Dynamic natural components and morphological changes in nonculprit subclinical atherosclerosis in patients with acute coronary syndrome and mild chronic kidney disease at the 1-year follow-up and clinical significance at the 5-year follow-up.

INTRODUCTION: The natural outcome of coronary plaque in acute coronary syndrome (ACS) patients with chronic kidney disease (CKD) is unique, which can be analyzed quantitatively by optical flow ratio (OFR) software. METHODS: A total of 184 ACS patients with at least one nonculprit subclinical atherosclerosis (NSA) detected by optical coherence tomography (OCT) at baseline and 1-year follow-up were divided into non-CKD group (n = 106, estimated glomerular filtration rate (eGFR)> 90 mL/(min×1.73 m2)) and mild CKD group (n = 78, 60≤eGFR<90 mL/(min×1.73 m2)). Changes of normalized total atheroma volume (TAVn) of NSA was the primary endpoint at the 1-year follow-up. RESULTS: Patients with mild CKD showed more TAVn progression of NSA than non-CKD (p = 0.019) from baseline to the 1-year follow-up, which was mainly due to an increase in calcium TAVn (p<0.001). The morphological change in the maximal calcification thickness (p = 0.026) was higher and the change in the distance from the calcified surface to the contralateral coronary media membrane (ΔC-to-M) at the maximal cross-sectional calcium area was lower (p<0.001) in mild CKD group than in non-CKD group. Mild CKD had more NSA related MACEs at the 5-year follow-up than non-CKD (30.8% vs. 5.8%, p = 0.045). CONCLUSIONS: Mild CKD patients had more plaque progression of NSA which showed the increase of calcium component with more protrusion into the lumen morphologically at the 1-year follow-up and a higher corresponding incidence of NSA-related MACEs at the 5-year follow-up. TRIAL REGISTRATION: Clinical Trial registration ClinicalTrials.gov. NCT02140801. https://classic.clinicaltrials.gov/ct2/show/NCT02140801.

A Key regulatory protein QRICH2 governing sperm function with profound antioxidant properties, enhancing sperm viability.

Infertility poses a global health and social challenge, affecting approximately 15% of couples at childbearing age, with half of the cases attributed to male factors, wherein genetic factors exert a substantial role. In our prior investigation, we identified loss-of-function variants within the gene encoding glutamine-rich protein 2 (QRICH2) in two consanguineous families, leading to various morphological abnormalities in sperm flagella and male infertility. Moreover, our observations in Qrich2 knockout mice revealed a pronounced reduction in spermatozoa count. However, the underlying mechanism remains elusive, prompting further investigation in the current study. By conducting experiments such as Hematoxylin-eosin (HE) staining, immunofluorescence staining, flow cytometry, and single sperm metabolism analysis on the testes and spermatozoa of Qrich2 knockout mice, we found a strong antioxidant capacity mediated by QRICH2 both in vivo and in vitro. Qrich2 knockout led to elevated levels of ROS, consequently inducing DNA damage in spermatids, which in turn triggered increased autophagy and apoptosis, ultimately causing a significant decrease in spermatozoa count. Incubation with the N-terminal purified protein of QRICH2 exhibited potent strong antioxidant activity at the cell and spermatozoa levels in vitro, thereby enhancing spermatozoa viability and motility. Therefore, QRICH2 plays a crucial role in safeguarding spermatids from excessive ROS-induced damage by augmenting antioxidant capacity, thereby promoting spermatozoa survival and improving motility. Furthermore, the N-terminal purified protein of QRICH2 shows promise as an additive for protecting spermatozoa during preservation and cryopreservation.

Identification of a novel mutation in chibby family member 2 in a non-obstructive azoospermic patient.

