Association Between Carotid Plaque and Alzheimer's Disease Cerebrospinal Fluid Biomarkers and Cognitive Function in Cognitively Intact Adults: The CABLE Study.

Background: The association between carotid plaque and cognitive decline has recently been reported. However, the current research evidence is insufficient, and the possible causes of cognitive changes are unknown. Objective: This study aims to explore the relationships between carotid plaque and cognition functions, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cognitively intact adults, and try to study the underlying mechanisms. Methods: We enrolled 165 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, who had CSF AD biomarker measurements and carotid ultrasound. Linear modeling was used to assess the association of carotid plaque with CSF biomarkers and cognition. Additionally, mediation analysis was conducted through 10,000 bootstrapped iterations to explore potential links between carotid plaque, AD pathology, and cognition. Results: We found that carotid plaque exhibited significant correlations with Aß42 (ß = -1.173, p = 0.022), Aß42/Aß40 (ß = -0.092, p < 0.001), P-tau/Aß42 (ß = 0.110, p = 0.045), and T-tau/Aß42 (ß = 0.451, p = 0.010). A significant correlation between carotid plaque and cognition decline was also found in men (ß = -0.129, p = 0.021), and mediation analyses revealed that the effect of carotid plaque on cognitive function could be mediated by Aß42/Aß40 (proportion of mediation = 55.8%), P-tau/Aß42 (proportion of mediation = 51.6%, p = 0.015) and T-tau/Aß42 (proportion of mediation = 43.8%, p = 0.015) mediated. Conclusions: This study demonstrated the link between carotid plaque and CSF AD biomarkers in cognitively intact adults, and the important role that AD pathology may play in the correlation between carotid plaque and cognitive changes.

Berberine ameliorates chronic intermittent hypoxia-induced cardiac remodelling by preserving mitochondrial function, role of SIRT6 signalling.

Chronic intermittent hypoxia (CIH) is associated with an increased risk of cardiovascular diseases. Previously, we have shown that berberine (BBR) is a potential cardioprotective agent. However, its effect and mechanism on CIH-induced cardiomyopathy remain uncovered. This study was designed to determine the effects of BBR against CIH-induced cardiac damage and to explore the molecular mechanisms. Mice were exposed to 5 weeks of CIH with or without the treatment of BBR and adeno-associated virus 9 (AAV9) carrying SIRT6 or SIRT6-specific short hairpin RNA. The effect of BBR was evaluated by echocardiography, histological analysis and western blot analysis. CIH caused the inactivation of myocardial SIRT6 and AMPK-FOXO3a signalling. BBR dose-dependently ameliorated cardiac injury in CIH-induced mice, as evidenced by increased cardiac function and decreased fibrosis. Notably, SIRT6 overexpression mimicked these beneficial effects, whereas infection with recombinant AAV9 carrying SIRT6-specific short hairpin RNA abrogated them. Mechanistically, BBR reduced oxidative stress damage and preserved mitochondrial function via activating SIRT6-AMPK-FOXO3a signalling, enhancing mitochondrial biogenesis as well as PINK1-Parkin-mediated mitophagy. Taken together, these data demonstrate that SIRT6 activation protects against the pathogenesis of CIH-induced cardiac dysfunction. BBR attenuates CIH-induced myocardial injury by improving mitochondrial biogenesis and PINK1-Parkin-dependent mitophagy via the SIRT6-AMPK-FOXO3a signalling pathway.

Identifying High-Quality Non-Instrumental Dysphagia Screening Tools for Detection of Adult Dysphagia Case in Acute-Care Settings: A Systematic Review.

