A Sacrifice-for-Survival Mechanism Protects Root Stem Cell Niche from Chilling Stress.

Temperature has a profound influence on plant and animal development, but its effects on stem cell behavior and activity remain poorly understood. Here, we characterize the responses of the Arabidopsis root to chilling (low but above-freezing) temperature. Chilling stress at 4°C leads to DNA damage predominantly in root stem cells and their early descendants. However, only newly generated/differentiating columella stem cell daughters (CSCDs) preferentially die in a programmed manner. Inhibition of the DNA damage response in these CSCDs prevents their death but makes the stem cell niche more vulnerable to chilling stress. Mathematical modeling and experimental validation indicate that CSCD death results in the re-establishment of the auxin maximum in the quiescent center (QC) and the maintenance of functional stem cell niche activity under chilling stress. This mechanism improves the root's ability to withstand the accompanying environmental stresses and to resume growth when optimal temperatures are restored.

The nucleocapsid protein facilitates p53 ubiquitination-dependent proteasomal degradation via recruiting host ubiquitin ligase COP1 in PEDV infection.

Porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric pathogen of the coronavirus family and caused severe economic losses to the global swine industry. Previous studies have established that p53 is a host restriction factor for PEDV infection, and p53 degradation occurs in PEDV-infected cells. However, the underlying molecular mechanisms through which PEDV viral proteins regulate p53 degradation remain unclear. In this study, we found that PEDV infection or expression of the nucleocapsid protein downregulates p53 through a post-translational mechanism: increasing the ubiquitination of p53 and preventing its nuclear translocation. We also show that the PEDV N protein functions by recruiting the E3 ubiquitin ligase COP1 and suppressing COP1 self-ubiquitination and protein degradation, thereby augmenting COP1-mediated degradation of p53. Additionally, COP1 knockdown compromises N-mediated p53 degradation. Functional mapping using truncation analysis showed that the N-terminal domains of N protein were responsible for interacting with COP1 and critical for COP1 stability and p53 degradation. The results presented here suggest the COP1-dependent mechanism for PEDV N protein to abolish p53 activity. This study significantly increases our understanding of PEDV in antagonizing the host antiviral factor p53 and will help initiate novel antiviral strategies against PEDV.

Diagnostic Potential of Serum Glycome Analysis in Lung Cancer: A Glycopattern Study.

Lung cancer is the leading cause of cancer-related death, with high morbidity and mortality rates due to the lack of reliable methods for diagnosing lung cancer at an early stage. Low-dose computed tomography can help detect abnormal areas in the lungs, but only 16% of cases are diagnosed early. Tests for lung cancer markers are often employed to determine genetic expression or mutations in lung carcinogenesis. Serum glycome analysis is a promising new method for early lung cancer diagnosis as glycopatterns exhibit significant differences in lung cancer patients. In this study, we employed a solid-phase chemoenzymatic method to systematically compare glycopatterns in benign cases, adenocarcinoma before and after surgery, and advanced stages of adenocarcinoma. Our findings indicate that serum high-mannose levels are elevated in both benign cases and adenocarcinoma, while complex N-glycans, including fucose and 2,6-linked sialic acid, are downregulated in the serum. Subsequently, we developed an algorithm that utilizes 16 altered N-glycans, 7 upregulated and 9 downregulated, to generate a score based on their intensity. This score can predict the stages of cancer progression in patients through glycan characterization. This methodology offers a potential means of diagnosing lung cancer through serum glycome analysis.

Uncovering the Recent Progress of CNC-Derived Chirality Nanomaterials: Structure and Functions.

Cellulose nanocrystal (CNC), as a renewable resource, with excellent mechanical performance, low thermal expansion coefficient, and unique optical performance, is becoming a novel candidate for the development of smart material. Herein, the recent progress of CNC-based chirality nanomaterials is uncovered, mainly covering structure regulations and function design. Undergoing a simple evaporation process, the cellulose nanorods can spontaneously assemble into chiral nematic films, accompanied by a vivid structural color. Various film structure-controlling strategies, including assembly means, physical modulation, additive engineering, surface modification, geometric structure regulation, and external field optimization, are summarized in this work. The intrinsic correlation between structure and performance is emphasized. Next, the applications of CNC-based nanomaterials is systematically reviewed. Layer-by-layer stacking structure and unique optical activity endow the nanomaterials with wide applications in the mineralization, bone regeneration, and synthesis of mesoporous materials. Besides, the vivid structural color broadens the functions in anti-counterfeiting engineering, synthesis of the shape-memory and self-healing materials. Finally, the challenges for the CNC-based nanomaterials are proposed.

