Interaction between microglial cells and CD1C+ B dendritic cells leads to CD8+ T cells depletion during the early stages of renal clear cell carcinoma.

Renal clear cell carcinoma (RCC) is a type of malignant tumor, which, in addition to surgical resection, radiotherapy, and chemotherapy, has been widely treated through immunotherapy recently. However, the influence of the tumor microenvironment and the infiltrating immune cells within it on immunotherapy remains unclear. It is imperative to study the interactions between various immune cells of RCC. The scRNA-seq dataset from GEO's database was used to analyze the immune cells present in tumor tissue and peripheral blood samples. Through quality control, clustering, and identification, the types and proportions of infiltrating immune cells were determined. The cellular differences were determined, and gene expression levels of the differentially present cells were investigated. A protein-protein interaction network analysis was performed using string. KEGG and GO analyses were performed to investigate abnormal activities. The microglia marker CD68 and CD1C+ B dendritic cells marker CD11C were detected using multiplex immunofluorescence staining. Many depleted CD8+ T cells (exhausted CD8+ T cells) appeared in tumor tissues as well as microglia. CD1C+ B dendritic cells did not infiltrate tumor tissues. HSPA1A was correlated with DNAJB1 in microglia. Compared with Paracancer tissues, microglia increased while CD1C+ B dendritic cells decreased in pathological stages I and I-II in cancerous tissues. An altered tumor microenvironment caused by increases in microglia in RCC in the early stage resulted in an inability of CD1C+ B dendritic cells to infiltrate, resulting in CD8+ T cells being unable to receive the antigens presented by them, and in turn being depleted in large quantities.

Improving Microstructural Estimation in Time-Dependent Diffusion MRI With a Bayesian Method.

BACKGROUND: Accurately fitting diffusion-time-dependent diffusion MRI (td-dMRI) models poses challenges due to complex and nonlinear formulas, signal noise, and limited clinical data acquisition. PURPOSE: Introduce a Bayesian methodology to refine microstructural fitting within the IMPULSED (Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion) model and optimize the prior distribution within the Bayesian framework. STUDY TYPE: Retrospective. POPULATION: Involving 69 pediatric patients (median age 6 years, interquartile range [IQR] 3-9 years, 61% male) with 41 low-grade and 28 high-grade gliomas, of which 76.8% were identified within the brainstem or cerebellum. FIELD STRENGTH/SEQUENCE: 3 T, oscillating gradient spin-echo (OGSE) and pulsed gradient spin-echo (PGSE). ASSESSMENT: The Bayesian method's performance in fitting cell diameter ( d $$ d $$ ), intracellular volume fraction ( f in $$ {f}_{in} $$ ), and extracellular diffusion coefficient ( D ex $$ {D}_{ex} $$ ) was compared against the NLLS method, considering simulated and experimental data. The tumor region-of-interest (ROI) were manually delineated on the b0 images. The diagnostic performance in distinguishing high- and low-grade gliomas was assessed, and fitting accuracy was validated against H&E-stained pathology. STATISTICAL TESTS: T-test, receiver operating curve (ROC), area under the curve (AUC) and DeLong's test were conducted. Significance considered at P < 0.05. RESULTS: Bayesian methodology manifested increased accuracy with robust estimates in simulation (RMSE decreased by 29.6%, 40.9%, 13.6%, and STD decreased by 29.2%, 43.5%, and 24.0%, respectively for d $$ d $$ , f in $$ {f}_{in} $$ , and D ex $$ {D}_{ex} $$ compared to NLLS), indicating fewer outliers and reduced error. Diagnostic performance for tumor grade was similar in both methods, however, Bayesian method generated smoother microstructural maps (outliers ratio decreased by 45.3% ± 19.4%) and a marginal enhancement in correlation with H&E staining result (r = 0.721 for f in $$ {f}_{in} $$ compared to r = 0.698 using NLLS, P = 0.5764). DATA CONCLUSION: The proposed Bayesian method substantially enhances the accuracy and robustness of IMPULSED model estimation, suggesting its potential clinical utility in characterizing cellular microstructure. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 1.

