ABSTRACT
The brassinosteroid (BR) receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1) plays a critical role in plant growth and development. Although much is known about how BR signaling regulates growth and development in many crop species, the role of StBRI1 in regulating potato (Solanum tuberosum) tuber development is not well understood. To address this question, a series of comprehensive genetic and biochemical methods were applied in this investigation. It was determined that StBRI1 and Solanum tuberosum PLASMA MEMBRANE (PM) PROTON ATPASE2 (PHA2), a PM-localized proton ATPase, play important roles in potato tuber development. The individual overexpression of StBRI1 and PHA2 led to a 22% and 25% increase in tuber yield per plant, respectively. Consistent with the genetic evidence, in vivo interaction analysis using double transgenic lines and PM H+-ATPase activity assays indicated that StBRI1 interacts with the C-terminus of PHA2, which restrains the intramolecular interaction of the PHA2 C-terminus with the PHA2 central loop to attenuate autoinhibition of PM H+-ATPase activity, resulting in increased PHA2 activity. Furthermore, the extent of PM H+-ATPase autoinhibition involving phosphorylation-dependent mechanisms corresponds to phosphorylation of the penultimate Thr residue (Thr-951) in PHA2. These results suggest that StBRI1 phosphorylates PHA2 and enhances its activity, which subsequently promotes tuber development. Altogether, our results uncover a BR-StBRI1-PHA2 module that regulates tuber development and suggest a prospective strategy for improving tuberous crop growth and increasing yield via the cell surface-based BR signaling pathway.
ABSTRACT
Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2-deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut.
Subject(s)
Carcinoma, Squamous Cell , Signal Transduction , Animals , Mice , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Carcinoma, Squamous Cell/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Homeostasis , Signal Transduction/genetics , Stem Cells/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , YAP-Signaling ProteinsABSTRACT
Our recent investigation has indicated that the global deletion of MBD2 can mitigate the progression of AKI induced by VAN. Nevertheless, the role and regulatory mechanisms of proximal tubular MBD2 in this pathophysiological process have yet to be elucidated. Our preceding investigation revealed that autophagy played a crucial role in advancing AKI induced by VAN. Consequently, we postulated that MBD2 present in the proximal tubule could upregulate the autophagic process to expedite the onset of AKI. In the present study, we found for the first time that MBD2 mediated the autophagy production induced by VAN. Through the utilization of miRNA chip analysis, we have mechanistically demonstrated that MBD2 initiates the activation of miR-597-5p through promoter demethylation. This process leads to the suppression of S1PR1, which results in the induction of autophagy and apoptosis in renal tubular cells. Besides, PT-MBD2-KO reduced autophagy to attenuate VAN-induced AKI via regulation of the miR-597-5p/S1PR1 axis, which was reversed by rapamycin. Finally, the overexpression of MBD2 aggravated the diminished VAN-induced AKI in autophagy-deficient mice (PT-Atg7-KO). These data demonstrate that proximal tubular MBD2 facilitated the process of autophagy via the miR-597-5p/S1PR1 axis and subsequently instigated VAN-induced AKI through the induction of apoptosis. The potentiality of MBD2 being a target for AKI was established.
Subject(s)
Acute Kidney Injury , MicroRNAs , Animals , Mice , Vancomycin , Acute Kidney Injury/chemically induced , Acute Kidney Injury/genetics , Kidney , MicroRNAs/genetics , Apoptosis/physiology , AutophagyABSTRACT
Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single-cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK-8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2-related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+ ). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH-MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH-MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH-MB cells and sensitized SHH-MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH-MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH-MB cell-derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH-MB and silencing FANCD2 could sensitize SHH-MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.
