Glymphatic dysfunction in patients with early-stage amyotrophic lateral sclerosis.

Recently, an astrocytic aquaporin 4-dependent drainage system, that is, the glymphatic system, has been identified in the live murine and human brain. Growing evidence suggests that glymphatic function is impaired in patients with several neurodegenerative diseases, including Alzheimer's and Parkinson's disease. As the third most common neurodegenerative disease, although animal studies have indicated that early glymphatic dysfunction is likely an important pathological mechanism underpinning amyotrophic lateral sclerosis (ALS), no available study has been conducted to thoroughly assess glymphatic function in vivo in ALS patients to date, particularly in patients with early-stage ALS. Thus, using diffusion tensor imaging analysis along the perivascular space (ALPS) index, an approximate measure of glymphatic function in vivo, we aimed to explore whether glymphatic function is impaired in patients with patients with early-stage ALS, and the diagnostic performance of the ALPS index in distinguishing between patients with early-stage ALS and healthy subjects. We also aimed to identify the relationships between glymphatic dysfunction and clinical disabilities and sleep problems in patients with early-stage ALS. In this retrospective study, King's Stage 1 ALS patients were defined as patients with early-stage ALS. We enrolled 56 patients with early-stage ALS and 32 age- and sex-matched healthy control subjects. All participants completed clinical screening, sleep assessment and ALPS index analysis. For the sleep assessment, the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and polysomnography were used. Compared with healthy control subjects, patients with early-stage ALS had a significantly lower ALPS index after family-wise error correction (P < 0.05). Moreover, receiver operating characteristic analysis showed that the area under the curve for the ALPS index was 0.792 (95% confidence interval 0.700-0.884). Partial correlation analyses showed that the ALPS index was significantly correlated with clinical disability and sleep disturbances in patients with early-stage ALS. Multivariate analysis showed that sleep efficiency (r = 0.419, P = 0.002) and periodic limb movements in sleep index (r = -0.294, P = 0.017) were significant predictive factors of the ALPS index in patients with early-stage ALS. In conclusion, our study continues to support an important role for glymphatic dysfunction in ALS pathology, and we provide additional insights into the early diagnostic value of glymphatic dysfunction and its correlation with sleep disturbances in vivo in patients with early-stage ALS. Moreover, we suggest that early improvement of glymphatic function may be a promising strategy for slowing the neurodegenerative process in ALS. Future studies are needed to explore the diagnostic and therapeutic value of glymphatic dysfunction in individuals with presymptomatic-stage neurodegenerative diseases.

Cortical thickness reveals sex differences in verbal and visuospatial memory.

Although previous studies have reported the sex differences in behavior/cognition and the brain, the sex difference in the relationship between memory abilities and the underlying neural basis in the aging process remains unclear. In this study, we used a machine learning model to estimate the association between cortical thickness and verbal/visuospatial memory in females and males and then explored the sex difference of these associations based on a community-elderly cohort (n = 1153, age ranged from 50.42 to 86.67 years). We validated that females outperformed males in verbal memory, while males outperformed females in visuospatial memory. The key regions related to verbal memory in females include the medial temporal cortex, orbitofrontal cortex, and some regions around the insula. Further, those regions are more located in limbic, dorsal attention, and default-model networks, and are associated with face recognition and perception. The key regions related to visuospatial memory include the lateral prefrontal cortex, anterior cingulate gyrus, and some occipital regions. They overlapped more with dorsal attention, frontoparietal and visual networks, and were associated with object recognition. These findings imply the memory performance advantage of females and males might be related to the different memory processing tendencies and their associated network.

Antidepressant-like effect of CP-101,606: Evidence of mTOR pathway activation.