Quercetin in Osteoporosis Treatment: A Comprehensive Review of Its Mechanisms and Therapeutic Potential.

PURPOSE OF REVIEW: This review aims to provide a theoretical basis and insights for quercetin's clinical application in the prevention and treatment of osteoporosis (OP), analyzing its roles in bone formation promotion, bone resorption inhibition, anti-inflammation, antioxidant effects, and potential mechanisms. RECENT FINDINGS: OP, a prevalent bone disorder, is marked by reduced bone mineral density and impaired bone architecture, elevating the risk of fractures in patients. The primary approach to OP management is pharmacotherapy, with quercetin, a phytochemical compound, emerging as a focus of recent interest. This natural flavonoid exerts regulatory effects on bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts and promotes bone health and metabolic equilibrium via anti-inflammatory and antioxidative pathways. Although quercetin has demonstrated significant potential in regulating bone metabolism, there is a need for further high-quality clinical studies focused on medicinal quercetin.

Deep-learning-enabled brain hemodynamic mapping using resting-state fMRI.

Cerebrovascular disease is a leading cause of death globally. Prevention and early intervention are known to be the most effective forms of its management. Non-invasive imaging methods hold great promises for early stratification, but at present lack the sensitivity for personalized prognosis. Resting-state functional magnetic resonance imaging (rs-fMRI), a powerful tool previously used for mapping neural activity, is available in most hospitals. Here we show that rs-fMRI can be used to map cerebral hemodynamic function and delineate impairment. By exploiting time variations in breathing pattern during rs-fMRI, deep learning enables reproducible mapping of cerebrovascular reactivity (CVR) and bolus arrival time (BAT) of the human brain using resting-state CO2 fluctuations as a natural "contrast media". The deep-learning network is trained with CVR and BAT maps obtained with a reference method of CO2-inhalation MRI, which includes data from young and older healthy subjects and patients with Moyamoya disease and brain tumors. We demonstrate the performance of deep-learning cerebrovascular mapping in the detection of vascular abnormalities, evaluation of revascularization effects, and vascular alterations in normal aging. In addition, cerebrovascular maps obtained with the proposed method exhibit excellent reproducibility in both healthy volunteers and stroke patients. Deep-learning resting-state vascular imaging has the potential to become a useful tool in clinical cerebrovascular imaging.

[Application of absorbable anchor combined with Kirschner wire in reconstruction of extension function of old mallet finger].

Objective: To investigate the feasibility and effectiveness of absorbable anchor combined with Kirschner wire fixation in the reconstruction of extension function of old mallet finger. Methods: Between January 2020 and January 2022, 23 cases of old mallet fingers were treated. There were 17 males and 6 females with an average age of 42 years (range, 18-70 years). The cause of injury included sports impact injury in 12 cases, sprain in 9 cases, and previous cut injury in 2 cases. The affected finger included index finger in 4 cases, middle finger in 5 cases, ring finger in 9 cases, and little finger in 5 cases. There were 18 patients of tendinous mallet fingers (Doyle type Ⅰ), 5 patients were only small bone fragments avulsion (Wehbe type ⅠA). The time from injury to operation was 45-120 days, with an average of 67 days. The patients were treated with Kirschner wire to fix the distal interphalangeal joint in a mild back extension position after joint release. The insertion of extensor tendon was reconstructed and fixed with absorbable anchors. After 6 weeks, the Kirschner wire was removed, and the patients started joint flexion and extension training. Results: The postoperative follow-up ranged from 4 to 24 months (mean, 9 months). The wounds healed by first intention without complications such as skin necrosis, wound infection, and nail deformity. The distal interphalangeal joint was not stiff, the joint space was good, and there was no complication such as pain and osteoarthritis. At last follow-up, according to Crawford function evaluation standard, 12 cases were excellent, 9 cases were good, 2 cases were fair, and the good and excellent rate was 91.3%. Conclusion: Absorbable anchor combined with Kirschner wire fixation can be used to reconstruct the extension function of old mallet finger, which has the advantages of simple operation and less complications.

Non-contrast assessment of blood-brain barrier permeability to water in mice: An arterial spin labeling study at cerebral veins.