Azoospermia constitutes a significant factor in male infertility, defined by the absence of spermatozoa in the ejaculate, afflicting 15% of infertile men. However, a subset of azoospermic cases remains unattributed to known genetic variants. Prior investigations have identified the chibby family member 2 (CBY2) as prominently and specifically expressed in the testes of both humans and mice, implicating its potential involvement in spermatogenesis. In this study, we conducted whole exome sequencing (WES) on an infertile family to uncover novel genetic factors contributing to azoospermia. Our analysis revealed a homozygous c .355 C>A variant of CBY2 in a non-obstructive azoospermic patient. This deleterious variant significantly diminished the protein expression of CBY2 both in vivo and in vitro, leading to a pronounced disruption of spermatogenesis at the early round spermatid stage post-meiosis. This disruption was characterized by a nearly complete loss of elongating and elongated spermatids. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation assays demonstrated the interaction between CBY2 and Piwi-like protein 1 (PIWIL1). Immunofluorescence staining further confirmed the co-localization of CBY2 and PIWIL1 in the testes during the spermatogenic process in both humans and mice. Additionally, diminished PIWIL1 expression was observed in the testicular tissue from the affected patient. Our findings suggest that the homozygous c .355 C>A variant of CBY2 compromises CBY2 function, contributing to defective spermatogenesis at the round spermiogenic stage and implicating its role in the pathogenesis of azoospermia.

Novel phenanthrene/bibenzyl trimers from the tubers of Bletilla striata attenuate neuroinflammation via inhibition of NF-κB signaling pathway.

Five novel (9,10-dihydro) phenanthrene and bibenzyl trimers, as well as two previously identified biphenanthrenes and bibenzyls, were isolated from the tubers of Bletilla striata. Their structures were elucidated through comprehensive analyses of NMR and HRESIMS spectroscopic data. The absolute configurations of these compounds were determined by calculating rotational energy barriers and comparison of experimental and calculated ECD curves. Compounds 5b and 6 exhibited inhibitory effects on LPS-induced NO production in BV-2 cells, with IC50 values of 12.59 ± 0.40 and 15.59 ± 0.83 µmol·L-1, respectively. A mechanistic study suggested that these compounds may attenuate neuroinflammation by reducing the activation of the AKT/IκB/NF-κB signaling pathway. Additionally, compounds 3a, 6, and 7 demonstrated significant PTP1B inhibitory activities, with IC50 values of 1.52 ± 0.34, 1.39 ± 0.11, and 1.78 ± 0.01 µmol·L-1, respectively. Further investigation revealed that compound 3a might inhibit LPS-induced PTP1B overexpression and NF-κB activation, thereby mitigating the neuroinflammatory response in BV-2 cells.

Ammonia stripping by in situ biogas self-circulation to upgrade continuous thermophilic and mesophilic digestion of hydrothermal high-solid sludge.

High-solid anaerobic digestion of hydrothermal sewage sludge has been developed. In order to upgrade the process by focusing on ammonia inhibition, a simply-equipped stripping system without additional alkali or heat supply was introduced by in situ biogas self-circulation. As the determined limit of total ammonia nitrogen at 1500 mg/L and 1000 mg/L for the mesophilic (MAD) and thermophilic anaerobic digestion (TAD) respectively and stripping rate at 5 L/min, continuous MAD and TAD was conducted in parallel. The stripping system successfully polished up the ammonia inhibition, and methanogenic capability of the TAD was promoted to approximately 90.0 % of the potential. Intermittent stripping mode proved usable. More frequent stripping was inevitable for the TAD as compared to the MAD. Hydraulic retention time below 20 d resulted in failure of the stripping mode due to rapid ammonia generation. Overall, this technology was practical in upgrading high-solid sludge digestion by effective ammonia control.

Serum lipopolysaccharide associated with new-onset atrial fibrillation in patients with non-small-cell lung cancer a retrospective observational study.

