RESUMO
Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.
Assuntos
Neoplasias , Pericitos , Humanos , Pericitos/patologia , Pericitos/fisiologia , Guanilil Ciclase Solúvel , Células Endoteliais/fisiologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neoplasias/genética , Neoplasias/patologia , Guanilato Ciclase , Microambiente TumoralRESUMO
Parvalbumin-positive neurons (PVs) are the main class of inhibitory neurons in the mammalian central nervous system. By examining diurnal changes in synaptic and neuronal activity of PVs in the supragranular layer of the mouse primary visual cortex (V1), we found that both PV input and output are modulated in a time- and sleep-dependent manner throughout the 24-h day. We first show that PV-evoked inhibition is stronger by the end of the light cycle (ZT12) relative to the end of the dark cycle (ZT0), which is in line with the lower inhibitory input of PV neurons at ZT12 than at ZT0. Interestingly, PV inhibitory and excitatory synaptic transmission slowly oscillate in opposite directions during the light/dark cycle. Although excitatory synapses are predominantly regulated by experience, inhibitory synapses are regulated by sleep, via acetylcholine activating M1 receptors. Consistent with synaptic regulation of PVs, we further show in vivo that spontaneous PV activity displays daily rhythm mainly determined by visual experience, which negatively correlates with the activity cycle of surrounding pyramidal neurons and the dorsal lateral geniculate nucleus-evoked responses in V1. These findings underscore the physiological significance of PV's daily modulation.
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Neurônios , Parvalbuminas , Animais , Camundongos , Parvalbuminas/metabolismo , Neurônios/metabolismo , Células Piramidais/metabolismo , Transmissão Sináptica , Sono , MamíferosRESUMO
Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.
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Síndrome de Rett , Animais , Camundongos , Ácido Glutâmico/metabolismo , Inflamação/genética , Inflamação/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos Knockout , Microglia/metabolismo , Síndrome de Rett/metabolismoRESUMO
Synaptic dysfunction is one of the earliest pathological processes that contribute to the development of many neurological disorders, including Alzheimer's disease and frontotemporal lobar degeneration. However, the synaptic function of many disease-causative genes and their contribution to the pathogenesis of the related diseases remain unclear. In this study, we investigated the synaptic role of fused in sarcoma, an RNA-binding protein linked to frontotemporal lobar degeneration and amyotrophic lateral sclerosis, and its potential pathological role in frontotemporal lobar degeneration using pyramidal neuron-specific conditional knockout mice (FuscKO). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the frontotemporal lobar degeneration-linked behavioural disinhibition. Electrophysiological study and molecular pathway analyses further reveal that fused in sarcoma differentially regulates synaptic and neuronal properties in the ventral hippocampus and medial prefrontal cortex, respectively. Moreover, fused in sarcoma selectively modulates the ventral hippocampus-prefrontal cortex projection, which is known to mediate the anxiety-like behaviour. Our findings unveil the brain region- and synapse-specific role of fused in sarcoma, whose impairment might lead to the emotional symptoms associated with frontotemporal lobar degeneration.
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Esclerose Lateral Amiotrófica , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Sarcoma , Animais , Camundongos , Esclerose Lateral Amiotrófica/metabolismo , Encéfalo/patologia , Demência Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Proteína FUS de Ligação a RNA/genética , Sarcoma/metabolismo , Sarcoma/patologiaRESUMO
Heterozygous point mutations of α-synuclein (α-syn) have been linked to the early onset and rapid progression of familial Parkinson's diseases (fPD). However, the interplay between hereditary mutant and wild-type (WT) α-syn and its role in the exacerbated pathology of α-syn in fPD progression are poorly understood. Here, we find that WT mice inoculated with the human E46K mutant α-syn fibril (hE46K) strain develop early-onset motor deficit and morphologically different α-syn aggregation compared with those inoculated with the human WT fibril (hWT) strain. By using cryo-electron microscopy, we reveal at the near-atomic level that the hE46K strain induces both human and mouse WT α-syn monomers to form the fibril structure of the hE46K strain. Moreover, the induced hWT strain inherits most of the pathological traits of the hE46K strain as well. Our work suggests that the structural and pathological features of mutant strains could be propagated by the WT α-syn in such a way that the mutant pathology would be amplified in fPD.