Blood-brain barrier (BBB) plays a critical role in protecting the brain from toxins and pathogens. However, in vivo tools to assess BBB permeability are scarce and often require the use of exogenous contrast agents. In this study, we aimed to develop a non-contrast arterial-spin-labeling (ASL) based MRI technique to estimate BBB permeability to water in mice. By determining the relative fraction of labeled water spins that were exchanged into the brain tissue as opposed to those that remained in the cerebral veins, we estimated indices of global BBB permeability to water including water extraction fraction (E) and permeability surface-area product (PS). First, using multiple post-labeling delay ASL experiments, we estimated the bolus arrival time (BAT) of the labeled spins to reach the great vein of Galen (VG) to be 691.2 ± 14.5 ms (N = 5). Next, we investigated the dependence of the VG ASL signal on labeling duration and identified an optimal imaging protocol with a labeling duration of 1200 ms and a PLD of 100 ms. Quantitative E and PS values in wild-type mice were found to be 59.9 ± 3.2% and 260.9 ± 18.9 ml/100 g/min, respectively. In contrast, mice with Huntington's disease (HD) revealed a significantly higher E (69.7 ± 2.4%, P = 0.026) and PS (318.1 ± 17.1 ml/100 g/min, P = 0.040), suggesting BBB breakdown in this mouse model. Reproducibility studies revealed a coefficient-of-variation (CoV) of 4.9 ± 1.7% and 6.1 ± 1.2% for E and PS, respectively. The proposed method may open new avenues for preclinical research on pathophysiological mechanisms of brain diseases and therapeutic trials in animal models.

Differences in the intrinsic chondrogenic potential of human mesenchymal stromal cells and iPSC-derived multipotent cells.

BACKGROUND: Human multipotent progenitor cells (hiMPCs) created from induced pluripotent stem cells (iPSCs) represent a new cell source for cartilage regeneration. In most studies, bone morphogenetic proteins (BMPs) are needed to enhance transforming growth factor-ß (TGFß)-induced hiMPC chondrogenesis. In contrast, TGFß alone is sufficient to result in robust chondrogenesis of human primary mesenchymal stromal cells (hMSCs). Currently, the mechanism underlying this difference between hiMPCs and hMSCs has not been fully understood. METHODS: In this study, we first tested different growth factors alone or in combination in stimulating hiMPC chondrogenesis, with a special focus on chondrocytic hypertrophy. The reparative capacity of hiMPCs-derived cartilage was assessed in an osteochondral defect model created in rats. hMSCs isolated from bone marrow were included in all studies as the control. Lastly, a mechanistic study was conducted to understand why hiMPCs and hMSCs behave differently in responding to TGFß. RESULTS: Chondrogenic medium supplemented with TGFß3 and BMP6 led to robust in vitro cartilage formation from hiMPCs with minimal hypertrophy. Cartilage tissue generated from this new method was resistant to osteogenic transition upon subcutaneous implantation and resulted in a hyaline cartilage-like regeneration in osteochondral defects in rats. Interestingly, TGFß3 induced phosphorylation of both Smad2/3 and Smad1/5 in hMSCs, but only activated Smad2/3 in hiMPCs. Supplementing BMP6 activated Smad1/5 and significantly enhanced TGFß's compacity in inducing hiMPC chondrogenesis. The chondro-promoting function of BMP6 was abolished by the treatment of a BMP pathway inhibitor. CONCLUSIONS: This study describes a robust method to generate chondrocytes from hiMPCs with low hypertrophy for hyaline cartilage repair, as well as elucidates the difference between hMSCs and hiMPCs in response to TGFß. Our results also indicated the importance of activating both Smad2/3 and Smad1/5 in the initiation of chondrogenesis.

Research progress on the circRNA/lncRNA-miRNA-mRNA axis in gastric cancer.

