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1.
Nat Immunol ; 20(7): 865-878, 2019 07.
Article in English | MEDLINE | ID: mdl-31086333

ABSTRACT

Natural killer (NK) cells are critical mediators of host immunity to pathogens. Here, we demonstrate that the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1α) and its substrate transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1α-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mammalian target of rapamycin signaling pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1α downregulated c-Myc, and NK cells with c-Myc haploinsufficency phenocopied IRE1α-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1α-/- NK cells. Like c-Myc, IRE1α-XBP1 also promotes oxidative phosphorylation in NK cells. Overall, our study identifies a IRE1α-XBP1-cMyc axis in NK cell immunity, providing insight into host protection against infection and cancer.


Subject(s)
Endoplasmic Reticulum Stress/genetics , Endoribonucleases/genetics , Gene Expression Regulation , Genes, myc , Immunity/genetics , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Protein Serine-Threonine Kinases/genetics , Animals , Biomarkers , Cell Survival/genetics , Cell Survival/immunology , Cytotoxicity, Immunologic , Host-Pathogen Interactions/immunology , Humans , Lymphocyte Activation/immunology , Melanoma, Experimental , Mice , Mice, Knockout , Mitochondria/metabolism , Oxidative Phosphorylation , Signal Transduction , X-Box Binding Protein 1/metabolism
2.
Nature ; 602(7896): 229-233, 2022 02.
Article in English | MEDLINE | ID: mdl-35140383

ABSTRACT

Ultracold assembly of diatomic molecules has enabled great advances in controlled chemistry, ultracold chemical physics and quantum simulation with molecules1-3. Extending the ultracold association to triatomic molecules will offer many new research opportunities and challenges in these fields. A possible approach is to form triatomic molecules in a mixture of ultracold atoms and diatomic molecules by using a Feshbach resonance between them4,5. Although ultracold atom-diatomic-molecule Feshbach resonances have been observed recently6,7, using these resonances to form triatomic molecules remains challenging. Here we report on evidence of the association of triatomic molecules near the Feshbach resonance between 23Na40K molecules in the rovibrational ground state and 40K atoms. We apply a radio-frequency pulse to drive the free-bound transition in ultracold mixtures of 23Na40K and 40K and monitor the loss of 23Na40K molecules. The association of triatomic molecules manifests itself as an additional loss feature in the radio-frequency spectra, which can be distinguished from the atomic loss feature. The observation that the distance between the association feature and the atomic transition changes with the magnetic field provides strong evidence for the formation of triatomic molecules. The binding energy of the triatomic molecules is estimated from the measurements. Our work contributes to the understanding of the complex ultracold atom-molecule Feshbach resonances and may open up an avenue towards the preparation and control of ultracold triatomic molecules.

3.
Nature ; 609(7925): 46-51, 2022 09.
Article in English | MEDLINE | ID: mdl-36045238

ABSTRACT

Superlattices-a periodic stacking of two-dimensional layers of two or more materials-provide a versatile scheme for engineering materials with tailored properties1,2. Here we report an intrinsic heterodimensional superlattice consisting of alternating layers of two-dimensional vanadium disulfide (VS2) and a one-dimensional vanadium sulfide (VS) chain array, deposited directly by chemical vapour deposition. This unique superlattice features an unconventional 1T stacking with a monoclinic unit cell of VS2/VS layers identified by scanning transmission electron microscopy. An unexpected Hall effect, persisting up to 380 kelvin, is observed when the magnetic field is in-plane, a condition under which the Hall effect usually vanishes. The observation of this effect is supported by theoretical calculations, and can be attributed to an unconventional anomalous Hall effect owing to an out-of-plane Berry curvature induced by an in-plane magnetic field, which is related to the one-dimensional VS chain. Our work expands the conventional understanding of superlattices and will stimulate the synthesis of more extraordinary superstructures.