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Amiloide/genética , Mutação de Sentido Incorreto , Doenças do Sistema Nervoso/genética , Doença de Parkinson/genética , Agregação Patológica de Proteínas/genética , alfa-Sinucleína/genética , Amiloide/metabolismo , Amiloide/ultraestrutura , Animais , Microscopia Crioeletrônica , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Força Atômica , Microscopia Confocal , Atividade Motora/genética , Atividade Motora/fisiologia , Doenças do Sistema Nervoso/metabolismo , Doença de Parkinson/metabolismo , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/química , alfa-Sinucleína/metabolismoRESUMO
In this work, a straightforward approach utilizing distillers' grains (DG) waste and sodium alginate (SA) was developed to prepare functional and bioactive packaging films. Deep eutectic solvents (DESs) were initially synthesized from choline chloride (CO), betaine (BO), glycerol (GO), and oxalic acid. Composite films were then prepared from DES-treated DG slurry and SA at different ratios. Characterization and analysis revealed that adding 75 % CO-treated DG slurry reduced the water vapor permeability (WVP) by over 66 % compared to that of the SA film. Composite films containing CO/BO-treated DG slurry had an ultraviolet light barrier rate exceeding 99 %, while those with 75 % DES-treated DG slurry demonstrated excellent antioxidant activity, with a 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) free radical scavenging rate of 80.14 %-88.35 %, representing a 322.45 %-365.73 % increase compared to that of the pure SA film. These composite films also exhibited favorable mechanical properties (31.58 MPa, 5.53 % EB), thermal stability, and biodegradability, extending the shelf life of grapes by 1.8 times. In conclusion, bioactive composite films derived from DES-treated DG are expected to replace petroleum-based plastics, enhancing sustainable biomass use and environmental responsibility.
Assuntos
Alginatos , Antioxidantes , Solventes Eutéticos Profundos , Permeabilidade , Alginatos/química , Antioxidantes/química , Antioxidantes/farmacologia , Solventes Eutéticos Profundos/química , Vapor , Colina/química , Glicerol/químicaRESUMO
Urban green spaces provide multiple ecosystem services and have great influences on human health. However, the compositions and properties of urban soil are not well understood yet. In this study, soil samples were collected from 45 parks in Ningbo to investigate the relationships among soil physicochemical properties, heavy metals and bacterial communities. The results showed that soil dissolved organic matter (DOM) was of high molecular weight, high aromaticity, and low degree of humification. The contents of heavy metals were all below the China's national standard safety limit (GB 3660-2018). The bioavailability of heavy metals highly correlated with soil pH, the content of DOC, the fluorescent component, the degree of humification and the source of DOM. The most abundant genera were Gemmatimonadaceae_uncultured, Xanthobacteraceae_uncultured, and Acidothermus in all samples, which were related to nitrogen cycle and bioavailability of heavy metals. Soil pH, bioavailability of Zn, Cd, and Pb (CaCl2 extracted) were the main edaphic factors influencing bacterial community composition. It should be noted that there was no significant impact of urbanization on soil physicochemical properties and bacterial composition, but they were determined by the source of soil in urban green spaces. However, with the passage of time, the effect of urbanization on urban green spaces cannot be ignored. Overall, this study provided new insight for understanding the linkage among soil physicochemical properties, heavy metals, and bacterial communities in urban green spaces.
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Metais Pesados , Microbiologia do Solo , Poluentes do Solo , Solo , Urbanização , Solo/química , China , Metais Pesados/análise , Poluentes do Solo/análise , Monitoramento Ambiental , BactériasRESUMO
Autophagy is a lysosome-dependent degradation pathway essential for cellular homeostasis, which decreases with age. However, it is unclear how aging induces autophagy decline. Here we show the role of protein S-palmitoylation in autophagy. We identify the palmitoyl acyltransferase DHHC5 as a regulator of autophagy by mediating the palmitoylation of beclin 1, which in turn promotes the formation of ATG14L-containing class III phosphatidylinositol-3-kinase complex I and its lipid kinase activity by promoting the hydrophobic interactions between beclin 1 and adapter proteins ATG14L and VPS15. In aging brains of human and nonhuman primate, the levels of DHHC5 exhibit a marked decrease in expression. We show that DHHC5 deficiency in neurons leads to reduced cellular protein homeostasis in two established murine models of Alzheimer's disease, which exaggerates neurodegeneration in an autophagy-dependent manner. These findings identify reduction of DHHC5-mediated beclin 1 S-palmitoylation as an underlying mechanism by which aging induces autophagy decline.