Subject(s)
Cerebellar Neoplasms , Fanconi Anemia , Ferroptosis , Medulloblastoma , Mice , Animals , Humans , Medulloblastoma/genetics , Medulloblastoma/radiotherapy , Ferroptosis/genetics , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/radiotherapy , Cell Line, Tumor , Fanconi Anemia Complementation Group D2 Protein/geneticsABSTRACT
Given the widespread use and relapse of methamphetamine (METH), it has caused serious public health burdens globally. However, the neurobiological basis of METH addiction remains poorly understood. Therefore, this study aimed to use magnetic resonance imaging (MRI) to investigate changes in brain networks and their connection to impulsivity and drug craving in abstinent individuals with METH use disorder (MUDs). A total of 110 MUDs and 55 age- and gender-matched healthy controls (HCs) underwent resting-state functional MRI and T1-weighted imaging scans, and completed impulsivity and cue-induced craving measurements. We applied independent component analysis to construct functional brain networks and multivariate analysis of covariance to investigate group differences in network connectivity. Mediation analyses were conducted to explore the relationships among brain-network functional connectivity (FC), impulsivity, and drug craving in the patients. MUDs showed increased connectivity in the salience network (SN) and decreased connectivity in the default mode network compared to HCs. Impulsivity was positively correlated with FC within the SN and played a completely mediating role between METH craving and FC within the SN in MUDs. These findings suggest alterations in functional brain networks underlying METH dependence, with SN potentially acting as a core neural substrate for impulse control disorders.
Subject(s)
Amphetamine-Related Disorders , Brain , Craving , Cues , Impulsive Behavior , Magnetic Resonance Imaging , Methamphetamine , Humans , Male , Amphetamine-Related Disorders/diagnostic imaging , Amphetamine-Related Disorders/physiopathology , Amphetamine-Related Disorders/psychology , Adult , Craving/physiology , Impulsive Behavior/physiology , Female , Brain/diagnostic imaging , Brain/physiopathology , Methamphetamine/adverse effects , Nerve Net/diagnostic imaging , Nerve Net/physiopathology , Neural Pathways/physiopathology , Neural Pathways/diagnostic imaging , Young AdultABSTRACT
Methamphetamine is a highly addictive psychostimulant drug that is abused globally and is a serious threat to health worldwide. Unfortunately, the specific mechanism underlying addiction remains unclear. Thus, this study aimed to investigate the characteristics of functional connectivity in the brain network and the factors influencing methamphetamine use disorder in patients using magnetic resonance imaging. We included 96 abstinent male participants with methamphetamine use disorder and 46 age- and sex-matched healthy controls for magnetic resonance imaging. Compared with healthy controls, participants with methamphetamine use disorder had greater impulsivity, fewer small-world attributes of the resting-state network, more nodal topological attributes in the cerebellum, greater functional connectivity strength within the cerebellum and between the cerebellum and brain, and decreased frontoparietal functional connectivity strength. In addition, after controlling for covariates, the partial correlation analysis showed that small-world properties were significantly associated with methamphetamine use frequency, psychological craving, and impulsivity. Furthermore, we revealed that the small-word attribute significantly mediated the effect of methamphetamine use frequency on motor impulsivity in the methamphetamine use disorder group. These findings may further improve our understanding of the neural mechanism of impulse control dysfunction underlying methamphetamine addiction and assist in exploring the neuropathological mechanism underlying methamphetamine use disorder-related dysfunction and rehabilitation.
