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Vesicle trafficking is a fundamental process that allows for the sorting and transport of specific proteins (i.e., "cargoes") to different compartments of eukaryotic cells. Cargo recognition primarily occurs through coats and the associated proteins at the donor membrane. However, it remains unclear whether cargoes can also be selected at other stages of vesicle trafficking to further enhance the fidelity of the process. The WDR11-FAM91A1 complex functions downstream of the clathrin-associated AP-1 complex to facilitate protein transport from endosomes to the TGN. Here, we report the cryo-EM structure of human WDR11-FAM91A1 complex. WDR11 directly and specifically recognizes a subset of acidic clusters, which we term super acidic clusters (SACs). WDR11 complex assembly and its binding to SAC-containing proteins are indispensable for the trafficking of SAC-containing proteins and proper neuronal development in zebrafish. Our studies thus uncover that cargo proteins could be recognized in a sequence-specific manner downstream of a protein coat.
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Microscopía por Crioelectrón , Transporte de Proteínas , Pez Cebra , Humanos , Animales , Endosomas/metabolismo , Células HEK293 , Células HeLa , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/química , Unión ProteicaRESUMEN
Pontocerebellar hypoplasia (PCH) is a group of rare neurodevelopmental disorders with limited diagnostic and therapeutic options. Mutations in WDR11, a subunit of the FAM91A1 complex, have been found in patients with PCH-like symptoms; however, definitive evidence that the mutations are causal is still lacking. Here, we show that depletion of FAM91A1 results in developmental defects in zebrafish similar to that of TBC1D23, an established PCH gene. FAM91A1 and TBC1D23 directly interact with each other and cooperate to regulate endosome-to-Golgi trafficking of KIAA0319L, a protein known to regulate axonal growth. Crystal structure of the FAM91A1-TBC1D23 complex reveals that TBC1D23 binds to a conserved surface on FAM91A1 by assuming a Z-shaped conformation. More importantly, the interaction between FAM91A1 and TBC1D23 can be used to predict the risk of certain TBC1D23-associated mutations to PCH. Collectively, our study provides a molecular basis for the interaction between TBC1D23 and FAM91A1 and suggests that disrupted endosomal trafficking underlies multiple PCH subtypes.
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Enfermedades Cerebelosas , Pez Cebra , Animales , Humanos , Enfermedades Cerebelosas/genética , Variación Genética , Aparato de Golgi , Pez Cebra/genéticaRESUMEN
Understanding of the evolution of metazoans from their unicellular ancestors is a fundamental question in biology. In contrast to fungi which utilize the Mon1-Ccz1 dimeric complex to activate the small GTPase RAB7A, metazoans rely on the Mon1-Ccz1-RMC1 trimeric complex. Here, we report a near-atomic resolution cryogenic-electron microscopy structure of the Drosophila Mon1-Ccz1-RMC1 complex. RMC1 acts as a scaffolding subunit and binds to both Mon1 and Ccz1 on the surface opposite to the RAB7A-binding site, with many of the RMC1-contacting residues from Mon1 and Ccz1 unique to metazoans, explaining the binding specificity. Significantly, the assembly of RMC1 with Mon1-Ccz1 is required for cellular RAB7A activation, autophagic functions and organismal development in zebrafish. Our studies offer a molecular explanation for the different degree of subunit conservation across species, and provide an excellent example of how metazoan-specific proteins take over existing functions in unicellular organisms.
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Proteínas de Drosophila , Proteínas de Unión al GTP rab , Animales , Microscopía por Crioelectrón , Proteínas de Unión al GTP rab/metabolismo , Pez Cebra/metabolismo , Drosophila , Proteínas de Drosophila/ultraestructuraRESUMEN
Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development.