Efficacy and safety of mesenchymal stem cells therapy in COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has become a serious public health issue. In COVID-19 patients, the elevated levels of inflammatory cytokines lead to the manifestation of COVID-19 symptoms, such as lung tissue edema, lung diffusion dysfunction, acute respiratory distress syndrome (ARDS), secondary infection, and ultimately mortality. Mesenchymal stem cells (MSCs) exhibit anti-inflammatory and immunomodulatory properties, thus providing a potential treatment option for COVID-19. The number of clinical trials of MSCs for COVID-19 has been rising. However, the treatment protocols and therapeutic effects of MSCs for COVID-19 patients are inconsistent. This meta-analysis was performed to systematically determine the safety and efficacy of MSC infusion in COVID-19 patients. METHODS: We conducted a comprehensive literature search from PubMed/Medline, Web of Science, EMBASE, and Cochrane Library up to 22 November 2023 to screen for eligible randomized controlled trials. Inclusion and exclusion criteria for searched literature were formulated according to the PICOS principle, followed by the use of literature quality assessment tools to assess the risk of bias. Finally, outcome measurements including therapeutic efficacy, clinical symptoms, and adverse events of each study were extracted for statistical analysis. RESULTS: A total of 14 randomized controlled trials were collected. The results of enrolled studies demonstrated that patients with COVID-19 pneumonia who received MSC inoculation showed a decreased mortality compared with counterparts who received conventional treatment (RR: 0.76; 95% CI [0.60, 0.96]; p = 0.02). Reciprocally, MSC inoculation improved the clinical symptoms in patients (RR: 1.28; 95% CI [1.06, 1.55]; p = 0.009). In terms of immune biomarkers, MSC treatment inhibited inflammation responses in COVID-19 patients, as was indicated by the decreased levels of CRP and IL-6. Importantly, our results showed that no significant differences in the incidence of adverse reactions or serious adverse events were monitored in patients after MSC inoculation. CONCLUSION: This meta-analysis demonstrated that MSC inoculation is effective and safe in the treatment of patients with COVID-19 pneumonia. Without increasing the incidence of adverse events or serious adverse events, MSC treatment decreased patient mortality and inflammatory levels and improved the clinical symptoms in COVID-19 patients. However, large-cohort randomized controlled trials with expanded numbers of patients are required to further confirm our results.

Regulation of NCOA4-mediated iron recycling ameliorates paraquat-induced lung injury by inhibiting ferroptosis.

Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast-acting and broad-spectrum. However, PQ was classified as the most prevailing poisoning substance for suicide with no specific antidote. Therefore, it is imperative to develop more effective therapeutic agents for the treatment of PQ poisoning. In the present study, both the RNA-Seq and the application of various cell death inhibitors reflected that ferroptosis exerts a crucial regulatory role in PQ poisoning. Moreover, we found PQ strengthens lipid peroxidation as evidenced by different experimental approaches. Of note, pretreatment of iron chelation agent DFO could ameliorate the ferroptotic cell death and alleviate the ferroptosis-related events. Mechanistically, PQ treatment intensively impaired mitochondrial homeostasis, enhanced phosphorylation of AMPK, accelerated the autophagy flux and triggered the activation of Nuclear receptor coactivator 4-ferritin heavy chain (NCOA4-FTH) axis. Importantly, the activation of autophagy was observed prior to the degradation of ferritin, and inhibition of autophagy could inhibit the accumulation of iron caused by the ferritinophagy process. Genetic and pharmacological inhibition of ferritinophagy could alleviate the lethal oxidative events, and rescue the ferroptotic cell death. Excitingly, in the mouse models of PQ poisoning, both the administration of DFO and adeno-associated virus-mediated FTH overexpression significantly reduced PQ-induced ferroptosis and improved the pathological characteristics of pulmonary fibrosis. In summary, the current work provides an in-depth study on the mechanism of PQ intoxication, describes a framework for the further understanding of ferroptosis in PQ-associated biological processes, and demonstrates modulation of iron metabolism may act as a promising therapeutic agent for the management of PQ toxicity.