4.
EMBO J ; 42(4): e111549, 2023 02 15.
Article in English | MEDLINE | ID: mdl-36598329

ABSTRACT

YAP/TAZ transcriptional co-activators play pivotal roles in tumorigenesis. In the Hippo pathway, diverse signals activate the MST-LATS kinase cascade that leads to YAP/TAZ phosphorylation, and subsequent ubiquitination and proteasomal degradation by SCFß-TrCP . When the MST-LATS kinase cascade is inactive, unphosphorylated or dephosphorylated YAP/TAZ translocate into the nucleus to mediate TEAD-dependent gene transcription. Hippo signaling-independent YAP/TAZ activation in human malignancies has also been observed, yet the mechanism remains largely elusive. Here, we report that the ubiquitin E3 ligase HERC3 can promote YAP/TAZ activation independently of its enzymatic activity. HERC3 directly binds to ß-TrCP, blocks its interaction with YAP/TAZ, and thus prevents YAP/TAZ ubiquitination and degradation. Expression levels of HERC3 correlate with YAP/TAZ protein levels and expression of YAP/TAZ target genes in breast tumor cells and tissues. Accordingly, knockdown of HERC3 expression ameliorates tumorigenesis of breast cancer cells. Our results establish HERC3 as a critical regulator of the YAP/TAZ stability and a potential therapeutic target for breast cancer.


Subject(s)
Adaptor Proteins, Signal Transducing , Breast Neoplasms , Humans , Female , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , YAP-Signaling Proteins , beta-Transducin Repeat-Containing Proteins/genetics , beta-Transducin Repeat-Containing Proteins/metabolism , Transcriptional Coactivator with PDZ-Binding Motif Proteins , Transcription Factors/genetics , Transcription Factors/metabolism , Cell Transformation, Neoplastic/genetics , Carcinogenesis/genetics , Ubiquitination , Breast Neoplasms/genetics , Ubiquitins/metabolism , Ligases/genetics , Phosphoproteins/genetics , Phosphoproteins/metabolism
5.
Small ; 20(26): e2311203, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38233210

ABSTRACT

Designing a cost-effective and multifunctional separator that ensures dendrite-free and stable Zn metal anode remains a significant challenge. Herein, a multifunctional cellulose-based separator is presented consisting of industrial waste-fly ash particles and cellulose nanofiber using a facile solution-coating method. The resulting fly ash-cellulose (FACNF) separators enable a high ion conductivity (5.76 mS cm-1) and low desolvation energy barrier of hydrated Zn2+. These features facilitate fast ion transfer kinetics and inhibit water-induced side reactions. Furthermore, experimental results and theoretical simulations confirm that the presence of fly ash particles in FACNF separators effectively accommodate the preferential deposition of Zn(002) planes, due to the weak chemical affinity between Zn(002) plane and fly ash, to mitigate dendrite formation and growth. Consequently, the utilization of FACNF separators causes an impressive cycling performance in both Zn||Zn symmetric cells (1600 h at 2 mA cm-2/1 mAh cm-2) and Zn||(NH4)2V10O25 (NVO) full cells (4000 cycles with the capacity retention of 92.1% at 5 A g-1). Furthermore, the assembled pouch cells can steadily support digital thermometer over two months without generating gas and volume expansion. This work provides new insights for achieving crystallographic uniformity in Zn anodes and realizing cost-effective and long-lasting aqueous zinc-ion batteries (AZIBs).