INTRODUCTION: As patients nowadays tend to have multiple diseases and complex medical histories, our aim was to identify high-quality, non-instrumental dysphagia screening tools used for the detection of adult dysphagia cases in all disease categories in acute-care settings. METHOD: A literature search was conducted in five databases from each database's earliest inception to 31 July 2021 and guided by five keywords: 'dysphagia', 'deglutition', 'screening', 'test' and 'measure'. Without limiting the search in any specific disease category, reviewers assessed original studies and identified tools if they had been validated against instrumental evaluations and if they had been designed as a pass-fail procedure to screen whether dysphagia is absent or present. We further excluded any tool if it was (1) for pediatric focus, or (2) a patient self-report questionnaire. All final tool candidates underwent a methodological quality appraisal using the Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). RESULT: Out of 195 studies with 165 tools identified, 20 tool candidates underwent QUADAS-2 review. We found six high-quality, non-instrumental screening tools for detecting adult dysphagia cases in acute-care settings, including the Yale Swallow Protocol, Gugging Swallowing Screen, Toronto Bedside Swallowing Screening Test (both English and Portuguese versions), Sapienza Global Bedside Evaluation of Swallowing and Two-Step Thickened Water Test. These high-quality tools were developed primarily for patients with stroke. Only Yale Swallow Protocol was originally tested for heterogeneous populations with stroke, multiple sclerosis, traumatic brain injury, oesophageal surgery, neurosurgery and head-and-neck cancer. CONCLUSIONS: The results highlight the gap in the unavailability of high-quality dysphagia screening tool in several emerged high-risk populations including elderly inpatients, or patients following endotracheal extubation. Further research is needed to determine whether these six tools can be effectively applied across different high-risk populations in acute-care settings to screen for cases finding.

Low-level mosaic trisomy 21 at amniocentesis and cordocentesis in the second trimester in a pregnancy associated with positive non-invasive prenatal testing for trisomy 21, perinatal progressive decrease of the trisomy 21 cell line and a favorable fetal outcome.

OBJECTIVE: We present low-level mosaic trisomy 21 at amniocentesis and cordocentesis in a pregnancy associated with a favorable fetal outcome. CASE REPORT: A 26-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of positive non-invasive prenatal testing (NIPT) for trisomy 21 at 16 weeks of gestation. Amniocentesis revealed a karyotype of 47,XX,+21[3]/46,XX[17], and multiplex ligation-dependent probe amplification (MLPA) on uncultured amniocytes revealed rsa X(P095) × 2, (13, 18, 21) × 2. She underwent cordocentesis (cord blood sampling) at 21 weeks of gestation which revealed a karyotype of 47,XX,+21[2]/46,XX[48]. At 27 weeks of gestation, she was referred to our hospital for genetic counseling, and repeat amniocentesis revealed a karyotype of 46,XX in 20/20 colonies. Quantitative fluorescent polymerase chain reaction (QF-PCR) analysis on the DNA extracted from uncultured amniocytes and parental bloods excluded uniparental disomy (UPD) 21. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (1-22,X) × 2, Y × 0 with no genomic imbalance. Interphase fluorescence in situ hybridization (FISH) analysis on 104 uncultured amniocytes detected one cell (1/104 = 0.9%) with trisomy 21, while the rest cells were disomy 21, compared with 0% (0/100) in the normal control. The woman was encouraged to continue the pregnancy. The pregnancy was carried to 38 weeks of gestation, and a 2771-g female baby was delivered no phenotypic abnormality. aCGH analysis on the cord blood showed arr (1-22,X) × 2, Y × 0 with no genomic imbalance. The umbilical cord had a karyotype of 47,XX,+21[3]/46,XX[37]. The placenta had a karyotype of 46,XX. When follow-up at age 3½ months, the neonate was phenotypically normal and had normal development. The peripheral blood had a karyotype of 46,XX in 40/40 cells. Interphase FISH analysis on buccal mucosal cells detected normal disomy 21 cells in 100/100 cells. CONCLUSION: Low-level mosaic trisomy 21 at amniocentesis and cordocentesis in the second trimester can be associated with perinatal progressive decrease of the trisomy 21 cell line and a favorable fetal outcome.

Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke.

The accumulation of self-renewed polarized microglia in the penumbra is a critical neuroinflammatory process after ischemic stroke, leading to secondary demyelination and neuronal loss. Although known to regulate tumor cell proliferation and neuroinflammation, HDAC3's role in microgliosis and microglial polarization remains unclear. We demonstrated that microglial HDAC3 knockout (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. RNA-seq analysis revealed mitosis as the primary process affected in HDAC3-deficent microglia following stroke. Notably, HDAC3-miKO specifically inhibited proliferation of proinflammatory microglia without affecting anti-inflammatory microglia, preventing microglial transition to a proinflammatory state. Moreover, ATAC-seq showed that HDAC3-miKO induced closing of accessible regions enriched with PU.1 motifs. Overexpressing microglial PU.1 via an AAV approach reversed HDAC3-miKO-induced proliferation inhibition and protective effects on ischemic stroke, indicating PU.1 as a downstream molecule that mediates HDAC3's effects on stroke. These findings uncovered that HDAC3/PU.1 axis, which mediated differential proliferation-related reprogramming in different microglia populations, drove poststroke inflammatory state transition, and contributed to pathophysiology of ischemic stroke.