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Postictal generalized electroencephalographic suppression is a possible electroencephalographic marker for sudden unexpected death in epilepsy. We aimed to investigate the cortical surface area abnormalities in epilepsy patients with postictal generalized electroencephalographic suppression. We retrospectively included 30 epilepsy patients with postictal generalized electroencephalographic suppression (PGES+), 21 epilepsy patients without postictal generalized electroencephalographic suppression (PGES-), and 30 healthy controls. Surface-based analysis on high-resolution T1-weighted images was conducted and cortical surface areas were compared among the three groups, alongside correlation analyses with seizure-related clinical variables. Compared with PGES- group, we identified reduced surface area in the bilateral insula with more extensive distribution in the right hemisphere in PGES+ group. The reduced right insular surface area was associated with younger seizure-onset age. When compared with healthy controls, PGES- group presented reduced surface area in the left caudal middle frontal gyrus; PGES+ group presented more widespread surface area reductions in the right posterior cingulate gyrus, left postcentral gyrus, middle frontal gyrus, and middle temporal gyrus. Our results suggested cortical microstructural impairment in patients with postictal generalized electroencephalographic suppression. The significant surface area reductions in the insular cortex supported the autonomic network involvement in the pathology of postictal generalized electroencephalographic suppression, and its right-sided predominance suggested the potential shared abnormal brain network for postictal generalized electroencephalographic suppression and sudden unexpected death in epilepsy.
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Epilepsia , Muerte Súbita e Inesperada en la Epilepsia , Humanos , Estudios Retrospectivos , Epilepsia/diagnóstico por imagen , Electroencefalografía/métodos , Convulsiones , Muerte SúbitaRESUMEN
Alzheimer's disease (AD) and mild cognitive impairment (MCI) both show abnormal resting-state functional connectivity (rsFC) of default mode network (DMN), but it is unclear to what extent these abnormalities are shared. Therefore, we performed a comprehensive meta-analysis, including 31 MCI studies and 20 AD studies. MCI patients, compared to controls, showed decreased within-DMN rsFC in bilateral medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC), precuneus/posterior cingulate cortex (PCC), right temporal lobes, and left angular gyrus and increased rsFC between DMN and left inferior temporal gyrus. AD patients, compared to controls, showed decreased rsFC within DMN in bilateral mPFC/ACC and precuneus/PCC and between DMN and left inferior occipital gyrus and increased rsFC between DMN and right dorsolateral prefrontal cortex. Conjunction analysis showed shared decreased rsFC in mPFC/ACC and precuneus/PCC. Compared to MCI, AD had decreased rsFC in left precuneus/PCC and between DMN and left inferior occipital gyrus and increased rsFC in right temporal lobes. MCI and AD share a decreased within-DMN rsFC likely underpinning episodic memory deficits and neuropsychiatric symptoms, but differ in DMN rsFC alterations likely related to impairments in other cognitive domains such as language, vision, and execution. This may throw light on neuropathological mechanisms in these two stages of dementia.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Red en Modo Predeterminado , Disfunción Cognitiva/patología , Giro del Cíngulo , Lóbulo Temporal/patología , Imagen por Resonancia Magnética , Encéfalo , Mapeo EncefálicoRESUMEN
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumourigenesis that is implicated in immune surveillance, but remains elusive in PDAC. DESIGN: To identify the factors that modulate immune surveillance, we employed in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice. RESULTS: Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of Med12 significantly promoted infiltration and cytotoxicity of immune cells including CD8+ T cells, natural killer (NK) and NK1.1+ T cells in tumours, thereby heightening the sensitivity of ICB treatment in a mouse model of PDAC. Mechanistically, MED12 stabilised heterochromatin protein HP1A to repress H3K9me3-marked endogenous retroelements. The derepression of retrotransposons induced by MED12 loss triggered cytosolic nucleic acid sensing and subsequent activation of type I interferon pathways, ultimately leading to robust inflamed TME . Moreover, we uncovered a negative correlation between MED12 expression and immune resposne pathways, retrotransposon levels as well as the prognosis of patients with PDAC undergoing ICB therapy. CONCLUSION: In summary, our findings underscore the pivotal role of MED12 in remodelling immnue TME through the epigenetic silencing of retrotransposons, offering a potential therapeutic target for enhancing tumour immunogenicity and overcoming immunotherapy resistance in PDAC.
