Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.

BACKGROUND: The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats (Uchl1-/-), and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1-/- animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice (Gadd45α-/-) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

Risk factors of neonatal stroke from different origins: a systematic review and meta-analysis.

Given the persistent ambiguity regarding the etiology of neonatal stroke across diverse origins, our objective was to conduct a comprehensive evaluation of both qualitative and quantitative risk factors. An exhaustive search of eight databases was executed to amass all pertinent observational studies concerning risk factors for neonatal stroke from various origins. Subsequent to independent screening, data extraction, and bias assessment by two researchers, a meta-analysis was conducted utilizing RevMan and Stata software. Nineteen studies, encompassing a total of 30 factors, were incorporated into this analysis. Beyond established risk factors, our investigation unveiled gestational diabetes (OR, 5.51; P < 0.00001), a history of infertility (OR, 2.44; P < 0.05), placenta previa (OR, 3.92; P = 0.02), postdates (OR, 2.07; P = 0.01), preterm labor (OR, 2.32; P < 0.00001), premature rupture of membranes (OR, 3.02; P = 0.007), a prolonged second stage of labor (OR, 3.94; P < 0.00001), and chorioamnionitis (OR, 4.35; P < 0.00001) as potential risk factors for neonatal cerebral arterial ischemic stroke. Additionally, postdates (OR, 4.31; P = 0.003), preterm labor (OR, 1.60; P < 0.00001), an abnormal CTG tracing (OR, 9.32; P < 0.0001), cesarean section (OR, 4.29; P = 0.0004), male gender (OR, 1.73; P = 0.02), and vaginal delivery (OR, 1.39; P < 0.00001) were associated with an elevated risk for neonatal hemorrhagic stroke. CONCLUSIONS: This study provides a succinct overview and comparative analysis of maternal, perinatal, and additional risk factors associated with neonatal cerebral artery ischemic stroke and neonatal hemorrhagic stroke, furnishing critical insights for healthcare practitioners involved in the diagnosis and prevention of neonatal stroke. This research also broadens the conceptual framework for future investigations. WHAT IS KNOWN: • Research indicates that prenatal, perinatal, and neonatal risk factors can elevate the risk of neonatal arterial ischemic stroke (NAIS). However, the risk factors for neonatal cerebral arterial ischemic stroke remain contentious, and those for neonatal hemorrhagic stroke (NHS) and neonatal cerebral venous sinus thrombosis (CVST) are still not well-defined. WHAT IS NEW: • This study is the inaugural comprehensive review and meta-analysis encompassing 19 studies that explore maternal, perinatal, and various risk factors linked to neonatal stroke of differing etiologies. Notably, our analysis elucidates eight risk factors associated with NAIS: gestational diabetes mellitus, a history of infertility, placenta previa, postdates, preterm birth, premature rupture of membranes, a prolonged second stage of labor, and chorioamnionitis. Furthermore, we identify six risk factors correlated with NHS: postdates, preterm birth, an abnormal CTG, the method of delivery, male gender, and vaginal delivery. Additionally, our systematic review delineates risk factors associated with CVST.

TGFß1 Stimulates the Proliferation of Quiescent Oogonial Stem Cells in Chicken.

Oogonial stem cells (OSCs) are a type of germ stem cell present in the adult ovary. They have the ability to self-renew through mitosis and differentiate into oocytes through meiosis. We have previously identified a population of OSCs in chicken ovary, but the underlying mechanism control their activation and proliferation were unclear. In this study, we observed that OSCs showed robust proliferation when cultured on a layer of chicken embryo fibroblasts (CEF), suggesting that CEF may secrete certain crucial factors that activate OSC proliferation. We further detected Transforming Growth Factor beta 1 (TGF-ß1) as a potent signaling molecule to promote OSC proliferation. Additionally, we revealed the signaling pathways that play important roles in the downstream of TGF-ß1-induced OSC proliferation. These findings provide insights into the mechanisms underlying OSC proliferation in chickens and offer a foundation for future research on in situ activation of OSC proliferation in ovary and improvement of egg-laying performance in chickens.