Subject(s)
Amphetamine-Related Disorders , Central Nervous System Stimulants , Methamphetamine , Humans , Male , Methamphetamine/adverse effects , Brain/diagnostic imaging , Amphetamine-Related Disorders/diagnostic imaging , Amphetamine-Related Disorders/psychology , Brain Mapping , Magnetic Resonance ImagingABSTRACT
BACKGROUND: We sought to explore the associations of outdoor light at night (LAN) and air pollution with the risk of cerebrovascular disease (CeVD). METHODS: We included a total of 28â 302 participants enrolled in Ningbo, China from 2015 to 2018. Outdoor LAN and air pollution were assessed by Satellite-derived images and land-use regression models. CeVD cases were confirmed by medical records and death certificates and further subdivided into ischemic and hemorrhagic stroke. Cox proportional hazard models were used to estimate hazard ratios and 95% CIs. RESULTS: A total of 1278 CeVD cases (including 777 ischemic and 133 hemorrhagic stroke cases) were identified during 127â 877 person-years of follow-up. In the single-exposure models, the hazard ratios for CeVD were 1.17 (95% CI, 1.06-1.29) for outdoor LAN, 1.25 (1.12-1.39) for particulate matter with an aerodynamic diameter ≤2.5 µm, 1.14 (1.06-1.22) for particulate matter with aerodynamic diameter ≤10 µm, and 1.21 (1.06-1.38) for NO2 in every interquartile range increase. The results were similar for ischemic stroke, whereas no association was observed for hemorrhagic stroke. In the multiple-exposure models, the associations of outdoor LAN and PM with CeVD persisted but not for ischemic stroke. Furthermore, no interaction was observed between outdoor LAN and air pollution. CONCLUSIONS: Levels of exposure to outdoor LAN and air pollution were positively associated with the risk of CeVD. Furthermore, the detrimental effects of outdoor LAN and air pollution might be mutually independent.
Subject(s)
Air Pollutants , Air Pollution , Cerebrovascular Disorders , Hemorrhagic Stroke , Ischemic Stroke , Humans , Cohort Studies , Air Pollutants/adverse effects , Air Pollutants/analysis , Environmental Exposure/adverse effects , Air Pollution/adverse effects , Air Pollution/analysis , Particulate Matter/adverse effects , Particulate Matter/analysis , Cerebrovascular Disorders/epidemiology , Cerebrovascular Disorders/etiology , China/epidemiologyABSTRACT
BACKGROUND: Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated. METHODS: RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3. RESULTS: Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients. CONCLUSIONS: Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.
Subject(s)
Disease Progression , Exosomes , Gene Expression Regulation, Neoplastic , Glucose , RNA, Circular , Triple Negative Breast Neoplasms , Humans , Female , Exosomes/metabolism , RNA, Circular/genetics , Glucose/metabolism , Mice , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/genetics , Animals , Prognosis , Glycolysis , Cell Line, Tumor , Biomarkers, Tumor/metabolism , Cell Proliferation , Metabolic Reprogramming , Membrane Proteins , Intracellular Signaling Peptides and ProteinsABSTRACT
Persistently elevated glycolysis in kidney has been demonstrated to promote chronic kidney disease (CKD). However, the underlying mechanism remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced in kidney proximal tubular cells (PTCs) following ischemia-reperfusion injury (IRI) in mice, as well as in multiple etiologies of patients with CKD. PFKFB3 expression was positively correlated with the severity of kidney fibrosis. Moreover, patients with CKD and mice exhibited increased urinary lactate/creatine levels and kidney lactate, respectively. PTC-specific deletion of PFKFB3 significantly reduced kidney lactate levels, mitigated inflammation and fibrosis, and preserved kidney function in the IRI mouse model. Similar protective effects were observed in mice with heterozygous deficiency of PFKFB3 or those treated with a PFKFB3 inhibitor. Mechanistically, lactate derived from PFKFB3-mediated tubular glycolytic reprogramming markedly enhanced histone lactylation, particularly H4K12la, which was enriched at the promoter of NF-κB signaling genes like Ikbkb, Rela, and Relb, activating their transcription and facilitating the inflammatory response. Further, PTC-specific deletion of PFKFB3 inhibited the activation of IKKß, I κ B α, and p65 in the IRI kidneys. Moreover, increased H4K12la levels were positively correlated with kidney inflammation and fibrosis in patients with CKD. These findings suggest that tubular PFKFB3 may play a dual role in enhancing NF-κB signaling by promoting both H4K12la-mediated gene transcription and its activation. Thus, targeting the PFKFB3-mediated NF-κB signaling pathway in kidney tubular cells could be a novel strategy for CKD therapy.