Prognostic value of lymph node-to-primary tumor ratio of PET standardized uptake value for nasopharyngeal carcinoma: a recursive partitioning risk stratification analysis.

Background: Induction chemotherapy (IC) combined with concurrent chemoradiotherapy has become the standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Data on the prognostic value of the lymph node-to-primary tumor ratio (NTR) of positron emission tomography (PET) standardized uptake value (SUV) for patients treated with IC were limited. Objectives: To evaluate the prognostic value of the SUV NTR for patients with LA-NPC treated with IC. Design: In all, 467 patients with pretreatment 18F-fluorodeoxyglucose PET/computed tomography (CT) scans between September 2017 and November 2020 were retrospectively reviewed. Methods: The receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off value of SUV NTR. Kaplan-Meier method was used to evaluate survival rates. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. Results: The optimal cutoff value of SUV NTR was 0.74. Multivariate analyses showed that SUV NTR and overall stage were independent predictors for distant metastasis-free survival (DMFS) and regional recurrent-free survival (RRFS). Therefore, an RPA model based on the endpoint of DMFS was generated and categorized the patients into three distinct risk groups: RPA I (low risk: SUV NTR < 0.74 and stage III), RPA II (medium risk: SUV NTR < 0.74 and stage IVa, or SUV NTR ⩾ 0.74 and stage III), and RPA III (high risk: SUV NTR ⩾ 0.74 and stage IVa), with a 3-year DMFS of 98.9%, 93.4%, and 84.2%, respectively. ROC analysis showed that the RPA model had superior predictive efficacy than the SUV NTR or overall stage alone. Conclusion: SUV NTR was an independent prognosticator for distant metastasis and regional recurrence in locoregionally advanced NPC. The RPA risk stratification model based on SUV NTR provides improved DMFS and RRFS prediction over the eighth edition of the TNM (Tumor Node Metastasis) staging system.

A Review on Chemical Structures and Biological Activities of Dopamine Derivatives from Medicinal Insects.

Medicinal insects play an important role in the treatment of refractory diseases due to their unique and rich pharmacological activities. However, compared to plants, microorganisms, and marine organisms, medicinal insects have been largely ignored. Some small molecules isolated from insects are known to have defensive effects, but their majority roles remain unknown. In-depth research on the small molecules of medicinal insects has been conducted in recent years. Then alkaloids, dopamine derivatives, nucleoside derivatives, and other components are obtained. Among them, dopamine derivatives are a unique class of components from medicinal insects. Thus, we present a comprehensive overview of chemical structures and biological activities of dopamine derivatives from some medicinal insects, which will bring more attention to other researchers for further chemical and biological investigations on the unique dopamine derivatives as well as medicinal insects.

Construction of a high-density genetic map for yardlong bean and identification of ANT1 as a regulator of anthocyanin biosynthesis.

Because its long, tender pods supply essential proteins, vitamins, and fibers to humans, yardlong bean (Vigna unguiculata ssp. sesquipedalis) is a commonly consumed vegetable, especially in Southeast Asia. To provide insights into the genetic bases of key agricultural traits in yardlong bean, we here created a high-density bin-map with 2084 bin markers using 514 227 SNPs from a recombinant-inbred line (RIL) population. Quantitative trait loci (QTL) mapping was carried out to identify loci associated with anthocyanin content (ANT), vitamin E content (VE), total soluble protein content (TSP), pod length (PL), hundred-seed weight (HSW), seed length and width (SL and SW, respectively), and seed coat color (SCC). In total, 20 related QTLs were isolated, explaining 7.58-56.03% of the phenotypic variation. Of these, five major QTLs (qANT5, qTSP11, qVE7, qPL3, and qSCC9) were detected in 2020, 2021, and the combined environment, explaining 11.96-56.03% of the phenotypic variation. VuANT1 was identified as a causal gene for the QTL qANT5, which regulated anthocyanin content; VuANT1 was highly expressed in immature purple pods but barely detectable in white pods. VuANT1 overexpression in tobacco leaves and yardlong bean hairy roots resulted in purple coloration as a result of anthocyanin accumulation. These findings suggested that VuANT1 was a key regulator of anthocyanin accumulation in yardlong bean. Our results lay a firm foundation for target agricultural trait improvement and clarification of the genetic mechanisms underlying agricultural traits in yardlong bean.