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Xing 9 Ling tablet candy (X9LTC) effectively treats alcoholic liver disease (ALD), but its potential mechanism and molecular targets remain unstudied. We aimed to address this gap using network pharmacology. Furthermore, high-performance liquid chromatography (HPLC) and database analysis revealed a total of 35 active ingredients and 311 corresponding potential targets of X9LTC. Protein interaction analysis revealed PTGS2, JUN, and FOS as its core targets. Enrichment analysis indicated that chemical carcinogenesis-receptor activation, IL-17 and TNF signaling pathway were enriched by multiple core targets, which might be the main pathway of action. Further molecular docking validation showed that the core targets had good binding activities with the identified compounds. Animal experiments showed that X9LTC could reduce the high expression of ALT, AST and TG in the serum of ALD mice, alleviate the lesions in liver tissues, and reverse the high expression of PTGS2, JUN, and FOS proteins in the liver tissues. In this study, we established a method for the determination of X9LTC content for the first time, and predicted its active ingredient and mechanism of action in treating ALD, providing theoretical basis for further research.
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Medicamentos Herbarios Chinos , Hepatopatías Alcohólicas , Simulación del Acoplamiento Molecular , Farmacología en Red , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/tratamiento farmacológico , Animales , Ratones , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Masculino , Comprimidos , Ciclooxigenasa 2/metabolismo , Ratones Endogámicos C57BL , Cromatografía Líquida de Alta Presión , Hígado/metabolismo , Hígado/efectos de los fármacosRESUMEN
BACKGROUND: Mild cognitive deficits (MCD) emerge before the first episode of psychosis (FEP) and persist in the clinical high-risk (CHR) stage. This study aims to refine risk prediction by developing MCD models optimized for specific early psychosis stages and target populations. METHODS: A comprehensive neuropsychological battery assessed 1059 individuals with FEP, 794 CHR, and 774 matched healthy controls (HCs). CHR subjects, followed up for 2 years, were categorized into converters (CHR-C) and non-converters (CHR-NC). The MATRICS Consensus Cognitive Battery standardized neurocognitive tests were employed. RESULTS: Both the CHR and FEP groups exhibited significantly poorer performance compared to the HC group across all neurocognitive tests (all p < 0.001). The CHR-C group demonstrated poorer performance compared to the CHR-NC group on three sub-tests: visuospatial memory (p < 0.001), mazes (p = 0.005), and symbol coding (p = 0.023) tests. Upon adjusting for sex and age, the performance of the MCD model was excellent in differentiating FEP from HC, as evidenced by an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.895 (p < 0.001). However, when applied in the CHR group for predicting CHR-C (AUC = 0.581, p = 0.008), the performance was not satisfactory. To optimize the efficiency of psychotic risk assessment, three distinct MCD models were developed to distinguish FEP from HC, predict CHR-C from CHR-NC, and identify CHR from HC, achieving accuracies of 89.3%, 65.6%, and 80.2%, respectively. CONCLUSIONS: The MCD exhibits variations in domains, patterns, and weights across different stages of early psychosis and diverse target populations. Emphasizing precise risk assessment, our findings highlight the importance of tailored MCD models for different stages and risk levels.
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The deliquescence phase transition of atmospheric aerosols is crucial for radiative forcing and atmospheric chemistry. However, the deliquescence kinetics of micrometer-sized aerosols, especially the formation and evolution of surface solution films, remain poorly understood. In this study, IR spectral characteristics were employed for the first time to quantify the solute concentration evolution in surface solution films. At a constant relative humidity (RH) of â¼65%, solution films on NaCl crystals exhibited a very low solute concentration (3.06 ± 0.18 mol/L), comparable to aqueous NaCl droplets above 90% RH. These films reached saturation at â¼74% RH, i.e., the deliquescence RH of NaCl, maintaining a nearly constant saturation level during deliquescence. In contrast, amorphous NaNO3 solids showed supersaturated solution films before deliquescence. Following deliquescence, the saturation level of solution phases increased due to faster solid dissolution rates than liquid water condensation. These findings address knowledge gaps in the complex nonequilibrium dissolution processes of crystalline or amorphous atmospheric aerosols.