[Cloning and functional analysis of AcFMO from onion during alliine biosynthesis].

Flavin-containing monooxygenase (FMO) is the key enzyme in the biosynthesis pathway of CSOs with sulfur oxidation. In order to explore the molecular regulatory mechanism of FMO in the synthesis of onion CSOs, based on transcriptome database and phylogenetic analysis, one AcFMO gene that may be involved in alliin synthesis was obtained, the AcFMO had a cDNA of 1 374 bp and encoded 457 amino acids, which was evolutionarily closest to the AsFMO of garlic. Real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) indicated that AcFMO was the highest in the flowers and the lowest in the leaf sheaths. The results of subcellular localization showed that the AcFMO gene product was widely distributed throughout the cell A yeast expression vector was constructed, and the AcFMO gene was ecotopically overexpressed in yeast to further study the enzyme function in vitro and could catalyze the synthesis of alliin by S-allyl-l-cysteine. In summary, the cloning and functional identification of AcFMO have important reference value for understanding the biosynthesis of CSOs in onions.

Reconstructing dynamics correlation network to simultaneously improve activity and stability of 2,3-butanediol dehydrogenase by design of distal interchain disulfide bonds.

The complete enzyme catalytic cycle includes substrate binding, chemical reaction and product release, in which different dynamic conformations are adopted. Due to the complex relationship among enzyme activity, stability and dynamics, the directed evolution of enzymes for improved activity or stability commonly leads to a trade-off in stability or activity. It hence remains a challenge to engineer an enzyme to have both enhanced activity and stability. Here, we have attempted to reconstruct the dynamics correlation network involved with active center to improve both activity and stability of a 2,3-butanediol dehydrogenase (2,3-BDH) by introducing inter-chain disulfide bonds. A computational strategy was first applied to evaluate the effect of introducing inter-chain disulfide bond on activity and stability of three 2,3-BDHs, and the N258C mutation of 2,3-BDH from Corynebacterium glutamicum (CgBDH) was proved to be effective in improving both activity and stability. In the results, CgBDH-N258C showed a different unfolding curve from the wild type, with two melting temperatures (Tm) of 68.3 °C and 50.8 °C, 19.7 °C and 2 °C higher than 48.6 °C of the wild type. Its half-life was also improved by 14.8-fold compared to the wild type. Catalytic efficiency (kcat/Km) of the mutant was increased by 7.9-fold toward native substrate diacetyl and 8.8-fold toward non-native substrate 2,5-hexanedione compared to the wild type. Molecular dynamics simulations revealed that an interaction network formed by Cys258, Arg162, Ala144 and the catalytic residues was reconstructed in the mutant and the dynamics change caused by the disulfide bond could be propagated through the interactions network. This improved the enzyme stability and activity by decreasing the flexibility and locking more "reactive" pose, respectively. Further construction of mutations including A144G showing a 44-fold improvement in catalytic efficiency toward meso-2,3-BD confirmed the role of modifying dynamics correlation network in tunning enzyme activity and selectivity. This study provided important insights into the relationship among dynamics, enzyme catalysis and stability, and will be useful in the designing new enzymes with co-evolution of stability, activity and selectivity.