6.
J Transl Med ; 22(1): 261, 2024 03 10.
Article in English | MEDLINE | ID: mdl-38461333

ABSTRACT

BACKGROUND: The mitochondria and endoplasmic reticulum (ER) communicate via contact sites known as mitochondria associated membranes (MAMs). Many important cellular functions such as bioenergetics, mitophagy, apoptosis, and calcium signaling are regulated by MAMs, which are thought to be closely related to ischemic reperfusion injury (IRI). However, there exists a gap in systematic proteomic research addressing the relationship between these cellular processes. METHODS: A 4D label free mass spectrometry-based proteomic analysis of mitochondria associated membranes (MAMs) from the human renal proximal tubular epithelial cell line (HK-2 cells) was conducted under both normal (N) and hypoxia/reperfusion (HR) conditions. Subsequent differential proteins analysis aimed to characterize disease-relevant signaling molecules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was applied to total proteins and differentially expressed proteins, encompassing Biological Process (BP), Cell Component (CC), Molecular Function (MF), and KEGG pathways. Further, Protein-Protein Interaction Network (PPI) exploration was carried out, leading to the identification of hub genes from differentially expressed proteins. Notably, Mitofusion 2 (MFN2) and BCL2/Adenovirus E1B 19-kDa interacting protein 3(BNIP3) were identified and subsequently validated both in vitro and in vivo. Finally, the impact of MFN2 on MAMs during hypoxia/reoxygenation was explored through regulation of gene expression. Subsequently, a comparative proteomics analysis was conducted between OE-MFN2 and normal HK-2 cells, providing further insights into the underlying mechanisms. RESULTS: A total of 4489 proteins were identified, with 3531 successfully quantified. GO/KEGG analysis revealed that MAM proteins were primarily associated with mitochondrial function and energy metabolism. Differential analysis between the two groups showed that 688 proteins in HR HK-2 cells exhibited significant changes in expression level with P-value < 0.05 and HR/N > 1.5 or HR/N < 0.66 set as the threshold criteria. Enrichment analysis of differentially expressed proteins unveiled biological processes such as mRNA splicing, apoptosis regulation, and cell division, while molecular functions were predominantly associated with energy metabolic activity. These proteins play key roles in the cellular responses during HR, offering insights into the IRI mechanisms and potential therapeutic targets. The validation of hub genes MFN2 and BNIP3 both in vitro and vivo was consistent with the proteomic findings. MFN2 demonstrated a protective role in maintaining the integrity of mitochondria associated membranes (MAMs) and mitigating mitochondrial damage following hypoxia/reoxygenation injury, this protective effect may be associated with the activation of the PI3K/AKT pathway. CONCLUSIONS: The proteins located in mitochondria associated membranes (MAMs) are implicated in crucial roles during renal ischemic reperfusion injury (IRI), with MFN2 playing a pivotal regulatory role in this context.


Subject(s)
Mitochondria Associated Membranes , Reperfusion Injury , Humans , Phosphatidylinositol 3-Kinases , Proteomics , Hypoxia
7.
Phys Rev Lett ; 132(9): 093403, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38489622

ABSTRACT

We report on the observation of photoassociation resonances in ultracold collisions between ^{23}Na^{40}K molecules and ^{40}K atoms. We perform photoassociation in a long-wavelength optical dipole trap to form deeply bound triatomic molecules in electronically excited states. The atom-molecule Feshbach resonance is used to enhance the free-bound Franck-Condon overlap. The photoassociation into well-defined quantum states of excited triatomic molecules is identified by observing resonantly enhanced loss features. These loss features depend on the polarization of the photoassociation lasers, allowing us to assign rotational quantum numbers. The observation of ultracold atom-molecule photoassociation resonances paves the way toward preparing ground-state triatomic molecules, provides a new high-resolution spectroscopy technique for polyatomic molecules, and is also important to atom-molecule Feshbach resonances.

8.
Diabetes Obes Metab ; 2024 Sep 30.
Article in English | MEDLINE | ID: mdl-39344843

ABSTRACT

AIM: To explore the trend of burden and care quality of chronic kidney disease due to type 2 diabetes mellitus (CKD-T2DM) and their cross-country inequalities from 1990 to 2021. MATERIALS AND METHODS: Data were from the Global Burden of Disease 2021 study. Disease burden and care quality were quantified using the disability-adjusted life years rate and the quality-of-care index (QCI). Trend analyses of the age-standardized disability-adjusted life years rate (ASDR) and age-standardized QCI from 1990 to 2021 were conducted using the estimated annual percentage change. The associations of disease burden and care quality with the socio-demographic index (SDI) were explored. Cross-country inequalities in disease burden and care quality were assessed using the slope index of inequality (SII) and concentration index. RESULTS: From 1990 to 2021, the global ASDR for CKD-T2DM increased, while the age-standardized QCI slightly decreased, with an estimated annual percentage change of 0.81 [95% confidence interval (CI): 0.75, 0.87] and -0.08 (95% CI: -0.09, -0.07). The ASDR escalated with increasing SDI, reaching a peak at mid-level SDI, followed by a decrease. The age-standardized QCI was higher with increasing SDI. Globally, ASDR concentrated on countries/territories with a lower SDI. The SII of ASDR was -96.64 (95% CI: -136.94, -56.35) in 1990 and -118.15 (95% CI: -166.36, -69.94) in 2021,  with a concentration index of -0.1298 (95% CI: -0.1904, -0.0692) in 1990 and -0.1104 (95% CI: -0.1819, -0.0389) in 2021. In 1990 and 2021, countries/territories at higher SDI levels exhibited increased age-standardized QCI, indicated by an SII of 15.09 (95% CI: 10.74, 19.45) and 15.75 (95% CI: 10.92, 20.59), and a concentration index of 0.0393 (95% CI: 0.0283, 0.0503) and 0.0400 (95% CI: 0.0264, 0.0536). CONCLUSIONS: Our study highlights considerable disparities in the burden and care quality of CKD-T2DM. Regions experiencing an increasing burden and a declining care quality simultaneously underscore the need for further research and tailored health interventions.