Utilizing plasma drug levels and genetic testing to achieve optimal treatment response in a patient with treatment-resistant schizoaffective disorder.

We report the case of a Chinese male with schizoaffective disorder, an active smoker and a nonresponder to clozapine (600 mg daily). Therapeutic clozapine monitoring was analyzed, revealing a low concentration-dose ratio. A pharmacogenetic test showed that the patient had the CYP1A2*1F/*1F genotype, indicating an ultra-rapid clozapine metabolizer. In combination with fluvoxamine, a CYP1A2 enzyme inhibitor, clozapine plasma concentrations approached the reference range and achieved clinical improvement. This case demonstrates how pharmacogenetics can help understand the value of therapeutic drug monitoring to enhance the treatment of refractory schizoaffective disorder.

Unfolded Protein Response Differentially Modulates the Platelet Phenotype.

BACKGROUND: Unfolded protein response (UPR) is a multifaceted signaling cascade that alleviates protein misfolding. Although well studied in nucleated cells, UPR in absence of transcriptional regulation has not been described. Intricately associated with cardiovascular diseases, platelets, despite being anucleate, respond rapidly to stressors in blood. We investigate the UPR in anucleate platelets and explore its role, if any, on platelet physiology and function. METHODS: Human and mouse platelets were studied using a combination of ex vivo and in vivo experiments. Platelet lineage-specific knockout mice were generated independently for each of the 3 UPR pathways, PERK (protein kinase RNA [PKR]-like endoplasmic reticulum kinase), XBP1 (X-binding protein), and ATF6 (activating transcription factor 6). Diabetes patients were prospectively recruited, and platelets were evaluated for activation of UPR under chronic pathophysiological disease conditions. RESULTS: Tunicamycin induced the IRE1α (inositol-requiring enzyme-1alpha)-XBP1 pathway in human and mouse platelets, while oxidative stress predominantly activated the PERK pathway. PERK deletion significantly increased platelet aggregation and apoptosis and phosphorylation of PLCγ2, PLCß3, and p38 MAPK. Deficiency of XBP1 increased platelet aggregation, with higher PLCß3 and PKCδ activation. ATF6 deletion mediated a relatively modest effect on platelet phenotype with increased PKA (protein kinase A). Platelets from diabetes patients exhibited a positive correlation between disease severity, platelet activation, and protein aggregation, with only IRE1α-XBP1 activation. Moreover, IRE1α inhibition increased platelet aggregation, while clinically approved chemical chaperone, sodium 4-phenylbutyrate reduced the platelet hyperactivation. CONCLUSIONS: We show for the first time, that UPR activation occurs in platelets and can be independent of genomic regulation, with selective induction being specific to the source and severity of stress. Each UPR pathway plays a key role and can differentially modulate the platelet activation pathways and phenotype. Targeting the specific arms of UPR may provide a new antiplatelet strategy to mitigate thrombotic risk in diabetes and other cardiovascular diseases.

Effect of low-molecular-weight heparin calcium combined with magnesium sulfate and labetalol on coagulation, vascular endothelial function and pregnancy outcome in early-onset severe preeclampsia.