Durable Effects of Acupuncture for Knee Osteoarthritis: A Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Knee osteoarthritis (KOA) is a degenerative joint disease which can result in chronic pain and disability. The current interventions available for KOA often fail to provide long-lasting effects, highlighting the need for new treatment options that can offer durable benefits. Previous studies have suggested the efficacy of acupuncture for knee osteoarthritis (KOA) with its durability remaining uncertain. In this review, we aimed to investigate the durability of the efficacy after completion of treatment. RECENT FINDINGS: We performed thorough searches of PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials from inception to November 4, 2023. The outcomes were assessed at all available time points after completion of treatment. Primary outcomes were changes from baseline in pain and function measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function subscales. Secondary outcomes included response rate, overall pain, the WOMAC stiffness subscale, total WOMAC index, and physical and mental health components of 12/36-item Short-Form Health Survey. A total of 10 randomized controlled trials (RCTs) involving 3221 participants were included. Pooled estimates suggested that acupuncture may offer potential improvements in function and overall pain for 4.5 months post-treatment versus sham acupuncture (SA). Acupuncture may provide durable clinically important pain relief and functional improvement up to 5 months post-treatment versus usual care, and up to 6 months post-treatment versus diclofenac. For acupuncture versus no treatment, one trial with large sample size indicated that improvements in pain and function persisted for 3 months post-treatment, while the other trial reported that significant pain reduction and functional improvement were only observed at the end of the treatment, not at 9 months post-treatment. However, acupuncture as adjunct to exercise-based physical therapy (EPT) showed no superiority to SA as an adjunct to EPT or EPT alone up to 11.25 months after completion of treatment. Acupuncture may provide pain alleviation and functional improvements in KOA patients for 3 to 6 months after completion of treatment with a good safety profile.

Sleep-disordered breathing and nocturnal hypoxemia in chronic thromboembolic pulmonary disease.

BACKGROUND AND AIMS: Sleep-disordered breathing (SDB) and nocturnal hypoxemia were known to be present in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the difference between SDB and nocturnal hypoxemia in patients who have chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension (PH) at rest remains unknown. METHODS: Patients who had CTEPH (n = 80) or CTEPD without PH (n = 40) and who had undergone sleep studies from July 2020 to October 2022 at Shanghai Pulmonary Hospital were enrolled. Nocturnal mean SpO2 (Mean SpO2) <90% was defined as nocturnal hypoxemia, and the percentage of time with a saturation below 90% (T90%) exceeding 10% was used to evaluate the severity of nocturnal hypoxemia. Logistic and linear regression analyses were performed to investigate the difference and potential predictor of SDB or nocturnal hypoxemia between CTEPH and CTEPD without PH. RESULTS: SDB was similarly prevalent in CTEPH and CTEPD without PH (P = 0.104), both characterised by obstructive sleep apnoea (OSA). Twenty-two patients with CTEPH were diagnosed with nocturnal hypoxemia, whereas only three were diagnosed with CTEPD without PH (P = 0.021). T90% was positively associated with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance in patients with CTEPH and CTEPD without PH (P < 0.001); T90% was also negatively related to cardiac output in these patients. Single-breath carbon monoxide diffusing capacity, sex and mPAP were all correlated with nocturnal hypoxemia in CTEPH and CTEPD without PH (all P < 0.05). CONCLUSION: Nocturnal hypoxemia was worse in CTEPD with PH; T90%, but not SDB, was independently correlated with the hemodynamics in CTEPD with or without PH.

High ambient temperature may increase the risk of anemia in pregnancy: Identifying susceptible exposure windows.

Anemia in pregnancy (AIP) is associated with multiple severe maternal and perinatal adverse outcomes. However, there is a lack of evidence on the association between environmental factors and AIP. Aim to explore the association between ambient temperature and the risk of AIP, and identify susceptible exposure windows, we conducted a matched case-control study from 2013 to 2016 in Xi'an, China, which included 710 women with AIP and 1420 women without AIP. The conditional logistic regression model was used to evaluate the association between ambient temperature and AIP at different gestational weeks and gestational months. The association between extreme temperature and AIP was evaluated using the distributed lag nonlinear model (DLNM). We conducted stratified analyses of age, parity, and season of conception, and estimated the interaction between ambient temperature and air pollutants on AIP. Ambient temperature was significantly positively associated with the risk of AIP, and the susceptible exposure windows were 2-25 gestational weeks and 1-6 gestational months, respectively. The strongest effect was observed in the week 8 and month 2, for each 1 °C increase in weekly and monthly mean temperature, the odds ratio (OR) for AIP was 1.038 (95 % confidence interval (CI): 1.022, 1.055) and 1.040 (95 % CI: 1.020, 1.060), respectively. Extreme heat may increase the risk of AIP. Stratified analyses showed that there was no significant difference among different age, parity, and season of conception groups. No significant interaction effect of ambient temperature with air pollution on AIP was found. In summary, high ambient temperature may increase the risk of AIP, and the first and second trimesters may be susceptible exposure windows. Understanding the effect of temperature on pregnant women will be beneficial to reduce the occurrence of AIP.