Automatic detection of mild cognitive impairment based on deep learning and radiomics of MR imaging.

Purpose: Early and rapid diagnosis of mild cognitive impairment (MCI) has important clinical value in improving the prognosis of Alzheimer's disease (AD). The hippocampus and parahippocampal gyrus play crucial roles in the occurrence of cognitive function decline. In this study, deep learning and radiomics techniques were used to automatically detect MCI from healthy controls (HCs). Method: This study included 115 MCI patients and 133 normal individuals with 3D-T1 weighted MR structural images from the ADNI database. The identification and segmentation of the hippocampus and parahippocampal gyrus were automatically performed with a VB-net, and radiomics features were extracted. Relief, Minimum Redundancy Maximum Correlation, Recursive Feature Elimination and the minimum absolute shrinkage and selection operator (LASSO) were used to reduce the dimensionality and select the optimal features. Five independent machine learning classifiers including Support Vector Machine (SVM), Random forest (RF), Logistic Regression (LR), Bagging Decision Tree (BDT), and Gaussian Process (GP) were trained on the training set, and validated on the testing set to detect the MCI. The Delong test was used to assess the performance of different models. Result: Our VB-net could automatically identify and segment the bilateral hippocampus and parahippocampal gyrus. After four steps of feature dimensionality reduction, the GP models based on combined features (11 features from the hippocampus, and 4 features from the parahippocampal gyrus) showed the best performance for the MCI and normal control subject discrimination. The AUC of the training set and test set were 0.954 (95% CI: 0.929-0.979) and 0.866 (95% CI: 0.757-0.976), respectively. Decision curve analysis showed that the clinical benefit of the line graph model was high. Conclusion: The GP classifier based on 15 radiomics features of bilateral hippocampal and parahippocampal gyrus could detect MCI from normal controls with high accuracy based on conventional MR images. Our fully automatic model could rapidly process the MRI data and give results in 1 minute, which provided important clinical value in assisted diagnosis.

Branched-chain amino acid catabolic defect in vascular smooth muscle cells drives thoracic aortic dissection via mTOR hyperactivation.

Metabolic reprogramming of vascular smooth muscle cell (VSMC) plays a critical role in the pathogenesis of thoracic aortic dissection (TAD). Previous researches have mainly focused on dysregulation of fatty acid or glucose metabolism, while the impact of amino acids catabolic disorder in VSMCs during the development of TAD remains elusive. Here, we identified branched-chain amino acid (BCAA) catabolic defect as a metabolic hallmark of TAD. The bioinformatics analysis and data from human aorta revealed impaired BCAA catabolism in TAD individuals. This was accompanied by upregulated branched-chain α-ketoacid dehydrogenase kinase (BCKDK) expression and BCKD E1 subunit alpha (BCKDHA) phosphorylation, enhanced vascular inflammation, and hyperactivation of mTOR signaling. Further in vivo experiments demonstrated that inhibition of BCKDK with BT2 (a BCKDK allosteric inhibitor) treatment dephosphorylated BCKDHA and re-activated BCAA catabolism, attenuated VSMCs phenotypic switching, alleviated aortic remodeling, mitochondrial reactive oxygen species (ROS) damage and vascular inflammation. Additionally, the beneficial actions of BT2 were validated in a TNF-α challenged murine VSMC cell line. Meanwhile, rapamycin conferred similar beneficial effects against VSMC phenotypic switching, cellular ROS damage as well as inflammatory response. However, co-treatment with MHY1485 (a classic mTOR activator) reversed the beneficial effects of BT2 by reactivating mTOR signaling. Taken together, the in vivo and in vitro evidence showed that impairment of BCAA catabolism resulted in aortic accumulation of BCAA and further caused VSMC phenotypic switching, mitochondrial ROS damage and inflammatory response via mTOR hyperactivation. BCKDK and mTOR signaling may serve as the potential drug targets for the prevention and treatment of TAD.

Radiation-induced nasopharyngeal ulcers after re-irradiation with intensity-modulated radiotherapy in locoregional recurrent nasopharyngeal carcinoma patients: a dose-volume-outcome analysis.