Lipopolysaccharide (LPS) is related to atrial fibrillation (AF). But so far, the relationship between LPS and new-onset AF (NOAF) in patients with lung cancer is unrevealed. This study was to investigate the association between LPS and NOAF in patients after lung cancer surgery. This was a single-center retrospective clinical observational study. Patients diagnosed with non-small-cell lung cancer (NSCLC) were enrolled. All patients receiving lung cancer surgery and at least 24 h electrocardiogram (ECG) examination was recorded during the hospitalization. The incidence of NOAF in this study was 34/406 (8.4%). The univariate analysis showed that NOAF was associated with age, intraoperative blood transfusion (IBT), chronic obstructive pulmonary disorder (COPD), and LPS. After adjusting risk factors, it was found that age, IBT and LPS (OR, 1.031; 95% CI: 1.001-1.042; P = 0.002) were still risk factors for NOAF. The area under curve (AUC) value was 0.709 for the LPS. When the LPS was added to the conventional model, the Net reclassification index (NRI) and integrated discrimination index (IDI) were improved significantly. Elevated LPS is associated with an increased risk of NOAF in patients after lung cancer surgery. LPS contributed to the discrimination of the NOAF risk model and improved it markedly.

Design, Synthesis, and Biological Activity of Novel Triketone-Containing Phenoxy Nicotinyl Inhibitors of HPPD.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target enzyme in albino herbicides. The inhibition of HPPD activity interferes with the synthesis of carotenoids, blocking photosynthesis and resulting in bleaching and necrosis. To develop herbicides with excellent activity, a series of 3-hydroxy-2-(6-substituted phenoxynicotinoyl)-2-cyclohexen-1-one derivatives were designed via active substructure combination. The title compounds were characterized via infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The structure of compound III-17 was confirmed via single-crystal X-ray diffraction. Preliminary tests demonstrated that some compounds had good herbicidal activity. Crop safety tests revealed that compound III-29 was safer than the commercial herbicide mesotrione in wheat and peanuts. Moreover, the compound exhibited the highest inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD), with a half-maximal inhibitory concentration of 0.19 µM, demonstrating superior activity compared with mesotrione (0.28 µM) in vitro. A three-dimensional quantitative structure-activity relationship study revealed that the introduction of smaller groups to the 5-position of cyclohexanedione and negative charges to the 3-position of the benzene ring enhanced the herbicidal activity. A molecular structure comparison demonstrated that compound III-29 was beneficial to plant absorption and conduction. Molecular docking and molecular dynamics simulations further verified the stability of the complex formed by compound III-29 and AtHPPD. Thus, this study may provide insights into the development of green and efficient herbicides.

Use of artificial intelligence chatbots in clinical management of immune-related adverse events.

BACKGROUND: Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed. Their utility to answer questions surrounding immune-related adverse events (irAEs), common and potentially dangerous toxicities from cancer immunotherapy, are not well defined. METHODS: We developed 50 distinct questions with answers in available guidelines surrounding 10 irAE categories and queried two AI chatbots (ChatGPT and Bard), along with an additional 20 patient-specific scenarios. Experts in irAE management scored answers for accuracy and completion using a Likert scale ranging from 1 (least accurate/complete) to 4 (most accurate/complete). Answers across categories and across engines were compared. RESULTS: Overall, both engines scored highly for accuracy (mean scores for ChatGPT and Bard were 3.87 vs 3.5, p<0.01) and completeness (3.83 vs 3.46, p<0.01). Scores of 1-2 (completely or mostly inaccurate or incomplete) were particularly rare for ChatGPT (6/800 answer-ratings, 0.75%). Of the 50 questions, all eight physician raters gave ChatGPT a rating of 4 (fully accurate or complete) for 22 questions (for accuracy) and 16 questions (for completeness). In the 20 patient scenarios, the average accuracy score was 3.725 (median 4) and the average completeness was 3.61 (median 4). CONCLUSIONS: AI chatbots provided largely accurate and complete information regarding irAEs, and wildly inaccurate information ("hallucinations") was uncommon. However, until accuracy and completeness increases further, appropriate guidelines remain the gold standard to follow.

Surgically-Relevant Quality of Life Thresholds for the Short Inflammatory Bowel Disease Questionnaire in Crohn's disease.