CircALMS1 Alleviates Pulmonary Microvascular Endothelial Cell Dysfunction in Pulmonary Hypertension.

BACKGROUND: Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains undefined. Thus, we aimed to identify specifically expressed circular RNAs in pulmonary microvascular endothelial cells (PMECs) under hypoxia and PH. METHODS AND RESULTS: Deep RNA sequencing and quantitative real-time polymerase chain reaction revealed that circALMS1 (circular RNA Alstrom syndrome protein 1) was reduced in human PMECs under hypoxia (P<0.0001). Molecular biology and histopathology experiments were used to elucidate the roles of circALMS1 in regulating PMEC dysfunction among patients with PH. The circALMS1 expression was decreased in the plasma of patients with PH (P=0.0315). Patients with lower circALMS1 levels had higher risk of death (P=0.0006). Moreover, the circALMS1 overexpression of adeno-associated viruses improved right ventricular function and reduced pulmonary vascular remodeling in monocrotaline-PH and sugen/hypoxia-PH rats (P<0.05). Furthermore, circALMS1 overexpression promoted apoptosis and inhibited PMEC proliferation and migration under hypoxia by directly downregulating miR-17-3p (P<0.05). Dual luciferase assay confirmed the direct binding of circALMS1 to miR-17-3p and miR-17-3p binding to its target gene YT521-B homology domain-containing family protein 2 (YTHDF2) (P<0.05). The YTHDF2 levels were also downregulated in hypoxic PMECs (P<0.01). The small interfering RNA YTHDF2 reversed the effects of miR-17-3p inhibitors on PMEC proliferation, migration, and apoptosis. Finally, the results indicated that, although YTHDF2, as an N(6)-methyladenosine reader protein, contributes to the degradation of many circular RNAs, it could not regulate the circALMS1 levels in PMECs (P=0.9721). CONCLUSIONS: Our study sheds new light on circALMS1-regulated dysfunction of PMECs by the miR-17-3p/YTHDF2 pathway under hypoxia and provides insights into the underlying pathogenesis of PH.

Impact on early outcome after endovascular repair of type B dissection without proximal landing zone using Castor single-branched stent graft-a retrospective cohort study.

Background: The early safety and efficacy of Castor branch stents have been demonstrated. However, the effect of aortic arch morphology on endovascular therapy remains an unresolved issue. This study aims to assess the impact of aortic arch morphology on the early outcomes of endovascular repair using Castor stent graft in patients who have acute type B aortic dissection involving the left subclavian artery (LSA). Methods: This is a retrospective cohort study. From January 2019 to December 2021, forty-one patients scheduled for thoracic endovascular aortic repair (TEVAR) of TBADs from Beijing Anzhen Hospital were enrolled in this retrospective cohort study and divided into two groups based on the length of the proximal landing zone left common carotid artery-LSA (PLZ LCCA-LSA), specifically the distance between the LCCA and the LSA (group A ≤10 mm and group B >10 mm). The study recorded technical success, mortality and aortic-related post-operative adverse events. Morphological indices were analyzed including the bird-beak configuration. The bird-beak configuration refers to the wedge-shaped gap between the undersurface of the endograft and the lesser curvature of the arch. The relationship between the risk of bird-beak configuration and PLZ was assessed with logistic regression analysis. Meanwhile, the relationship between the risk of aortic-related adverse events and bird-beak configuration was assessed with logistic regression analysis. Follow-up data were analyzed by Kaplan-Meier life table analysis. Results: The study included 41 patients with a mean age of 63.1±9.2 years, of which 80.5% were male. 18 patients from group A and 23 patients from group B were included in the comparative analysis. There were no significant differences in aortic-related adverse events, bird-beak phenomenon and re-intervention between groups A and B in 30-day outcomes. Six-month outcomes: aortic-related adverse events and the bird-beak phenomenon were observed in 11 (26.8%) and 12 (29.3%) patients, respectively. There was a significant difference in the occurrence of aortic-related adverse events (P=0.036) and bird-beak phenomenon (P=0.002) between groups A and B. In comparison to group B, the aortic-related adverse event rate was significantly higher in group A, with event-free rates of 83.3%, 83.3%, and 72.2% at 1, 3, and 6 months, respectively (P=0.020). Multivariable logistic regression analyses revealed that PLZ LCCA-LSA length [odds ratio (OR) 0.79; 95% CI: 0.64 to 0.97; P=0.026] was significantly associated with the occurrence of the bird-beak configuration, and bird-beak (OR 17.19; 95% CI: 2.24 to 131.81; P=0.006) was a significant risk factor for aortic-related adverse events. Conclusions: TEVAR with LSA revascularization has good early outcomes. However, it is more susceptible to aortic adverse events when the PLZ LCCA-LSA is less than 10 mm in length. This should be carefully considered, taking into account the risks and benefits.