BACKGROUND: As a non-competitive N-methyl d-aspartate receptor antagonist, ketamine exerts rapid-onset and long-lasting antidepressant effects on depression, but some side effects limit its use. To identify a safer compound that may provide similar antidepressant effects, here we investigated whether CP-101,606, a selective NR2B receptor inhibitor, provides similar antidepressant effects and explored its underlying mechanisms. METHODS: To mimic depressive-like behavior, mice were subjected to chronic unpredictable mild stress (CUMS) for 21 days. Mice were treated with CP-101,606 at 10, 20, and 40 mg/kg doses for 7, 14, and 21 days, respectively, followed by a sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). Western blot analysis was performed on several targets (mTOR, p-mTOR, p70S6K, p-p70S6K, PSD-95, and GluA1), along with immunohistochemistry (GluA1) and immunofluorescence (p-mTOR) assays, using hippocampal tissue. RESULTS: CP-101,606 at 20 and 40 mg/kg doses for 7 and 14 days and fluoxetine 10 mg/kg and CP-101606 20 mg/kg for 21 days ameliorated depression-like behaviors in the SPT, TST, and FST. The effects of CP-101,606 were associated with a reversal of the CUMS-induced decrease in mTOR (Ser2448) and p70S6K (Thr389) phosphorylation and increasing PSD95 and GluA1 synthesis in the hippocampus. CONCLUSIONS: Our results demonstrate that CP-101,606 produces antidepressant effects in CUMS mice, which may be mediated by mTOR signaling cascade upregulation. Our findings suggest the possible utility of CP-101,606 as a treatment for depression.

The dimethadione-exposed rat fetus: an animal model for the prenatal ultrasound characterization of ventricular septal defect.

BACKGROUND: Ventricular septal defect (VSD) is the most prevalent congenital heart disease (CHD) and is easily misdiagnosed or missed. An appropriate VSD animal model could be used to analyze the ultrasound characteristics and their related pathological bases, and provides the opportunity to further explore the pathogenesis of VSD. Currently, little is known about whether ultrahigh-frequency ultrasound biomicroscopy (UBM) is suitable to diagnose VSD of fetal rats. There is no research on whether a dimethadione (DMO)-induced fetal VSD model is suitable for the observation and analysis of imaging characteristics and the associated pathological basis. METHODS: We used DMO to induce VSD. UBM was used to perform the prenatal ultrasound characterization. With the pathological results used as the gold standard, the ultrasound characteristics and their related pathological bases were analyzed. RESULTS: The incidence of VSD in the DMO group was 42.05% and 39.71% (diagnosed by UBM and pathology, respectively, P > 0.05). The prenatal ultrasound findings and pathological basis of various diseases, including isolated VSD, complex CHD containing VSD, and extracardiac lesions, were detected and discussed. It was discovered that some fetuses showed features of noncompacted ventricular myocardium, and for the first time, clusters of red blood cell traversing the cardiomyocytes. CONCLUSIONS: The DMO-induced VSD model is a low-cost model with a high success rate and is suitable for the observation and analysis of VSD. UBM is suitable for evaluating VSD.

Cognitive Decline Associated with Aging.

Cognitive decline is one of the most distinct signs of aging, and age-related cognitive decline is a heterogeneous issue varying in different cognitive domains and has significant differences among older adults. Identifying characteristics of cognitive aging is the basis of cognitive disease for early-detection and healthy aging promotion. In the current chapter, age-related decline of main cognitive domains, including sensory perception, memory, attention, executive function, language, reasoning, and space navigation ability are introduced respectively. From these aspects of cognition, we focus on the age-related effects, age-related cognitive diseases, and possible mechanisms of cognitive aging.

Classification of normal and abnormal fetal heart ultrasound images and identification of ventricular septal defects based on deep learning.