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Quantitative magnetic resonance (MR) has been used to study cyto- and myelo-architecture of the human brain non-invasively. However, analyzing brain cortex using high-resolution quantitative MR acquisition can be challenging to perform using 3T clinical scanners. MR fingerprinting (MRF) is a highly efficient and clinically feasible quantitative MR technique that simultaneously provides T1 and T2 relaxation maps. Using 3D MRF from 40 healthy subjects (mean age = 25.6 ± 4.3 years) scanned on 3T magnetic resonance imaging, we generated whole-brain gyral-based normative MR relaxation atlases and investigated cortical-region-based T1 and T2 variations. Gender and age dependency of T1 and T2 variations were additionally analyzed. The coefficient of variation of T1 and T2 for each cortical-region was 3.5% and 7.3%, respectively, supporting low variability of MRF measurements across subjects. Significant differences in T1 and T2 were identified among 34 brain regions (P < 0.001), lower in the precentral, postcentral, paracentral lobule, transverse temporal, lateral occipital, and cingulate areas, which contain sensorimotor, auditory, visual, and limbic functions. Significant correlations were identified between age and T1 and T2 values. This study established whole-brain MRF T1 and T2 atlases of healthy subjects using a clinical 3T scanner, which can provide a quantitative and region-specific baseline for future brain studies and pathology detection.
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Encéfalo , Imagen por Resonancia Magnética , Humanos , Adulto Joven , Adulto , Lactante , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Fantasmas de Imagen , Voluntarios Sanos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
The current study examined the characteristics of physiological synchrony between grandmothers and grandchildren in Chinese three-generation families, and the associations between physiological synchrony and child emotion regulation. The participants included 92 children (age 8-10-year old) and their grandmothers. Respiratory sinus arrhythmia (RSA) was collected from both grandmothers and their grandchildren throughout a collaborative drawing task and a conflict discussion task. Child emotion regulation was measured using the Children's Emotional Management Scale. We found no evidence for an overall pattern of concordant or discordant synchrony within dyads. Instead, there was great variability in patterns of synchrony across dyads. During the collaborative drawing task, concordance in grandmother's RSA and grandchildren's subsequent RSA was linked with better emotion regulation. During the conflict discussion, concordance in grandmother's RSA and grandchildren's simultaneous RSA was linked with poorer emotion regulation. These results suggest that grandmother-grandchild synchrony in different directions, time lags, and contexts has different influences on children's emotion regulation. The findings of this study highlight the importance of contextual physiological co-regulation between Chinese children and their grandmothers for children's social-emotional development.
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Regulación Emocional , Abuelos , Arritmia Sinusal Respiratoria , Humanos , Arritmia Sinusal Respiratoria/fisiología , Femenino , Niño , Masculino , Regulación Emocional/fisiología , China , Relaciones Intergeneracionales , Persona de Mediana Edad , Adulto , Anciano , Pueblos del Este de AsiaRESUMEN
OBJECTIVES: A seizure lasting >15 s has been considered to indicate treatment for magnetic seizure therapy (MST), a modification of electroconvulsive therapy (ECT), without much validation. This study aimed to investigate whether this seizure duration was suitable for the treatment of schizophrenia. METHODS: Altogether, 34 and 33 in-patients with schizophrenia received 10 sessions of MST and ECT, respectively. Clinical symptoms were assessed using the Positive and Negative Symptom Scale at baseline and at the 4-week follow-up. Electroencephalogram (EEG) was monitored during each MST or ECT treatment using bifrontal electrodes. RESULTS: The proportion of participants who achieved the 15-second threshold was only 28.6% in the MST group, with a significant difference between responders and nonresponders. For patients receiving MST, the average EEG seizure duration correlated with the percentage of Positive and Negative Symptom Scale reduction (t(32) = 2.51, P = 0.017, uncorrected; t(32) = 2.00, P = 0.055, corrected with clinical characteristics). The average EEG seizure duration predicted the clinical response at a trend level (Z = 1.76, P = 0.078) with an optimal cutoff of 11.3 seconds. All patients in the ECT group achieved the 15-second threshold. However, their average EEG seizure duration was uncorrelated with clinical improvement. CONCLUSIONS: The duration of EEG seizures may be associated with the antipsychotic effects of MST. This association may have been influenced by various clinical and technical factors. More research is needed to define the specific criteria for adequate MST in schizophrenia in order to achieve personalized dosing.