OBJECTIVE: To analyze the interrelation between radiation dose and radiation-induced nasopharyngeal ulcer (RINU) in locoregional recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). METHODS: Clinical data were collected from 363 patients with locoregional recurrent NPC who received re-irradiated with definitive IMRT from 2009 to 2017. Twenty-nine patients were diagnosed with RINU. Univariate and multivariate analyses were used to re-evaluate the first and second radiotherapy plans and to identify predictive dosimetric factors. RESULTS: All dosimetric parameters were notably associated with the progression to RINU (p < 0.01) using paired samples Wilcoxon signed rank tests. Multivariate analysis showed that EQD2_ [Formula: see text]D80 (dose for 80 percent volume of the unilateral nasopharynx lesion) was an independent prognostic factor for RINU (p = 0.001). The area under the ROC curve for EQD2_ [Formula: see text]D80 was 0.846 (p < 0.001), and the cutoff point of 137.035 Gy could potentially be the dose tolerance of the nasopharyngeal mucosa. CONCLUSIONS: The sum of equivalent dose in 2 Gy fractions (EQD2) in the overlapping volumes between initial and re-irradiated nasopharyngeal mucosal tissue can be effective in predicting the hazard of developing RINU in NPC patients undergoing radical re­irradiation with IMRT and we propose a EQD2_ [Formula: see text]D80 threshold of 137.035 Gy for the nasopharynx.

Amyloid Pathology Modulates the Associations of Neuropsychiatric Symptoms with Cognitive Impairments and Neurodegeneration in Non-Demented Elderly.

BACKGROUND: The associations between neuropsychiatric symptoms (NPSs) and Alzheimer's disease (AD) have been well-studied, yet gaps remain. OBJECTIVE: We aimed to examine the associations of four subsyndromes (hyperactivity, psychosis, affective symptoms, and apathy) of NPSs with cognition, neurodegeneration, and AD pathologies. METHODS: Totally 1,040 non-demented elderly (48.07% males) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. We assessed the relationships between NPSs and AD neuropathologies, cognition, neurodegeneration, and clinical correlates in cross-sectional and longitudinal via multiple linear regression, linear mixed effects, and Cox proportional hazard models. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition and neurodegeneration. RESULTS: We found that individuals with hyperactivity, psychosis, affective symptoms, or apathy displayed a poorer cognitive status, a lower CSF amyloid-ß (Aß) level and a higher risk of clinical conversion (p < 0.05). Hyperactivity and affective symptoms were associated with increasing cerebral Aß deposition (p < 0.05). Except psychosis, the other three subsyndromes accompanied with faster atrophy of hippocampal volume (p < 0.05). Specific NPSs were predominantly associated with different cognitive domains decline through an 8-year follow-up (p < 0.05). Moreover, the relationships between NPSs and cognitive decline, neurodegeneration might be associated with Aß, the mediation percentage varied from 6.05% to 17.51% (p < 0.05). CONCLUSIONS: NPSs could be strongly associated with AD. The influences of NPSs on cognitive impairments, neurodegeneration might be partially associated with Aß.

Corrigendum: Integrated GWAS and transcriptomic analysis reveal the candidate salt-responding genes regulating Na+/K+ balance in barley (Hordeum vulgare L.).

[This corrects the article DOI: 10.3389/fpls.2022.1004477.].

Association between Cesarean section delivery and increased risk of childhood Kawasaki disease.

AIM: Cesarean section delivery is associated with microbiota disruption and immuno-dysregulation during childhood, but the association with Kawasaki disease remains uncertain. We aimed to evaluate the association between Cesarean section and Kawasaki disease. METHODS: We examined the association between Kawasaki disease between six and eighteen months and Cesarean section within a birth cohort of 15,796 mother-infant pairs in Taiwan. The associations were assessed with Poisson regression in the study population, in the 1:2 propensity score-matched subpopulation, and compared with febrile convulsion, trauma and accidents during the same interval as negative control outcomes. RESULTS: Cesarean section was found to increase the risk of Kawasaki disease among overall population (adjusted relative risk [aRR]: 2.22, 95 % confidence interval (CI): 1.14-4.34) and the matched subpopulation (aRR: 2.29, 95 % CI: 1.14-4.68 in PS-matched subpopulation). Meanwhile, there was no association between Cesarean section and the clinic visits for febrile convulsion, trauma and accidents. CONCLUSION: In conclusion, this study identified a potential association between Cesarean section delivery and a higher risk of Kawasaki disease during six-to eighteen months of the prospective birth cohort in Taiwan.

