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1.
Clin Kidney J ; 15(5): 974-984, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35498901

RESUMO

Background: Critically ill patients with severe acute kidney injury (AKI) requiring kidney replacement therapy (KRT) have a grim prognosis. Recently, multiple studies focused on the impact of KRT initiation time [i.e., accelerated versus watchful waiting KRT initiation (WWS-KRT)] on patient outcomes. We aim to review the results of all related clinical trials. Methods: In this systematic review, we searched all relevant randomized clinical trials from January 2000 to April 2021. We assessed the impacts of accelerated versus WWS-KRT on KRT dependence, KRT-free days, mortality and adverse events, including hypotension, infection, arrhythmia and bleeding. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. Results: A total of 4932 critically ill patients with AKI from 10 randomized clinical trials were included in this analysis. The overall 28-day mortality rate was 38.5%. The 28-day KRT-dependence rate was 13.0%. The overall incident of KRT in the accelerated group was 97.4% and 62.8% in the WWS-KRT group. KRT in the accelerated group started 36.7 h earlier than the WWS-KRT group. The two groups had similar risks of 28-day [pooled log odds ratio (OR) 1.001, P = 0.982] and 90-day (OR 0.999, P = 0.991) mortality rates. The accelerated group had a significantly higher risk of 90-day KRT dependence (OR 1.589, P = 0.007), hypotension (OR 1.687, P < 0.001) and infection (OR 1.38, P = 0.04) compared with the WWS-KRT group. Conclusions: This meta-analysis revealed that accelerated KRT leads to a higher probability of 90-day KRT dependence and dialysis-related complications without any impact on mortality rate when compared with WWS-KRT. Therefore, we suggest the WWS-KRT strategy for critically ill patients.

3.
Front Endocrinol (Lausanne) ; 13: 825431, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35573984

RESUMO

Follicle arrest is one of the main characteristics of polycystic ovary syndrome (PCOS), the most common endocrinological disorder in reproductive-aged women. Increasing evidence proves that high anti-Mullerian hormone (AMH) levels may play an important role in follicular development. Long noncoding RNA (lncRNA) with a length of more than 200 nt is widely involved in the directional differentiation, growth, and development of cells, whereas whether lncRNA is involved in AMH's role in follicular development is unknown. In this study, we analyzed lncRNA expression in ovarian granulosa cells (GCs) collected from women with and without PCOS via high-throughput sequencing. The results showed that a total of 79 noncoding transcripts were differently expressed in GCs of PCOS patients, including upregulated lncRNA MALAT1. The upregulation of MALAT1 was further confirmed by RT-qPCR in GCs from a larger cohort of PCOS patients. Furthermore, knockdown MALAT1 can promote the proliferation of KGN cell in vitro. These data suggested a role for MALAT1 in the development of PCOS. Meanwhile, MALAT1 and phosphorylated SMAD 1/5 (Ser463/465) protein were upregulated in KGN cells after exogenous AMH stimulation, which identified AMH perhaps as a regulator for the expression of MALAT1. We also found that MALAT1 can predict clinical pregnancy outcome to a certain extent by ROC curve analysis (area: 0.771, p = 0.007, 95% CI: 0.617-0.925, sensitivity: 57.1%, specificity: 91.7%). Thus, our findings revealed a role of lncRNA MALAT1 in inhibiting granulosa cell proliferation and may be correlated with pregnancy outcome in PCOS.

4.
Nat Genet ; 54(5): 625-636, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35534561

RESUMO

DNA methyltransferase 3a (DNMT3A) plays a crucial role during mammalian development. Two isoforms of DNMT3A are differentially expressed from stem cells to somatic tissues, but their individual functions remain largely uncharacterized. Here we report that the long isoform DNMT3A1, but not the short DNMT3A2, is essential for mouse postnatal development. DNMT3A1 binds to and regulates bivalent neurodevelopmental genes in the brain. Strikingly, Dnmt3a1 knockout perinatal lethality could be partially rescued by DNMT3A1 restoration in the nervous system. We further show that the intrinsically disordered N terminus of DNMT3A1 is required for normal development and DNA methylation at DNMT3A1-enriched regions. Mechanistically, a ubiquitin-interacting motif embedded in a putative α-helix within the N terminus binds to mono-ubiquitinated histone H2AK119, probably mediating recruitment of DNMT3A1 to Polycomb-regulated regions. These data demonstrate an isoform-specific role for DNMT3A1 in mouse postnatal development and reveal the N terminus as a necessary regulatory domain for DNMT3A1 chromatin occupancy and functions in the nervous system.