9.
Anal Bioanal Chem ; 416(22): 4999-5012, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39093417

ABSTRACT

Oat products have gained widespread recognition as a health food due to their rich and balanced nutritional profile and convenience. However, the unique matrix composition of oats, which differs significantly from other cereals, presents specific challenges for mycotoxin analysis. This study presents an ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method enhanced with an innovative egg white gel pretreatment for the simultaneous analysis of 13 regulated and unregulated trichothecenes in oats. The method demonstrated excellent performance with high accuracy (> 87.5%), repeatability (< 5.7%), and reproducibility (< 8.1%). Analysis of 100 commercial oat products revealed a concerning detection rate (78%) for at least one of the 11 trichothecenes investigated. Notably, deoxynivalenol, exceeding the standard limit in 2% of samples, exhibited the highest detection rate (62%). Additionally, concerning co-occurrence patterns and positive correlations were observed, highlighting potential synergistic effects. The first-time detection of unregulated mycotoxins (T-2 triol, 4,15-diacetoxyscirpenol, 15-acetoxyscirpenol, and neosolaniol) underscores the need for comprehensive monitoring. This method, while developed for oats, shows potential for broader application to other cereals, though further investigation and confirmation are necessary. These findings suggest a potentially underestimated risk of trichothecenes in oats, necessitating continuous monitoring to ensure consumer safety.


Subject(s)
Avena , Food Contamination , Limit of Detection , Tandem Mass Spectrometry , Trichothecenes , Avena/chemistry , Tandem Mass Spectrometry/methods , Chromatography, High Pressure Liquid/methods , Trichothecenes/analysis , Food Contamination/analysis , Gels/chemistry , Reproducibility of Results
10.
J Nat Prod ; 87(4): 976-983, 2024 04 26.
Article in English | MEDLINE | ID: mdl-38438310

ABSTRACT

Three unique linear oligomeric depsipeptides, designated as cavomycins A-C (1-3), were identified from Streptomyces cavourensis, a gut bacterium associated with the annelid Paraleonnates uschakovi. The structures of these depsipeptides were determined through a combination of spectroscopic methods and chemical derivatization techniques, including methanolysis, the modified Mosher's method, advanced Marfey's methods, and phenylglycine methyl ester derivatization. The unique dipeptidyl residue arrangements in compounds 1-3 indicate that they are not degradation products of valinomycin. Compound 2 and its methylation derivative 2a exhibited antiproliferative activity against PANC-1 pancreatic cancer cells with IC50 values of 1.2 and 1.7 µM, respectively.


Subject(s)
Depsipeptides , Streptomyces , Streptomyces/chemistry , Depsipeptides/pharmacology , Depsipeptides/chemistry , Depsipeptides/isolation & purification , Humans , Molecular Structure , Animals , Drug Screening Assays, Antitumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification
11.
Cereb Cortex ; 33(20): 10584-10594, 2023 Oct 09.
Article in English | MEDLINE | ID: mdl-37653604