OBJECTIVES: Congenital heart defects (CHDs) are the most common birth defects. Recently, artificial intelligence (AI) was used to assist in CHD diagnosis. No comparison has been made among the various types of algorithms that can assist in the prenatal diagnosis. METHODS: Normal and abnormal fetal ultrasound heart images, including five standard views, were collected according to the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) Practice guidelines. You Only Look Once version 5 (YOLOv5) models were trained and tested. An excellent model was screened out after comparing YOLOv5 with other classic detection methods. RESULTS: On the training set, YOLOv5n performed slightly better than the others. On the validation set, YOLOv5n attained the highest overall accuracy (90.67 %). On the CHD test set, YOLOv5n, which only needed 0.007 s to recognize each image, had the highest overall accuracy (82.93 %), and YOLOv5l achieved the best accuracy on the abnormal dataset (71.93 %). On the VSD test set, YOLOv5l had the best performance, with a 92.79 % overall accuracy rate and 92.59 % accuracy on the abnormal dataset. The YOLOv5 models achieved better performance than the Fast region-based convolutional neural network (RCNN) & ResNet50 model and the Fast RCNN & MobileNetv2 model on the CHD test set (p<0.05) and VSD test set (p<0.01). CONCLUSIONS: YOLOv5 models are able to accurately distinguish normal and abnormal fetal heart ultrasound images, especially with respect to the identification of VSD, which have the potential to assist ultrasound in prenatal diagnosis.

Chromosomal abnormalities in fetuses with congenital heart disease: a meta-analysis.

PURPOSE: The aim of this meta-analysis was to evaluate the risk of chromosomal abnormalities in fetuses with congenital heart disease (CHD). METHODS: Four literature databases were searched until 17th January 2022 using the relevant medical subject heading terms, word variants, and keywords for "congenital heart defect, fetal, and chromosomal abnormalities". The prevalence of overall chromosomal abnormality, aneuploidy, 22q11 deletion, other copy number variants (CNVs), and variants of unknown significance (VOUS) was analyzed. RESULTS: 45 studies met the inclusion criteria for the analysis. The pooled proportion of overall chromosomal abnormalities, aneuploidy, 22q11 deletion, and other CNVs in fetuses with CHD was 23% (95% CI: 20-26%), 19% (95% CI, 16-22%), 2% (95% CI, 2-3%), and 4% (95% CI, 3-5%), respectively. The incidence of overall chromosomal abnormalities, aneuploidy, and other CNVs in non-isolated CHD was higher than in isolated CHD, with odds ratios of 3.08, 3.45, and 4.02, respectively. The incidence of overall chromosomal abnormalities in septal defects was higher than in conotruncal defects and other defects, with odds ratios of 1.60 and 3.61, respectively. In addition, the pooled proportion of VOUS in CHD was 4%. CONCLUSION: CHD is commonly associated with chromosomal abnormalities. If karyotyping or fluorescence in situ hybridization is normal, chromosomal microarray should be performed to look for submicroscopic abnormalities, especially in fetuses with non-isolated CHD and septal defects.

Contributions of early-life cognitive reserve and late-life leisure activity to successful and pathological cognitive aging.

BACKGROUND: The identification of factors that specifically influence pathological and successful cognitive aging is a prerequisite for implementing disease prevention and promoting successful aging. However, multi-domain behavioral factors that characterize the difference between successful and pathological cognitive aging are not clear yet. METHODS: A group of community-dwelling older adults (N = 1347, aged 70-88 years) in Beijing was recruited in this cross-sectional study, and a sub-cohort was further divided into successful cognitive aging (SCA, N = 154), mild cognitive impairment (MCI, N = 256), and cognitively normal control (CNC, N = 173) groups. Analyses of variance, regression models with the Shapley value algorithm, and structural equation model (SEM) analyses were conducted to determine specific influencing factors and to evaluate their relative importance and interacting relationships in altering cognitive performance. RESULTS: We found that abundant early-life cognitive reserve (ECR, including the level of education and occupational attainment) and reduced late-life leisure activity (LLA, including mental, physical, and social activities) were distinct characteristics of SCA and MCI, respectively. The level of education, age, mental activity, and occupational attainment were the top four important factors that explained 31.6% of cognitive variability. By SEM analyses, we firstly found that LLA partially mediated the relationship between ECR and cognition; and further multi-group SEM analyses showed ECR played a more direct role in the SCA group than in the MCI group: in the SCA group, only the direct effect of ECR on cognition was significant, and in the MCI group, direct effects between ECR, LLA and cognition were all significant. CONCLUSIONS: Results of this large-sample community-based study suggest it is important for older adults to have an abundant ECR for SCA, and to keep a high level of LLA to prevent cognitive impairment. This study clarifies the important rankings of behavioral characteristics of cognitive aging, and the relationship that ECR has a long-lasting effect on LLA and finally on cognition, providing efficient guidance for older adults to improve their cognitive function and new evidence to explain the heterogeneity of cognitive aging.