Gastric cancer is one of the most common malignant tumours worldwide. Genetic and epigenetic alterations are key factors in gastric carcinogenesis and drug resistance to chemotherapy. Competing endogenous RNA (ceRNA) regulation models have defined circRNA/lncRNA as miRNA sponges that indirectly regulate miRNA downstream target genes. The ceRNA regulatory network is related to the malignant biological behaviour of gastric cancer. The circRNA/lncRNA-miRNA-mRNA axis may be a marker for the early diagnosis and prognosis of gastric cancer and a potential therapeutic target for gastric cancer. Exosomal ncRNAs play an important role in gastric cancer and are expected to be ideal biomarkers for the diagnosis, prognosis, and treatment of gastric cancer. This review summarizes the specific ceRNA regulatory network (circRNA/lncRNA-miRNA-mRNA) discovered in gastric cancer in recent years, which may provide new ideas or strategies for early clinical diagnosis, further development, and application.

Blood-brain barrier permeability in response to caffeine challenge.

PURPOSE: Caffeine is known to alter brain perfusion by acting as an adenosine antagonist, but its effect on blood-brain barrier (BBB) permeability is not fully elucidated. This study aimed to dynamically monitor BBB permeability to water after a single dose of caffeine tablet using a non-contrast MRI technique. METHODS: Ten young healthy volunteers who were not regular coffee drinkers were studied. The experiment began with a pre-caffeine measurement, followed by four measurements at the post-caffeine stage. Water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI was used to assess the time dependence of BBB permeability to water following the ingestion of 200 mg caffeine. Other cerebral physiological parameters including cerebral blood flow (CBF), venous oxygenation (Yv ), and cerebral metabolic rate of oxygen (CMRO2 ) were also examined. The relationships between cerebral physiological parameters and time were studied with mixed-effect models. RESULTS: It was found that, after caffeine ingestion, CBF and Yv showed a time-dependent decrease (p < 0.001), while CMRO2 did not change significantly. The fraction of arterial water crossing the BBB (E) showed a significant increase (p < 0.001). In contrast, the permeability-surface-area product (PS), i.e., BBB permeability to water, remained constant (p = 0.94). Additionally, it was observed that changes in physiological parameters were non-linear with regard to time and occurred at as early as 9 min after caffeine tablet ingestion. CONCLUSION: These results suggest an unchanged BBB permeability despite alterations in perfusion during a vasoconstrictive caffeine challenge.

Human Mesenchymal Stem Cell-Derived Miniature Joint System for Disease Modeling and Drug Testing.

Diseases of the knee joint such as osteoarthritis (OA) affect all joint elements. An in vitro human cell-derived microphysiological system capable of simulating intraarticular tissue crosstalk is desirable for studying etiologies/pathogenesis of joint diseases and testing potential therapeutics. Herein, a human mesenchymal stem cell-derived miniature joint system (miniJoint) is generated, in which engineered osteochondral complex, synovial-like fibrous tissue, and adipose tissue are integrated into a microfluidics-enabled bioreactor. This novel design facilitates different tissues communicating while still maintaining their respective phenotypes. The miniJoint exhibits physiologically relevant changes when exposed to interleukin-1ß mediated inflammation, which are similar to observations in joint diseases in humans. The potential of the miniJoint in predicting in vivo efficacy of drug treatment is confirmed by testing the "therapeutic effect" of the nonsteroidal anti-inflammatory drug, naproxen, as well as four other potential disease-modifying OA drugs. The data demonstrate that the miniJoint recapitulates complex tissue interactions, thus providing a robust organ chip model for the study of joint pathology and the development of novel therapeutic interventions.

Engineering pre-vascularized bone-like tissue from human mesenchymal stem cells through simulating endochondral ossification.