ABSTRACT

Patients with knee osteoarthritis (KOA) often suffer from cognitive decline and increased dementia risk, but the neurobiological mechanisms remain unclear. In this study, we evaluated cognitive performance and collected brain magnetic resonance imaging (MRI) data and blood samples from cognitively normal KOA patients at baseline sessions and reevaluated their cognition after 5 years. We also collected MRI data from matched healthy controls. Results showed that KOA patients exhibited dysregulated functional connectivities between the hippocampus and thalamus/superior frontal gyrus compared with healthy controls. The altered hippocampal functional connectivities were associated with serum brain-derived neurotrophic factor (BDNF) levels and spatial expression of genes enriched in synaptic plasticity. The hippocampus-thalamus functional connectivity was significantly correlated with patients' memory scores. Moreover, the baseline hippocampus-thalamus functional connectivity and BDNF levels significantly predicted the development of cognitive decline in KOA patients in the follow-up session. Our findings provide insight into the neurobiological underpinnings of KOA and cognitive decline.

12.
Nutr Metab Cardiovasc Dis ; 34(4): 988-997, 2024 04.
Article in English | MEDLINE | ID: mdl-38176957

ABSTRACT

BACKGROUND AND AIMS: No consensus has been reached on the association between serum uric acid (SUA) and hypertension. This study aimed to investigate the associations between SUA and hypertension, including its status, stages, phenotypes and progressions, among middle-aged and older Chinese. METHODS AND RESULTS: Data were obtained from the China Health and Retirement Longitudinal Study 2011-2015. Binary logistic regression was used to evaluate the association between SUA and hypertension status. Multinomial logistic regression was used to explore the associations of SUA with hypertension stages, phenotypes and hypertension status progressions. Models were adjusted for potential confounders and stratified by sex. A total of 7931 individuals aged ≥45 years were included, with 39.16 % of hypertension. Significant associations were found of SUA with stage2 and above hypertension (quartile 4 [Q4] vs quartile 1 [Q1]: odds ratio 1.78, 95 % confidence interval 1.31-2.42, P < 0.001), and systolic diastolic hypertension (SDH) (Q4 vs Q1: 1.53, 1.14-2.06, P = 0.005). In sex stratification, significant associations were found between SUA and stage2 and above hypertension and SDH only for men. Moreover, higher quartiles of baseline SUA showed increased risks of maintained hypertension from 2011 to 2015 (Q3 vs Q1: 1.23, 1.03-1.48, P = 0.024; Q4 vs Q1: 1.73, 1.43-2.10, P < 0.001). CONCLUSION: Higher SUA was associated with hypertension and maintained hypertension among Chinese middle-aged and elderly. Sex-specific associations of SUA with hypertension stages and phenotypes were observed. Regular measurement of SUA in clinical practice may indicate hypertension and its progression, particularly among men.


Subject(s)
Hypertension , Uric Acid , Aged , Middle Aged , Male , Female , Humans , Risk Factors , Longitudinal Studies , Hypertension/diagnosis , Hypertension/epidemiology , China/epidemiology , Phenotype
13.
J Opt Soc Am A Opt Image Sci Vis ; 41(3): 371-381, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38437423

ABSTRACT

Using the extended Huygens-Fresnel principle and the Rytov approximation, the analytical formula for the propagation of a partially coherent electromagnetic hyperbolic-sine-Gaussian vortex beam (PCEShVB) in anisotropic atmospheric turbulence has been theoretically derived. Detailed studies have been conducted on the evolution characteristics of the average intensity, the degree of coherence (DOC), and the degree of polarization (DOP) of the beam in turbulence. The results show that during propagation, the intensity distribution of the beam will exhibit a spiral structure, and the overall distribution of the light spots will rotate in a direction related to the sign of the topological charge. The DOC distribution of PCEShVB will display a pattern reminiscent of beam interference fringes with an increase in propagation distance, with the number of "interference fringes" greatly impacted by the hyperbolic sine parameter. Furthermore, PCEShVB with a large initial coherent length and hyperbolic sine parameter will increase the degree of separation of the spots and yield a large DOP. Finally, for the validation of the theoretical findings, the random phase screen method was employed to simulate the propagation of PCEShVB through anisotropic atmospheric turbulence. The studies revealed a consistent alignment between the simulation results and the theoretical predictions.

