary central nervous system lymphoma (PCNSL). Methods: In this study, a cohort of 68 individuals, including patients with primary central nervous system lymphoma (PCNSL), non-malignant disease controls, and patients with other brain tumors, was recruited. Their cerebrospinal fluid samples were analyzed using the Ultra-high performance liquid chromatography - tandem mass spectrometer (UHPLC-MS/MS) technique for targeted metabolomics analysis. Multivariate statistical analysis and logistic regression modeling were employed to identify biomarkers for both diagnosis (Dx) and differential diagnosis (Diff) purposes. The Dx and Diff models were further validated using a separate cohort of 34 subjects through logistic regression modeling. Results: A targeted analysis of 45 metabolites was conducted using UHPLC-MS/MS on cerebrospinal fluid (CSF) samples from a cohort of 68 individuals, including PCNSL patients, non-malignant disease controls, and patients with other brain tumors. Five metabolic features were identified as biomarkers for PCNSL diagnosis, while nine metabolic features were found to be biomarkers for differential diagnosis. Logistic regression modeling was employed to validate the Dx and Diff models using an independent cohort of 34 subjects. The logistic model demonstrated excellent performance, with an AUC of 0.83 for PCNSL vs. non-malignant disease controls and 0.86 for PCNSL vs. other brain tumor patients. Conclusion: Our study has successfully developed two logistic regression models utilizing metabolic markers in cerebrospinal fluid (CSF) for the diagnosis and differential diagnosis of PCNSL. These models provide valuable insights and hold promise for the future development of a non-invasive and reliable diagnostic tool for PCNSL.