Currently, most in vitro engineered bone tissues do not contain viable blood vessel systems, so the vascularization depends on post-implantation angiogenesis from the host, which is often insufficient for repairing large bone defects. In this study, we aimed to create pre-vascularized bone-like tissue from human bone marrow-derived mesenchymal stem cells (HBMSCs) within the self-generated extracellular matrix by simulating the developmental endochondral ossification. Afterward, a three-dimensional (3D) culture of human umbilical vein endothelial cells (HUVECs)/HBMSCs was introduced to cover bone-like constructs surface for vascularization. Lastly, the pre-vascularized bone-like tissues were subcutaneously implanted into mice and the quality of newly formed blood vessels and bones were later assessed. We particularly examined whether the pre-existing HUVECs/HBMSCs vascular networks within the implants were able to integrate with the host's blood vessels and facilitate bone formation. Our results showed that this developmentally informed procedure resulted in a robust osteogenic differentiation of HBMSCs. Moreover, the bone-like constructs markedly promoted HUVEC/HBMSCs network formation in vitro. After 28 days of implantation in mice, the experimental group, in which bone-like constructs were pre-vascularized with HUVEC/HBMSCs networks, exhibited significantly more functional blood vessels than the control group that contained HUVEC and HBMSC single cells. Interestingly, increased levels of bone formation and absorption markers were also observed in the pre-vascularized bone-like constructs. Taken together, these findings demonstrated the potential of pre-vascularized bone-like constructs in repairing bone defects.

Graphene oxide-functionalized nanocomposites promote osteogenesis of human mesenchymal stem cells via enhancement of BMP-SMAD1/5 signaling pathway.

Biomaterials that can harness the intrinsic osteogenic potential of stem cells offer a promising strategy to accelerate bone regeneration and repair. Previously, we had used methacrylated gelatin (GelMA)-based scaffolds to achieve bone formation from human mesenchymal stem cells (hMSCs). In this study, we aimed to further enhance hMSC osteogenesis by incorporating graphene oxide (GO)-based nanosheets into GelMA. In vitro results showed high viability and metabolic activities in hMSCs encapsulated in the newly developed nanocomposites. Incorporation of GO markedly increased mineralization within hMSC-laden constructs, which was further increased by replacing GO with silica-coated graphene oxide (SiGO). Mechanistic analysis revealed that the nanosheet enhanced the production, retention, and biological activity of endogenous bone morphogenetic proteins (BMPs), resulting in robust osteogenesis in the absence of exogenous osteoinductive growth factors. Specifically, the osteoinductive effect of the nanosheets was abolished by inhibiting the BMP signaling pathway with LDN-193189 treatment. The bone formation potential of the technology was further tested in vivo using a mouse subcutaneous implantation model, where hMSCs-laden GO/GelMA and SiGO/GelMA samples resulted in bone volumes 108 and 385 times larger, respectively, than the GelMA control group. Taken together, these results demonstrate the biological activity and mechanism of action of GO-based nanosheets in augmenting the osteogenic capability of hMSCs, and highlights the potential of leveraging nanomaterials such as GO and SiGO for bone tissue engineering applications.

DJ-1 inhibits microglial activation and protects dopaminergic neurons in vitro and in vivo through interacting with microglial p65.

Parkinson's disease (PD), one of the most common neurodegenerative disorders, is characterized by progressive neurodegeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). DJ-1 acts essential roles in neuronal protection and anti-neuroinflammatory response, and its loss of function is tightly associated with a familial recessive form of PD. However, the molecular mechanism of DJ-1 involved in neuroinflammation is largely unclear. Here, we found that wild-type DJ-1, rather than the pathogenic L166P mutant DJ-1, directly binds to the subunit p65 of nuclear factor-κB (NF-κB) in the cytoplasm, and loss of DJ-1 promotes p65 nuclear translocation by facilitating the dissociation between p65 and NF-κB inhibitor α (IκBα). DJ-1 knockout (DJ-1-/-) mice exhibit more microglial activation compared with wild-type littermate controls, especially in response to lipopolysaccharide (LPS) treatment. In cellular models, knockdown of DJ-1 significantly upregulates the gene expression and increases the release of LPS-treated inflammatory cytokines in primary microglia and BV2 cells. Furthermore, DJ-1 deficiency in microglia significantly enhances the neuronal toxicity in response to LPS stimulus. In addition, pharmacological blockage of NF-κB nuclear translocation by SN-50 prevents microglial activation and alleviates the damage of DA neurons induced by microglial DJ-1 deficiency in vivo and in vitro. Thus, our data illustrate a novel mechanism by which DJ-1 facilitates the interaction between IκBα and p65 by binding to p65 in microglia, and thus repressing microglial activation and exhibiting the protection of DA neurons from neuroinflammation-mediated injury in PD.