BACKGROUND OR PURPOSE: Despite interest in patient-reported outcome measures to track progression in Crohn's disease, frameworks to apply these questionnaires in the preoperative setting are lacking. Using the short inflammatory bowel disease questionnaire (sIBDQ), this study aimed to describe interpretable quality of life thresholds and examine potential associations with future bowel resection in Crohn's disease. METHODS: Adult Crohn's disease patients completing an sIBDQ at a clinic visit between 2020-2022 were eligible. A stoplight framework was adopted for sIBDQ scores, including a 'Resection Red zone' suggesting poor quality of life that may benefit from discussions about surgery as well as a 'Nonoperative Green' zone. Thresholds were identified with both anchor- and distribution-based methods using receiver operating characteristic curve analysis and subgroup percentile scores, respectively. To quantify associations between sIBDQ scores and subsequent bowel resection, multivariable logistic regression models were fit with covariates of age, sex, body mass index, medications, disease pattern and location, resection history, and the Harvey Bradshaw Index. Incremental discriminatory value of the sIBDQ beyond clinical factors was assessed through area under the receiver operating characteristics curve (AUC) with an internal validation through bootstrap resampling. RESULTS: Of 2003 included patients, 102 underwent Crohn's-related bowel resection. The sIBDQ Nonoperative Green zone threshold ranged from 61 to 64 and the Resection Red zone from 36 to 38. When adjusting for clinical covariates, a worse sIBDQ score was associated with greater odds of subsequent 90-day bowel resection when considered as a one-point (OR [95% CI], 1.05 [1.03-1.07]) or five-point change (OR [95% CI], 1.25 [1.13-1.40]). Inclusion of the sIBDQ modestly improved discriminative performance (AUC [95% CI] 0.85 [0.85 - 0.86]) relative to models that included only demographics (0.57 [0.57 - 0.58]) or demographics with clinical covariates (0.83 [0.83 - 0.84]). DISCUSSION OR CONCLUSION: In the decision-making process for bowel resection, disease-specific patient-reported outcome measures may be useful to identify Crohn's disease patients with poor quality of life and promote shared understanding of personalized burden.

Efficacy and safety of intrapleural perfusion with hyperthermic chemotherapy for malignant pleural effusion: a meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of intrapleural perfusion with hyperthermic chemotherapy (IPHC) in treating malignant pleural effusion (MPE). METHODS: PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), VIP Chinese Science and Technology Journal Full-text Database (VP-CSJFD), and Wanfang database were searched by computer from database establishment to January 17, 2024. Relevant randomized controlled articles with IPHC as the observational group and intrapleural perfusion chemotherapy (IPC) as the control group for MPE were included. Then, the methodological quality of the included articles was evaluated and statistically analyzed using Stata 16.0. RESULTS: Sixteen trials with 647 patients receiving IPHC and 661 patients receiving IPC were included. The meta-analysis found that MPE patients in the IPHC group had a more significant objective response rate [RR = 1.31, 95%CI (1.23, 1.38), P < 0.05] and life quality improvement rate [RR = 2.88, 95%CI (1.95, 4.24), P < 0.05] than those in the IPC group. IPHC and IPC for MPE patients had similar incidence rates of asthenia, thrombocytopenia, hepatic impairment, and leukopenia. CONCLUSION: Compared with IPC, IPHC has a higher objective response rate without significantly increasing adverse reactions. Therefore, IPHC is effective and safe. However, this study is limited by the quality of the literature. Therefore, more high-quality, multi-center, large-sample, rigorously designed randomized controlled clinical studies are still needed for verification and evaluation.

Precise and automated lung cancer cell classification using deep neural network with multiscale features and model distillation.