14.
Molecules ; 29(15)2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39125006

ABSTRACT

The aim of individuals consuming health supplements is to attain a robust state through nutritional regulation. However, some unscrupulous manufacturers, motivated by profit, fraudulently incorporate drugs or unauthorized components with therapeutic effects into the product for instant product performance enhancement. The long-term use of these products may inadvertently inflict harm on human health and fail to promote nutritive healthcare. The illegal inclusion of these substances is prevalent in kidney-tonifying and sexuality-enhancing products. Developing effective analytical methods to identify these products and screen for illegal added ingredients can effectively prevent such products from reaching and remaining on the market. A target screening method for the detection and quantification of 90 phosphodiesterase type 5 inhibitors (PDE-5is) in 5 kinds of health products was developed and validated. The type of dietary supplements varied from tablets, capsules, and protein powder to wine and beverages. Sample preparation was completed with a one-step liquid phase extraction. The screening process of 90 PDE-5is was done efficiently within 25 min by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) using the dynamic multiple reaction monitoring (dMRM) technique. The LODs of 90 PDE-5is were detected at levels ranging from 25 to 85 ng/g or ng/mL. This novel targeting methodology was effective and can be applied to routine market supervision. Among 286 batches of samples, 8 batches were found to be positive. Three kinds of PDE-5is were first detected in healthy products. The screening method demonstrated herein will be a promising and powerful tool for rapid screening of PDE-5is.


Subject(s)
Dietary Supplements , Liquid Chromatography-Mass Spectrometry , Phosphodiesterase 5 Inhibitors , Humans , Chromatography, High Pressure Liquid/methods , Dietary Supplements/analysis , Liquid Chromatography-Mass Spectrometry/methods , Phosphodiesterase 5 Inhibitors/analysis , Phosphodiesterase 5 Inhibitors/chemistry , Tandem Mass Spectrometry/methods
15.
Molecules ; 29(12)2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38930942

ABSTRACT

Naturally occurring substances and their derivatives function as vital resources for pesticides that can be used in fields, such as insecticide production and fungicide development. As a botanical entity displaying multifaceted biological functions, wormwood has received thorough scrutiny across multiple sectors. The insect repellency potency combined with antibacterial and antifungal activities of wormwood position it as a potential candidate for prospective development into eco-friendly chemical pesticides. In this research, Wormwood essential oil was procured via ethanol water under ultrasonic scenarios and subsequently diluted with PEG 400 to formulate green chemical pesticides. The defensive efficacy of this green pesticide on plants was validated through 2 weeks of clustered plant growth experiments. Active constituents that exerted their effects were scrutinized by GC-MS. Furthermore, this green pesticide also displays efficacious effects on the prevention and management of aphids, exhibiting a dose-dependent relationship. 4-terpenol, eucalyptol, carvacrol, and L-borneol were identified by GC-MS as the predominant active constituents in this green chemical pesticide. Wormwood can be leveraged to develop green chemical pesticides, which can protect plants without contaminating the environment.


Subject(s)
Insecticides , Oils, Volatile , Insecticides/chemistry , Insecticides/pharmacology , Animals , Oils, Volatile/chemistry , Oils, Volatile/pharmacology , Gas Chromatography-Mass Spectrometry , Cymenes/chemistry , Cymenes/pharmacology , Green Chemistry Technology/methods , Aphids/drug effects , Eucalyptol/chemistry , Eucalyptol/pharmacology , Camphanes
16.
J Headache Pain ; 25(1): 93, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38840235