Joint Genome-Wide Association Analyses Identified 49 Novel Loci For Age at Natural Menopause.

BACKGROUND: Age at natural menopause (ANM) is an important index for women's health. Either early or late ANM is associated with a series of adverse outcomes later in life. Despite being an inheritable trait, its genetic determinant has not yet been fully understood. METHODS: Aiming to better characterize the genetic architecture of ANM, we conducted genome-wide association study (GWAS) meta-analyses in European-specific as well as trans-ancestry samples by using GWAS summary statistics from the following 3 large studies: the Reproductive Genetics Consortium (ReproGen; N = 69 626), the UK Biobank cohort (UKBB; N = 111 593) and the BioBank Japan Project (BBJ; N = 43 861), followed by a series of bioinformatical assessments and functional annotations. RESULTS: By integrating the summary statistics from the 3 GWAS of up to 225 200 participants, this largest meta-analysis identified 49 novel loci and 3 secondary signals that were associated with ANM at the genome-wide significance level (P < 5 × 10-8). No population specificity or heterogeneity was observed at most of the associated loci. Functional annotations prioritized 90 candidate genes at the newly identified loci. Among the 26 traits that were genetically correlated with ANM, hormone replacement therapy (HRT) exerted a causal relationship, implying a causal pattern by which HRT was determined by ANM. CONCLUSION: Our findings improved our understanding of the etiology of female menopause, as well as shed light on potential new therapies for abnormal menopause.

Cerebrovascular Reactivity Mapping Using Resting-State BOLD Functional MRI in Healthy Adults and Patients with Moyamoya Disease.

Background Cerebrovascular reserve, the potential capacity of brain tissue to receive more blood flow when needed, is a desirable marker in evaluating ischemic risk. However, current measurement methods require acetazolamide injection or hypercapnia challenge, prompting a clinical need for resting-state (RS) blood oxygen level-dependent (BOLD) functional MRI data to measure cerebrovascular reactivity (CVR). Purpose To optimize and evaluate an RS CVR MRI technique and demonstrate its relationship to neurosurgical treatment. Materials and Methods In this HIPAA-compliant study, RS BOLD functional MRI data collected in 170 healthy controls between December 2008 and September 2010 were retrospectively evaluated to identify the optimal frequency range of temporal filtering on the basis of spatial correlation with the reference standard CVR map obtained with CO2 inhalation. Next, the optimized RS method was applied in a new, prospective cohort of 50 participants with Moyamoya disease who underwent imaging between June 2014 and August 2019. Finally, CVR values were compared between brain hemispheres with and brain hemispheres without revascularization surgery by using Mann-Whitney U test. Results A total of 170 healthy controls (mean age ± standard deviation, 51 years ± 20; 105 women) and 100 brain hemispheres of 50 participants with Moyamoya disease (mean age, 41 years ± 12; 43 women) were evaluated. RS CVR maps based on a temporal filtering frequency of [0, 0.1164 Hz] yielded the highest spatial correlation (r = 0.74) with the CO2 inhalation CVR results. In patients with Moyamoya disease, 77 middle cerebral arteries (MCAs) had stenosis. RS CVR in the MCA territory was lower in the group that did not undergo surgery (n = 30) than in the group that underwent surgery (n = 47) (mean, 0.407 relative units [ru] ± 0.208 vs 0.532 ru ± 0.182, respectively; P = .006), which is corroborated with the CO2 inhalation CVR data (mean, 0.242 ru ± 0.273 vs 0.437 ru ± 0.200; P = .003). Conclusion Cerebrovascular reactivity mapping performed by using resting-state blood oxygen level-dependent functional MRI provided a task-free method to measure cerebrovascular reserve and depicted treatment effect of revascularization surgery in patients with Moyamoya disease comparable to that with the reference standard of CO2 inhalation MRI. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Wolf and Ware in this issue.

Characterisation of gas exchange in COPD with dissolved-phase hyperpolarised xenon-129 MRI.