Lung diseases globally impose a significant pathological burden and mortality rate, particularly the differential diagnosis between adenocarcinoma, squamous cell carcinoma, and small cell lung carcinoma, which is paramount in determining optimal treatment strategies and improving clinical prognoses. Faced with the challenge of improving diagnostic precision and stability, this study has developed an innovative deep learning-based model. This model employs a Feature Pyramid Network (FPN) and Squeeze-and-Excitation (SE) modules combined with a Residual Network (ResNet18), to enhance the processing capabilities for complex images and conduct multi-scale analysis of each channel's importance in classifying lung cancer. Moreover, the performance of the model is further enhanced by employing knowledge distillation from larger teacher models to more compact student models. Subjected to rigorous five-fold cross-validation, our model outperforms existing models on all performance metrics, exhibiting exceptional diagnostic accuracy. Ablation studies on various model components have verified that each addition effectively improves model performance, achieving an average accuracy of 98.84% and a Matthews Correlation Coefficient (MCC) of 98.83%. Collectively, the results indicate that our model significantly improves the accuracy of disease diagnosis, providing physicians with more precise clinical decision-making support.

Semiconservative transmission of DNA N6-adenine methylation in a unicellular eukaryote.

While DNA N6-adenine methylation (6mA) is best known in prokaryotes, its presence in eukaryotes has generated great interest recently. Biochemical and genetic evidence supports that AMT1, a MT-A70 family methyltransferase (MTase), is crucial for 6mA deposition in unicellular eukaryotes. Nonetheless, 6mA transmission mechanism remains to be elucidated. Taking advantage of Single Molecule Real-Time Circular Consensus Sequencing (SMRT CCS), here we provide definitive evidence for semiconservative transmission of 6mA in Tetrahymena thermophila In wild-type (WT) cells, 6mA occurs at the self-complementary ApT dinucleotide, mostly in full methylation (full-6mApT); after DNA replication, hemi-methylation (hemi-6mApT) is transiently present on the parental strand, opposite to the daughter strand readily labeled by 5-bromo-2'-deoxyuridine (BrdU). In ΔAMT1 cells, 6mA predominantly occurs as hemi-6mApT. Hemi-to-full conversion in WT cells is fast, robust, and processive, while de novo methylation in ΔAMT1 cells is slow and sporadic. In Tetrahymena, regularly spaced 6mA clusters coincide with linker DNA of nucleosomes arrayed in the gene body. Importantly, in vitro methylation of human chromatin by reconstituted AMT1 complex recapitulates preferential targeting of hemi-6mApT sites in linker DNA, supporting AMT1's intrinsic and autonomous role in maintenance methylation. We conclude that 6mA is transmitted by a semiconservative mechanism: full-6mApT is split by DNA replication into hemi-6mApT, which is restored to full-6mApT by AMT1-dependent maintenance methylation. Our study dissects AMT1-dependent maintenance methylation and AMT1-independent de novo methylation, reveals a 6mA transmission pathway with striking similarity to 5-methyl cytosine (5mC) transmission at the CpG dinucleotide, and establishes 6mA as a bona fide eukaryotic epigenetic mark.

Direct electrospinning for producing multiple activity nanofibers consisting of aggregated luteolin/hydroxypropyl-gamma-cyclodextrin inclusion complex.

Hydroxypropyl-gamma-cyclodextrin (HPγCD) inclusion complex nanofibers (Lut/HPγCD-IC-NF) containing Luteolin (Lut) were prepared by electrospinning technology. Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) spectra confirmed the formation of Lut/HPγCD-IC-NF. Scanning electron microscopy (SEM) images showed that the morphology of Lut/HPγCD-IC-NF was uniform and bead-free, suggesting that self-assembled aggregates, macromolecules with higher molecular weights, were formed by strong hydrogen bonding interactions between the cyclodextrin inclusion complexes. Confocal laser scanning microscopy (CLSM) images showed that Lut was distributed in Lut/HPγCD-IC-NF. Proton nuclear magnetic resonance (1H NMR) spectroscopy revealed the change in chemical shift of the proton peak between Lut and HPγCD, confirming the formation of inclusion complex. Thermogravimetric analysis (TGA) proved that Lut/HPγCD-IC-NF had good thermal stability. The phase solubility test confirmed that HPγCD had a solubilizing effect on Lut. When the solubility of HPγCD reached 10 mM, the solubility of Lut increased by 15-fold. The drug loading test showed that the content of Lut in fibers reached 8.57 ± 0.02 %. The rapid dissolution experiment showed that Lut/HPγCD-IC-NF dissolved within 3 s. The molecular simulation provides three-dimensional evidence for the formation of inclusion complexes between Lut and HPγCD. Antibacterial experiments showed that Lut/HPγCD-IC-NF had enhanced antibacterial activity against S. aureus. Lut/HPγCD-IC-NF exhibited excellent antioxidant properties with a free radical scavenging ability of 89.5 ± 1.1 %. In vitro release experiments showed Lut/HPγCD-IC-NF had a higher release amount of Lut. In conclusion, Lut/HPγCD-IC-NF improved the physicochemical properties and bioavailability of Lut, providing potential applications of Lut in the pharmaceutical field.