ABSTRACT

BACKGROUND: Migraine is a neurological disease with a significant genetic component and is characterized by recurrent and prolonged episodes of headache. Previous epidemiological studies have reported a higher risk of dementia in migraine patients. Neuroimaging studies have also shown structural brain atrophy in regions that are common to migraine and dementia. However, these studies are observational and cannot establish causality. The present study aims to explore the genetic causal relationship between migraine and dementia, as well as the mediation roles of brain structural changes in this association using Mendelian randomization (MR). METHODS: We collected the genome-wide association study (GWAS) summary statistics of migraine and its two subtypes, as well as four common types of dementia, including Alzheimer's disease (AD), vascular dementia, frontotemporal dementia, and Lewy body dementia. In addition, we collected the GWAS summary statistics of seven longitudinal brain measures that characterize brain structural alterations with age. Using these GWAS, we performed Two-sample MR analyses to investigate the causal effects of migraine and its two subtypes on dementia and brain structural changes. To explore the possible mediation of brain structural changes between migraine and dementia, we conducted a two-step MR mediation analysis. RESULTS: The MR analysis demonstrated a significant association between genetically predicted migraine and an increased risk of AD (OR = 1.097, 95% CI = [1.040, 1.158], p = 7.03 × 10- 4). Moreover, migraine significantly accelerated annual atrophy of the total cortical surface area (-65.588 cm2 per year, 95% CI = [-103.112, -28.064], p = 6.13 × 10- 4) and thalamic volume (-9.507 cm3 per year, 95% CI = [-15.512, -3.502], p = 1.91 × 10- 3). The migraine without aura (MO) subtype increased the risk of AD (OR = 1.091, 95% CI = [1.059, 1.123], p = 6.95 × 10- 9) and accelerated annual atrophy of the total cortical surface area (-31.401 cm2 per year, 95% CI = [-43.990, -18.811], p = 1.02 × 10- 6). The two-step MR mediation analysis revealed that thalamic atrophy partly mediated the causal effect of migraine on AD, accounting for 28.2% of the total effect. DISCUSSION: This comprehensive MR study provided genetic evidence for the causal effect of migraine on AD and identified longitudinal thalamic atrophy as a potential mediator in this association. These findings may inform brain intervention targets to prevent AD risk in migraine patients.


Subject(s)
Atrophy , Brain , Dementia , Genome-Wide Association Study , Mendelian Randomization Analysis , Migraine Disorders , Humans , Atrophy/pathology , Migraine Disorders/genetics , Migraine Disorders/pathology , Migraine Disorders/diagnostic imaging , Migraine Disorders/complications , Migraine Disorders/epidemiology , Brain/pathology , Brain/diagnostic imaging , Dementia/genetics , Dementia/epidemiology , Dementia/pathology , Dementia/etiology , Female , Longitudinal Studies , Male
17.
J Headache Pain ; 25(1): 148, 2024 Sep 11.
Article in English | MEDLINE | ID: mdl-39261750

ABSTRACT

BACKGROUND: Migraine is a highly prevalent and complex neurovascular disease. However, the currently available therapeutic drugs often fall to adequately meet clinical needs due to limited effectiveness and numerous undesirable side effects. This study aims to identify putative novel targets for migraine treatment through proteome-wide Mendelian randomization (MR). METHODS: We utilized MR to estimate the causal effects of plasma proteins on migraine and its two subtypes, migraine with aura (MA) and without aura (MO). This analysis integrated plasma protein quantitative trait loci (pQTL) data with genome-wide association studies (GWAS) findings for these migraine phenotypes. Moreover, we conducted a phenome-wide MR assessment, enrichment analysis, protein-protein interaction networks construction, and mediation MR analysis to further validate the pharmaceutical potential of the identified protein targets. RESULTS: We identified 35 protein targets for migraine and its subtypes (p < 8.04 × 10-6), with prioritized targets showing minimal side effects. Phenome-wide MR identified novel protein targets-FCAR, UBE2L6, LATS1, PDCD1LG2, and MMP3-that have no major disease side effects and interacted with current acute migraine medication targets. Additionally, MMP3, PDCD1LG2, and HBQ1 interacted with current preventive migraine medication targets. The causal effects of plasma protein on migraine were partly mediated by plasma metabolites (proportion of mediation from 3.8% to 21.0%). CONCLUSIONS: A set of potential protein targets for migraine and its subtypes were identified. These proteins showed rare side effects and were responsible for biological mechanisms involved in migraine pathogenesis, indicating priority for the development of migraine treatments.