Subject(s)
Disease Models, Animal , Fibrosis , Glycolysis , Histones , NF-kappa B , Phosphofructokinase-2 , Renal Insufficiency, Chronic , Reperfusion Injury , Animals , Phosphofructokinase-2/genetics , Phosphofructokinase-2/metabolism , Renal Insufficiency, Chronic/pathology , Renal Insufficiency, Chronic/metabolism , Humans , Mice , Male , Reperfusion Injury/pathology , Reperfusion Injury/metabolism , NF-kappa B/metabolism , Histones/metabolism , Mice, Knockout , Mice, Inbred C57BL , Signal Transduction , Kidney Tubules, Proximal/pathology , Kidney Tubules, Proximal/metabolism , Lactic Acid/metabolism , Kidney/pathology , Kidney/metabolismABSTRACT
Alzheimer's disease (AD) is recognized as the predominant cause of dementia, and neuroimmune processes play a pivotal role in its pathological progression. The involvement of long non-coding RNAs (lncRNAs) in AD has attracted widespread attention. Herein, transcriptomic analysis of 262 unique samples extracted from five hippocampal-entorhinal system subfields of individuals with AD pathology and without AD pathology revealed distinctive lncRNA expression profiles. Through differential expression and coexpression analyses, we identified 16 pivotal lncRNAs. Notably, RN7SL1 knockdown significantly modulated microglial responses upon oligomeric amyloid-ß stimulation, resulting in a considerable decrease in proinflammatory cytokine production and subsequent neuronal damage. These findings highlight RN7SL1 as an essential neuroimmune-related lncRNA that could serve as a prospective target for AD diagnosis and treatment.
Subject(s)
Alzheimer Disease , RNA, Long Noncoding , Humans , Alzheimer Disease/pathology , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Amyloid beta-Peptides/metabolism , Hippocampus/metabolism , Gene ExpressionABSTRACT
Next-generation batteries have long been considered a transition to more sustainable storage technologies. Among them, metal-air batteries (MABs) with low cost, high safety, and environmental friendliness have shown great potential for future large-scale applications. Motivated by the desirable characteristics, significant progress is made in suppressing serious parasitic reactions, improving electrochemical performance, and increasing the energy density in MABs. Compared to the widely reported liquid electrolyte strategy, solid-state electrolytes (SSEs) can thoroughly solve the volatilization challenges of liquid electrolytes and protect the oxygen electrodes without the formation of diffusion-blocking oxide phases. Notably, SSEs for MABs are still in their infancy, and many thorny challenges still need to be solved. In this review, the main electrochemical mechanism, key challenges, and some important progress are sorted out for solid-state MABs, such as lithium-air, zinc-air, aluminum-air, and magnesium-air batteries. Besides their fundamental significance, these configurations are further compared in terms of energy density, cost, carbon footprint, energy consumption, rate performance, cycle performance, safety, and air stability of prevailing electrolytes.
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Bone infection poses a major clinical challenge that can hinder patient recovery and exacerbate postoperative complications. This study has developed a bioactive composite scaffold through the co-assembly and intrafibrillar mineralization of collagen fibrils and zinc oxide (ZnO) nanowires (IMC/ZnO). The IMC/ZnO exhibits bone-like hierarchical structures and enhances capabilities for osteogenesis, antibacterial activity, and bacteria-infected bone healing. During co-cultivation with human bone marrow mesenchymal stem cells (BMMSCs), the IMC/ZnO improves BMMSC adhesion, proliferation, and osteogenic differentiation even under inflammatory conditions. Moreover, it suppresses the activity of Gram-negative Porphyromonas gingivalis and Gram-positive Streptococcus mutans by releasing zinc ions within the acidic infectious microenvironment. In vivo, the IMC/ZnO enables near-complete healing of infected bone defects within the intricate oral bacterial milieu, which is attributed to IMC/ZnO orchestrating M2 macrophage polarization, and fostering an osteogenic and anti-inflammatory microenvironment. Overall, these findings demonstrate the promise of the bioactive scaffold IMC/ZnO for treating bacteria-infected bone defects.