Metabolic characterization of amniotic fluid of fetuses with isolated choroid plexus cyst.

OBJECTIVES: To investigate the amino acid (AA)-related metabolic characteristics of amniotic fluid (AF) obtained by ultrasound-guided amniocentesis from fetuses with isolated choroid plexus cysts of the central nervous system. METHODS: Ultrasound-guided amniocentesis was performed on 17 fetuses with isolated choroid plexus cysts (ICPCs) and 17 normal fetuses. The AF samples from normal pregnancies were matched with the case samples in a 1:1 ratio based upon gestational age. The AF samples from the 34 fetuses were analyzed by liquid chromatography-mass spectrometry (LC-MS). Then, the peak areas of the metabolites were analyzed by principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and univariate statistical analysis. RESULTS: This study ultimately identified 31 AAs. Seven differentially abundant AAs were screened out, including citrulline, ethanolamine, aspartic acid, valine, 5-hydroxylysine, proline, and isoleucine (p-value<0.05). A total of 4 metabolic pathways were significantly altered in the ICPC group: valine, leucine and isoleucine biosynthesis; valine, leucine and isoleucine degradation; pantothenate and coenzyme A (CoA) biosynthesis; and arginine biosynthesis. CONCLUSIONS: The results of this study indicate that fetuses with ICPC have disrupted levels of citrulline, ethanolamine, aspartic acid, valine, 5-hydroxylysine, proline, and isoleucine, which may ultimately affect fetal glucose and lipid metabolism.

Vascular Risk Factors and Brain Health in Aging: Insights from a Community-Based Cohort Study.

Background: The aging population and high rates of Alzheimer's disease (AD) create significant medical burdens, prompting a need for early prevention. Targeting modifiable risk factors like vascular risk factors (VRFs), closely linked to AD, may provide a promising strategy for intervention. Objective: This study investigates how VRFs influence cognitive performance and brain structures in a community-based cohort. Methods: In this cross-sectional study, 4,667 participants over 50 years old, drawn from the Beijing Ageing Brain Rejuvenation Initiative project, were meticulously examined. Cognitive function and VRFs (diabetes mellitus, hypertension, hyperlipidemia, obesity, and smoking), were comprehensively assessed through one-to-one interviews. Additionally, a subset of participants (n = 719) underwent MRI, encompassing T1-weighted and diffusion-weighted scans, to elucidate gray matter volume and white matter structural network organization. Results: The findings unveil diabetes as a potent detriment to memory, manifesting in atrophy within the right supramarginal gyrus and diminished nodal efficiency and degree centrality in the right inferior parietal lobe. Hypertension solely impaired memory without significant structural changes. Intriguingly, individuals with comorbid diabetes and hypertension exhibited the most pronounced deficits in both brain structure and cognitive performance. Remarkably, hyperlipidemia emerged as a factor associated with enhanced cognition, and preservation of brain structure. Conclusions: This study illuminates the intricate associations between VRFs and the varied patterns of cognitive and brain structural damage. Notably, the synergistic effect of diabetes and hypertension emerges as particularly deleterious. These findings underscore the imperative to tailor interventions for patients with distinct VRF comorbidities, especially when addressing cognitive decline and structural brain changes.

Atrophy in the supramarginal gyrus associated with impaired cognitive inhibition in grieving Chinese Shidu parents.