Assuntos
Aciltransferases , Proteínas Reguladoras de Apoptose , Autofagia , Proteína Beclina-1 , Lipoilação , Animais , Humanos , Camundongos , Aciltransferases/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Proteínas de Membrana/metabolismo , FosforilaçãoRESUMO
Loss of a sensory modality elicits both unimodal changes in the deprived cortex and cross-modal alterations in the remaining sensory systems. Unimodal changes are proposed to recruit the deprived cortex for processing the remaining senses, while cross-modal changes are thought to refine processing of spared senses. Hence coordinated unimodal and cross-modal changes are likely beneficial. Despite this expectation, we report in mice that losing behaviorally relevant patterned vision is sufficient to trigger cross-modal synaptic changes in the primary somatosensory cortex barrel fields, but is insufficient to drive unimodal synaptic plasticity in visual cortex (V1), which requires a complete loss of visual activity. In addition, cross-modal changes depend on whisker inputs. Our results demonstrate that unimodal and cross-modal synaptic plasticity occur independently of each other and rely on distinct sensory requirements.
Assuntos
Homeostase/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Animais , Cegueira/fisiopatologia , Escuridão , Potenciais Pós-Sinápticos Excitadores/fisiologia , Enucleação Ocular , Pálpebras/fisiologia , Feminino , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Receptores de AMPA/fisiologia , Recrutamento Neurofisiológico/fisiologia , Privação Sensorial/fisiologia , Córtex Somatossensorial/fisiologia , Vibrissas/inervação , Visão Ocular/fisiologia , Córtex Visual/fisiologiaRESUMO
AMPAR-lacking silent synapses are prevailed and essential for synaptic refinement and synaptic plasticity in developing brains. In mature brain, they are sparse but could be induced under several pathological conditions. How they are regulated molecularly is far from clear. miR-34a is a highly conserved and brain-enriched microRNA with age-dependent upregulated expression profile. Its neuronal function in mature brain remains to be revealed. Here by analyzing synaptic properties of the heterozygous miR-34a knock out mice (34a_ht), we have discovered that mature but not juvenile 34a_ht mice have more silent synapses in the hippocampus accompanied with enhanced synaptic NMDAR but not AMPAR function and increased spine density. As a result, 34a_ht mice display enhanced long-term potentiation (LTP) in the Schaffer collateral synapses and better spatial learning and memory. We further found that Creb1 is a direct target of miR-34a, whose upregulation and activation may mediate the silent synapse increment in 34a_ht mice. Hence, we reveal a novel physiological role of miR-34a in mature brains and provide a molecular mechanism underlying silent synapse regulation.
Assuntos
MicroRNAs , Plasticidade Neuronal , Camundongos , Animais , Plasticidade Neuronal/fisiologia , Potenciação de Longa Duração/fisiologia , Hipocampo/metabolismo , Sinapses/metabolismo , MicroRNAs/metabolismo , Camundongos KnockoutRESUMO
The widespread noradrenergic innervation in the brain promotes arousal and learning by molecular mechanisms that remain largely undefined. Recent work shows that the ß(2)-adrenergic receptor (ß(2)AR) is linked to the AMPA-type glutamate receptor subunit GluA1 via stargazin and PSD-95 (Joiner ML, Lise MF, Yuen EY, Kam AY, Zhang M, Hall DD, Malik ZA, Qian H, Chen Y, Ulrich JD, Burette AC, Weinberg RJ, Law PY, El-Husseini A, Yan Z, Hell JW. EMBO J 29: 482-495, 2010). We now demonstrate that the ß(2)AR plays a prominent role in long-term potentiation (LTP) induced by a train of 900 stimuli at 5 Hz (prolonged theta-tetanus-LTP, or PTT-LTP) in the hippocampal CA1 region in mice, which requires simultaneous ß-adrenergic stimulation. Although PTT-LTP was impaired in hippocampal slices from ß(1)AR and ß(2)AR knockout (KO) mice, only ß(2)AR-selective stimulation with salbutamol supported this PTT-LTP in wild-type (WT) slices, whereas ß(1)AR-selective stimulation with dobutamine (+ prazosin) did not. Furthermore, only the ß(2)AR-selective antagonist ICI-118551 and not the ß(1)AR-selective antagonist CGP-20712 inhibited PTT-LTP and phosphorylation of GluA1 on its PKA site S845 in WT slices. Our analysis of S845A knockin (KI) mice indicates that this phosphorylation is relevant for PTT-LTP. These results identify the ß(2)AR-S845 signaling pathway as a prominent regulator of synaptic plasticity.