A novel fluorescence platform for specific detection of tetracycline antibiotics based on [MQDA-Eu3+] system.

Tetracycline antibiotics (TCs) are extensively used in clinical medicine, animal husbandry, and aquaculture because of their cost-effectiveness and high antibacterial efficacy. However, the presence of TCs residues in the environment poses risks to humans. In this study, an inner filter effect (IFE) fluorescent probe, 2,2'-(ethane-1,2-diylbis((2-((2-methylquinolin-8-yl)amino)-2-oxoethyl)azanediyl))diacetic acid (MQDA), was developed for the rapid detection of Eu3+ within 30 s. And its complex [MQDA-Eu3+] was successfully used for the detection of TCs. Upon coordination of a carboxyl of MQDA with Eu3+ to form a [MQDA-Eu3+] complex, the carboxyl served as an antenna ligand for the effective detection of Eu3+ to intensify the emission intensity of MQDA via "antenna effect", the process was the energy absorbed by TCs via UV excitation was effectively transferred to Eu3+. Fluorescence quenching of the [MQDA-Eu3+] complex was caused by the IFE in multicolor fluorescence systems. The limits of detection of [MQDA-Eu3+] for oxytetracycline, chlorotetracycline hydrochloride, and tetracycline were 0.80, 0.93, and 1.7 µM in DMSO/HEPES (7:3, v/v, pH = 7.0), respectively. [MQDA-Eu3+] demonstrated sensitive detection of TCs in environmental and food samples with satisfactory recoveries and exhibited excellent imaging capabilities for TCs in living cells and zebrafish with low cytotoxicity. The proposed approach demonstrated considerable potential for the quantitative detection of TCs.

Wnt/ß-catenin signaling is a therapeutic target in anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy that has consistently shown Wnt/ß-catenin (canonical) signaling activation in various study populations. There are currently no targetable treatments for BRAF-wildtype ATC and a lack of effective treatment for BRAFV600EATC. Our aim is to identify whether Wnt inhibitors could be potential therapeutic agents for ATC patients with limited treatment options. METHODS: In this Institutional Review Board-approved study, we utilize a cohort of 32 ATCs and 20 non-neoplastic multinodular goiters (MNG). We also use 4 ATC spheroid cell lines (THJ-16T, THJ-21T, THJ-29T, and THJ-11T) and two primary patient-derived ATC organoid cultures (VWL-T5 and VWL-T60). Finally, we use a murine xenograft mouse model of ATC for in vivo treatment studies. RESULTS: Using a large patient cohort, we demonstrate that this near-universal Wnt signaling activation is associated with ligand expression- rather than being mutationally-driven. We show that pyrvinium pamoate, a potent Wnt inhibitor, exhibits in vitro efficacy against both ATC cell lines and primary patient-derived ATC organoids VWL-T5 (p < 0.05) and VWL-T60 (p < 0.01) Finally, using a murine xenograft model of ATC, we show that pyrvinium significantly delays the growth of ATC tumors in THJ-16T (p < 0.005) and THJ-21T (p < 0.001). CONCLUSIONS: We tested Wnt inhibitor treatment, both in vitro and in vivo, as a potential novel therapy for this highly lethal disease. Future large-scale studies utilizing multiple Wnt inhibitors will lay the foundation for the development of these novel therapies for patients with ATC.