Background: The loss of an only child, known as Shidu in China, is a profoundly distressing experience, often leading to Prolonged Grief Disorder (PGD). Despite its impact, the structural brain alterations associated with PGD, potentially influencing cognitive impairments in Shidu parents, remain understudied.Objective: This study aims to identify brain structural abnormalities related to prolonged grief and their relation with cognitive inhibition in Shidu parents.Methods: The study included 40 Shidu parents and 42 non-bereaved participants. Prolonged grief was evaluated using the Prolonged Grief Questionnaire (PG-13). We employed voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) to assess brain structural alterations and their correlation with cognitive inhibition, as measured by Stroop interference scores.Results: Findings suggest that greater prolonged grief intensity correlates with reduced grey matter volume in the right amygdala and the left supramarginal gyrus (SMG). Additionally, enhanced amygdala-to-whole-brain structural connectivity showed a marginal association with prolonged grief, particularly with emotional-related symptoms. Furthermore, a decrease in SMG volume was found to mediate the relation between prolonged grief and Stroop Time Inference (TI) score, indicating an indirect effect of prolonged grief on cognitive inhibition.Conclusions: The study provides insight into the neural correlates of prolonged grief in Shidu parents, highlighting the SMG's role in cognitive inhibition. These findings emphasise the need for comprehensive grief interventions to address the complex cognitive and emotional challenges faced by this unique bereaved population.

The Shidu parents had a delay in cognitive inhibition when performing the Stroop test, compared to the control group.Prolonged grief intensity was linked to decreased grey matter in the right amygdala and a potential increase in amygdala-to-whole-brain structural connectivity. These volumes were associated with prolonged grief symptoms related to emotions.A higher level of prolonged grief was also associated with reduced grey matter volume in the left supramarginal gyrus, mediating the relationship between prolonged grief and Stroop Time Inference score, which indicates cognitive inhibition.

Choroid plexus enlargement in amyotrophic lateral sclerosis patients and its correlation with clinical disability and blood-CSF barrier permeability.

BACKGROUND: Using in vivo neuroimaging techniques, growing evidence has demonstrated that the choroid plexus (CP) volume is enlarged in patients with several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. However, although animal and postmortem findings suggest that CP abnormalities are likely important pathological mechanisms underlying amyotrophic lateral sclerosis (ALS), the third most common neurodegenerative disease, no available study has been conducted to thoroughly assess CP abnormalities and their clinical relevance in vivo in ALS patients to date. Thus, we aimed to determine whether in vivo CP enlargement may occur in ALS patients. We also aimed to identify the relationships of CP volume with clinical disabilities and blood-CSF barrier (BCSFB) permeability in ALS patients. METHODS: In this retrospective study, based on structural MRI data, CP volume was assessed using a Gaussian mixture model and underwent further manual correction in 155 ALS patients and 105 age- and sex-matched HCs from October 2021 to April 2023. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess clinical disability. The CSF/serum albumin quotient (Qalb) was used to assess BCSFB permeability. Moreover, all the ALS patients completed genetic testing, and according to genetic testing, the ALS patients were further divided into genetic ALS subgroup and sporadic ALS subgroup. RESULTS: We found that compared with HCs, ALS patients had a significantly higher CP volume (p < 0.001). Moreover, compared with HCs, CP volume was significantly increased in both ALS patients with and without known genetic mutations after family-wise error correction (p = 0.006 and p < 0.001, respectively), while there were no significant differences between the two ALS groups. Furthermore, the CP volume was significantly correlated with the ALSFRS-r score (r = -0.226; p = 0.005) and the Qalb (r = 0.479; p < 0.001) in ALS patients. CONCLUSION: Our study first demonstrates CP enlargement in vivo in ALS patients, and continues to suggest an important pathogenetic role for CP abnormalities in ALS. Moreover, assessing CP volume is likely a noninvasive and easy-to-implement approach for screening BCSFB dysfunction in ALS patients.

Effects of soil type and genotype on lead concentration in rootstalk vegetables and the selection of cultivars for food safety.