OBJECTIVE: This paper was aimed at unveiling the effect of low-molecular-weight heparin calcium (LMWH) combined with magnesium sulfate and labetalol on coagulation, vascular endothelial function, and pregnancy outcome in early-onset severe preeclampsia (EOSP). METHODS: Pregnant women with EOSP were divided into the control group and the study group, each with 62 cases. Patients in the control group were treated with labetalol and magnesium sulfate, and those in the study group were treated with LMWH in combination with the control grou Blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), 24-h urine protein, coagulation indices [D-dimer (D-D), plasma fibrinogen (Fg), prothrombin time (PT), activated partial thromboplastin time (APTT), and prothrombin time (TT)], endothelial function [endothelin (ET-1) and nitric oxide (NO)], oxidative stress indices [oxidized low-density lipoproteins (ox-LDL), lipid peroxidation (LPO), superoxide dismutase (SOD), and malondialdehyde (MDA)], pregnancy outcome, and adverse effects occurred in the two groups were compared. RESULTS: After treatment, lower SBP, DBP, and 24-h urine protein levels; lower Fg and D-D levels; higher PT, APPT, and TT levels; higher NO levels; lower ET-1 levels; lower ox-LDL, MDA, and LPO levels; higher SOD levels; and lower incidence of adverse pregnancy and adverse reactions were noted in the study group in contrast to the control group. CONCLUSION: EOSP patients given with LMWH combined with magnesium sulfate and labetalol can effectively reduce the patient's blood pressure and urinary protein level; improve coagulation function, oxidative stress, and vascular endothelial function indices; reduce the adverse pregnancy outcomes; and improve the safety of treatment.

Association between drinking water sources and cognitive functioning in Chinese older adults residing in rural areas.

OBJECTIVES: To explore the association between drinking water sources and cognitive functioning among older adults residing in rural China. METHODS: Data were extracted from the 2008-2018 Chinese Longitudinal Healthy Longevity Survey. Drinking water sources were categorized according to whether purification measures were employed. The Chinese version of the Mini-Mental State Examination was used for cognitive functioning assessment, and the score of <24 was considered as having cognitive dysfunction. Cox regression analyses were conducted to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the effects of various drinking water sources, changes in such sources, and its interaction with exercise on cognition dysfunction. RESULTS: We included 2304 respondents aged 79.67 ± 10.02 years; of them, 1084 (44.49%) were men. Our adjusted model revealed that respondents consistently drinking tap water were 21% less likely to experience cognitive dysfunction compared with those drinking untreated water (HR = 0.79, 95% CI: 0.70-0.90). Respondents transitioning from natural to tap water showed were 33% less likely to experience cognitive dysfunction (HR = 0.67, 95% CI: 0.58-0.78). Moreover, the HR (95% CI) for the interaction between drinking tap water and exercising was 0.86 (0.75-1.00) when compared with that between drinking untreated water and not exercising. All results adjusted for age, occupation, exercise, and body mass index. CONCLUSIONS: Prolonged tap water consumption and switching from untreated water to tap water were associated with a decreased risk of cognitive dysfunction in older individuals. Additionally, exercising and drinking tap water was synergistically associated with the low incidence of cognitive dysfunction. These findings demonstrate the importance of prioritizing drinking water health in rural areas, indicating that purified tap water can enhance cognitive function among older adults.

White matter brain age as a biomarker of cerebrovascular burden in the ageing brain.

As the brain ages, it almost invariably accumulates vascular pathology, which differentially affects the cerebral white matter. A rich body of research has investigated the link between vascular risk factors and the brain. One of the less studied questions is that among various modifiable vascular risk factors, which is the most debilitating one for white matter health? A white matter specific brain age was developed to evaluate the overall white matter health from diffusion weighted imaging, using a three-dimensional convolutional neural network deep learning model in both cross-sectional UK biobank participants (n = 37,327) and a longitudinal subset (n = 1409). White matter brain age gap (WMBAG) was the difference between the white matter age and the chronological age. Participants with one, two, and three or more vascular risk factors, compared to those without any, showed an elevated WMBAG of 0.54, 1.23, and 1.94 years, respectively. Diabetes was most strongly associated with an increased WMBAG (1.39 years, p < 0.001) among all risk factors followed by hypertension (0.87 years, p < 0.001) and smoking (0.69 years, p < 0.001). Baseline WMBAG was associated significantly with processing speed, executive and global cognition. Significant associations of diabetes and hypertension with poor processing speed and executive function were found to be mediated through the WMBAG. White matter specific brain age can be successfully targeted for the examination of the most relevant risk factors and cognition, and for tracking an individual's cerebrovascular ageing process. It also provides clinical basis for the better management of specific risk factors.

Clinical practice guidelines for the nutrition of colorectal cancer patients: a systematic review.