To investigate whether hyperpolarised xenon-129 MRI (HXeMRI) enables regional and physiological resolution of diffusing capacity limitations in chronic obstructive pulmonary disease (COPD), we evaluated 34 COPD subjects and 11 healthy volunteers. We report significant correlations between airflow abnormality quantified by HXeMRI and per cent predicted forced expiratory volume in 1 s; HXeMRI gas transfer capacity to red blood cells and carbon monoxide diffusion capacity (%DLCO); and HXeMRI gas transfer capacity to interstitium and per cent emphysema quantified by multidetector chest CT. We further demonstrate the capability of HXeMRI to distinguish varying pathology underlying COPD in subjects with low %DLCO and minimal emphysema.

Brain Oxygen Extraction Is Differentially Altered by Alzheimer's and Vascular Diseases.

BACKGROUND: Alzheimer's disease and vascular cognitive impairment (VCI), as well as their concurrence, represent the most common types of cognitive dysfunction. Treatment strategies for these two conditions are quite different; however, there exists a considerable overlap in their clinical manifestations, and most biomarkers reveal similar abnormalities between these two conditions. PURPOSE: To evaluate the potential of cerebral oxygen extraction fraction (OEF) as a biomarker for differential diagnosis of Alzheimer's disease and VCI. We hypothesized that in Alzheimer's disease OEF will be reduced (decreased oxygen consumption due to decreased neural activity), while in vascular diseases OEF will be elevated (increased oxygen extraction due to abnormally decreased blood flow). STUDY TYPE: Prospective cross-sectional. POPULATION: Sixty-five subjects aged 52-89 years, including 33 mild cognitive impairment (MCI), 7 dementia, and 25 cognitively normal subjects. FIELD STRENGTH/SEQUENCE: 3T T2 -relaxation-under-spin-tagging (TRUST) and fluid-attenuated inversion recovery imaging (FLAIR). ASSESSMENT: OEF, consensus diagnoses of cognitive impairment, vascular risk factors (such as hypertension, hypercholesterolemia, diabetes, smoking, and obesity), cognitive assessments, and cerebrospinal fluid concentration of amyloid and tau were assessed. STATISTICAL TESTS: Multiple linear regression analyses of OEF with diagnostic category (normal, MCI, or dementia), vascular risks, cognitive performance, amyloid and tau pathology. RESULTS: When evaluating the entire group, OEF was found to be lower with more severe cognitive impairment (ß = -2.70 ± 1.15, T = -2.34, P = 0.02), but was higher with greater vascular risk factors (ß = 1.36 ± 0.55, T = 2.48, P = 0.02). Further investigation of the subgroup of participants with low vascular risks (N = 44) revealed that lower OEF was associated with worse cognitive performance (ß = 0.04 ± 0.01, T = 3.27, P = 0.002) and greater amyloid burden (ß = 92.12 ± 41.23, T = 2.23, P = 0.03). Among cognitively impaired individuals (N = 40), higher OEF was associated with greater vascular risk factors (ß = 2.19 ± 0.71, T = 3.08, P = 0.004). DATA CONCLUSION: These findings suggest that OEF is differentially affected by Alzheimer's disease and VCI pathology and may be useful in etiology-based diagnosis of cognitive impairment. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3 J. MAGN. RESON. IMAGING 2020;52:1829-1837.

Engineering hyaline cartilage from mesenchymal stem cells with low hypertrophy potential via modulation of culture conditions and Wnt/ß-catenin pathway.

Mesenchymal stem cells (MSCs) represent a promising cell source to regenerate articular cartilage, but current chondroinduction protocols, commonly using transforming growth factor-ß (TGFß), lead to concomitant chondrocytic hypertrophy with ossification risk. Here, we showed that a 14-day culture of MSC-laden hyaluronic acid hydrogel in the presence of TGFß, followed by 7 days culture in TGFß-free medium, with the supplement of Wnt/ß-catenin inhibitor XAV939 from day 10-21, resulted in significantly reduced hypertrophy phenotype. The stability of the hyaline phenotype of the MSC-derived cartilage, generated with a standard protocol (Control) or the optimized (Optimized) method developed in this study, was further examined through intramuscular implantation in nude mice. After 4 weeks, constructs from the Control group showed obvious mineralization; in contrast, the Optimized group displayed no signs of mineralization, and maintained cartilaginous histology. Further analysis showed that TGFß treatment time affected p38 expression, while exposure to XAV939 significantly inhibited P-Smad 1/5 level, which together resulted in decreased level of Runx2. These findings suggest a novel treatment regimen to generate hyaline cartilage from human MSCs-loaded scaffolds, which have a minimal risk of eliciting endochondral ossification.

