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Brain reorganization following spinal cord injury (SCI) has been well-established using animal and human studies. Yet, much is unknown regarding functional recovery and adverse secondary outcomes after SCI. Functional near-infrared spectroscopy (fNIRS) is a neuroimaging technique that offers methodological flexibility in a real-world setting. We used fNIRS to examine the cortical functional differences between 12 males with thoracolumbar SCI (46.41 ± 11.09 years of age) and 12 healthy males (47.61 ± 11.94 years of age) during resting state and task conditions-bilateral finger tapping (FT), mental imagery of bilateral FT with action observation (FTI+AO), and bilateral ankle tapping (AT). We found an overall decrease in hemodynamic response of the SCI group during all three task conditions. Task modulated functional connectivity (FC) computed using beta series correlation technique was compared using independent sample t -tests at α = 0.05. Connectivity between the right mediolateral sensorimotor network (SMN) and the right medial SMN was reduced during the FT task in SCI. A mixed analysis of variance revealed that the FC within the right mediolateral SMN was reduced during FT but preserved during FTI+AO (i.e., comparable to controls) in the SCI group. Lower FC of these regions was associated with longer injury durations. Additionally, we found a general decrease in resting state FC of the SCI group, specifically in the Slow-3 frequency range (0.073 to 0.1 Hz). These results, though preliminary, are consistent with past studies and highlight the potential of fNIRS in SCI and rehabilitative research.

Purpose: Warfarin is associated with paradoxical procoagulant effect that leads to a transient hypercoagulable state and acute ischemic stroke (AIS). This clinical dilemma is further confounded when the patient has multiple comorbidities and the optimal treatment strategies are unclear., Case Report: We report a 78-year-old male with valvular heart disease, congestive heart failure, and atrial fibrillation, who received bioprosthetic valve replacement and developed AIS related to the paradoxical procoagulant effect of warfarin. Emergent cerebral angiography with mechanical thrombectomy was performed, and recanalization was successfully achieved. After shifting warfarin to nonvitamin K oral anticoagulant (NOAC), the paradoxical procoagulant effect ameliorated., Conclusion: This report describes the roles of endovascular therapy and NOAC in patients with similar highly complex conditions and has clinical relevance for therapeutic plans in the clinical setting.

A novel and flexible approach for the stereo-controlled synthesis of vicinal tertiary carbinols is reported. The developed strategy featured a highly diastereoselective singlet-oxygen (O 2 1 ) [4+2] cycloaddition of rationally designed cyclohexadienones (derived from oxidative dearomatization of the corresponding carboxylic-acid appended phenol precursors), followed by programmed "O-O" and "C-C" bond cleavage. In doing so, a highly functionalized and versatile intermediate was identified and prepared in synthetically useful quantity as a plausible precursor to access a variety of designed and naturally occurring vicinal tertiary carbinol containing compounds. Most notably, the developed strategy was successfully applied in the stereo-controlled synthesis of advanced core structures of zaragozic acid, pactamycin and ryanodol., (© 2023 Wiley-VCH GmbH.)

Background: Patients with idiopathic inflammatory myopathy (IIM) often express a different type of myositis-specific autoantibodies (MSAs), each associated with different clinical symptoms. Understanding the immunopathogenesis of various IIM subgroups can help improve the diagnosis and prognosis of IIM patients with different MSAs. However, the immune cell profiles of these IIM patients with anti-aminoacyl tRNA synthetase (ARS) or anti-melanoma differentiation-associated gene 5 (MDA5) autoantibodies remain unclear. We focused on the immune cell profiles of IIM patients with anti-ARS or anti-MDA5 autoantibodies., Results: The peripheral blood from IIM patients with anti-MDA5 autoantibody (MDA5 + group, n = 24) or one of the anti-ARS autoantibodies (ARS + group, n = 40) autoantibodies, and healthy controls (HC group, n = 60) were collected and examined. We found that IIM patients had a lower CD3 T cell population compared to the HC group. IIM patients showed a significantly lower T N cell population and a higher T EMRA cell population. Higher Th17 and Treg cell populations were found in these IIM patients than in the HC group. In these IIM patients, the MDA5 + group exhibited the higher percentages of Th17 and Treg cells than the ARS + group. It is noteworthy that the percentage of Th1 cells in the survival subgroup was higher than in the death subgroup in IIM patients with ARS + or MDA5 + . Furthermore, in the MDA5 + group, the percentage of Treg cells was higher in the survival subgroup compared to the death subgroup., Conclusions: Our study demonstrated that elevated Th1 may be a good prognostic indicator in IIM patients with ARS + or MDA5 + . Elevated Treg may also help predict a good prognosis in MDA5 + IIM patients. However, more large-scale studies and clinical samples are needed to verify the significance of Th1 and Treg cell subsets in clinical outcomes for these IIM patients with ARS + or MDA5 + . These data may help design a therapeutic approach that specifically targets the pathogenic immune molecular responsible for autoimmune attacks in IIM., (© 2023. The Author(s).)

The left-right symmetry breaking of vertebrate embryos requires nodal flow. However, the molecular mechanisms that mediate the asymmetric gene expression regulation under nodal flow remain elusive. Here, we report that heat shock factor 1 (HSF1) is asymmetrically activated in the Kupffer's vesicle of zebrafish embryos in the presence of nodal flow. Deficiency in HSF1 expression caused a significant situs inversus and disrupted gene expression asymmetry of nodal signaling proteins in zebrafish embryos. Further studies demonstrated that HSF1 is a mechanosensitive protein. The mechanical sensation ability of HSF1 is conserved in a variety of mechanical stimuli in different cell types. Moreover, cilia and Ca 2+ -Akt signaling axis are essential for the activation of HSF1 under mechanical stress in vitro and in vivo . Considering the conserved expression of HSF1 in organisms, these findings unveil a fundamental mechanism of gene expression regulation by mechanical clues during embryonic development and other physiological and pathological transformations., Competing Interests: There are no competing interests., (© 2023 The Authors.)

Background: We conducted a retrospective observational study to explore the potential application of impulse oscillometry (IOS) as an alternative to high-resolution computed tomography (HRCT) for detecting pulmonary involvement in patients with rheumatoid arthritis (RA) because clinically evident interstitial lung disease (ILD) and airway involvement are common in this population., Methods: We enrolled 72 patients with RA who underwent pulmonary function tests (PFTs) and IOS between September 2021 and September 2022. We aimed to identify the PFT and IOS variables associated with lung diseases shown on HRCT images., Results: In our cohort of 72 patients, 48 underwent HRCT; of these, 35 had airway disease or ILD and 13 showed no obvious abnormalities on HRCT. Abnormal IOS and PFT parameters were observed in 34 and 23 patients, respectively, with abnormal HRCT images. The predicted percentages for forced vital capacity, the ratio of forced expiratory volume in the first one second to forced vital capacity, and forced mid-expiratory flow value were significantly lower in patients with abnormal HRCT. Lung resistance at 5 Hz, difference in resistance between 5 and 20 Hz, resonant frequency (Fres), and reactance area were higher in these patients and reactance at 5 Hz was lower. Compared to other parameters, Fres > 14.14 was significantly associated with alterations in HRCT and may be used as an indicator for monitoring disease., Conclusion: Fres > 14.14 is significantly associated with lung involvement in RA patients. Performance of spirometry with IOS is more beneficial than spirometry alone for evaluating lung involvement in RA patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Immune-related toxicities, otherwise known as immune-related adverse events (irAEs), occur in a substantial fraction of cancer patients treated with immune checkpoint inhibitors (ICIs). Ranging from asymptomatic to life-threatening, ICI-induced irAEs can result in hospital admission, high-dose corticosteroid treatment, ICI discontinuation, and in some cases, death. A deeper understanding of the factors underpinning severe irAE development will be essential for improved irAE prediction and prevention, toward maximizing the benefits and safety profiles of ICIs. In recent work, we applied mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing, and bulk T-cell receptor (TCR) sequencing to identify pretreatment determinants of severe irAE development in patients with advanced melanoma. Across 71 patients separated into three cohorts, we found that two baseline features in circulation-elevated activated CD4 effector memory T-cell abundance and TCR diversity-are associated with severe irAE development, independent of the affected organ system within 3 months of ICI treatment initiation. Here, we provide an extended perspective on this work, synthesize and discuss related literature, and summarize practical considerations for clinical translation. Collectively, these findings lay a foundation for data-driven and mechanistic insights into irAE development, with the potential to reduce ICI morbidity and mortality in the future., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We recently reported that mutations in both the spike glycoprotein and nonstructural protein 6 (nsp6) were associated with attenuation of the SARS-CoV-2 Omicron BA.1 variant. While mutations in spike allow evasion of neutralizing antibodies and promote specific modes of viral entry, the role of nsp6 mutations in pathogenesis is less clear. Nsp6 is essential for modifying the endoplasmic reticulum and generating double-membrane vesicles, the site of viral RNA replication. To investigate the evolution of nsp6, we evaluated 91,596 high-confidence human SARS-CoV-2 whole-genome sequences across 19 variants and lineages. While nsp6 of early variants of concern, such as Alpha, Beta, and Gamma, carried a triple amino acid deletion (106-108, termed ΔSGF), the Delta, Epsilon, and Mu lineages retained the ancestral nsp6 sequence. For nsp6 in the emerging Omicron variants, we report a transition from an amino acid 105-107 ΔLSG deletion in BA.1 to increased dominance of the ΔSGF in BA.2 and subsequent lineages. Our findings indicate that deletion within nsp6 was independently selected in multiple lineages of SARS-CoV-2, both early and late in the pandemic. Analysis of SARS-CoV-2-related coronaviruses in bats and pangolins revealed nsp6 sequences similar to the ancestral SARS-CoV-2 virus, indicating that the deletion in nsp6 may be an adaptation to replication in humans. Analysis of nsp6 sequences from multiple coronaviruses predicts a multipass transmembrane protein with a conserved C-terminal domain. Monitoring and evaluating changes in nsp6 and other nonstructural proteins will contribute to our understanding of factors associated with the attenuation of pandemic coronaviruses. IMPORTANCE There is an ongoing need to evaluate genetic changes in SARS-CoV-2 for effects on transmission and pathogenesis. We recently reported an unexpected role for replicase component nsp6, in addition to changes in spike, in the attenuation of Omicron BA.1. In this commentary, we document a triple-amino-acid deletion in a predicted lumenal domain of nsp6 that was found in multiple, independent variants of SARS-CoV-2, including all recent Omicron lineages. Furthermore, we modeled the predicted structure of nsp6, implicating a multipass transmembrane architecture as conserved in members of the Coronaviridae family. This information can guide future studies investigating the role of nsp6 in the pathogenesis of existing and emerging coronaviruses., Competing Interests: The authors declare no conflict of interest.