PURPOSE: The aim of this study is to rigorously assess the methodological quality of published clinical practice guidelines (CPGs) related to nutrition among colorectal cancer patients, to compile consensus recommendations, and to evaluate the quality of the included CPGs. METHODS: The systematic search covered eight electronic databases, two relevant professional association websites, and six guideline websites from their inception up to January 22, 2023. The methodological quality of the eligible guidelines was evaluated using the Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument, and then, consensus recommendations were synthesized. The scores for each domain were expressed as the mean ± standard deviation (SD). Using the mean score as the benchmark for comparison, they were subsequently ranked from highest to lowest. The included guidelines were then categorized as having "high," "moderate," or "low" quality based on their scores. RESULTS: The literature search yielded ten guidelines. The findings indicated that the "Clarity of presentation" domain had the highest mean score (65.2 ± 7.7). This demonstrates how the guidelines effectively articulate recommendations. Additionally, the "Scope and purpose" domain achieved a mean score of 60.7 ± 10.9, followed by "Rigor of development" (51.7 ± 15.7), "Editorial independence" (51.1 ± 21), "Stakeholder involvement" (48 ± 16.8), and "Applicability" domains (47.5 ± 17.3). Two CPGs received an overall rating of "high quality" and were recommended; four CPGs received an overall rating of "moderate" and were recommended with modifications; and four CPGs received an overall rating of "low quality" and were not recommended. Furthermore, this study compiled twenty consensus recommendations related to nine distinct clinical issues. CONCLUSION: This study identified disparities in the methodological quality of the included CPGs, particularly in the "Applicability" domain, thus emphasizing the need for advancement in clinical feasibility and implementation. Notably, there is few guidelines specifically targeting colorectal cancer nutrition. These synthesized findings provided an intuitive, convenient, and comprehensive reference for evaluating nutrition among colorectal cancer patients. When applying these results, users should make careful decisions based on their specific situations.

Bacteriocins attenuate Listeria monocytogenes-induced intestinal barrier dysfunction and inflammatory response.

Bacteriocins have the potential to effectively improve food-borne infections or gastrointestinal diseases and hold promise as viable alternatives to antibiotics. This study aimed to explore the antibacterial activity of three bacteriocins (nisin, enterocin Gr17, and plantaricin RX-8) and their ability to attenuate intestinal barrier dysfunction and inflammatory responses induced by Listeria monocytogenes, respectively. Bacteriocins have shown excellent antibacterial activity against L. monocytogenes without causing any cytotoxicity. Bacteriocins inhibited the adhesion and invasion of L. monocytogenes on Caco-2 cells, lactate dehydrogenase (LDH), trans-epithelial electrical resistance (TEER), and cell migration showed that bacteriocin improved the permeability of Caco-2 cells. These results were attributed to the promotion of tight junction proteins (TJP) assembly, specifically zonula occludens-1 (ZO-1), occludin, and claudin-1. Furthermore, bacteriocins could alleviate inflammation by inhibiting the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways and reducing the secretion of interleukin-6 (IL-6), interleukin-1 ß (IL-1ß) and tumor necrosis factor α (TNF-α). Among three bacteriocins, plantaricin RX-8 showed the best antibacterial activity against L. monocytogenes and the most pronounced protective effect on the intestinal barrier due to its unique structure. Based on our findings, we hypothesized that bacteriocins may inhibit the adhesion and invasion of L. monocytogenes by competing adhesion sites. Moreover, they may further enhance intestinal barrier function by inhibiting the expression of L. monocytogenes virulence factors, increasing the expression of TJP and decreasing the secretion of inflammatory factors. Therefore, bacteriocins will hopefully be an effective alternative to antibiotics, and this study provides valuable insights into food safety concerns. KEY POINTS: • Bacteriocins show excellent antibacterial activity against L. monocytogenes • Bacteriocins improve intestinal barrier damage and inflammatory response • Plantaricin RX-8 has the best protective effect on Caco-2 cells damage.

Role of reactive oxygen species in myelodysplastic syndromes.

Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy.

Safety and efficacy of peripheral blood stem cells collection in healthy children and pediatric patients with thalassemia major weighing 20 kg or less.