Clinical Value of the Quantitative Flow Ratio to Predict Long-term Target Vessel Failure in Patients with In-stent Restenosis after Drug-coated Balloon Angioplasty.

OBJECTIVE: The study sought to investigate the clinical predictive value of quantitative flow ratio (QFR) for the long-term target vessel failure (TVF) outcome in patients with in-stent restenosis (ISR) by using drug-coated balloon (DCB) treatment after a long-term follow-up. METHODS: This was a retrospective study. A total of 186 patients who underwent DCB angioplasty for ISR in two hospitals from March 2014 to September 2019 were enrolled. The QFR of the entire target vessel was measured offline. The primary endpoint was TVF, including target vessel-cardiac death (TV-CD), target vessel-myocardial infarction (TV-MI), and clinically driven-target vessel revascularization (CD-TVR). RESULTS: The follow-up time was 3.09±1.53 years, and 50 patients had TVF. The QFR immediately after percutaneous coronary intervention (PCI) was significantly lower in the TVF group than in the no-TVF group. Multivariable Cox regression analysis indicated that the QFR immediately after PCI was an excellent predictor for TVF after the long-term follow-up [hazard ratio (HR): 5.15×10-5 (6.13×10-8-0.043); P<0.01]. Receiver-operating characteristic (ROC) curve analysis demonstrated that the optimal cut-off value of the QFR immediately after PCI for predicting the long-term TVF was 0.925 (area under the curve: 0.886, 95% confidence interval: 0.834-0.938; sensitivity: 83.40%, specificity: 88.00; P<0.01). In addition, QFR≤0.925 post-PCI was strongly correlated with the TVF, including TV-MI and CD-TVR (P<0.01). CONCLUSION: The QFR immediately after PCI showed a high predictive value of TVF after a long-term follow-up in ISR patients who underwent DCB angioplasty. A lower QFR immediately after PCI was associated with a worse TVF outcome.

Discovery of neuroprotective Agents: Potent, brain Penetrating, lipoic acid derivatives for the potential treatment of ischemic stroke by regulating oxidative stress and inflammation - a Preliminary study.

Stroke poses a serious risk to the physical and mental health of patients. Endogenous compounds are widely used to treat ischemic stroke. Lipoic acid, a naturally occurring (R)-5-(1,2-dithiolan-3-yl)pentanoic acid, has therapeutic potential for the treatment of ischemic stroke. However, the direct application of lipoic acid is limited by its relatively low efficacy and instability. Therefore, there is a need to modify the structure of lipoic acid to improve its pharmaceutical capabilities. Currently, 37 lipoic acid derivatives have been synthesized, and compound AA-9 demonstrated optimal therapeutic potential in an in vitro model of induced oxidative damage using tert-butyl hydroperoxide (t-BHP). In addition, in vitro experiments have shown that compound AA-9 has an excellent safety profile. Subsequently, the therapeutic effect of AA-9 was significant in the rat MCAO ischemic stroke model, which may be attributed to the antioxidant and anti-inflammatory effects of compound AA-9 by activating PGC-1α and inhibiting NLRP3. Notably, compound AA-9 exhibited higher stability and better bioavailability properties than ALA in plasma stability and pharmacokinetic properties. In conclusion, AA-9 may be a promising neuroprotective agent for the treatment of ischemic stroke and warrants further investigation.

Metabolic profiling identifies Qrich2 as a novel glutamine sensor that regulates microtubule glutamylation and mitochondrial function in mouse sperm.