Subject(s)
Bone Regeneration , Collagen , Mesenchymal Stem Cells , Nanowires , Osteogenesis , Tissue Scaffolds , Zinc Oxide , Zinc Oxide/chemistry , Zinc Oxide/pharmacology , Nanowires/chemistry , Bone Regeneration/drug effects , Tissue Scaffolds/chemistry , Humans , Collagen/chemistry , Mesenchymal Stem Cells/cytology , Osteogenesis/drug effects , Animals , Porphyromonas gingivalis/drug effects , Cell Differentiation/drug effects , Streptococcus mutans/physiology , Streptococcus mutans/drug effects , Cell Proliferation/drug effectsABSTRACT
Bamboo with its remarkable growth rate and economic significance, offers an ideal system to investigate the molecular basis of organogenesis in rapidly growing plants, particular in monocots, where gene regulatory networks governing the maintenance and differentiation of shoot apical and intercalary meristems remain a subject of controversy. We employed both spatial and single-nucleus transcriptome sequencing on 10× platform to precisely dissect the gene functions in various tissues and early developmental stages of bamboo shoots. Our comprehensive analysis reveals distinct cell trajectories during shoot development, uncovering critical genes and pathways involved in procambium differentiation, intercalary meristem formation, and vascular tissue development. Spatial and temporal expression patterns of key regulatory genes, particularly those related to hormone signaling and lipid metabolism, strongly support the hypothesis that intercalary meristem origin from surrounded parenchyma cells. Specific gene expressions in intercalary meristem exhibit regular and dispersed distribution pattern, offering clues for understanding the intricate molecular mechanisms that drive the rapid growth of bamboo shoots. The single-nucleus and spatial transcriptome analysis reveal a comprehensive landscape of gene activity, enhancing the understanding of the molecular architecture of organogenesis and providing valuable resources for future genomic and genetic studies relying on identities of specific cell types.
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Reflective cholesteric liquid crystal (CLC) Pancharatnam-Berry phase lens (PBL) devices have attracted significant attention in augmented reality (AR) display due to their wide spectral and angular response bandwidths, high diffraction efficiency, and polarization selectivity. However, currently reported CLC reflective PBLs are either limited by monochrome display or suffers from complicated design for colorful display. Herein, we demonstrate a colorful multi-plane AR display system with dynamically tunable reflective PBL. The reflective PBL is fabricated by polymer-stabilized cholesteric liquid crystal (PSCLC) that provides dynamical and continuous tunability of color and focal length by direct current (DC) voltage. A proof-of-concept colorful multi-plane AR device is demonstrated, where over 90% diffraction efficiency at desired wavelength has been obtained. The proposed simple, compact, and light AR display system capable of color-imaging with multi-depth shows great application potential in the vehicle-mounted head-up display (HUD).
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AIMS: The role of maternal genetic factors in the association between high glycated haemoglobin (HbA1c) levels and adverse birth outcomes remains unclear. MATERIALS AND METHODS: In this study, the maternal HbA1c levels of 5108 normoglycemic pregnant women in China were measured, and A1298C and C677T polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were genotyped. RESULTS: Elevated HbA1c levels during the second trimester were associated with increased risks of macrosomia, large-for-gestational age (LGA), preterm birth (PTB), and reduced gestational age (p < 0.05). Pregnant women with MTHFR A1298C AA or C677T CT + TT genotypes were susceptible to adverse pregnancy outcomes related to HbA1c levels. Among pregnant women with the A1298C AA genotype, each standard deviation (SD) increase in HbA1c levels increased the risk of PTB by 1.32-times and reduced the gestational age by 0.11 weeks (p < 0.05). For MTHFR C677T CC + TT genotype carriers, higher HbA1c levels were associated with 1.49-, 1.24-, and 1.23-times increased risks of macrosomia, LGA, and PTB, respectively (p < 0.05). A U-shaped curve for PTB risk in relation to HbA1c levels was observed among the C677T CC + TT participants, with a cut-off value of 4.58%. Among subjects with the A1298C AA genotype combined with the C677T CT + TT genotype, each SD increase in HbA1c levels was associated with 1.40 and 1.37-times increased risks of LGA and PTB, respectively. CONCLUSIONS: Our findings highlight the importance of glycaemic control during pregnancy and the potential impact of genetic factors on birth outcomes. However, further large-scale studies are required to confirm these findings.