Background: Fluoroquinolone use can be associated with an increased risk of aortic aneurysm (AA) or aortic dissection (AD). The US Food and Drug Administration recently warned against fluoroquinolone use for high-risk patients, such as those with Marfan syndrome. However, the association between fluoroquinolone use and AA/AD risk was unknown in these high-risk patients and therefore it was studied in this work., Methods and results: Data were collected from a national database between 2000 and 2017 for 550 patients with AA/AD and any congenital aortic disease (mean age 41.5 years; 415 with Marfan syndrome). A case cross-over study was conducted to compare the risk of aortic events (AA/AD) associated with fluoroquinolone and amoxicillin use between the hazard period (from -60 days to -1 day) and a randomly selected reference period (-180 to -121 days; -240 to -181 days; and -300 to -241 days). Compared to the reference period without fluoroquinolone use, fluoroquinolone use during the hazard period was not associated with a greater risk of AA/AD (1.09% vs. 1.09%; odds ratio [OR] 1.000; 95% confidence interval [CI] 0.32-3.10), AA (OR 0.67; 95% CI 0.11-3.99), or AD (OR 1.33; 95% CI 0.30-5.96) in patients with congenital aortic disease or Marfan syndrome. This lack of association was maintained in subgroup analysis, including Marfan syndrome or not, age (≤50 vs. >50 years) and sex., Conclusions: Fluoroquinolone use was not associated with an increased risk of AA/AD in patients with congenital aortic disease, including Marfan syndrome. More evidence is required for a fluoroquinolone pharmacovigilance plan in these patients.

A new lithophytic species of Gesneriaceae, Petrocodonrubrostriatus K.Tan, X.Q.Song & M.X.Ren, sp. nov. from Lvchun County, South Yunnan, China, is described and illustrated here. It closest resembles P.mollifolius (W.T.Wang) A.Weber & Mich.Möller, but the new species is differentiated from it by red to brownish-red stripes in the yellow corolla throat and 4.5 mm long bract lobes, a ca. 10 mm long style, and staminodes inserted at 2.5-3 mm from the corolla base. The species is preliminarily assessed as 'Critically Endangered' (CR) according to IUCN criteria, since currently only one single locality is known with a few subpopulations on a fragmented limestone cliff, with fewer than 300 individuals., Competing Interests: The authors have declared that no competing interests exist., (Ke Tan, Di-Ya Chen, Xi-Qiang Song, Ming-Xun Ren.)

Plant-based flavonoids have been evaluated as inhibitors of β-coronavirus replication and as therapies for COVID-19 on the basis of their safety profile and widespread availability. The SARS-CoV-2 main protease (Mpro) has been implicated as a target for flavonoids in silico . Yet no comprehensive in vitro testing of flavonoid activity against SARS-CoV-2 Mpro has heretofore been performed. We screened 1,019 diverse flavonoids for their ability to inhibit SARS-CoV-2 Mpro. Multiple structure-activity relationships were identified among active compounds such as enrichment of galloylated flavonoids and biflavones, including multiple biflavone analogs of apigenin. In a cell-based SARS-CoV-2 replication assay, the most potent inhibitors were apigenin and the galloylated pinocembrin analog, pinocembrin 7-O-(3''-galloyl-4'',6''-(S)-hexahydroxydiphenoyl)-beta-D-glucose (PGHG). Molecular dynamic simulations predicted that PGHG occludes the S1 binding site via a galloyl group and induces a conformational change in Mpro. These studies will advance the development of plant-based flavonoids-including widely available natural products-to target β-coronaviruses., Competing Interests: RF and LL have a patent pending entitled, “Compounds and Methods for Treating Viral Infections”. RF is on the Scientific Advisory Board of NytroPonix and is a founder and consultant at PlateletDiagnostics, LLC., (© 2023 The Authors.)

Introduction: Elderly-onset rheumatoid arthritis (EORA) is associated with an increased mortality risk; however, the effect of conventional synthetic, biologics or targeted synthetic disease-modifying anti-rheumatic drugs (csDMARDs, bDMARDs or tsDMARDs) on the EORA-specific mortality risk is unknown. In this study, we investigated the risk factors for all-cause mortality of patients with EORA., Methods: Data of EORA patients diagnosed with RA at age > 60 years between January 2007 and June 2021 were extracted from the electronic health record of Taichung Veterans General Hospital, Taiwan. Multivariable Cox regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). The survival of patients with EORA was analyzed by Kaplan-Meier method., Results: Among the 980 EORA patients who were enrolled (survivors 852 and non-survivor 128), the significant mortality-associated risk factors [HR (95% CI)] included higher age (1.10 [1.07-1.12], p < 0.001), male sex (1.92 [1.22-3.00], p = 0.004), current smoker (2.31 [1.10-4.87], p = 0.027) and underlying malignancy (1.89 [1.20-2.97], p = 0.006). Hydroxychloroquine treatment conferred protection against mortality in patients with EORA (HR 0.30, 95% CI 0.14-0.64, p = 0.002). Patients with malignancy who did not receive hydroxychloroquine treatment had the highest mortality risk compared with their counterparts. Patients with a monthly cumulative dose of hydroxychloroquine dose < 1374.5 mg had the lowest survival rate compared to patients who received hydroxychloroquine 1374.5-5778.5 and ≥ 5778.5 mg., Conclusion: Hydroxychloroquine treatment is associated with survival benefits in patients with EORA, and prospective studies are needed to validate the abovementioned findings., (© 2023. The Author(s).)