Lead (Pb) contamination of soil poses severe health risks to humans through vegetable consumption. The variations of Pb concentration in different parts of rootstalk vegetables (radish, carrot and potato) were investigated by using twelve cultivars grown in acidic Ferralsols and neutral Cambisols under two Pb treatments (125 mg kg(-1) and 250 mg kg(-1) for Ferralsols; 150 mg kg(-1) and 300 mg kg(-1) for Cambisols) in a pot experiment. The Pb concentration in edible parts was higher in Ferralsols under two Pb treatments, with range from 0.28 to 4.14, 0.42-10.66 mg kg(-1) (fresh weight) respectively, and all of them exceeded the food safety standard (0.1 mg kg(-1)) recommended by the Codex Alimentarius Commission of FAO and WHO. The Pb concentration in edible parts was significantly affected by genotype, soil type and the interaction between these two factors. The variation of Pb concentration in different cultivars was partially governed by Pb absorption and the transfer of Pb from aerial to edible part. The results revealed that caution should be paid to the cultivation of rootstalk vegetables in Pb-contaminated Ferralsols without any agronomic management to reduce Pb availability and plant uptake. For Cambisols with slight to moderate Pb contamination, growing potato cultivar Shandong No.1 and Chongqing No.1 was effective in reducing the risk of Pb entering human food chain. The results suggest the possibility of developing cultivar- and soil-specific planting and monitoring guidelines for the cultivation of rootstalk vegetables on slight to moderate Pb-contaminated soils.

Tobacco rattle virus-induced VcANS gene silencing in blueberry fruit.

Blueberry (Vaccinium corymbosum L.), a woody perennial bush in the genus Vaccinium, is an economically important and popular fruit crop worldwide. Development the superior cultivars, which including excellent fruit traits, not only means higher yielding and economic efficiency, but also produce fruit that to meet the preferences of different consumers. Excavating fruit quality-related genes, studying their functions, and using transgenic or molecular-assisted breeding are beneficial to the development of excellent blueberry varieties. Genetic transformation is an excellent way to study the function of genes in plants, however, it is a labor-intensive and time-consuming process to genetically transform many woody plants, including blueberry. Virus-induced gene silencing (VIGS) provides an efficient approach to knock-down the expression of target genes for functional analysis. In this study, tobacco rattle virus induced genes silencing (TRV-VIGS) was established in blueberry fruits using the VcANS gene as a reporter. The silenced sector of the skin of blueberry fruits injected with pTRV2 (plasmid Tobacco Rattle Virus, TRV-RNA2)::VcANS remained green or white at 25 days after agroinfiltration. In agroinfiltrated materials, the VcANS transcript levels were much lower in fruits with phenotypic changes (delayed color change) than in those infiltrated with the pTRV2 empty vector. Silencing of VcANS also affected the expression of other genes involved in the anthocyanin synthesis pathway. The experimental results support that VcANS can be used as an effective marker gene for VIGS system. In addition, the TRV-VIGS system has been successfully established in blueberry fruits, which provided an effective verification method for functional identification of unknown genes in blueberry fruits.

Circulating microRNA: Myocardium-derived prenatal biomarker of ventricular septal defects.

Background: Recently, circulating microRNAs (miRNAs) from maternal blood and amniotic fluid have been used as biomarkers for ventricular septal defect (VSD) diagnosis. However, whether circulating miRNAs are associated with fetal myocardium remains unknown. Methods: Dimethadione (DMO) induced a VSD rat model. The miRNA expression profiles of the myocardium, amniotic fluid and maternal serum were analyzed. Differentially expressed microRNAs (DE-microRNAs) were verified by qRT-PCR. The target gene of miR-1-3p was confirmed by dual luciferase reporter assays. Expression of amniotic fluid-derived DE-microRNAs was verified in clinical samples. Results: MiRNAs were differentially expressed in VSD fetal rats and might be involved in cardiomyocyte differentiation and apoptosis. MiR-1-3p, miR-1b and miR-293-5p were downregulated in the myocardium and upregulated in amniotic fluid/maternal serum. The expression of amniotic fluid-derived DE-microRNAs (miR-1-3p, miR-206 and miR-184) was verified in clinical samples. Dual luciferase reporter assays confirmed that miR-1-3p directly targeted SLC8A1/NCX1. Conclusion: MiR-1-3p, miR-1b and miR-293-5p are downregulated in VSD myocardium and upregulated in circulation and may be released into circulation by cardiomyocytes. MiR-1-3p targets SLC8A1/NCX1 and participates in myocardial apoptosis. MiR-1-3p upregulation in circulation is a direct and powerful indicator of fetal VSD and is expected to serve as a prenatal VSD diagnostic marker.