The blockade of lipophagy pathway is necessary for docosahexaenoic acid to regulate lipid droplet turnover in hepatic stellate cells.

Hepatic stellate cell (HSC) activation is treated as a dominator segment in hepatic fibrosis, which is accompanied by significant loss of lipid droplets (LDs). However, the regulatory network of LD disappearance is still unclear. It has been reported that lipophagy activation contributed to LD loss by upregulating RAB25 expression. In the present study, we sought to determine the regulation of docosahexaenoic acid (DHA) on LD disappearance, and to further examine potential molecular mechanisms. Interestingly, DHA treatment completely impaired LD disappearance during HSC activation. Moreover, treatment with DHA evidently promoted LD regeneration in activated HSCs that displayed matrix-producing myofibroblasts. Attractively, DHA-induced LD regeneration was coupled with the inhibition of lipophagy signaling. DHA treatment increased autophagosome generation and autophagic flux, but inhibited the target recognition of lipophagy for LDs by inhibiting RAB25 expression. Importantly, up-regulation of RAB25 expression, using RAB25 plasmid, completely blocked DHA-induced LD regeneration in activated HSCs. Noteworthy, treatment of DHA prominently alleviated murine liver fibrosis by reversing HSC lipocyte phenotype. HSC-specific overexpression of RAB25 impaired DHA-induced LD regeneration of activated HSCs, and in turn abolished anti-hepatic fibrosis effect of DHA in murine liver fibrosis. Overall, these results showed that DHA induced LD regeneration by inhibiting lipophagy signaling in activated HSCs, and also identified RAB25 dependent lipophagy as an important target for the prevention of hepatic fibrosis.

[Analysis of anti-fatigue mechanism and potential targets of ginseng].

Ginseng has effects in reinforcing vital energy,invigorating health effectively and relieving fatigue symptoms,and ginsenoside( GS) is the main component of its anti-fatigue effect. Totally 17 active components and 92 drug targets of ginseng compounds were screened from Traditional Chinese Medicine Systems Pharmacology; and 78 intersecting genes of diseases and drug targets were obtained based on R Language Technology. The protein-protein interaction( PPI) network was constructed by STRING 11. 0 software,and Matthews Correlation Coefficient( MCC) algorithm was used to screen core target genes. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were used to analyze the major genes and their roles in regulatory networks. The results indicated that ginseng could regulate the core target genes,including AKT serine/threonine kinase( AKT1),interleukin-1ß,Toll-like receptor binding molecule 1( ICAM1),mitogen-activated protein kinase 8( MAPK8),AP-1 transcription factor subunit( JUN),transducer and activator of transcription 1( STAT1) and prostaglandin peroxidase synthase 2( PTGS2). It could participate in the functions of cytokine receptor binding,cell adhesion molecule binding and tumor necrosis factor receptor superfamily binding,and also regulate the signal pathways of tumor necrosis factor,interleukin 17 and c-type lectin receptor,so as to exert an anti-fatigue effect. Based on the results of network analysis,32 four-week-old male SPFACR mice were randomly divided into control group,low-dose ginsenoside group,middle-dose ginsenoside group and high-dose ginsenoside group. The corresponding drugs were administrated for 3 weeks. The results showed that GS could significantly up-regulate the expressions of STAT1 and AKT1( P<0. 01,P<0. 05),and downregulate the expressions of PTGS2 and JUN( P<0. 01). However,there was no significant effect on MAPK8,IL-1ß and ICAM1. Ginseng's anti-fatigue regulation network was constructed through network pharmacology,and the results were verified by experiments,in order to reveal the anti-fatigue mechanism of ginseng and provide scientific basis for its clinical application.