Irisin is a muscle-derived hormone that promotes the survival of motor neurons and enhances muscle size following injury. In this study, we investigated the beneficial effects and mechanism(s) of action of irisin in response to cerebral ischemia-reperfusion injury (CIRI). Right-middle cerebral artery occlusion (MCAO) and hypoxia/reoxygenation (H/R) models were generated in C57BL/6 J mice. Mouse neuronal cell lines (NSC-34) were used to confirm the molecular mechanisms of the protection afforded by irisin in response to CIRI. We found that irisin (250 μg/kg) improved cerebral function and reduced the cerebral infarct volume following CIRI. Irisin also protected neuronal cells against ischemia-reperfusion (I/R) induced apoptosis, assessed via TUNEL, and cleaved Caspase-3 staining. Western blotting of neuronal tissue from irisin treated I/R mice showed lower expression of pro-apoptotic Bax and caspase-9 (P < 0.001 and P < 0.01) and increased levels of the pro-survival protein Bcl-2 (P < 0.01 & P < 0.001 vs. I/R). Irisin also reduced the levels of reactive oxygen species (ROS) characterized through malondialdehyde (MDA) assays. Irisin was found to maintain mitochondrial homeostasis through the suppression of mitochondrial fission-linked dynamin-related protein 1 in CIRI mice (P < 0.01 and P < 0.05 v. I/R cohort). Moreover, mitochondrial fusion-related protein (Mfn2) and Opa1 expression were rescued following irisin treatment (P < 0.001 and P < 0.01 v. I/R cohort). Cell-based assays showed that irisin activates PI3K/AKT/mTOR signaling in the neurons of CIRI mice. Furthermore, the beneficial effects of irisin on NSC-34 cell-survival, mitochondrial function, and ROS generation were reversed by VS-5584, a highly specific PI3K/AKT/mTOR inhibitor. Collectively, these data highlight the ability of irisin to alleviate CIRI in vivo and in vitro. The mechanisms of action of irisin include the attenuation of apoptosis through the prevention of mitochondrial fission and increased mitochondrial fusion and the alleviation of oxidative stress through activation of the PI3K/AKT/mTOR axis. We therefore identify irisin as a much-needed therapeutic for CIRI., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Abnormal functional connectivity (FC) and structure in the brain are found in patients with fibromyalgia (FM). This study investigated FC and structural alterations of the visual cortical system, the emerging contributor to pain processing, in patients with FM., Methods: Thirty pain-free participants and 26 patients with FM were enrolled. Clinical characteristics were evaluated using standardized scales. Structural and resting-state functional magnetic resonance imaging were conducted. Seed-based FC analyses, voxel-based morphometry, and surface-based morphometry were performed. The FC and cortical structure of the visual system were compared between the 2 groups. The correlation between functional and structural changes in the visual cortical system with clinical presentation in the FM group was analyzed., Results: The patients with FM showed increased FCs within visual networks, of which the FC between the visual medial network and the right lingual gyrus (LG) was positively correlated with the Fibromyalgia Impact Questionnaire (FIQ) score. However, the FM group showed decreased FCs from the visual occipital network (VON) to several regions, of which the FCs from the VON to the bilateral frontal orbital cortices were negatively correlated with the FIQ and Pittsburgh Sleep Quality Index scores. Cortical thickness of the lateral occipital cortex, LG, and pericalcarine in FM tended to increase., Conclusion: Altered FCs and structure in the visual cortical system might be involved in the pathomechanisms and clinical presentation in FM. These findings could potentially support further studies that seek to find diagnostic methods and mechanism-based therapies in patients with FM., (Copyright © 2023 by the Journal of Rheumatology.)

Background: The optimal revascularization strategy for elderly patients with acute coronary syndrome (ACS) remains uncertain. We evaluated the impact of complete revascularization (CR) vs. incomplete revascularization (IR) in elderly ACS patients with multivessel disease (MVD) undergoing percutaneous coronary intervention (PCI)., Methods: Using registry data from 2011 to 2019, we conducted a propensity-score matched cohort study. Elderly patients (≥75 years) with ACS and MVD who underwent PCI were divided into CR and IR groups based on angiography during index hospitalization. Major adverse cardiovascular events (MACEs), including all-cause mortality, recurrent non-fatal myocardial infarction, and any revascularization, were assessed at 3-year follow-up., Results: Among 1,018 enrolled patients, 496 (48.7%) underwent CR and 522 (51.3%) received IR. After 1:1 propensity-score matching, we analyzed 395 pairs. At 3-year follow-up, CR was significantly associated with lower MACE risk compared to IR (16.7% vs. 25.6%, HR = 0.65, 95% CI: 0.47-0.88, p  = 0.006), driven by reduced all-cause mortality. This benefit was consistent across all pre-specified subgroups, particularly in ST segment elevation (STE)-ACS patients. In non-STE (NSTE)-ACS subgroup analysis, CR was also associated with a lower risk of cardiac mortality compared to IR (HR = 0.30, 95% CI: 0.12-0.75, p  = 0.01)., Conclusion: In elderly ACS patients with MVD undergoing PCI, CR demonstrates superior long-term outcomes compared to IR, irrespective of STE- or NSTE-ACS presentation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Lu, Lee, Chen, Chen, Ho, Yeh, Huang, Chang, Wang, Chang, Hsieh and Hsieh.)

Background: The tumor-adipose microenvironment (TAME) is characterized by the enrichment of adipocytes, and is considered a special ecosystem that supports cancer progression. However, the heterogeneity and diversity of adipocytes in TAME remains poorly understood., Methods: We conducted a single-cell RNA sequencing analysis of adipocytes in mouse and human white adipose tissue (WAT). We analyzed several adipocyte subtypes to evaluate their relationship and potential as prognostic factors for overall survival (OS). The potential drugs are screened by using bioinformatics methods. The tumor-promoting effects of a typical adipocyte subtype in breast cancer are validated by performing in vitro functional assays and immunohistochemistry (IHC) in clinical samples., Results: We profiled a comprehensive single-cell atlas of adipocyte in mouse and human WAT and described their characteristics, origins, development, functions and interactions with immune cells. Several cancer-associated adipocyte subtypes, namely DPP4 + adipocytes in visceral adipose and ADIPOQ + adipocytes in subcutaneous adipose, are identified. We found that high levels of these subtypes are associated with unfavorable outcomes in four typical adipose-associated cancers. Some potential drugs including Trametinib, Selumetinib and Ulixertinib are discovered. Emphatically, knockdown of adiponectin receptor 1 (AdipoR1) and AdipoR2 impaired the proliferation and invasion of breast cancer cells. Patients with AdipoR2-high breast cancer display significantly shorter relapse-free survival (RFS) than those with AdipoR2-low breast cancer., Conclusion: Our results provide a novel understanding of TAME at the single-cell level. Based on our findings, several adipocyte subtypes have negative impact on prognosis. These cancer-associated adipocytes may serve as key prognostic predictor and potential targets for treatment in the future., (© 2023. The Author(s).)

Objectives: This study investigates the efficacy and adverse events of beta-3 agonists and antimuscarinic agents for managing overactive bladder syndrome in Sjogren syndrome., Methods: Sjogren's syndrome patients with an Overactive Bladder Symptom Score (OABSS) >5 were enrolled and were randomly assigned to mirabegron 50 mg/day or solifenacin 5 mg/day. Patients were evaluated on the recruitment day and reassessed at Week 1, 2, 4, and 12. The study's primary endpoint was to have a significant change in OABSS at Week 12. The secondary endpoint was the adverse event and crossover rate., Results: A total of 41 patients were included in the final analysis, with 24 in the mirabegron group and 17 in the solifenacin group. The study's primary outcome was a change of the OABSS at Week 12. We found that both mirabegron and solifenacin significantly reduce patients' OABSS after 12 weeks of treatment. The evolution of the OABSS was -3.08 for mirabegron and -3.71 for solifenacin (p = .56). Six out of 17 patients from the solifenacin group crossed over to the mirabegron arm due to severe dry mouth or constipation, while none from the mirabegron arm crossed over to the solifenacin group. Sjogren's syndrome-related pain was also improved in the mirabegron group (4.96-1.67, p = .008) compared to the solifenacin group (4.39-3.4, p = .49)., Conclusions: Our study showed that mirabegron is equally effective as solifenacin in treating Sjogren's syndrome patients with overactive bladder. Mirabegron is superior to solifenacin in terms of treatment-related adverse events., (© 2023 John Wiley & Sons Australia, Ltd.)