Cabozantinib promotes erythroid differentiation in K562 erythroleukemia cells through global changes in gene expression and JNK activation.

Cabozantinib is a potent tyrosine kinase inhibitor with multiple targets including MET, VEGFR2, RET, KIT, and FLT3. Cabozantinib is widely used for the treatment of medullary thyroid cancer and renal cell carcinoma. We recently suggested cabozantinib as a potential therapeutic alternative for acute myeloid leukemia (AML) patients with FLT3-internal tandem duplication (FLT3-ITD). Here, we report that cabozantinib can promote differentiation in erythroid leukemia cells. We found that K562 erythroid leukemia cells treated with 1 µM cabozantinib for 72 h underwent erythroid lineage differentiation. Transcriptomic analysis revealed that various pathways associated with heme biosynthesis, hemoglobin production, and GATA1 targets were upregulated, whereas cell survival pathways were downregulated. Further examination revealed that cabozantinib-induced erythroid differentiation is at least in part regulated by JNK activation and phosphorylation. Levels of phosphorylated BCR-ABL, AKT, STAT5, ERK, and p38 also decreased following cabozantinib treatment. Therefore, we indicate that cabozantinib has dual functions. First, it induces K562 cell differentiation toward the erythroid lineage by upregulating heme biosynthesis, globin synthesis, and erythroid-associated reactions. Second, cabozantinib inhibits K562 cell proliferation by inhibiting the phosphorylation of BCR-ABL and the downstream MAPK, PI3K-AKT, and JAK-STAT signaling pathways.

Change in Urine Albumin-to-Creatinine Ratio and Risk of Diabetic Peripheral Neuropathy in Type 2 Diabetes: A Retrospective Cohort Study.

PURPOSE: This study aimed to assess association between change in urine albumin-to-creatinine ratio (UACR) and the risk of diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus. PATIENTS AND METHODS: A retrospective study was performed, which included 185 individuals with type 2 diabetes. At baseline, and at two-year follow-up, we collected basic data, recorded symptoms and signs of DPN, measured biochemical indicators, composite motor nerve conduction velocity (composite MCV), and composite sensory nerve conduction velocity (composite SCV). RESULTS: Changes of composite SCV, MCV and TCSS among different changes in UACR in patients without DPN and with DPN were not significantly different. An increase in UACR ≥30% (OR 3.059, 95%; CI: 1.012-9.249) suggested a risk for new-onset DPN. Based on ROC curve analysis, the areas under the curve were 0.654 ± 0.066 for change of UACR levels in non-DPN patients. CONCLUSION: Change in UACR and NCV was not related in patients without DPN and with DPN; change in UACR ≥30% suggested a risk for new-onset DPN.

Community-based Model for Dementia Risk Screening: The Beijing Aging Brain Rejuvenation Initiative (BABRI) Brain Health System.