In our prior investigation, we discerned loss-of-function variants within the gene encoding glutamine-rich protein 2 (QRICH2) in two consanguineous families, leading to various morphological abnormalities in sperm flagella and male infertility. The Qrich2 knockout (KO) in mice also exhibits multiple morphological abnormalities of the flagella (MMAF) phenotype with a significantly decreased sperm motility. However, how ORICH2 regulates the formation of sperm flagella remains unclear. Abnormal glutamylation levels of tubulin cause dysplastic microtubules and flagella, eventually resulting in the decline of sperm motility and male infertility. In the current study, by further analyzing the Qrich2 KO mouse sperm, we found a reduced glutamylation level and instability of tubulin in Qrich2 KO mouse sperm flagella. In addition, we found that the amino acid metabolism was dysregulated in both testes and sperm, leading to the accumulated glutamine (Gln) and reduced glutamate (Glu) concentrations, and disorderly expressed genes responsible for Gln/Glu metabolism. Interestingly, mice fed with diets devoid of Gln/Glu phenocopied the Qrich2 KO mice. Furthermore, we identified several mitochondrial marker proteins that could not be correctly localized in sperm flagella, which might be responsible for the reduced mitochondrial function contributing to the reduced sperm motility in Qrich2 KO mice. Our study reveals a crucial role of a normal Gln/Glu metabolism in maintaining the structural stability of the microtubules in sperm flagella by regulating the glutamylation levels of the tubulin and identifies Qrich2 as a possible novel Gln sensor that regulates microtubule glutamylation and mitochondrial function in mouse sperm.

Association between neutrophil-to-lymphocyte ratio and outcomes in hospitalized patients with left ventricular thrombus.

BACKGROUND: Left ventricular thrombus (LVT) is a severe cardiovascular complication occurring in approximately 10% of patients with acute anterior ST-segment elevation myocardial infarction. This study aimed to evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and in-hospital major adverse cardiovascular and cerebrovascular events (MACCE) in patients with LVT. MATERIAL AND METHODS: This multicenter retrospective study was conducted between January 2000 and June 2022 in hospitalized patients with LVT. The outcome included in-hospital MACCE. The association between NLR and in-hospital MACCE was measured by odds ratios (ORs). The restricted cubic spline model was used for dose-response analysis. RESULTS: A total of 197 LVT patients from four centers were included for analysis in this study. MACCE occurred in 13.7% (27/197) of the patients. After adjusting for estimated glomerular filtration rate (eGFR), D-dimer, and age, the OR for MACCE comparing first to the third tertile of NLR was 13.93 [95% confidence interval: 2.37-81.77, P = 0.004, P-trend = 0.008]. When further adjusting for etiology and heart failure with reduced ejection fraction (HFrEF), the association remained statistically significant. Spline regression models showed an increasing trend in the incidence of MACCEs with NLR both in crude and adjusted models. Subgroup analyses showed that a high NLR may be correlated with poorer outcomes for LVT patients older than 65 years, or with hypertension, dyslipidemia, low ejection fraction, liver, and renal dysfunctions. CONCLUSION: In conclusion, these findings suggested that higher NLR may be associated with an increased risk of in-hospital MACCE in patients with LVT.

Assessing the clinical diagnostic value of anti-Müllerian hormone in polycystic ovarian syndrome and its correlation with clinical and metabolism indicators.

BACKGROUND: This study investigated the association between Anti-Müllerian Hormone (AMH) and relevant metabolic parameters and assessed its predictive value in the clinical diagnosis of polycystic ovarian syndrome (PCOS). METHODS: A total of 421 women aged 20-37 years were allocated to the PCOS (n = 168) and control (n = 253) groups, and their metabolic and hormonal parameters were compared. Spearman correlation analysis was conducted to investigate associations, binary logistic regression was used to determine PCOS risk factors, and receiver operating characteristic (ROC) curves were generated to evaluate the predictive value of AMH in diagnosing PCOS. RESULTS: The PCOS group demonstrated significantly higher blood lipid, luteinizing hormone (LH), and AMH levels than the control group. Glucose and lipid metabolism and hormonal disorders in the PCOS group were more significant than in the control group among individuals with and without obesity. LH, TSTO, and AMH were identified as independent risk factors for PCOS. AMH along with LH, and antral follicle count demonstrated a high predictive value for diagnosing PCOS. CONCLUSION: AMH exhibited robust diagnostic use for identifying PCOS and could be considered a marker for screening PCOS to improve PCOS diagnostic accuracy. Attention should be paid to the effect of glucose and lipid metabolism on the hormonal and related parameters of PCOS populations.