Subject(s)
Polymorphism, Single Nucleotide , Premature Birth , Infant, Newborn , Humans , Female , Pregnancy , Glycated Hemoglobin , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Fetal Macrosomia/genetics , Premature Birth/genetics , Genotype , Genetic Predisposition to DiseaseABSTRACT
BACKGROUND: Cognitive impairment is commonly observed in hydrocephalus patients. Ventricular enlargement compresses brain parenchyma, especially the white matter (WM). PURPOSE: To investigate whether the relationship between ventricular dilation and cognitive decline in hydrocephalus patients is mediated by WM alterations. STUDY TYPE: Retrospective. POPULATION: 51 communicating hydrocephalus patients (median age, 54 years), 50 obstructive hydrocephalus patients (median age, 49 years), and 53 control subjects (median age, 50 years). FIELD STRENGTH/SEQUENCE: Diffusion tensors imaging, 3D T1 BRAVO, 3D FIESTA, CUBE T2, and FLAIR sequences at 3T. ASSESSMENT: DTI parameters (skeletonized fractional anisotropy (FA), skeletonized mean diffusivity (MD), and peak width of skeletonized mean diffusivity p(PSMD)) were extracted using FSL software. Global, periventricular, and deep white matter hyperintensity (WMH) volumes, degree of ventricular enlargement (Evans index), and other conventional imaging markers (number of lacunes and perivascular spaces, intracranial and brain volume) were extracted using united imaging intelligence. Cognitive tests included Montreal cognitive assessment (MoCA), clock drawing test (CDT), and vocabulary fluency test (VFT). STATISTICAL TESTS: Multivariable linear regression analysis, mediation analyses, and dominance analysis. P-value <0.05 was considered significant. RESULTS: The degree of ventricular dilation, DTI parameters, and cognitive function scores were interrelated. The skeletonized FA values (ß = -0.0917, 95% confidence interval (CI): -0.205, -0.024) and normalized global WMH volume (ß = -0.0635, 95% CI: -0.13, -0.0005) together mediated 37.2% of the association between Evans index and MoCA. A comparable causal pathway was found for periventricular WMHs but not for deep WMHs. Dominance analysis indicated skeletonized FA values had a greater impact on cognition than WMH volume. The skeletonized FA values also mediated the association between Evans index and CDT (ß = -0.0897, 95% CI: -0.165, -0.026) and VFT (ß = -0.1589, 95% CI: -0.27, -0.083). CONCLUSION: WM alterations were causal mediators between ventricular dilation and cognitive decline in hydrocephalus patients. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 3.
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AIMS: To establish which components of energy balance mediate the clinically significant weight loss demonstrated with use of cotadutide, a glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist, in early-phase studies. MATERIALS AND METHODS: We conducted a phase 2a, single-centre, randomized, placebo-controlled trial in overweight and obese adults with type 2 diabetes. Following a 16-day single-blind placebo run-in, participants were randomized 2:1 to double-blind 42-day subcutaneous treatment with cotadutide (100-300 µg daily) or placebo. The primary outcome was percentage weight change. Secondary outcomes included change in energy intake (EI) and energy expenditure (EE). RESULTS: A total of 12 participants (63%) in the cotadutide group and seven (78%) in the placebo group completed the study. The mean (90% confidence interval [CI]) weight change was -4.0% (-4.9%, -3.1%) and -1.4% (-2.7%, -0.1%) for the cotadutide and placebo groups, respectively (p = 0.011). EI was lower with cotadutide versus placebo (-41.3% [-66.7, -15.9]; p = 0.011). Difference in EE (per kJ/kg lean body mass) for cotadutide versus placebo was 1.0% (90% CI -8.4, 10.4; p = 0.784), assessed by doubly labelled water, and -6.5% (90% CI -9.3, -3.7; p < 0.001), assessed by indirect calorimetry. CONCLUSION: Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE.