OBJECTIVES: To address the condition that community-based geriatric services for the assessment and promotion of older adults' cognitive ability systemically aimed at delaying or preventing dementia is lacking in China. DESIGN: A community-based model including cognitive assessment and training, geriatric health guidance and long-term support was designed based on a prospective cohort study. SETTING AND PARTICIPANTS: Participants (N = 5593) were all from an ongoing cohort study, the Beijing Aging Brain Rejuvenation Initiative (BABRI) study. METHODS: We conducted receiver operating characteristic, stepwise logistic regression and branch-and-bound algorithm analyses to select the most effective tests from the BABRI neuropsychological test battery. Canonical discriminant analysis was conducted to extract the first canonical variable as a composite index of the tests. In addition, we developed comprehensive surveys and computerized cognitive trainings targeting every cognitive domain. RESULTS: The BABRI brain health system (BABRI-BHS) was designed to include SCREEN, ASSESS, and DIAGNOSE sessions. When distinguishing cognitively impaired older adults from cognitively healthy older adults, the canonical variable extracted from tests in the SCREEN session achieved an area under the curve (AUC) of 0.730 [95% confidence interval (95% CI) 0.671-0.789], with a sensitivity of 0.630 and a specificity of 0.780; in the ASSESS session, the AUC was 0.906 (95% CI 0.894-0.917), the sensitivity was 0.809, and the specificity was 0.854. A stepwise screening pathway is recommended when using the BABRI-BHS in communities to divide older adults into subtypes and to provide targeted interventions and long-term geriatric health guidance. CONCLUSIONS AND IMPLICATIONS: The BABRI-BHS is an effective and efficient geriatric health care solution that is suitable for community-based dementia risk screening, providing stepwise cognitive assessments and helping older adults acquire tailored interventions and guidance conveniently.

White Matter Microstructural Change Contributes to Worse Cognitive Function in Patients With Type 2 Diabetes.

Patients with type 2 diabetes mellitus (T2DM) have a considerably high risk of developing dementia, especially for those with mild cognitive impairment (MCI). The investigation of the microstructural change of white matter (WM) between T2DM with amnesic MCI (T2DM-aMCI) and T2DM with normal cognition (T2DM-NC) and their relationships to cognitive performances can help to understand the brain variations in T2DM-related amnesic cognitive impairment. In the current study, 36 T2DM-aMCI patients, 40 T2DM-NC patients, and 40 healthy control (HC) individuals underwent diffusion tensor image and T1-weighted MRI scans and comprehensive cognition assessments. All of these cognitive functions exhibited intergroup ranking differences in patients. The T2DM-NC patients and HC individuals did not reveal any significant differences in WM integrity. The T2DM-aMCI patients showed disrupted integrity in multiple WM tracts compared with HC and T2DM-NC. Specifically, the damaged WM integrity of the right inferior fronto-occipital fasciculus and the right inferior longitudinal fasciculus exhibited significant correlations with episodic memory and attention function impairment in T2DM patients. Furthermore, cognitive impairment-related WM microstructural damage was associated with the degeneration of cortex connected to the affected WM tract. These findings indicate that degeneration exists extensively in WM tracts in T2DM-aMCI, whereas no brain WM damage is evident in T2DM-NC.

Brain Network Connectivity Mediates Education-related Cognitive Performance in Healthy Elderly Adults.

BACKGROUND: Among the protective factors for cognitive decline related to aging and Alzheimer's disease, education level is one of the most prominent. However, the mechanisms underlying the protective effects of education on cognition remain to be elucidated. In this study, we aimed to systematically assess the role of Functional Connectivity (FC) of resting-state brain networks playing in the cognition-protection effect of education. METHODS: Data from a battery of neuropsychological tests and functional magnetic resonance imaging in resting-state were acquired in 77 cognitively normal elderly participants from local communities in Beijing, China. Six resting-state networks related to primary function or complex cognition were extracted through independent component analysis. We then explored the relationships between education level, cognition, and FC of these networks. RESULTS: We found that education level was positively associated with a wide range of complex cognitive domains including general mental status, episodic memory, language, attention, executive function and visuospatial processing, and it showed significantly negative correlations with FC of multiple areas in the Default Mode Network (DMN) and Left Frontal-parietal Network (LFP) which are related to complex cognition. And regional connectivity of DMN was significantly negatively correlated with episodic memory performance. Further mediation analysis suggested that higher education level was associated with higher episodic memory performance through lower regional connectivity of DMN. CONCLUSION: Our findings indicate that inhibitory modulation in the resting-state brain networks related to complex cognition is one of the main routes through which education exerts its protective effects on cognition in normal aging.