Neural stem cell-derived exosomes regulate cell proliferation, migration, and cell death of brain microvascular endothelial cells via the miR-9/Hes1 axis under hypoxia.

BACKGROUND: Our previous study found that mouse embryonic neural stem cell (NSC)-derived exosomes (EXOs) regulated NSC differentiation via the miR-9/Hes1 axis. However, the effects of EXOs on brain microvascular endothelial cell (BMEC) dysfunction via the miR-9/Hes1 axis remain unknown. Therefore, the current study aimed to determine the effects of EXOs on BMEC proliferation, migration, and death via the miR-9/Hes1 axis. METHODS: Immunofluorescence, quantitative real-time polymerase chain reaction, cell counting kit-8 assay, wound healing assay, calcein-acetoxymethyl/propidium iodide staining, and hematoxylin and eosin staining were used to determine the role and mechanism of EXOs on BMECs. RESULTS: EXOs promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions. The overexpression of miR-9 promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions. Moreover, miR-9 downregulation inhibited BMEC proliferation and migration and also promoted cell death. Hes1 silencing ameliorated the effect of amtagomiR-9 on BMEC proliferation and migration and cell death. Hyperemic structures were observed in the regions of the hippocampus and cortex in hypoxia-induced mice. Meanwhile, EXO treatment improved cerebrovascular alterations. CONCLUSION: NSC-derived EXOs can promote BMEC proliferation and migration and reduce cell death via the miR-9/Hes1 axis under hypoxic conditions. Therefore, EXO therapeutic strategies could be considered for hypoxia-induced vascular injury.

Purification and Properties of a Plasmin-like Marine Protease from Clamworm (Perinereis aibuhitensis).

Marine organisms are a rich source of enzymes that exhibit excellent biological activity and a wide range of applications. However, there has been limited research on the proteases found in marine mudflat organisms. Based on this background, the marine fibrinolytic enzyme FELP, which was isolated and purified from clamworm (Perinereis aibuhitensis), has exhibited excellent fibrinolytic activity. We demonstrated the FELP with a purification of 10.61-fold by precipitation with ammonium sulfate, ion-exchange chromatography, and gel-filtration chromatography. SDS-PAGE, fibrin plate method, and LC-MS/MS indicated that the molecular weight of FELP is 28.9 kDa and identified FELP as a fibrinolytic enzyme-like protease. FELP displayed the maximum fibrinolytic activity at pH 9 (407 ± 16 mm2) and 50 °C (724 ± 27 mm2) and had excellent stability at pH 7-11 (50%) or 30-60 °C (60%), respectively. The three-dimensional structure of some amino acid residues of FELP was predicted with the SWISS-MODEL. The fibrinolytic and fibrinogenolytic assays showed that the enzyme possessed direct fibrinolytic activity and indirect fibrinolysis via the activation of plasminogen; it could preferentially degrade Aα-chains of fibrinogen, followed by Bß- and γ-chains. Overall, the fibrinolytic enzyme was successfully purified from Perinereis aibuhitensis, a marine Annelida (phylum), with favorable stability that has strong fibrinolysis activity in vitro. Therefore, FELP appears to be a potent fibrinolytic enzyme with an application that deserves further investigation.