Background and Aims: Low-density lipoprotein (LDL)-cholesterol (LDL-C) promotes atherosclerotic cardiovascular disease (ASCVD), with changes in LDL electronegativity modulating its pro-atherogenic/pro-thrombotic effects. Whether such alterations associate with adverse outcomes in patients with acute coronary syndromes (ACS), a patient population at particularly high cardiovascular risk, remains unknown., Methods: This is a case-cohort study using data from a subset of 2619 ACS patients prospectively recruited at four university hospitals in Switzerland. Isolated LDL was chromatographically separated into LDL particles with increasing electronegativity (L1-L5), with the L1-L5 ratio serving as a proxy of overall LDL electronegativity. Untargeted lipidomics revealed lipid species enriched in L1 (least) vs. L5 (most electronegative subfraction). Patients were followed at 30 days and 1 year. The mortality endpoint was reviewed by an independent clinical endpoint adjudication committee. Multivariable-adjusted hazard ratios (aHR) were calculated using weighted Cox regression models., Results: Changes in LDL electronegativity were associated with all-cause mortality at 30 days (aHR, 2.13, 95% CI, 1.07-4.23 per 1 SD increment in L1/L5; p=.03) and 1 year (1.84, 1.03-3.29; p=.04), with a notable association with cardiovascular mortality (2.29; 1.21-4.35; p=.01; and 1.88; 1.08-3.28; p=.03). LDL electronegativity superseded several risk factors for the prediction of 1-year death, including LDL-C, and conferred improved discrimination when added to the updated GRACE score (area under the receiver operating characteristic curve 0.74 vs. 0.79, p=.03). Top 10 lipid species enriched in L1 vs. L5 were: cholesterol ester (CE) (18:2), CE (20:4), free fatty acid (FA) (20:4), phosphatidyl-choline (PC) (36:3), PC (34:2), PC (38:5), PC (36:4), PC (34:1), triacylglycerol (TG) (54:3), and PC (38:6) (all p < .001), with CE (18:2), CE (20:4), PC (36:3), PC (34:2), PC (38:5), PC (36:4), TG (54:3), and PC (38:6) independently associating with fatal events during 1-year of follow-up (all p < .05)., Conclusions: Reductions in LDL electronegativity are linked to alterations of the LDL lipidome, associate with all-cause and cardiovascular mortality beyond established risk factors, and represent a novel risk factor for adverse outcomes in patients with ACS. These associations warrant further validation in independent cohorts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SK also received funding from the Swiss Heart Foundation, the Novartis Foundation for Medical-biological Research, and the Theodor-Ida-Herzog-Egli Foundation, and equipment and materials from Roche Diagnostics outside the submitted work. LR received funding from Abbott, Biotronik, Boston Scientific, Heartflow, Sanofi, and Regeneron, and declares consulting fees from Abbott, Amgen, AstraZeneca, Canon, Medtronic, NovoNordisk, Occlutech, Sanofi, and Vifor, payment or honoraria from Abbott and Occlutech, and travel support from AstraZeneca. FM has received research grants to the institution from Amgen, AstraZeneca, Boston Scientific, Biotronik, Eli Lilly, Medtronic, MSD, and St. Jude Medical, including speaker and/or consultant fees. AvE received speaker and/or consultant fees from Amgen, MSD, and Sanofi-Aventis. CMM received research grants to the institution from Eli Lilly, AstraZeneca, Roche, Amgen and MSD including speaker or consultant fees. GGC and LL are co-inventors on the international patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischaemia–reperfusion injury to the central nervous system. GGC.is a consultant to Sovida Solutions Limited. LL reports speaker fees from Daiichi Sankyo outside the submitted work. Outside this work, TFL declares institutional educational and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Vifor, and consulting fees from Daiichi Sankyo, Ineeo Inc, Philipps, and Pfizer outside the submitted work. TFL holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Kojic acid naturally appears in fermented foods and can be formed during the aerobic fermentation process induced by Aspergillus and Penicillium fungi . It is widely used in the food industry because it exhibits antibacterial and antifungal properties and does not affect food taste. However, recent studies indicate that kojic acid may be a potential carcinogen. Therefore, assessing the health risks of kojic acid in fermented foods are of great importance, and developing a sensitive and accurate analytical method for this compound is a significant endeavor. Much efforts have been devoted to the detection of kojic acid using electrochemistry, high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). HPLC and HPLC-MS/MS are the analytical techniques most often employed for this purpose. Of these two methods, HPLC-MS/MS displays excellent sensitivity and is the optimal selective technique. Pretreatment is usually necessary for kojic acid determination because of the complex matrix effects of fermented foods. However, few researches on the determination of kojic acid in food are available, and, to the best of our knowledge, the determination of kojic acid using solid-phase extraction (SPE) pretreatment has not been reported yet. Herein, a convenient, sensitive, and accurate method was developed to determine kojic acid in fermented foods using solid-phase extraction-ultra performance liquid chromatography-tandem mass spectrometry (SPE-UPLC-MS/MS). The pretreatment conditions, such as the extraction solvent, cartridge, rinse solvent, and eluent, were systematically optimized. The samples, including soy sauce, vinegar, liquor, sauce, fermented soya bean, and fermented bean curd, were extracted with 0.1% formic acid-absolute ethyl alcohol and purified using a PRiME HLB cartridge. Kojic acid was separated using an ACQUITY UPLC ® BEH C 18 column (100 mm×2.1 mm, 1.7 μm) with formic acid-acetonitrile (1∶999, v/v) and formic acid-5 mmol/L ammonium acetate (1∶999, v/v) solutions as the mobile phases under gradient elution mode. MS was performed in electrospray positive ionization (ESI + ) and multiple reaction monitoring (MRM) modes. An internal standard method was used for quantification. Under optimized conditions, good linearity was achieved at mass concentrations of 5.0-100.0 μg/L, with a correlation coefficient ( r ) of 0.9994. The limits of detection and quantification of the method for kojic acid were 2-5 μg/kg and 6-15 μg/kg, respectively. Good recoveries of 86.8%-111.7%, intra-day precisions of 1.0%-7.9% ( n =6), and inter-day precisions of 2.7%-10.2% ( n =5) were also obtained. The matrix effect was evaluated by establishing a matrix-matching calibration curve, and weak inhibitory effects were found in vinegar and liquor; moderate inhibitory effects in fermented bean curd, fermented soya bean, and soy sauce; and a strong inhibitory effect in sauce. The developed method was used to detect kojic acid in 240 fermented foods, and the results showed that the detection rate of vinegar was the highest, followed by liquor, sauce, soy sauce, fermented soya bean, and fermented bean curd, the contents were 5.69-2272 μg/kg. Matrix interferences can be significantly reduced by optimizing the pretreatment and detection procedures. The proposed method is sensitive, accurate, and can be used to analyze kojic acid in fermented foods.

Rheumatoid arthritis (RA), a chronic inflammatory disease, carries a significant burden of atherosclerotic cardiovascular diseases (ASCVD). With their heterogeneous composition, high-density lipoprotein (HDL) particles have varied athero-protective properties, and some may even increase ASCVD risk. In this prospective and cross-sectional study, we aimed to examine the relationship between HDL sizes/metabolites and inflammation in RA. Using 1 H-NMR-based lipid/metabolomics, differential HDL-related metabolites were identified between RA patients and healthy control (HC) subjects and between RA patients with and without anti-citrullinated peptide antibodies (ACPA). The correlation between the discriminative HDL-related metabolites and C-reactive protein (CRP) was evaluated in RA patients. RA patients demonstrated higher particle number, lipids, cholesterol, cholesterol ester, free cholesterol, and phospholipids in large/very large-sized HDLs. ACPA-positive patients had higher L-HDL-C and L-HDL-CE but lower small-/medium-sized HDL-TG levels than ACPA-negative patients. An inverse correlation was found between CRP levels and small-sized HDLs. Janus kinase inhibitor treatment was associated with increased serum small-sized HDL-related metabolites and decreased CRP levels. We are the first to reveal the significant associations between RA inflammation and HDL sizes/metabolites. A potential link between ACPA positivity and changes in serum levels of HDL-related metabolites was also observed in RA patients.

Pain is a multi-dimensional emotional experience, and pain sensation and pain emotion are the two main components. As for pain, previous studies only focused on a certain link of the pain transmission pathway or a certain key brain region, and there is a lack of evidence that connectivity of brain regions is involved in pain or pain regulation in the overall state. The establishment of new experimental tools and techniques has brought light to the study of neural pathways of pain sensation and pain emotion. In this paper, the structure and functional basis of the neural pathways involved in the formation of pain sensation and the regulation of pain emotion in the nervous system above the spinal cord level, including thalamus, amygdala, midbrain periaqueductal gray (PAG), parabrachial nucleus (PB) and medial prefrontal cortex (mPFC), are reviewed in recent years, providing clues for the in-depth study of pain.

Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)-related extrahepatic manifestation that is characterized by the abnormal presence of immune complexes (ICs). This may be due to the reduced uptake and clearance of ICs. The C-type lectin member 18A (CLEC18A) is a secretory protein that is expressed abundantly in hepatocytes. We previously observed that CLEC18A increased significantly in the phagocytes and sera of patients with HCV, particularly those with MC. Herein, we explored the biological functions of CLEC18A in the MC syndrome development of patients with HCV by using an in vitro cell-based assay with quantitative reverse transcription-PCR, immunoblotting, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. HCV infection or Toll-like receptor 3/7/8 activation could induce CLEC18A expression in Huh7.5 cells. Upregulated CLEC18A interacts with Rab5 and Rab7 and enhances type I/III interferon production to inhibit HCV replication in hepatocytes. However, overexpressed CLEC18A suppressed phagocytic activity in phagocytes. Significantly decreased levels of the Fc gamma receptor (FcγR) IIA were found in the neutrophils of HCV patients, particularly in those with MC ( P  < 0.005). We demonstrated that CLEC18A could inhibit FcγRIIA expression in a dose-dependent manner through the production of NOX-2-dependent reactive oxygen species to impair the uptake of ICs. Additionally, CLEC18A suppresses the Rab7 expression that is induced by starvation. Overexpressed CLEC18A does not affect autophagosome formation but does reduce the recruitment of Rab7 to autophagosomes, thereby retarding the maturation of autophagosomes and affecting autophagosome-lysosome fusion. We offer a novel molecular machinery with which to understand the association of HCV infection with autoimmunity and propose that CLEC18A may act as a candidate biomarker for HCV-associated MC. IMPORTANCE During infection, the host immune system produces cellular factors to protect against pathogen invasion. However, when the immune response overreacts and there is dysregulated cytokine homeostasis, autoimmunity occurs following an infection. We identified a cellular factor that is involved in HCV-related extrahepatic manifestation, namely, CLEC18A, which is expressed abundantly in hepatocytes and phagocytes. It inhibits HCV replication in hepatocytes by interacting with Rab5/7 and enhancing type I/III IFN expression. However, overexpressed CLEC18A inhibited FcγRIIA expression in phagocytes to impair phagocytosis. Furthermore, the interaction between CLEC18A and Rab5/7 may reduce the recruitment of Rab7 to autophagosomes and thereby retard autophagosome maturation and cause immune complex accumulation. A decreasing trend in CLEC18A levels that was accompanied by reduced HCV RNA titers and diminished cryoglobulin was observed in the sera of HCV-MC patients after direct-acting antiviral therapy. CLEC18A may be used for the evaluation of anti-HCV therapeutic drug effects and could be a potential predisposing factor for the development of MC syndrome., Competing Interests: The authors declare no conflict of interest.