High-level mosaic trisomy 21 at amniocentesis in a pregnancy associated with positive NIPT for trisomy 21, prenatal progressive decrease of the trisomy 21 cell line, acute fatty liver of pregnancy and intrauterine fetal death in late gestation.

OBJECTIVE: We present high-level mosaic trisomy 21 at amniocentesis in a pregnancy associated with positive non-invasive prenatal testing (NIPT) for trisomy 21, prenatal progressive decrease of the trisomy 21 cell line, acute fatty liver of pregnancy and intrauterine fetal death (IUFD) in late gestation. CASE REPORT: A 32-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of positive NIPT for trisomy 21 at 12 weeks of gestation. This pregnancy was conceived by in vitro fertilization. She did not have obesity, diabetes mellitus, hepatic biliary disorders and preeclampsia. Amniocentesis revealed a karyotype of 47,XY,+21[10]/46,XY[11], and array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed the result of arr (21) × 2-3. She was referred for genetic counseling, and repeat amniocentesis performed at 21 weeks of gestation revealed the karyotype of 47,XY,+21[10]/46,XY[28]. The parental karyotypes and fetal ultrasound findings were normal. Simultaneous molecular analysis on uncultured amniocytes showed no uniparental disomy 21, but a maternal origin of trisomy 21 by quantitative fluorescent polymerase chain reaction (QF-PCR) and the result of arr 21q11.2q22.3 × 2.5 by aCGH analysis. At 27 weeks of gestation, she underwent a third amniocentesis, of which conventional cytogenetic analysis revealed the result of 47,XY,+21[5]/46,XY[17] in cultured amniocytes, and aCGH analysis revealed arr 21q11.2q22.3 × 2.48, and interphase fluorescence in situ hybridization (FISH) analysis revealed 39% (39/100 cells) mosaicism fro trisomy 21 in uncultured amniocytes. At 36 weeks of gestation, the woman suffered from a sudden onset of acute fatty liver and IUFD. A 3522-g male baby was delivered without Down syndrome phenotype. The umbilical cord had a karyotype of 47,XY,+21[10]/46,XY[30]. aCGH analysis on the skin and placenta showed arr 21q11.2q22.3 × 2.73 and arr 21q11.2q22.3 × 2.75, respectively. QF-PCR analysis of umbilical cord, placenta and skin showed a maternal origin of trisomy 21. CONCLUSION: High-level mosaic trisomy 21 at amniocentesis can be associated with prenatal progressive decrease of the trisomy 21 cell line in cultured amniocytes and perinatal fetal mortality and maternal morbidity.

45,X/46,XX at the first amniocentesis, and 45,X/47,XXX/46,XX at the repeat amniocentesis and at birth in a pregnancy associated with a favorable fetal outcome, perinatal progressive decrease of the 45,X cell line and cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes.

OBJECTIVE: We present 45,X/46,XX at the first amniocentesis, and 45,X/47,XXX/46,XX at the repeat amniocentesis and at birth in a pregnancy associated with a favorable fetal outcome, perinatal progressive decrease of the 45,X cell line and cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes. CASE REPORT: A 43-year-old, gravida 3, para 1, woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 45,X[4]/46,XX[20]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (X) × 3 [0.24], consistent with 24% mosaicism for triple X. Repeat amniocentesis at 20 weeks of gestation revealed the result of 45,X[17]/47,XXX[8]/46,XX[121]. She was referred for genetic counseling, and the third amniocentesis performed at 30 weeks of gestation revealed the result of 45,X[3]/47,XXX[2]/46,XX[16]. The mother had a karyotype of 46,XX. aCGH analysis on the DNA extracted from uncultured amniocytes showed arr Xp22.33q28 × 2.2 (log2 ratio = 0.15), consistent with 20% mosaicism for triple X. Interphase fluorescence in situ hybridization (FISH) analysis on 100 uncultured amniocytes showed that 11 cells (11%) were monosomy X, seven cells (7%) were triple X, and the others were disomy X. At 39 weeks of gestation, a 3,620-g phenotypically normal female baby was delivered without any phenotypic abnormality. The karyotypes of cord blood, umbilical cord and placenta were 47,XXX[7]/45,X[1]/46,XX[32], 47,XXX[13]/46,XX[27] and 47,XXX[2]/46,XX[38], respectively. When follow-up at age one month, the neonate was phenotypically normal, and FISH analysis on 106 buccal mucosal cells showed that eight cells (7.5%) were monosomy X, seven cells (6.6%) were triple X, and the others were disomy X. CONCLUSION: Mosaic 45,X/46,XX at amniocentesis may be in fact mosaic 45,X/47,XXX/46,XX and can be associated with a favorable fetal outcome and perinatal progressive decrease of the 45,X cell line.