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BACKGROUND: Glaucoma is a public health problem among the worldwide population. Dietary as a modifiable factor have been reported to be associated with glaucoma. This study aimed to explore the association between quantity and quality of carbohydrate (CH) intake and glaucoma among U.S. adults. METHODS: In this cross-sectional study, data of participants aged ≥ 40 years old were extracted from the National Health and Nutrition Examination Survey (NHANES) 2005-2008. CH intake information were obtained by 24-h dietary recall interview. Glaucoma was defined by regraded disc images. Covariates included demographic information, physical examination, laboratory values, complications and nutrients intake. The weighted univariable and multivariate logistic regression models were used to assess the association between the quantity and quality of CH intake and glaucoma. Subgroup analyses based on the history of hypertension were further assessed the association. RESULTS: The weighted population included a total of 4789 participants, of whom 119 (2.48%) had glaucoma. After adjusting for age, adrenal cortical steroids, hypertension, chronic kidney diseases, diabetes and energy intake, high quantity (OR = 1.83, 95%CI: 1.08-3.11) and low quality (OR = 0.44, 95CI%: 0.20-0.98) of CH intake were associated with the higher odds of glaucoma. High quantity of CH intake (OR = 2.06, 95%CI: 1.15-3.69) was associated with the high odds of glaucoma in hypertension, while high quality of CH intake (fiber-to-CH ratio: OR = 0.23, 95%CI: 0.06-0.82; CH-to-fiber and fiber-to-added sugars ratio: OR = 0.10, 95%CI: 0.02-0.53) were associated with the lower odds of glaucoma in participants without hypertension. CONCLUSION: In NAHNES 2005-2008, higher quantity and lower quality CH intake were associated with the high odds of glaucoma, especially among patients without hypertension. This study provides a theoretical basis for the health management of glaucoma patients from the perspective of dietary intake.
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Carbohidratos de la Dieta , Glaucoma , Encuestas Nutricionales , Humanos , Estudios Transversales , Masculino , Femenino , Persona de Mediana Edad , Glaucoma/epidemiología , Glaucoma/fisiopatología , Estados Unidos/epidemiología , Carbohidratos de la Dieta/administración & dosificación , Adulto , Factores de Riesgo , AncianoRESUMEN
Reyanning Mixture is one of the superior Chinese patent medicine varieties of "Qin medicine". Based on the idea of quality by design(QbD), the extraction process of the Reyanning Mixture was optimized. The caffeic acid, polydatin, resveratrol, and emodin were used as critical quality attributes(CQAs). The material-liquid ratio, extraction temperature, and extraction time were taken as critical process parameters(CPPs) by the Plackett-Burman test. The mathematical model was established by the star design-effect surface method, and the design space was constructed and verified. The optimal extraction process of the Reyanning Mixture was obtained as follows: material-liquid ratio of 11.84 g·mL~(-1), extraction temperature at 81 â, and two extractions. A partial least-square(PLS) quantitative model for CQAs was established by using near-infrared spectroscopy(NIRS) combined with high-performance liquid chromatography(HPLC) under the optimal extraction process. The results showed that the correlation coefficients of the correction set(R_c) and validation set(R_p) of the quantitative models of four CQAs were more than 0.9. The root mean square error of the correction set(RMSEC) were 0.744, 6.71, 3.95, and 1.53 µg·mL~(-1), respectively, and the root mean square error of the validation set(RMSEP) were 0.709, 5.88, 2.92, and 1.59 µg·mL~(-1), respectively. Therefore, the optimized extraction process of the Reyanning Mixture is reasonable, feasible, stable, and reliable. The NIRS quantitative model has a good prediction, which can be used for the rapid content determination of CQAs during extraction. They can provide an experimental basis for the process research and quality control of Reyanning Mixture.