Halobenzoquinones (HBQs), which are emerging chlorinated disinfection byproducts (DBPs), have attracted increasing attention because they are frequently detected in treated tap water, entrainment water, etc. These compounds are mainly generated during the water treatment process using chlorine, chloramine, and chlorine dioxide as disinfectants, and display more toxic effects than regulated DBPs, such as trihalomethane and haloacetic acid. HBQs have been recognized as potential bladder carcinogens and are harmful to the nervous system. Additionally, they can exert genotoxic effects and cause oxidative damage to DNA and proteins. The risk of HBQs in aquatic products is expected to rise because the disinfection of public facilities has significantly increased in recent years. Therefore, developing a sensitive and accurate analytical method to detect HBQs in aquatic products is of great importance. Several analytical methods, including gas chromatography, gas chromatography-mass spectrometry, electrochemical methods, liquid chromatography, and liquid chromatography-tandem mass spectrometry, can be used to identify and quantify HBQs in water. However, to the best of our knowledge, no reports on the determination of HBQ levels in aquatic products are yet available. Further, pretreatment is essential for HBQ determination because of the complex matrix effects of aquatic products. Herein, a sensitive and accurate method based on the QuEChERS technique coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of five HBQs in aquatic products. For the QuEChERS procedure, the pretreatment conditions, such as the extraction solvent and adsorbent species, were systematically optimized. The sample was extracted with 10 mL of 10% methanol acetonitrile solution (containing 0.1% formic acid), dehydrated, and centrifuged with sodium chloride and anhydrous magnesium sulfate. The supernatant was purified using a QuEChERS packing material consisting of 50 mg N -propylethylenediamine (PSA), 30 mg of graphitized carbon black (GCB), and 30 mg of neutral alumina (Al 2 O 3 ), dried with nitrogen, and concentrated. The five HBQs were separated on a Waters ACQUITY UPLC BEH C 18 column (100 mm×2.1 mm, 1.7 μm) using 0.25% acetonitrile formate solution and 0.25% formic acid aqueous solution as the mobile phase under a gradient elution program and then detected using UPLC-MS/MS with negative electrospray ionization (ESI - ) under multiple reaction monitoring (MRM) mode. Quantitative analysis was performed using a matrix-matched external standard method. The five HBQs achieved rapid separation within 6 min, indicating that the proposed method has a much shorter separation time compared with previous studies. The matrix effect was evaluated by establishing a matrix-matched calibration curve. The results showed that 2,5-dichloro-1,4-benzoquinone (2,5-DCBQ) presented a matrix-enhancing effect, whereas the other HBQs displayed matrix-inhibiting effects. In particular, tetrachlorobenzoquinone (TCBQ) exhibited strong inhibitory effects. Under the optimized experimental conditions, the five HBQs demonstrated good linear relationships in the range of 1.0-50.0 μg/L, with correlation coefficients ( r )≥0.9992. The detection limits of the method were 0.15-0.8 μg/kg, and the recoveries of the target compounds were 85.9%-116.5%. The relative standard deviations were 1.4%-8.2%, which indicates good reproducibility. The proposed method was successfully applied to actual sample detection, and 2,6-dichloro-3-methyl-1,4-benzoquinone (2,6-DCMBQ) was detected in grass carp. The proposed method is convenient, sensitive, accurate, and suitable for the simultaneous determination of five HBQs in aquatic products. Moreover, the developed method provides a reliable reference for the routine monitoring of trace HBQs in food samples.

Purpose: To investigate the effect of collagen sponge on early bone healing process of alveolar fossa after tooth extraction in rats., Methods: A total of 16 healthy female SD rats were selected. Animal models with tooth extraction were established. The right alveolar fossa inserted with collagen sponge was as the experimental group, and the left alveolar fossa was as the control group with treatment. The rats were sacrificed 1, 2, 4 and 8 weeks after tooth extraction, and the osteogenesis of alveolar fossa was observed. Real-time quantitative PCR (qt-PCR) was used to detect the changes of osteogenesis related gene expression. SPSS 19.0 software package was used for statistical analysis., Results: After surgery, alveolar cavity healing was significantly better in the experimental group than in the control group. Osterix, Runx2 and Vegf genes were expressed in the experimental group and the control group, and the expression levels of related genes in the experimental group were significantly higher than the control group 1, 2, 4 and 8 weeks after surgery(P＜0.05)., Conclusions: Collagen sponge could promote early alveolar bone healing, possibly related to the expression level of osteogenic genes regulated by collagen sponge.

Background: Post-traumatic stress disorder (PTSD) is highly prevalent in the individuals at clinical-high risk for psychosis (CHR). The aim of this study was to examine the efficacy and safety of Eye Movement Desensitization and Reprocessing (EMDR) in individuals at CHR with comorbid PTSD or subthreshold PTSD in a randomized controlled trial., Methods: Fifty-seven individuals at CHR with PTSD or subthreshold PTSD formed the study sample. The eligible participants were randomly assigned to a 12 weeks EMDR treatment (N = 28) or a waiting list condition (WL, N = 29). The structured interview for psychosis risk syndrome (SIPS), the clinician administered post-traumatic stress disorder scale (CAPS) and a battery of self-rating inventories covering depressive, anxiety and suicidal symptoms were administered., Results: Twenty-six participants in the EMDR group and all the participants in the WL group completed the study. The analyses of covariance revealed greater reduction of the mean scores on CAPS (F = 23.2, Partial η 2  = 0.3, P < 0.001), SIPS positive scales (F = 17.8, Partial η 2  = 0.25, P < 0.001) and all the self-rating inventories in the EMDR group than in the WL group. Participants in the EMDR group were more likely to achieve remission of CHR compared to those in the WL group at endpoint (60.7 % vs. 31 %, P = 0.025)., Conclusions: EMDR treatment not only effectively improved traumatic symptoms, but also significantly reduced the attenuated psychotic symptoms and resulted in a higher remission rate of CHR. This study highlighted the necessity of adding a trauma-focused component to the present approach of early intervention in psychosis., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Mechanically ventilated patients suffering critical illness are at high risk of developing neurocognitive impairments. Angiotensin type 2 receptor (AGTR2) has been demonstrated to be anti-inflammatory and neuroprotective. The present study thus aimed to investigate whether AGTR2 can alleviate cerebral dysfunction in mice subjected to cochallenge with lipopolysaccharide (LPS) and mechanical ventilation (MV), and to reveal the underlying mechanism. We utilized a mice model that received a single injection of LPS (1 mg/kg, intraperitoneally) followed 2 h later by MV (10 ml/kg, lasting for 2 h). Pretreatment with the AGTR2 pharmacological agonist C21 (0.03, 0.3, and 3 mg/kg, intraperitoneally, once daily, lasting for 10 days). Locomotor activity and behavioral deficits were evaluated 24 h post-MV by open-field and fear-condition tests. Brain hippocampus and prefrontal cortex tissues were collected for immunofluorescence staining and western blotting to evaluate the resulting impacts on microglia, including morphological traits, functional markers, synaptic engulfment, superoxide production, and signaling molecules. Compared with vehicle-control, pre-administrated C21 reduced the branch endpoints and length of microglia processes in a dose-dependent manner in mice subjected to LPS/MV. The neuroprotective effect of AGTR2 was behaviorally confirmed by the improvement of memory decline in LPS/MV-treated mice following C21 pretreatment. In addition to morphological alterations, C21 reduced microglial functional markers and reduced microglial-dendrite contact and microglial engulfment of synaptic protein markers. In terms of the underlying molecular mechanism, AGTR2 stimulation by C21 leads to activation of protein phosphatase 2A, which subsequently mitigates microglial PKCδ and NF-κB activation, and inhibites NOX2-derived ROS production. The AGTR2 agonist C21 alleviates behavioral deficits in those mice subjected to LPS/MV, via mechanisms that involve reactive microglia and abnormal synaptic plasticity in NOX2-derived ROS and the PKCδ-NFκB pathway., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Parity-time (PT) symmetry challenges the long-held theoretical basis that only Hermitian operators correspond to observable phenomena in quantum mechanics. Non-Hermitian Hamiltonians satisfying PT symmetry also have a real-valued energy spectrum. In the field of inductor-capacitor ( LC ) passive wireless sensors, PT symmetry is mainly used for improving performance in terms of multi-parameter sensing, ultrahigh sensitivity, and longer interrogation distance. For example, the proposal of both higher-order PT symmetry and divergent exceptional points can utilize a more drastic bifurcation process around exceptional points (EPs) to accomplish a significantly higher sensitivity and spectral resolution. However, there are still many controversies regarding the inevitable noise and actual precision of the EP sensors. In this review, we systematically present the research status of PT-symmetric LC sensors in three working areas: exact phase, exceptional point, and broken phase, demonstrating the advantages of non-Hermitian sensing concerning classical LC sensing principles.