Subject(s)
Diabetes Mellitus, Type 2 , Energy Intake , Energy Metabolism , Obesity , Weight Loss , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Male , Female , Middle Aged , Double-Blind Method , Obesity/drug therapy , Obesity/complications , Energy Intake/drug effects , Weight Loss/drug effects , Energy Metabolism/drug effects , Adult , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/pharmacology , Receptors, Glucagon/agonists , Glucagon-Like Peptide 1/agonists , Single-Blind Method , Aged , Glucagon-Like Peptide-1 Receptor/agonists , Treatment Outcome , PeptidesABSTRACT
AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/drug therapy , Exenatide/adverse effects , Healthy Volunteers , Area Under Curve , Glucose Tolerance Test , Double-Blind Method , Dose-Response Relationship, DrugABSTRACT
Flexible strain sensors have drawn a lot of interest in various applications including human mobility tracking, rehabilitation/personalized health monitoring, and human-machine interaction, but suffer from interference of electromagnetic (EM). To overcome the EM interference, flexible force sensors without sensitive electronic elements have been developed, with drawbacks of bulky modules that hinders their applications in remote measurement with power-free environment. Therefore, it is highly desirable to fabricate a compact wireless flexible force sensor but it is still a challenge. Here, we demonstrate a fluorescent flexible force sensor based on aggregation-induced emission (AIE) doped liquid crystal elastomer (LCE) experimentally. The proposed force sensor film can be used to measure force through the variation of fluorescent intensity induced by the extension or contraction of LCE film, which leads to reduce or increase of the aggregation degree of AIE molecules within. This compact wireless force sensor features lightweight, low-cost, high flexibility, passivity and anti-EM interference, which also enables the naked eye observation. The proposed sensor provides inspiration and a platform for a new concept of non-contact detection, showing application potential in human-friendly interactive electronics and remote-control integration platform.
ABSTRACT
17ß-Estradiol (E2) is an important endogenous estrogen, which disturbs the endocrine system and poses a threat to human health because of its accumulation in the human body. Herein, a biofuel cell (BFC)-based self-powered electrochemical aptasensor was developed for E2 detection. Porous carbon nanocage/gold nanoparticle composite modified indium tin oxide (CNC/AuNP/ITO) and glucose oxidase modified CNC/AuNP/ITO were used as the biocathode and bioanode of BFCs, respectively. [Fe(CN)6]3- was selected as an electroactive probe, which was entrapped in the pores of positively charged magnetic Fe3O4 nanoparticles (PMNPs) and then capped with a negatively charged E2 aptamer to form a DNA bioconjugate. The presence of the target E2 triggered the entrapped [Fe(CN)6]3- probe release due to the removal of the aptamer via specific recognition, which resulted in the transfer of electrons produced by glucose oxidation at the bioanode to the biocathode and produced a high open-circuit voltage (EOCV). Consequently, a "signal-on" homogeneous self-powered aptasensor for E2 assay was realized. Promisingly, the BFC-based self-powered aptasensor has particularly high sensitivity for E2 detection in the concentration range of 0.5 pg mL-1 to 15 ng mL-1 with a detection limit of 0.16 pg mL-1 (S/N = 3). Therefore, the proposed BFC-based self-powered electrochemical aptasensor has great promise to be applied as a successful prototype of a portable and on-site bioassay in the field of environment monitoring and food safety.