Influencing factors of clinical efficacy of roxadustat among hemodialysis patients.

OBJECTIVE: To explore independent influencing factors for clinical efficacy of roxadustat in hemodialysis patients. METHODS: Hemodialysis patients treated with roxadustat were enrolled. The plasma trough concentrations of roxadustat were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A multiple logistic regression model was established to determine the factors that affect clinical efficacy of roxadustat in patients undergoing hemodialysis. RESULTS: A total of 67 hemodialysis patients were enrolled in the study. The results showed that age, blood trough concentration of roxadustat, and baseline hemoglobin (Hb) level were independent factors of clinical efficacy of roxadustat (OR = 1.06, p = .025 for age; OR = 1.001, p = .037 for plasma concentration; and OR = 0.941, p = .003 for baseline Hb), with an AUC score of 0.859. CONCLUSIONS: Age, blood trough concentration of roxadustat, and baseline Hb level were independent influencing factors of the response to roxadustat in hemodialysis patients.

Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention.

BACKGROUND & AIMS: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. METHODS: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. RESULTS: Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis. CONCLUSIONS: Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers.

The effects of adenoid hypertrophy and oral breathing on maxillofacial development: a review of the literature.

According to modern epidemiological surveys, the prevalence of adenoid hypertrophy in children and adolescents ranges from 42% to 70%. Adenoid hypertrophy can lead to airway obstruction; thus forces a child to breathe through their mouth, thus affecting the normal development of the dental and maxillofacial area, and can lead to malocclusion. Long-term mouth breathing can cause sagittal, vertical and lateral changes in the maxillofacial area. In this article, we review the current research status relating to the association between adenoid hypertrophy, oral breathing and maxillofacial growth and development in children and adolescents. We also discuss the personalized formulation of treatment plans.

Structure-based, deep-learning models for protein-ligand binding affinity prediction.

The launch of AlphaFold series has brought deep-learning techniques into the molecular structural science. As another crucial problem, structure-based prediction of protein-ligand binding affinity urgently calls for advanced computational techniques. Is deep learning ready to decode this problem? Here we review mainstream structure-based, deep-learning approaches for this problem, focusing on molecular representations, learning architectures and model interpretability. A model taxonomy has been generated. To compensate for the lack of valid comparisons among those models, we realized and evaluated representatives from a uniform basis, with the advantages and shortcomings discussed. This review will potentially benefit structure-based drug discovery and related areas.

Dietary inflammatory index is associated with Vitamin D in CKD patients.

OBJECTIVES: Multiple observational studies have shown that low serum level of 25-hydroxyvitamin D (25(OH)D) in patients with chronic kidney disease (CKD) have been associated with a faster progression of kidney disease and a higher risk of all-cause mortality. We aim to assess the association between dietary inflammatory index (DII) with Vitamin D in adults with CKD. METHOD: The National Health and Nutrition Examination Survey appropriated participants from 2009 to 2018 were enrolled. The patients who were under the age of 18, pregnant, and having incomplete data were excluded. DII score were calculated based on a single 24-h dietary recall interview for each participant. Mutivariable regression analysis and subgroup analysis were utilized to determine the independent associations between vitamin D with DII in CKD patients. RESULTS: In total, 4283 individuals were finally included. The results showed a negative association between DII scores and 25(OH)D with statistical significance (ß = - 1.83, 95% CI - 2.31, - 1.34, P < 0.001). In subgroup analysis stratified by gender, low eGFR, age and diabetes, the negative association between DII scores and 25(OH)D was still significant (all P for trend < 0.05). The results from interacion test indicated that the magnitude of the association was the same for the population with and without low eGFR (P for interacion = 0.464). CONCLUSION: Higher consumption of pro-inflammatory diet correlates negatively with the 25(OH)D level in CKD patients with and without low eGFR. Anti-inflammatory diet management may reduce the reduction of vitamin D in CKD patients.