The study aimed to investigate the cognitive processing of prospective memory (PM) in patients with schizophrenia spectrum disorders (SSDs) by using an eye-tracking paradigm. In addition, the facilitating effects of prosocial intention (the desire to help others) on PM in SSDs were also examined. In phase 1, 26 patients (group1) and 25 healthy controls (HCs) were compared in an eye-tracking PM paradigm in terms of the PM accuracy and eye-tracking indices. In phase 2, 21 more patients (group2) were recruited, and a prosocial intention was introduced in the eye-tracking PM paradigm. Their PM accuracy and eye-tracking indices were compared with those in group1. The PM cue monitoring was indicated by the total fixation counts and fixation time on distractor words. In phase 1, group1 showed lower PM accuracy, fewer fixation counts and less fixation time on distractor words than HCs. In phase 2, group2 (with prosocial intention) performed significantly better than group1 (with typical instruction) on both PM accuracy and fixation time on distractor words. In both groups of SSDs, the PM accuracy was significantly correlated with both the fixation counts and the fixation time of distractor words. After controlling for the cue monitoring indices, the difference in PM accuracy remained significant between group1 and HCs but disappeared between group1 and group2. The cue monitoring deficit contributes to the PM impairment in SSDs. The facilitating effect of prosocial intention disappears after the control of cue monitoring, also indicating its critical role in PM., (© 2023. The Author(s).)

A simple and robust cell culture system is essential for generating authentic SARS-CoV-2 stocks for evaluation of viral pathogenicity, screening of antiviral compounds, and preparation of inactivated vaccines. Evidence suggests that Vero E6, a cell line commonly used in the field to grow SARS-CoV-2, does not support efficient propagation of new viral variants and triggers rapid cell culture adaptation of the virus. We generated a panel of 17 human cell lines overexpressing SARS-CoV-2 entry factors and tested their ability to support viral infection. Two cell lines, Caco-2/AT and HuH-6/AT, demonstrated exceptional susceptibility, yielding highly concentrated virus stocks. Notably, these cell lines were more sensitive than Vero E6 cells in recovering SARS-CoV-2 from clinical specimens. Further, Caco-2/AT cells provided a robust platform for producing genetically reliable recombinant SARS-CoV-2 through a reverse genetics system. These cellular models are a valuable tool for the study of SARS-CoV-2 and its continuously emerging variants., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Preoperative renal dysfunction is associated with mortality in patients with acute type A aortic dissection (ATAAD) repair. However, the long-term outcome of chronic kidney dysfunction (CKD) in ATAAD is unclear. The study aimed to evaluate the long-term outcome of CKD in patients with ATAAD repair. We retrospectively studied patients with ATAAD repair using data from the Taiwan's National Health Insurance Research Database between July 1, 2004, and December 31, 2013. The outcomes of interest included all-cause mortality, readmission due to any cause, redo aortic surgery, major adverse cardiac and cerebrovascular events, and liver and renal outcomes. There were 3328 patients who received ATAAD repair. These patients were divided into CKD and non-CKD groups. In-hospital mortality in the CKD group was significantly higher than that in the non-CKD group (32.5% vs 18.8%, respectively, odds ratio 2.14, 95% confidence interval [CI] 1.37-3.36). During long-term follow-up, patients with CKD had higher risks of all-cause mortality including in-hospital death (52.6% vs 32.5%; hazard ratio 1.83, 95% CI 1.32-2.55), mortality after discharge (29.7% vs 16.8%; hazard ratio 2.09, 95% CI 1.02-4.29), and readmission rates (67.1% vs 51.6%; subdistribution hazard ratio 2.00, 95% CI 1.43-2.79). However, no significant difference was observed between the dialysis and non-dialysis groups. On the basis of our results, patients with CKD carry a poor long-term outcome after ATAAD repair. Cardiac surgeons should be aware of this condition when dealing with ATAAD repair., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Primulinajiulianshanensis F.Wen & G.L.Xu, a new species of Gesneriaceae from Jiulianshan National Nature Reserve of Jiangxi Province, China, is described and illustrated here. Molecular evidence showed it was sister to P.wenii Jian Li & L.J.Yan, while the morphological observation found clear differences between them, petiole, both sides of leaf blades, adaxial surface of the calyx lobes, corolla inside toward the bottom, bract margins covered glandular-pubescent hairs in P.jiulianshanensis ( vs. no glandular-pubescent hairs in P.wenii ); lateral bracts 4-9 × ca. 2 mm, the central one 2-5 × 1-1.5 mm, adaxially glabrous but sparsely pubescent at apex ( vs. lateral bracts 14-16 × 2.5-3.0 mm, the central one 10-12 × 1.3-1.6 mm, all adaxially pubescent); calyx lobes 8-11 × ca. 2 mm, each side with several brown serrate teeth at apex ( vs. 14-15 × ca. 2.5 mm, margin entire); filaments and staminodes sparsely yellow glandular-puberulent ( vs. white, glabrous)., (Guo-Liang Xu, Li-Fen Liang, Di-Ya Chen, Zhi-Fang Jing, Xiao-Hai Zuo, Zheng-Yu Zuo, Fang Wen.)

Alterations in epigenetic regulators are increasingly recognized as early events in tumorigenesis; thus, patients with acquired or inherited variants in epigenetic regulators may be at increased risk for developing multiple types of cancer. DNMT3A overgrowth syndrome (DOS), caused by germline pathogenic variants in the DNA methyltransferase gene DNMT3A , has been associated with a predisposition toward development of hematopoietic and neuronal malignancies. DNMT3A deficiency has been described to promote keratinocyte proliferation in mice. Although altered DNA methylation patterns are well-recognized in melanoma, the role of DNA methyltransferases in melanoma pathogenesis is not clear. We report the case of an adult DOS patient with a germline DNMT3A loss-of-function mutation, who developed an early-onset melanoma with regional lymph node metastatic disease. Exome sequencing of the primary tumor identified an additional acquired, missense DNMT3A mutation in the dominant tumor clone, suggesting that the loss of DNMT3A function was relevant for the development of this tumor., (© 2023 Chen et al.; Published by Cold Spring Harbor Laboratory Press.)

Objectives: Although 1H-nuclear magnetic resonance (NMR)-based lipid/metabolomics has been used to detect atherosclerosis, data regarding lipid/metabolomic signature in rheumatoid arthritis (RA)-related atherosclerosis are scarce. We aimed to identify the distinct lipid/metabolomic profiling and develop a prediction score model for RA patients with subclinical atherosclerosis (SA)., Methods: Serum levels of lipid metabolites were determined using 1H-NMR-based lipid/metabolomics in 65 RA patients and 12 healthy controls (HCs). The occurrence of SA was defined as the presence of carotid plaques revealed in ultrasound images., Results: Compared with HC, RA patients had significantly higher levels of phenylalanine and glycoprotein acetyls (GlycA) and lower levels of leucine and isoleucine. RA patients with SA had significantly higher levels of phenylalanine, creatinine, and glycolysis&#95;total and lower levels of total lipid in HDL(HDL&#95;L) than RA patients without SA. The Lasso logistic regression analysis revealed that age, creatinine, HDL&#95;L, and glycolysis&#95;total were significant predictors for the presence of SA. The prediction scoring algorithm was built as ( -0.657 + 0.011*Age + 0.004*Creatinine -0.120*HDL&#95;L + 0.056*glycolysis-related measures), with AUC 0.90, sensitivity 83.3%, and specificity 87.2%. Serum phenylalanine levels were significantly decreased, and the levels of HDL&#95;L and HDL&#95;Particle were significantly increased in 20 RA patients, paralleling the decrease in disease activity score for 28-joints., Conclusions: With 1H-NMR-based lipid/metabolomics, distinct profiling of lipid metabolites was identified between RA patients and HC or between RA patients with and without SA. We further developed a scoring model based on lipid/metabolomics profiling for predicting RA-associated SA.