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Medicamentos Herbarios Chinos , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/normas , Medicamentos Herbarios Chinos/análisis , Cromatografía Líquida de Alta Presión , Control de Calidad , Espectroscopía Infrarroja Corta/métodos , Temperatura , Glucósidos/análisis , Glucósidos/química , Ácidos CafeicosRESUMEN
BACKGROUND: Hypothermia is an effective method of reducing brain injury caused by a variety of neurological insults. It is aimed to elucidate whether a change in the expression of PERK-mediated pathway proteins is an indicator of the neuroprotective effect of mild hypothermia after cerebral ischaemia/reperfusion. METHODS: One hundred and ninety-two male C57BL/6 mice were randomly divided into three groups: a sham group, a cerebral normothermic ischaemia/reperfusion (I/R) group and a cerebral hypothermic I/R group. A cerebral ischaemia model was established by ligating the bilateral common carotid artery for 15 min. Mice in the hypothermia group stayed in a cage that was set at 33°C, sprayed with a spray of 70% ethanol, and blown with two high-speed fans. The state of neurons was assessed on micropreparations stained with haematoxylin-eosin and TUNEL. The expressions of GRP78, p-perk, p-eif2α, ATF4 and CHOP were measured by western blot analysis 6, 12, 24 and 72 h after reperfusion. RESULTS: The number of surviving cells was significantly higher in the hypothermia group than in the group without hypothermia (p < .05). The GRP78 expression in the hypothermia group was statistically higher (p < .05) than in the ischaemia/reperfusion group. Optical densities of p-perk, p-eif2α and ATF4 in hippocampus CA1 neurons ischaemia were statistically significantly lower in the hypothermia group than in the ischaemia/reperfusion group (p < .05). The CHOP expression in the hypothermia group was statistically lower (p < .05) than in the ischaemia/reperfusion group. CONCLUSION: Mild hypothermia for 6 h promoted moderate neuroprotection by mediating the expression of GRP78, p-PERK, p-eIF2α, ATF4 and CHOP.
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Isquemia Encefálica , Hipotermia , Daño por Reperfusión , Animales , Masculino , Ratones , Apoptosis , Infarto Cerebral , Chaperón BiP del Retículo Endoplásmico , Ratones Endogámicos C57BL , Reperfusión , Daño por Reperfusión/metabolismoRESUMEN
BACKGROUND: Schizophrenia is a severely debilitating psychiatric disorder with high heritability and polygenic architecture. A higher polygenic risk score for schizophrenia (SzPRS) has been associated with smaller gray matter volume, lower activation, and decreased functional connectivity (FC). However, the effect of polygenic inheritance on the brain white matter microstructure has only been sparsely reported. METHODS: Eighty-four patients with first-episode schizophrenia (FES) patients and ninety-three healthy controls (HC) with genetics, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI) data were included in our study. We investigated impaired white matter integrity as measured by fractional anisotropy (FA) in the FES group, further examined the effect of SzPRS on white matter FA and FC in the regions connected by SzPRS-related white matter tracts. RESULTS: Decreased FA was observed in FES in many commonly identified regions. Among these regions, we observed that in the FES group, but not the HC group, SzPRS was negatively associated with the mean FA in the genu and body of corpus callosum, right anterior corona radiata, and right superior corona radiata. Higher SzPRS was also associated with lower FCs between the left inferior frontal gyrus (IFG)-left inferior temporal gyrus (ITG), right IFG-left ITG, right IFG-left middle frontal gyrus (MFG), and right IFG-right MFG in the FES group. CONCLUSION: Higher polygenic risks are linked with disrupted white matter integrity and FC in patients with schizophrenia. These correlations are strongly driven by the interhemispheric callosal fibers and the connections between frontotemporal regions.