Assuntos
Região CA1 Hipocampal/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores Adrenérgicos beta/metabolismo , Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Dobutamina/farmacologia , Estimulação Elétrica , Imidazóis/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Propanolaminas/farmacologia , Coelhos , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
AMPA receptor (AMPAR) channel properties and function are regulated by its subunit composition and phosphorylation. Certain types of neural activity can recruit Ca(2+)-permeable (CP) AMPARs, such as GluR1 homomers, to synapses likely via lateral diffusion from extrasynaptic sites. Here we show that GluR1-S845 phosphorylation can alter the subunit composition of perisynaptic AMPARs by providing stability to GluR1 homomers. Using mice specifically lacking phosphorylation of the GluR1-S845 site (GluR1-S845A mutants), we demonstrate that this site is necessary for maintaining CP-AMPARs. Specifically, in the GluR1-S845A mutants, CP-AMPARs were absent from perisynaptic locations mainly due to lysosomal degradation. This regulation was mimicked by acute desphosphorylation of the GluR1-S845 site in wild-type mice by NMDA application. Furthermore, long-term depression (LTD) was associated with a reduction in perisynaptic CP-AMPAR levels. Our findings suggest that GluR1-S845 is necessary for maintaining CP-AMPARs on the surface, especially at perisynaptic sites, and suggest that the regulation of these receptors is involved in synaptic plasticity.
Assuntos
Cálcio/metabolismo , Receptores de AMPA/metabolismo , Serina/metabolismo , Sinapses/metabolismo , 2-Amino-5-fosfonovalerato/metabolismo , Animais , Antagonistas de Aminoácidos Excitatórios/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Depressão Sináptica de Longo Prazo/fisiologia , Lisossomos/enzimologia , Camundongos , Mutação , Plasticidade Neuronal/fisiologia , Antagonistas Nicotínicos/metabolismo , Fosforilação , Poliaminas/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de AMPA/genéticaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregated ß-amyloid (Aß) peptides. It is now recognized that soluble Aß oligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. Aß is produced by a sequential cleavage of amyloid precursor protein (APP) by the activity of ß- and γ-secretases, which have been identified as major candidate therapeutic targets of AD. This paper focuses on how Aß alters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for Aß generation. Abnormalities in synaptic function resulting from the absence or inhibition of the Aß-producing enzymes suggest that Aß itself may have normal physiological functions which are disrupted by abnormal accumulation of Aß during AD pathology. This interpretation suggests that AD therapeutics targeting the ß- and γ-secretases should be developed to restore normal levels of Aß or combined with measures to circumvent the associated synaptic dysfunction(s) in order to have minimal impact on normal synaptic function.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Inibidores Enzimáticos/farmacologia , Plasticidade Neuronal/fisiologia , Sinapses/enzimologia , Sinapses/fisiologia , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/fisiologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Ácido Aspártico Endopeptidases/fisiologia , Humanos , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Neurônios/fisiologia , Presenilinas/genética , Presenilinas/fisiologiaRESUMO
PURPOSE: To identify TOPORS mutations in patients with retinitis pigmentosa (RP) from our cohort and summarize the genotypes and phenotypes of TOPORS reported previously. METHOD: Probands with RP phenotypes were recruited from our genetic retinopathy screening work. DNA was extracted from the peripheral venous blood, and exome sequencing was performed. We further examined the clinical data and family history in detail in these patients. TOPORS mutations associated with RP were searched and summarized from the previous reports, and the results were combined with the data presented in our study. The mutation spectrum of TOPORS was systematically analyzed, and the phenotypes of truncated mutations and missense mutations were compared and described. RESULT: Mutations in TOPORS were detected in three families, including two novel mutations (c.2017C>T, p.Arg673Cys, c.2371A>T, p.Lys791Term) and a known frameshift mutation (c.2554_2557delGAGA, p. Glu852fsTer13). A comprehensive analysis showed that 64.1% (25/39) of the mutant alleles are truncated mutations, and 34.3% (12/39) are missense mutations. About 89.7% (35/39) of the mutations are located in the terminal half of exon 3, which affected the C-terminal of the TOPORS protein. Night blindness was a common onset symptom, and TOPORS-related ERG changes can be observed in early stage. In addition, patients with missense mutations retained better central vision in older age compared to the patients with truncated mutations. CONCLUSION: We expand the mutation spectrum and assess the possible genotype-phenotype correlations of TOPORS, which can provide a valuable reference for exploring the pathogenesis of adRP caused by TOPORS mutations.