Perinatal detection of disomy X cell line by fluorescence in situ hybridization in a pregnancy with 45,X/47,XXX at amniocentesis, cytogenetic discrepancy in various tissues and a favorable outcome.

OBJECTIVE: We present perinatal detection of disomy X cell line by fluorescence in situ hybridization (FISH) in a pregnancy with 45,X/47,XXX at amniocentesis, cytogenetic discrepancy in various tissues and a favorable outcome. CASE REPORT: A 34-year-old, gravida 3, para 1, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 45,X[22]/47,XXX[10]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr (X) × 1-2, (1-22) × 2, consistent with 32% mosaicism for monosomy X. She was referred for genetic counseling at 19 weeks of gestation. Prenatal ultrasound findings and parental karyotypes were normal. Repeat amniocentesis at 29 weeks of gestation revealed a karyotype of 45,X[36]/47,XXX[4] (Fig. 1) in cultured amniocytes. Simultaneous molecular analysis on uncultured amniocytes revealed the result of arr (1-22) × 2, Y × 0 by aCGH with no genomic imbalance, and 15% (15/100 cells) mosaicism for disomy X, 61% (61/100 cells) mosaicism for monosomy X and 24% (24/100 cells) mosaicism for triple X by interphase fluorescence in situ hybridization (FISH) analysis. The pregnancy was encouraged to continue and at 37 weeks of gestation, a 2834-g phenotypically normal female baby was delivered. The karyotypes of cord blood, umbilical cord and placenta were 45,X[33]/47,XXX[7], 45,X[30]/47,XXX[10] and 47,XXX[38]/45,X[2], respectively. When follow-up at age three months, the neonate was normal in development. FISH analysis on 99 buccal mucosal cells showed 49% (48/99 cells) mosaicism for monosomy X, 8% (8/99 cells) mosaicism for triple X and 43% (42/99 cells) mosaicism for disomy X (Fig. 2). Peripheral blood had a karyotype of 45,X[38]/47,XXX[2]. When follow-up at age nine months, the neonate was normal in development. FISH analysis on 102 buccal mucosal cells showed 11% (11/102 cells) mosaicism for monosomy X, 12% (12/102 cells) mosaicism for triple X and 77% (79/102 cells) mosaicism for disomy X. Peripheral blood had a karyotype of 45,X[30]/47,XXX[10]. CONCLUSION: 45,X/47,XXX at amniocentesis may detect disomy X cell line by FISH analysis and can be associated with postnatal progressive decrease of the aneuploid cell lines, increase of the disomy X cell line and a favorable outcome.

ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood-brain barrier integrity after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a significant worldwide public health concern that necessitates attention. Apoptosis signal-regulating kinase 1 (ASK1), a key player in various central nervous system (CNS) diseases, has garnered interest for its potential neuroprotective effects against ischemic stroke and epilepsy when deleted. Nonetheless, the specific impact of ASK1 on TBI and its underlying mechanisms remain elusive. Notably, mutation of ATP-binding sites, such as lysine residues, can lead to catalytic inactivation of ASK1. To address these knowledge gaps, we generated transgenic mice harboring a site-specific mutant ASK1 Map3k5-e (K716R), enabling us to assess its effects and elucidate potential underlying mechanisms following TBI. METHODS: We employed the CRIPR/Cas9 system to generate a transgenic mouse model carrying the ASK1-K716R mutation, aming to investigate the functional implications of this specific mutant. The controlled cortical impact method was utilized to induce TBI. Expression and distribution of ASK1 were detected through Western blotting and immunofluorescence staining, respectively. The ASK1 kinase activity after TBI was detected by a specific ASK1 kinase activity kit. Cerebral microvessels were isolated by gradient centrifugation using dextran. Immunofluorescence staining was performed to evaluate blood-brain barrier (BBB) damage. BBB ultrastructure was visualized using transmission electron microscopy, while the expression levels of endothelial tight junction proteins and ASK1 signaling pathway proteins was detected by Western blotting. To investigate TBI-induced neuroinflammation, we conducted immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analyses. Additionally, immunofluorescence staining and electrophysiological compound action potentials were conducted to evaluate gray and white matter injury. Finally, sensorimotor function and cognitive function were assessed by a battery of behavioral tests. RESULTS: The activity of ASK1-K716R was significantly decreased following TBI. Western blotting confirmed that ASK1-K716R effectively inhibited the phosphorylation of ASK1, JNKs, and p38 in response to TBI. Additionally, ASK1-K716R demonstrated a protective function in maintaining BBB integrity by suppressing ASK1/JNKs activity in endothelial cells, thereby reducing the degradation of tight junction proteins following TBI. Besides, ASK1-K716R effectively suppressed the infiltration of peripheral immune cells into the brain parenchyma, decreased the number of proinflammatory-like microglia/macrophages, increased the number of anti-inflammatory-like microglia/macrophages, and downregulated expression of several proinflammatory factors. Furthermore, ASK1-K716R attenuated white matter injury and improved the nerve conduction function of both myelinated and unmyelinated fibers after TBI. Finally, our findings demonstrated that ASK1-K716R exhibited favorable long-term functional and histological outcomes in the aftermath of TBI. CONCLUSION: ASK1-K716R preserves BBB integrity by inhibiting ASK1/JNKs pathway in endothelial cells, consequently reducing the degradation of tight junction proteins. Additionally, it alleviates early neuroinflammation by inhibiting the infiltration of peripheral immune cells into the brain parenchyma and modulating the polarization of microglia/macrophages. These beneficial effects of ASK1-K716R subsequently result in a reduction in white matter injury and promote the long-term recovery of neurological function following TBI.

SaPt-CNN-LSTM-AR-EA: a hybrid ensemble learning framework for time series-based multivariate DNA sequence prediction.

Biological sequence data mining is hot spot in bioinformatics. A biological sequence can be regarded as a set of characters. Time series is similar to biological sequences in terms of both representation and mechanism. Therefore, in the article, biological sequences are represented with time series to obtain biological time sequence (BTS). Hybrid ensemble learning framework (SaPt-CNN-LSTM-AR-EA) for BTS is proposed. Single-sequence and multi-sequence models are respectively constructed with self-adaption pre-training one-dimensional convolutional recurrent neural network and autoregressive fractional integrated moving average fused evolutionary algorithm. In DNA sequence experiments with six viruses, SaPt-CNN-LSTM-AR-EA realized the good overall prediction performance and the prediction accuracy and correlation respectively reached 1.7073 and 0.9186. SaPt-CNN-LSTM-AR-EA was compared with other five benchmark models so as to verify its effectiveness and stability. SaPt-CNN-LSTM-AR-EA increased the average accuracy by about 30%. The framework proposed in this article is significant in biology, biomedicine, and computer science, and can be widely applied in sequence splicing, computational biology, bioinformation, and other fields.

The effect of early oral nutritional supplements on improving nutritional outcomes and radiation-induced oral mucositis for nasopharyngeal carcinoma patients undergoing concurrent chemoradiotherapy.

BACKGROUND: To explore the value of early oral nutritional supplements (ONS) in patients with nasopharyngeal carcinoma (NPC) treated with concurrent chemoradiotherapy (CCRT). METHODS: Patients with newly diagnosed II-IVA stage NPC were analyzed and divided into Early and Routine ONS groups according to whether they received early ONS at the beginning of CCRT. Changes in nutritional indicators, incidence of treatment-related toxicity, radiation interruption, and completion of CCRT were compared. RESULTS: In total, 161 patients with NPC were analyzed, including 72 in the Early ONS group and 89 in the Routine ONS group. Multivariate analysis showed that early ONS was an independent protective factor for concurrent chemotherapy ≥2 cycles, and a protective factor against ≥grade 3 radiation-induced oral mucositis (RIOM) and weight loss >5%. In stage III-IVA patients, early ONS was beneficial in decreasing the risk of severe malnutrition. CONCLUSIONS: Early ONS can improve nutritional outcomes, reduce RIOM, and enhance treatment adherence.