Introduction: Slow wound repair in diabetes is a serious adverse event that often results in loss of a limb or disability. An advanced and encouraging vehicle is wanted to enhance clinically applicable diabetic wound care. Nanofibrous insulin/vildagliptin core-shell biodegradable poly (lactic-co-glycolic acid) (PLGA) scaffolds to prolong the effective drug delivery of vildagliptin and insulin for the repair of diabetic wounds were prepared. Methods: To fabricate core-shell nanofibrous membranes, vildagliptin mixture with PLGA, and insulin solution were pumped via separate pumps into two differently sized capillary tubes that were coaxially electrospun. Results and Discussion: Nanofibrous core-shell scaffolds slowly released effective vildagliptin and insulin over 2 weeks in vitro migration assay and in vivo wound-healing models. Water contact angle (68.3 ± 8.5° vs. 121.4 ± 2.0°, p = 0.006) and peaked water absorbent capacity (376% ± 9% vs. 283% ± 24%, p = 0.003) of the insulin/vildagliptin core-shell nanofibrous membranes remarkably exceeded those of a control group. The insulin/vildagliptin-loaded core-shell nanofibers improved endothelial progenitor cells migration in vitro (762 ± 77 cells/mm 2 vs. 424.4 ± 23 cells/mm 2 , p < 0.001), reduced the α-smooth muscle actin content in vivo (0.72 ± 0.23 vs. 2.07 ± 0.37, p < 0.001), and increased diabetic would recovery (1.9 ± 0.3 mm 2 vs. 8.0 ± 1.4 mm 2 , p = 0.002). Core-shell insulin/vildagliptin-loaded nanofibers extend the drug delivery of insulin and vildagliptin and accelerate the repair of wounds associated with diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Chen, Hsieh, Hung, Huang, Cho and Liu.)

In consideration of the severe hazards of radioactive uranium pollution and the growing demand of uranium resources, the novel sensor/adsorbent composite was creatively developed to integrate the dual functions for on-site detection of uranium contamination and efficient recovery of uranium resources. By hybridizing the luminescent 3D terbium (III) metal-organic framework (Tb-MOF) with sodium alginate (SA) gel using terbium (III) as cross-linker, the Tb-MOF/Tb-AG was fabricated with multi-luminescence centers and sufficient binding sites for uranium. Notably, the ultra-high sensitivity with detection limit as low as 1.2 ppt was achieved, which was 4 orders of magnitude lower than the uranium contamination standard in drinking water (USEPA) and even comparable to the sensitivity of the ICP-MS. Furthermore, the very wide quantification range (1.0 ×10 -9 -5.0 ×10 -4 mol/L), remarkable adsorption capacity (549.0 mg/g) and outstanding anti-interference ability have been achieved without sophisticated sample preparation procedures. Applied in complex natural water samples from Uranium Tailings and the Pearl River, this method has shown good detection accuracy. The ultra high sensitivity and great adsorption capacity for uranium could be ascribed to the synergistic coordination, hydrogen bonding and ion exchange between uranium and Tb-MOF/Tb-AG. The mechanisms were explored by infrared spectroscopy, batch experiments, X-ray photoelectron studies and energy dispersive spectroscopic studies. In addition, the Tb-MOF/Tb-AG can be reused for uranium adsorption., Competing Interests: Declaration of Competing Interest The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: The diagnosis of adult-onset Still's disease (AOSD) is often delayed due to its clinical heterogeneity and lack of pathognomic features. Hence, there is an unmet need for an efficient diagnostic process. The major aim of this study was to compare the differences in disease outcomes between two groups of AOSD patients with and without implementation of the streamlined diagnostic process (SDP)., Methods: Of 172 febrile patients with skin rash and/or arthralgia, 112 individuals had AOSD. The tentative diagnosis of AOSD or non-AOSD was made with or without the SDP implementation. The selection criteria for AOSD outcomes analysis were as follows: (1) age at study entry older than 20 years, (2) fulfillment of the Yamaguchi criteria for AOSD diagnosis, and (3) a follow-up period longer than 6 months after initiation of therapy. Three outcome parameters were evaluated, including diagnosis lag period, the proportion of "early diagnosis," and the proportion of achieving disease remission after a 6-month therapy., Results: The SDP was implemented for expediting AOSD diagnosis in 41 (36%) enrolled patients (SDP-implemented group). The diagnosis lag period was significantly shorter in the SDP-implemented group (median 2.0 weeks, interquartile range [IQR] 1.0-2.5 weeks) than in the non-SDP-implemented group (4.0 weeks, IQR 2.0-6.0 weeks, p < 0.001). A significantly higher proportion of "early diagnosis" was also found in the SDP-implemented group (75.6%) compared with the non-SDP-implemented group (33.8%, p < 0.001). We revealed a significantly higher proportion of achieving remission in the SDP-implemented group (85.4%) compared with the non-SDP-implemented group (67.6%, p < 0.05). Logistic regression analysis revealed SDP implementation as a potential predictor of achieving disease remission., Conclusions: Implementing an SDP for expediting diagnosis could improve outcomes for AOSD patients. This diagnostic process increased the early diagnosis rate and led to a higher disease remission rate. However, the beneficial effects of SDP implementation need further external validation., (© 2022. The Author(s).)

Animals living in estuaries suffer from rapid and continuous salinity fluctuations, while the global warming and extreme precipitation aggravate this situation. Osmoregulation is important for estuarine animals adapt to salinity fluctuations. The present study investigated the effects of low salinity stress on osmoregulation and gill transcriptome in two populations of mud crab from Hangzhou Bay and Zhangzhou Bay of China, respectively. Crabs were transferred from salinity 25 ppt to 5 ppt for 96 h. Edematous swelling in gill filaments was caused by low salinity stress and was more serious in Zhangzhou Bay population. Gill Na + /K + -ATPase activity increased (p < 0.01) in both populations under the low salinity stress and was significantly higher (p < 0.01) in Hangzhou Bay population than in Zhangzhou Bay population. According to transcriptome analysis, there were 191 genes differentially expressed under the low salinity stress in gill tissue of both populations. Several ion transport and energy metabolism related pathways, as well as the arginine and proline metabolism pathway, were enriched by these genes. On the other hand, 272 genes were identified to differentially express between two populations under the low salinity stress, but not under the control salinity. The enrichment analysis showed that these genes were mainly related to ion transport, energy metabolism, osmolytes metabolism and methyltransferase activity. In conclusion, the present study suggested that mud crab exploited a combination of extracellular anisosmotic regulation and intracellular isosmotic regulation for osmoregulation under the low salinity stress. Hangzhou Bay population showed a greater osmoregulatory capacity, which is probably due to the enhanced ion transport, energy supply, and osmolytes regulation. Meanwhile, epigenetic modification might also contribute to an inherent osmoregulation ability for Hangzhou Bay population to response to salinity fluctuation rapidly., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Infection is a significant risk factor that impacts for perioperative morbidity and mortality in liver transplantation (LTx) patients and is difficult to evaluate quantitatively in the early posttransplantation period. Thus, a biomarker to assess the risk of infection and the prognosis of the recipient is highly desirable., Methods: A total of 128 consecutive patients with end-stage liver diseases undergoing LTx between January 1, 2020 and December 31, 2021, at the First Affiliated Hospital of Zhejiang University School of Medicine, were screened retrospectively. Graft preservation fluid and blood samples were collected for culture, and other perioperative laboratory examination results were recorded, for assessment of infection status., Results: After a follow-up period of 30 days, the survival rate among the 128 LTx recipients was 94.5%. Multivariable regression analysis showed that the logarithmically transformed neutrophil-to-lymphocyte ratio (NLR) (HR = 3.548, 95% CI: ; p = .041) on post-LTx day 1 and graft preservation fluid culture positivity (HR = 12.032, 95% CI: ; p = .006) were independent predictive factors for early prognosis after LTx., Conclusions: Positive graft preservation fluid culture and the logarithmically transformed NLR on post-LTx day 1 were independent predictive factors for early prognosis after LTx. The logarithmically transformed NLR could provide an earlier indication than culture results in clinical practice., (© 2022 Wiley Periodicals LLC.)

Background: Long-term smoking is a risk factor for chronic pain, and chronic nicotine exposure induces pain-like effects in rodents. The anterior cingulate cortex (ACC) has been demonstrated to be associated with pain and substance abuse. This study aims to investigate whether ACC microglia are altered in response to chronic nicotine exposure and their interaction with ACC neurons and subsequent nicotine-induced allodynia in mice., Methods: We utilized a mouse model that was fed nicotine water for 28 days. Brain slices of the ACC were collected for morphological analysis to evaluate the impacts of chronic nicotine on microglia. In vivo calcium imaging and whole-cell patch clamp were used to record the excitability of ACC glutamatergic neurons., Results: Compared to the vehicle control, the branch endpoints and the length of ACC microglial processes decreased in nicotine-treated mice, coinciding with the hyperactivity of glutamatergic neurons in the ACC. Inhibition of ACC glutamatergic neurons alleviated nicotine-induced allodynia and reduced microglial activation. On the other hand, reactive microglia sustain ACC neuronal excitability in response to chronic nicotine, and pharmacological inhibition of microglia by minocycline or liposome-clodronate reduces nicotine-induced allodynia. The neuron-microglia interaction in chronic nicotine-induced allodynia is mediated by increased expression of neuronal CX3CL1, which activates microglia by acting on CX3CR1 receptors on microglial cells., Conclusion: Together, these findings underlie a critical role of ACC microglia in the maintenance of ACC neuronal hyperactivity and resulting nociceptive hypersensitivity in chronic nicotine-treated mice., (© 2023. The Author(s).)