BACKGROUND: Peripheral blood stem cell (PBSC) collection in children poses challenges due to their small size, low body weight (BW), and unique pediatric physiology, especially among children weighing 20 kg (kg) or less. METHODS: PBSC collection data of both healthy children and patients with thalassemia major (TM) weighing 20 kg or less between January 2013 and December 2020 were reviewed. Moreover, PBSCs characteristics along with various aspects of efficiency and safety between healthy donors and patients with TM were compared. RESULTS: A total of 262 PBSC procedures were performed on 255 children. Of these, 91 procedures were carried out on 85 allogeneic healthy donors, and 171 auto-backup collections were performed on 170 patients with TM to ensure PBSC availability and prevent transplantation failure. A minimum pre-apheresis hemoglobin (HGB) level of 60 g/L was discovered to be safe and feasible in patients with TM. The median CD34+ cell dose in the PBSC product during the initial apheresis procedure was higher in healthy donors compared to patients with TM (7.29 ± 5.28 × 106 cells/kg vs5.88 ± 4.23 × 106 cells/kg, P = .043). The total CD34+ cells/kg recipient weight exhibited a positive correlation with pre-apheresis monocyte counts, but a negative correlation with donor weight. Apheresis significantly reduced hematocrit and platelet counts in the allogeneic group compared to the autologous group. Patients with TM experienced a higher occurrence of bone pain related to granulocyte colony-stimulating factor treatment. Notably, no serious complications related to PBSCs mobilization, central venous catheter placement, or the apheresis procedure were observed in either group. CONCLUSIONS: PBSCs collection was both safe and effective in healthy children and pediatric patients with TM weighing 20 kg or less.

TEB/POLQ plays dual roles in protecting Arabidopsis from NO-induced DNA damage.

Nitric oxide (NO) is a key player in numerous physiological processes. Excessive NO induces DNA damage, but how plants respond to this damage remains unclear. We screened and identified an Arabidopsis NO hypersensitive mutant and found it to be allelic to TEBICHI/POLQ, encoding DNA polymerase θ. The teb mutant plants were preferentially sensitive to NO- and its derivative peroxynitrite-induced DNA damage and subsequent double-strand breaks (DSBs). Inactivation of TEB caused the accumulation of spontaneous DSBs largely attributed to endogenous NO and was synergistic to DSB repair pathway mutations with respect to growth. These effects were manifested in the presence of NO-inducing agents and relieved by NO scavengers. NO induced G2/M cell cycle arrest in the teb mutant, indicative of stalled replication forks. Genetic analyses indicate that Polθ is required for translesion DNA synthesis across NO-induced lesions, but not oxidation-induced lesions. Whole-genome sequencing revealed that Polθ bypasses NO-induced base adducts in an error-free manner and generates mutations characteristic of Polθ-mediated end joining. Our experimental data collectively suggests that Polθ plays dual roles in protecting plants from NO-induced DNA damage. Since Polθ is conserved in higher eukaryotes, mammalian Polθ may also be required for balancing NO physiological signaling and genotoxicity.

Associations between accelerometer-measured circadian rest-activity rhythm, brain structural and genetic mechanisms, and dementia.

AIM: Knowledge of how circadian rhythm influences brain health remains limited. We aimed to investigate the associations of accelerometer-measured circadian rest-activity rhythm (CRAR) with incident dementia, cognitive dysfunction, and structural brain abnormalities in the general population and underlying biological mechanisms. METHODS: Fifty-seven thousand five hundred and two participants aged over 60 years with accelerometer data were included to investigate the association of CRAR with incidental dementia. Non-parametric CRAR parameters were utilized, including activity level during active periods of the day (M10), activity level during rest periods of the day (L5), and the relative difference between the M10 and L5 (relative amplitude, RA). Associations of CRAR with cognitive dysfunction and brain structure were studied in a subset of participants. Neuroimaging-transcriptomics analysis was utilized to identify the underlying molecular mechanisms. RESULTS: Over 6.86 (4.94-8.78) years of follow-up, 494 participants developed dementia. The risk of incident dementia was associated with decreasing M10 (hazard ratio [HR] 1.45; 95% conference interval [CI], 1.28-1.64) and RA (HR 1.37; 95% CI, 1.28-1.64), increasing L5 (HR 1.14, 95% CI 1.07-1.21) and advanced L5 onset time (HR 1.12; 95% CI, 1.02-1.23). The detrimental associations were exacerbated by APOE ε4 status and age (>65 years). Decreased RA was associated with lower processing speed (Beta -0.04; SE 0.011), predominantly mediated by abnormalities in subcortical regions and white matter microstructure. The genes underlying CRAR-related brain regional structure variation were enriched for synaptic function. CONCLUSIONS: Our study underscores the potential of intervention targeting at maintaining a healthy CRAR pattern to prevent dementia risk.