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Esquizofrenia , Sustancia Blanca , Humanos , Sustancia Blanca/patología , Cuerpo Calloso/patología , Imagen de Difusión Tensora , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/genética , Esquizofrenia/patología , Herencia Multifactorial , Anisotropía , EncéfaloRESUMEN
OBJECTIVE: We aim to quantify whole-brain tissue-property changes in patients with magnetic resonance imaging (MRI)-negative pharmacoresistant focal epilepsy by three-dimensional (3D) magnetic resonance fingerprinting (MRF). METHODS: We included 30 patients with pharmacoresistant focal epilepsy and negative MRI by official radiology report, as well as 40 age- and gender-matched healthy controls (HCs). MRF scans were obtained with 1 mm3 isotropic resolution. Quantitative T1 and T2 relaxometry maps were reconstructed from MRF and registered to the Montreal Neurological Institute (MNI) space. A two-sample t test was performed in Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) to evaluate significant abnormalities in patients comparing to HCs, with correction by the threshold-free cluster enhancement (TFCE) method. Subgroups analyses were performed for extra-temporal epilepsy/temporal epilepsy (ETLE/TLE), and for those with/without subtle abnormalities detected by morphometric analysis program (MAP), to investigate each subgroup's pattern of MRF changes. Correlation analyses were performed between the mean MRF values in each significant cluster and seizure-related clinical variables. RESULTS: Compared to HCs, patients exhibited significant group-level T1 increase ipsilateral to the epileptic origin, in the mesial temporal gray matter (GM) and white matter (WM), temporal pole GM, orbitofrontal GM, hippocampus, and amygdala, with scattered clusters in the neocortical temporal and insular GM. No significant T2 changes were detected. The ETLE subgroup showed a T1-increase pattern similar to the overall cohort, with additional involvement of the ipsilateral anterior cingulate GM. The subgroup of MAP+ patients also showed a T1-increase pattern similar to the overall cohort, with additional cluster in the ipsilateral lateral orbitofrontal GM. Higher T1 was associated with younger seizure-onset age, longer epilepsy duration, and higher seizure frequency. SIGNIFICANCE: MRF revealed group-level T1 increase in limbic/paralimbic structures ipsilateral to the epileptic origin, in patients with pharmacoresistant focal epilepsy and no apparent lesions on MRI, suggesting that these regions may be commonly affected by seizures in the epileptic brain. The significant association between T1 increase and higher seizure burden may reflect progressive tissue damage.
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Epilepsias Parciales , Epilepsia , Humanos , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Convulsiones , Epilepsias Parciales/diagnóstico por imagenRESUMEN
OBJECTIVES: The efficacy of electroconvulsive therapy (ECT) in treating mood disorders (MDs) is hypothesized to be mediated by the induction of neurotrophic factors (denoted "angioneurins") that trigger neuronal plasticity. This study aimed to assess the effects of ECT on serum angioneurin levels in patients with MD. METHODS: A total of 110 patients with MDs including 30 with unipolar depression, 25 with bipolar depression (BD), 55 with bipolar mania (BM), and 50 healthy controls were included in the study. Patients were subdivided into two groups: those who received ECT + medication (12 ECT sessions) and those who received only medication (no-ECT). Depressive and manic symptom assessments and measurements of vascular endothelial growth factor (VEGF), fibroblast growth factor-2, nerve growth factor (NGF), and insulin-like growth factor-1 levels in blood samples were performed at baseline and week 8. RESULTS: Patients in the ECT group, specifically those with BD and BM, had significantly increased levels of VEGF compared to their baseline VEGF levels (p = 0.002). No significant changes in angioneurin levels were observed in the no-ECT group. Serum NGF levels were significantly associated with a reduction in depressive symptoms. Angioneurin levels were not associated with manic symptom reduction. CONCLUSIONS: This study hints that ECT may increase VEGF levels with angiogenic mechanisms that amplify NGF signaling to promote neurogenesis. It may also contribute to changes in brain function and emotional regulation. However, further animal experiments and clinical validation are needed.
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Trastorno Bipolar , Terapia Electroconvulsiva , Humanos , Trastornos del Humor/etiología , Trastornos del Humor/terapia , Trastorno Bipolar/terapia , Factor A de Crecimiento Endotelial Vascular , Factor de Crecimiento Nervioso , Manía , Resultado del TratamientoRESUMEN
IL-27, a heterodimeric cytokine of the IL-12 family, has diverse influences on the development of multiple inflammatory diseases. In this study, we identified the protective role of IL-27/IL-27R in host defense against Chlamydia muridarum respiratory infection and further investigated the immunological mechanism. Our results showed that IL-27 was involved in C. muridarum infection and that IL-27R knockout mice (WSX-1-/- mice) suffered more severe disease, with greater body weight loss, higher chlamydial loads, and more severe inflammatory reactions in the lungs than C57BL/6 wild-type mice. There were excessive IL-17-producing CD4+ T cells and many more neutrophils, neutrophil-related proteins, cytokines, and chemokines in the lungs of WSX-1-/- mice than in wild-type mice following C. muridarum infection. In addition, IL-17/IL-17A-blocking Ab treatment improved disease after C. muridarum infection in WSX-1-/- mice. Overall, we conclude that IL-27/IL-27R mediates protective immunity during chlamydial respiratory infection in mice by suppressing excessive Th17 responses and reducing neutrophil inflammation.