Assuntos
Proteínas de Neoplasias , Proteínas Nucleares , Retinose Pigmentar , Ubiquitina-Proteína Ligases , Análise Mutacional de DNA , Humanos , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Linhagem , Fenótipo , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Ubiquitina-Proteína Ligases/genéticaRESUMO
Objective: To investigate the clinical efficacy of the subxiphoid approach for early anterior mediastinal thymoma and evaluate its advantages over the lateral intercostal approach. Methods: A total of 345 patients with early anterior mediastinal thymoma were retrospectively analyzed from January 2016 to December 2020 in the First Affiliated Hospital of Soochow University. Out of these, 99 patients underwent subxiphoid video-assisted thoracoscopic thymectomy and 246 patients underwent transthoracic video-assisted thoracoscopic thymectomy. We compared the intraoperative conditions (such as operation time and intraoperative blood loss), postoperative conditions [such as postoperative pleural drainage volume, extubation time, postoperative hospital stay, and postoperative visual analogue scale (VAS) pain score], and postoperative complications (such as death, pneumonia, delayed wound healing, cardiac arrhythmia, and phrenic nerve injury) of the two groups and analyzed the clinical advantages of the subxiphoid approach for treating early anterior mediastinal thymoma. Results: There was no significant difference between the two groups in terms of general clinical features, operation time, and postoperative complications (P > 0.05).However, there was a significant difference in terms of intraoperative blood loss, postoperative pleural drainage volume, tube extubation time, postoperative hospital stay, postoperative VAS pain score, and postoperative analgesics (a significantly decreased flurbiprofen axetil amount) (P < 0.05). Conclusion: Compared with the lateral intercostal thoracic approach, the subxiphoid approach had advantages in terms of intraoperative blood loss, postoperative hospital stay, tube extubation time, postoperative pleural drainage volume, postoperative VAS pain score, and analgesics dosage. It could provide a better view of the bilateral pleural cavities and more thorough thymectomy and superior cosmesis, and it proved to be a safe and feasible minimally invasive surgical method.
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Mutations in the FERM domain containing 7 (FRMD7) gene have been proven to be responsible for infantile nystagmus (IN). The purpose of this study is to investigate FRMD7 gene mutations in patients with IN, and to evaluate the nystagmus intensity among patients with and without FRMD7 mutations. The affected males were subdivided into three groups according to whether or not having FRMD7 mutations and the types of mutations. Fifty-two mutations were detected in FRMD7 in 56 pedigrees and 34 sporadic patients with IN, including 28 novel and 24 previous reported mutations. The novel identified mutations further expand the spectrum of FRMD7 mutations. The parameters of nystagmus intensity and the patients' best corrected visual acuity were not statistically different among the patients with and without identified FRMD7 mutations, and also not different among patients with different mutant types. The FERM-C domain, whose amino acids are encoded by exons 7, 8 and 9, could be the harbor region for most mutations. Loss-of-function is suggested to be the common molecular mechanism for the X-linked infantile nystagmus.
Assuntos
Proteínas do Citoesqueleto , Doenças Genéticas Ligadas ao Cromossomo X , Proteínas de Membrana , Nistagmo Congênito , Proteínas do Citoesqueleto/genética , Análise Mutacional de DNA , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Proteínas de Membrana/genética , Mutação , Nistagmo Congênito/genética , LinhagemRESUMO
There are over 6,000 different rare diseases estimated to impact 300 million people worldwide. As genetic testing becomes more common practice in the clinical setting, the number of rare disease diagnoses will continue to increase, resulting in the need for novel treatment options. Identifying treatments for these disorders is challenging due to a limited understanding of disease mechanisms, small cohort sizes, interindividual symptom variability, and little commercial incentive to develop new treatments. A promising avenue for treatment is drug repurposing, where FDA-approved drugs are repositioned as novel treatments. However, linking disease mechanisms to drug action can be extraordinarily difficult and requires a depth of knowledge across multiple fields, which is complicated by the rapid pace of biomedical knowledge discovery. To address these challenges, The Hugh Kaul Precision Medicine Institute developed an artificial intelligence tool, mediKanren, that leverages the mechanistic insight of genetic disorders to identify therapeutic options. Using knowledge graphs, mediKanren enables an efficient way to link all relevant literature and databases. This tool has allowed for a scalable process that has been used to help over 500 rare disease families. Here, we provide a description of our process, the advantages of mediKanren, and its impact on rare disease patients.