Subject(s)
Genome-Wide Association Study , Mendelian Randomization Analysis , Proteome , Quantitative Trait Loci , Humans , Proteome/drug effects , Migraine Disorders/genetics , Migraine Disorders/drug therapy , Migraine Disorders/blood , Protein Interaction Maps/genetics , Migraine with Aura/genetics , Migraine with Aura/drug therapy , Migraine with Aura/blood , Migraine without Aura/genetics , Migraine without Aura/drug therapy , Migraine without Aura/blood , Blood Proteins/genetics , Blood Proteins/metabolism
18.
Angew Chem Int Ed Engl ; 63(29): e202319661, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38703353

ABSTRACT

Constructing artificial solid electrolyte interface on the Zn anode surface is recognized as an appealing method to inhibit zinc dendrites and side reactions, whereas the current techniques are complex and time-consuming. Here, a robust and zincophilic zinc tungstate (ZnWO4) layer has been in situ constructed on the Zn anode surface (denoted as ZWO@Zn) by an ultrafast chemical solution reaction. Comprehensive characterizations and theoretical calculations demonstrate that the ZWO layer can effectively modulate the interfacial electric field distribution and promote the Zn2+ uniform diffusion, thus facilitating the uniform Zn2+ nucleation and suppressing zinc dendrites. Besides, ZWO layer can prevent direct contact between the Zn/water and increase the hydrogen evolution reaction overpotential to eliminate side reactions. Consequently, the in situ constructed ZWO layer facilitates remarkable reversibility in the ZWO@Zn||Ti battery, achieving an impressive Coulombic efficiency of 99.36 % under 1.0 mA cm-2, unprecedented cycling lifespan exceeding 1800 h under 1.0 mA cm-2 in ZWO@Zn||ZWO@Zn battery, and a steady and reliable operation of the overall ZWO@Zn||VS2 battery. The work provides a simple, low cost, and ultrafast pathway to crafting protective layers for driving advancements in aqueous zinc-metal batteries.

19.
EMBO J ; 38(14): e99945, 2019 07 15.
Article in English | MEDLINE | ID: mdl-31304624

ABSTRACT

TGF-ß controls a variety of cellular functions during development. Abnormal TGF-ß responses are commonly found in human diseases such as cancer, suggesting that TGF-ß signaling must be tightly regulated. Here, we report that protein tyrosine phosphatase non-receptor 3 (PTPN3) profoundly potentiates TGF-ß signaling independent of its phosphatase activity. PTPN3 stabilizes TGF-ß type I receptor (TßRI) through attenuating the interaction between Smurf2 and TßRI. Consequently, PTPN3 facilitates TGF-ß-induced R-Smad phosphorylation, transcriptional responses, and subsequent physiological responses. Importantly, the leucine-to-arginine substitution at amino acid residue 232 (L232R) of PTPN3, a frequent mutation found in intrahepatic cholangiocarcinoma (ICC), disables its role in enhancing TGF-ß signaling and abolishes its tumor-suppressive function. Our findings have revealed a vital role of PTPN3 in regulating TGF-ß signaling during normal physiology and pathogenesis.


Subject(s)
Liver Neoplasms/pathology , Protein Tyrosine Phosphatase, Non-Receptor Type 3/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 3/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Amino Acid Substitution , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Mice , Neoplasm Transplantation , Phosphorylation , Protein Stability , Receptor, Transforming Growth Factor-beta Type I/chemistry , Receptor, Transforming Growth Factor-beta Type I/metabolism , Smad Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism
20.
Hum Brain Mapp ; 44(5): 1985-1996, 2023 04 01.
Article in English | MEDLINE | ID: mdl-36573391

ABSTRACT

Current studies have shown that perception of subject's own name (SON) involves multiple multimodal brain regions, while activities in unimodal sensory regions (i.e., primary auditory cortex) and their interaction with multimodal regions during the self-processing remain unclear. To answer this, we combined multivariate pattern analysis and dynamic causal modelling analysis to explore the regional activation pattern and inter-region effective connection during the perception of SON. We found that SON and other names could be decoded from the activation pattern in the primary auditory cortex. In addition, we found an excitatory effect of SON on connections from the anterior insula/inferior frontal gyrus to the primary auditory cortex, and to the temporoparietal junction. Our findings extended the current knowledge of self-processing by showing that primary auditory cortex could discriminate SON from other names. Furthermore, our findings highlighted the importance of influence of the insula on the primary auditory cortex during self-processing.


Subject(s)
Auditory Cortex , Names , Humans , Electroencephalography , Acoustic Stimulation , Auditory Cortex/diagnostic imaging , Brain/physiology , Brain Mapping , Magnetic Resonance Imaging
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