Bioinformatic analysis of the role of immune checkpoint genes and immune infiltration in the pathogenesis and development of premature ovarian insufficiency.

PURPOSE: With advances in immunology, increasing evidence suggests that immunity is involved in premature ovarian insufficiency (POI) pathogenesis. This study investigated the roles of immune checkpoint genes and immune cell infiltration in POI pathogenesis and development. METHODS: The GSE39501 dataset and immune checkpoint genes were obtained from the Gene Expression Omnibus database and related literature. The two datasets were intersected to obtain immune checkpoint-related differentially expressed genes (ICRDEGs), which were analyzed using Gene Ontology and Kyoto Encyclopedia of Gene and Genomes enrichment analysis, weighted correlation network analysis, protein-protein interaction and related microRNAs, transcription factors, and RNA binding proteins. The immune cell infiltration of ICRDEGs was explored, and receiver operating characteristic curves were used to validate the diagnostic value of ICRDEGs in POI. RESULTS: We performed ICRDEG functional enrichment analysis and found that these genes were closely related to immune processes, such as T cell activation. Specifically, they are enriched in various biological processes and pathways, such as cell adhesion molecule and T cell receptor signaling pathways. Weighted correlation network analysis identified seven hub genes: Cd200, Cd274, Cd28, neurociliary protein-1, Cd276, Cd40lg, and Cd47. Furthermore, we identified 112 microRNAs, 17 RNA-binding proteins, and 101 transcription factors. Finally, immune infiltration analysis showed a clear positive correlation between hub genes and multiple immune cell types. CONCLUSION: Bioinformatic analysis identified seven potential ICRDEGs associated with POI, among which the immune checkpoint molecules CD200 and neurociliary protein-1 may be involved in the pathogenesis of POI.

Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease.

INTRODUCTION: Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. METHODS: Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD dementia (n = 47), mild cognitive impairment (MCI; n = 137), and normal controls (n = 235) from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. DISCUSSION: Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD. HIGHLIGHTS: The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aß) positron emission tomography (PET) burden and Aß-positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aß42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aß PET and brain atrophy mediated the link of ALPS index with cognitive decline.

Influence of myoglobin on the antibacterial activity of carvacrol and the binding mechanism between the two compounds.

BACKGROUND: Myoglobin (MB), a pigmentation protein, can adversely affect the antibacterial activity of carvacrol (CAR) and weaken its bacteriostasis effect. This study aimed to clarify the influence of MB on the antibacterial activity of CAR and ascertain the mechanism involved in the observed influence, especially the interaction between the two compounds. RESULTS: Microbiological analysis indicated that the presence of MB significantly suppressed the antibacterial activity of CAR against Listeria monocytogenes. Ultraviolet-visible spectrometry and fluorescence spectroscopic analysis confirmed the interaction between CAR and MB. The stoichiometric number was determined as ~0.7 via double logarithmic Stern-Volmer equation analysis, while thermodynamic analysis showed that the conjugation of the two compounds occurred as an exothermal reaction (ΔH° = -32.3 ± 11.4 kJ mol-1 and ΔS° = -75 J mol-1 K-1 ). Circular dichroism, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy showed hydrogen bonding in the carvacrol-myoglobin complex (CAR-MB). Molecular docking analysis confirmed that amino acid residues, including GLY80 and HIS82, were most likely to form hydrogen bonds with CAR, while hydrogen bonds represented the main driving force for CAR-MB formation. CONCLUSION: CAR antibacterial activity was significantly inhibited by the presence of MB in the environment due to the notable reduction in the effective concentration of CAR caused by CAR-MB formation. © 2023 Society of Chemical Industry.