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The structure of dendritic spines is highly plastic and can be modified by neuronal activity. In addition, there is evidence that spine head size correlates with the synaptic α-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptor (AMPAR) content, which suggests that they may be coregulated. Although there is evidence that there are overlapping mechanisms for structural and functional plasticity, the extent of the overlap needs further investigation. Specifically, it is unknown whether AMPAR levels determine spine size or whether both are regulated via parallel pathways. We studied the correlation between spine structural plasticity and long-term synaptic plasticity following chemical-induced long-term depression (chemLTD). In particular, we examined whether the regulation of AMPARs, which is implicated in LTD, is critical for spine morphological plasticity. We used mutant mice specifically lacking the serine-845 site on the type 1 glutamate receptor (GluR1, or GluA1) subunit of AMPARs (mutants). These mice specifically lack N-methyl-D-aspartate (NMDA) receptor (NMDAR)-dependent LTD and NMDAR activation-induced AMPAR endocytosis. We found that chemLTD causes a rapid and persistent shrinkage in spine head volume of hippocampal CA1 pyramidal neurons in wild types similar to that reported in other studies using low-frequency stimulation (LFS)-induced LTD. Surprisingly, we found that although S845A mutant mice display impaired chemLTD, the shrinkage of spine head volume occurred to a similar magnitude to that observed in wild types. Our results suggest that there is dissociation in the molecular mechanisms underlying functional LTD and spine shrinkage and that GluR1-S845 regulation is not necessary for spine morphological plasticity.
Assuntos
Espinhas Dendríticas/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Receptores de AMPA/genética , Receptores de AMPA/fisiologia , Serina/genética , Animais , Região CA1 Hipocampal/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Modelos Animais , Mutação/genética , Plasticidade Neuronal/fisiologia , Transdução de Sinais/fisiologia , Sinapses/fisiologiaRESUMO
Neuromodulation can profoundly impact the gain and polarity of postsynaptic changes in Hebbian synaptic plasticity. An emerging pattern observed in multiple central synapses is a pull-push type of control in which activation of receptors coupled to the G-protein Gs promote long-term potentiation (LTP) at the expense of long-term depression (LTD), whereas receptors coupled to Gq promote LTD at the expense of LTP. Notably, coactivation of both Gs- and Gq-coupled receptors enhances the gain of both LTP and LTD. To account for these observations, we propose a simple kinetic model in which AMPA receptors (AMPARs) are trafficked between multiple subcompartments in and around the postsynaptic spine. In the model AMPARs in the postsynaptic density compartment (PSD) are the primary contributors to synaptic conductance. During LTP induction, AMPARs are trafficked to the PSD primarily from a relatively small perisynaptic (peri-PSD) compartment. Gs-coupled receptors promote LTP by replenishing peri-PSD through increased AMPAR exocytosis from a pool of endocytic AMPAR. During LTD induction AMPARs are trafficked in the reverse direction, from the PSD to the peri-PSD compartment, and Gq-coupled receptors promote LTD by clearing the peri-PSD compartment through increased AMPAR endocytosis. We claim that the model not only captures essential features of the pull-push neuromodulation of synaptic plasticity, but it is also consistent with other actions of neuromodulators observed in slice experiments and is compatible with the current understanding of AMPAR trafficking.
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Aberrant sterol lipid metabolism is associated with physiological dysfunctions in the aging brain and aging-dependent disorders such as neurodegenerative diseases. There is an unmet demand to comprehensively profile sterol lipids spatially and temporally in different brain regions during aging. Here, we develop an ion mobility-mass spectrometry based four-dimensional sterolomics technology leveraged by a machine learning-empowered high-coverage library (>2000 sterol lipids) for accurate identification. We apply this four-dimensional technology to profile the spatially resolved landscapes of sterol lipids in ten functional regions of the mouse brain, and quantitatively uncover ~200 sterol lipids uniquely distributed in specific regions with concentrations spanning up to 8 orders of magnitude. Further spatial analysis pinpoints age-associated differences in region-specific sterol lipid metabolism, revealing changes in the numbers of altered sterol lipids, concentration variations, and age-dependent coregulation networks. These findings will contribute to our understanding of abnormal sterol lipid metabolism and its role in brain diseases.