Background: A U-shaped relationship between temperature and acute myocardial infarction (AMI) was observed, but the risk factors were rarely included., Objectives: The authors sought to examine AMI's cold and heat exposure after considering their risk groups., Methods: Daily data on ambient temperature, newly diagnosed AMI, and 6 known risk factors of AMI for the Taiwan population from 2000 to 2017 were created by linking 3 Taiwan national databases. Hierarchical clustering analysis was performed. Poisson regression was performed on the AMI rate with the clusters along with the daily minimum temperature in cold months (November-March) and the daily maximum temperature in hot months (April-October)., Results: There were 319,737 patients with new-onset AMI over 109.13 billion person-days, corresponding to the incidence rate of 107.02 per 100,000 person-years (95% CI: 106.64-107.39 person-years). Hierarchical clustering analysis identified 3 distinct clusters (1: age <50 years, 2: age ≥50 years without hypertension, and 3: mainly age ≥50 years with hypertension) with AMI incidence rates of 16.04, 105.13, and 388.17 per 100,000 person-years, respectively. Poisson regression revealed that below 15 °C, cluster 3 had the highest risk of AMI per 1°C reduce in temperature (slope = 1.011) compared with clusters 1 (slope = 0.974) and 2 (slope = 1.009). However, above the 32 °C thresholds, cluster 1 had the highest risk of AMI per 1 °C increase in temperature (slope = 1.036) compared with clusters 2 (slope = 1.02) and 3 (slope = 1.025). Cross validation showed a good fit for the model., Conclusions: People ≥50 years of age with hypertension are more susceptible to cold-related AMI. However, heat-related AMI is more prominent in individuals <50 years of age., Competing Interests: This study was supported by Chang Gung Memorial Hospital (CMRPD1K0353). The funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Objectives: To investigate the difference in renal function outcomes for patients with oncocytomas undergoing active surveillance (AS) vs. partial nephrectomy (PN)., Methods: We reviewed our institutional database for patients with biopsy/surgically confirmed oncocytoma from 2000-2020. The primary outcome was to assess for differences in renal function outcomes in patients undergoing AS vs. PN. We fit two generalized estimating equation (GEE) with an interaction term between follow up time and management strategy to predict 1) mean eGFR for patients managed with AS and PN and 2) the probability of progression to CKD stage III or greater., Results: We identified 114 eligible patients, of which 32 were managed with AS. Median follow-up was 21 months vs. 44 months for PN vs. AS patients. AS patients tended to be older (median: 72 years vs. 65 years, P<0.001) and have lower baseline renal function (median: eGFR: 71 mL/min/1.73m 2 vs. 82 mL/min/1.73m 2 , P<0.001) compared with PN patients. Renal mass size from baseline imaging was similar between patients undergoing PN vs. AS (2.8 cm vs. 2.9 cm, P=0.634). For patients undergoing PN vs. AS, there was not a significant difference in predicted longitudinal eGFR (-0.079, 95% CI -0.18-0.023, P=0.129) or predicted probability of progression to CKD stage III or greater (OR: 0.61, 95% CI: 0.16-2.33, P=0.47)., Conclusions: In our institutional dataset, patients undergoing AS or PN with an oncocytoma had similar long-term renal function outcomes. Given similar renal function outcomes in patients undergoing AS and PN, surgery should remain reserved for select patients with oncocytomas., Competing Interests: Declaration of Competing Interest Kevin Ginsburg certifies that none of the authors have any direct or indirect conflicts of interest pertaining to this research., (Copyright © 2022. Published by Elsevier Inc.)

The SARS-CoV-2 Omicron variant is more immune evasive and less virulent than other major viral variants that have so far been recognized 1-12 . The Omicron spike (S) protein, which has an unusually large number of mutations, is considered to be the main driver of these phenotypes. Here we generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron (BA.1 lineage) in the backbone of an ancestral SARS-CoV-2 isolate, and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escaped vaccine-induced humoral immunity, mainly owing to mutations in the receptor-binding motif; however, unlike naturally occurring Omicron, it efficiently replicated in cell lines and primary-like distal lung cells. Similarly, in K18-hACE2 mice, although virus bearing Omicron S caused less severe disease than the ancestral virus, its virulence was not attenuated to the level of Omicron. Further investigation showed that mutating non-structural protein 6 (nsp6) in addition to the S protein was sufficient to recapitulate the attenuated phenotype of Omicron. This indicates that although the vaccine escape of Omicron is driven by mutations in S, the pathogenicity of Omicron is determined by mutations both in and outside of the S protein., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Neutralizing anti-interferon (IFN)-γ autoantibodies are linked to adult-onset immunodeficiency and opportunistic infections., Methods: To explore whether anti-IFN-γ autoantibodies are associated with disease severity of coronavirus disease 2019 (COVID-19), we examined the titers and functional neutralization of anti-IFN-γ autoantibodies in COVID-19 patients. In 127 COVID-19 patients and 22 healthy controls, serum titers of anti-IFN-γ autoantibodies were quantified using enzyme-linked immunosorbent assay, and the presence of autoantibodies was verified with immunoblotting assay. The neutralizing capacity against IFN-γ was evaluated with flow cytometry analysis and immunoblotting, and serum cytokines levels were determined using the MULTIPLEX platform., Results: A higher proportion of severe/critical COVID-19 patients had positivity for anti-IFN-γ autoantibodies (18.0%) compared with non-severe patients (3.4%, p < 0.01) or healthy control (HC) (0.0%, p < 0.05). Severe/critical COVID-19 patients also had higher median titers of anti-IFN-γ autoantibodies (5.01) compared with non-severe patients (1.33) or HC (0.44). The immunoblotting assay could verify the detectable anti-IFN-γ autoantibodies and revealed more effective inhibition of signal transducer and activator of transcription (STAT1) phosphorylation on THP-1 cells treated with serum samples from anti-IFN-γ autoantibodies-positive patients compared with those from HC (2.21 ± 0.33 versus 4.47 ± 1.64, p < 0.05). In flow-cytometry analysis, sera from autoantibodies-positive patients could also significantly more effectively suppress the STAT1 phosphorylation (median,67.28%, interquartile range [IQR] 55.2-78.0%) compared with serum from HC (median,106.7%, IQR 100.0-117.8%, p < 0.05) or autoantibodies-negative patients (median,105.9%, IQR 85.5-116.3%, p < 0.05). Multivariate analysis revealed that the positivity and titers of anti-IFN-γ autoantibodies were significant predictors of severe/critical COVID-19. Compared with non-severe COVID-19 patients, we reveal that a significantly higher proportion of severe/critical COVID-19 patients are positive for anti-IFN-γ autoantibodies with neutralizing capacity., Conclusion: Our results would add COVID-19 to the list of diseases with the presence of neutralizing anti-IFN-γ autoAbs. Anti-IFN-γ autoantibodies positivity is a potential predictor of severe/critical COVID-19., (© 2023. The Author(s).)

Cutaneous squamous cell carcinoma (cSCC) has among the highest mutation burdens of all cancers, reflecting its pathogenic association with the mutagenic effects of UV light exposure. Although mutations in cancer-relevant genes such as TP53 and NOTCH1 are common in cSCC, they are also tolerated in normal skin and suggest that other events are required for transformation; it is not yet clear whether epigenetic regulators cooperate in the pathogenesis of cSCC. KDM6A encodes a histone H3K27me2/me3 demethylase that is frequently mutated in cSCC and other cancers. Previous sequencing studies indicate that roughly 7% of cSCC samples harbor KDM6A mutations, including frequent truncating mutations, suggesting a role for this gene as a tumor suppressor in cSCC. Mice with epidermal deficiency of both Kdm6a and Trp53 exhibited 100% penetrant, spontaneous cSCC development within a year, and exome sequencing of resulting tumors reveals recurrent mutations in Ncstn and Vcan. Four of 16 tumors exhibited deletions in large portions of chromosome 1 involving Ncstn, whereas another 25% of tumors harbored deletions in chromosome 19 involving Pten, implicating the loss of other tumor suppressors as cooperating events for combined KDM6A- and TRP53-dependent tumorigenesis. This study suggests that KDM6A acts as an important tumor suppressor for cSCC pathogenesis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)