The relationship between dietary inflammatory index and bone mineral density in CKD patients.

INTRODUCTION: Chronic systemic inflammation was proposed as a critical factor in the development of osteoporosis. We aim to investigate the effect of the DII on bone mineral density (BMD) in CKD patients. METHODS: 2276 participants from NHANES were enrolled. The DII score was calculated based on a single 24-h dietary recall. Total BMD was measured using Dual-energy x-ray absorptiometry. A multiple-stepwise linear regression model was used to determine associations between BMD and DII in CKD patients. RESULTS: When DII >0.35, a negative correlation was obtained between DII and BMD (all ß = -0.008 and p < 0.05). In subgroup analysis, BMD levels decreased across increasing tertiles of the DII for patients with non-osteoporosis, postmenopause, and low eGFR (p for trend ≤0.01). CONCLUSION: Higher consumption of pro-inflammatory diet correlates negatively with the BMD levels in CKD patients.

Comparative proteomic analysis of vancomycin-sensitive and vancomycin-intermediate resistant Staphylococcus aureus.

PURPOSE: The extensive use of vancomycin has led to the development of Staphylococcus aureus strains with varying degrees of resistance to vancomycin. The present study aimed to explore the molecular causes of vancomycin resistance by conducting a proteomics analysis of subcellular fractions isolated from vancomycin-intermediate resistant S. aureus (VISA) and vancomycin-sensitive S. aureus (VSSA) strains. METHODS: We conducted proteomics analysis of subcellular fractions isolated from 2 isogenic S. aureus strains: strain 11 (VSSA) and strain 11Y (VISA). We used an integrated quantitative proteomics approach assisted by bioinformatics analysis, and comprehensively investigated the proteome profile. Intensive bioinformatics analysis, including protein annotation, functional classification, functional enrichment, and functional enrichment-based cluster analysis, was used to annotate quantifiable targets. RESULTS: We identified 128 upregulated proteins and 21 downregulated proteins in strain 11Y as compared to strain 11. The largest group of differentially expressed proteins was composed of enzymatic proteins associated with metabolic and catalytic activity, which accounted for 32.1% and 50% of the total proteins, respectively. Some proteins were indispensable parts of the regulatory networks of S. aureus that were altered with vancomycin treatment, and these proteins were related to cell wall metabolism, cell adhesion, proteolysis, and pressure response. CONCLUSION: Our proteomics study revealed regulatory proteins associated with vancomycin resistance in S. aureus. Some of these proteins were involved in the regulation of cell metabolism and function, which provides potential targets for the development of strategies to manage vancomycin resistance in S. aureus.

Adversarially robust neural networks with feature uncertainty learning and label embedding.

Deep neural networks (DNNs) are vulnerable to the attacks of adversarial examples, which bring serious security risks to the learning systems. In this paper, we propose a new defense method to improve the adversarial robustness of DNNs based on stochastic neural networks (SNNs), termed as Margin-SNN. The proposed Margin-SNN mainly includes two modules, i.e., feature uncertainty learning module and label embedding module. The first module introduces uncertainty to the latent feature space by giving each sample a distributional representation rather than a fixed point representation, and leverages the advantages of variational information bottleneck method in achieving good intra-class compactness in latent space. The second module develops a label embedding mechanism to take advantage of the semantic information underlying the labels, which maps the labels into the same latent space with the features, in order to capture the similarity between sample and its class centroid, where a penalty term is equipped to elegantly enlarge the margin between different classes for better inter-class separability. Since no adversarial information is introduced, the proposed model can be learned in standard training to improve adversarial robustness, which is much more efficient than adversarial training. Extensive experiments on data sets MNIST, FASHION MNIST, CIFAR10, CIFAR100 and SVHN demonstrate superior defensive ability of the proposed method. Our code is available at https://github.com/humeng24/Margin-SNN.