5.
Pestic Biochem Physiol ; 183: 105060, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35430063

RESUMO

Cytochrome P450-mediated detoxification plays an important role in the development of insecticide resistance. Previous studies have shown that cytochrome P450 CYP6B7 was induced by fenvalerate and involved in fenvalerate detoxification in Helicoverpa armigera. However, the transcriptional regulation of CYP6B7 induced by fenvalerate remains unclear. Here, a series of progressive 5' deletions of CYP6B7 promoter reporter genes were constructed, and the relative luciferase activities were detected. The results revealed that the relative luciferase activity of plasmid p (-655/-1) was significantly induced by fenvalerate. Further deletion of the region between -655 and -486 bp showed that the highest luciferase activity induced by fenvalerate was observed in plasmid p (-528/-1), while p (-485/-1) had the lowest fenvalerate-induced luciferase activity. Moreover, internal deletion and mutation in the region between -508 and -486 bp resulted in a significant reduction in fenvalerate-induced CYP6B7 promoter activity, suggesting that the cis-acting element responsible for fenvalerate in the CYP6B7 promoter was located between -508 and -486 bp. These results promote an understanding of the expression regulation mechanism of P450 genes that conferring resistance to insecticides.


Assuntos
Inseticidas , Mariposas , Piretrinas , Animais , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Luciferases , Mariposas/genética , Mariposas/metabolismo , Nitrilas , Piretrinas/farmacologia
6.
Int J Biol Sci ; 18(6): 2553-2567, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35414777

RESUMO

ENKUR plays a crucial role in lung and colorectal cancers. Chemically synthesized cinobufotalin (CB) showed its significant anti-cancer effect in nasopharyngeal carcinoma. However, the roles of ENKUR and CB along with their correlation are still unknown in hepatocellular carcinoma (HCC). In this study, ENKUR expression in HCC tissue and cells were detected. The relationship between ENKUR expression and clinical pathology was also assessed. In vivo and in vitro experiments were conducted to explore the effects and molecular basis of ENKUR and CB in HCC. ENKUR expression was correlated with HCC progression and patient prognosis. Furthermore, ENKUR could inhibit tumor proliferation, metastasis, and sorafenib resistance in HCC. Mechanistic studies showed that ENKUR or its Enkurin domain could bind to MYH9 and decrease its expression by binding to ß-catenin and inhibiting its nuclear transfer, thus decreasing c-Jun level. Low expression of MYH9 suppressed recruitment of deubiquitination enzyme USP7, promoting degradation of the c-Myc. Therefore, cell cycle and EMT signals were suppressed. CB as a safe and effective anti-cancer compound up-regulates the expression of ENKUR via inhibiting PI3K/AKT/c-Jun-mediated transcription suppression. These findings show that ENKUR induced by CB antagonizes ß-catenin/c-Jun/MYH9/USP7 pathway, thus increasing c-Myc ubiquitin degradation and finally suppressing cell cycle and EMT signals.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Adaptadoras de Transdução de Sinal , Bufanolídeos , Proteínas de Ligação a Calmodulina , Carcinoma Hepatocelular/metabolismo , Cateninas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Cadeias Pesadas de Miosina , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc , Peptidase 7 Específica de Ubiquitina/metabolismo , beta Catenina/metabolismo
8.
World J Clin Cases ; 10(9): 2710-2720, 2022 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-35434109

RESUMO

BACKGROUND: Endoscopic removal with forceps/baskets is favored in treating submandibular stones due to its minimal invasiveness. However, recent studies have found that endoscopic removal failure (ERF) is not unusual, and stones in such cases still need to be removed with other surgical methods. If the risk of ERF can be predicted preoperatively, it could be helpful for surgeons when choosing the appropriate therapy. AIM: To develop a predictive nomogram for the risk of ERF when treating submandibular stones based on their preoperative clinical features. METHODS: A total of 180 patients with 211 submandibular stones treated from January 2012 to December 2020 were included in the current study. Based on the preoperative clinical features of the stones, independent risk factors for ERF were identified by logistic regression analysis. The stones were then randomly divided into training and testing sets. A nomogram was constructed to predict the risk of ERF using the training set and then validated using both sets. The predictive performance of the nomogram was assessed by calibration curves and the concordance index (C-index). RESULTS: Three independent predictors, location (P = 0.040), transverse diameter (P < 0.001) and longitudinal diameter (P < 0.001) measured on the cone beam computed tomography (CBCT) images of the submandibular stones, were identified and included in the predictive nomogram. Calibration curves of the nomogram showed good agreement between the predicted and observed probabilities in both sets. The C-index in the training set was 0.917 (95%CI, 0.875-0.959) and that in the testing set was 0.925 (95%CI, 0.862-0.989). CONCLUSION: A nomogram based on the location, transverse and longitudinal diameters on CBCT images of submandibular stones showed satisfactory efficacy in predicting the risk of ERF preoperatively when treating submandibular stones.

9.
Transl Neurodegener ; 11(1): 20, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35395956

RESUMO

BACKGROUND: Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain and that lack of arginylation leads to neurodegeneration in mice. METHODS: Here, we tested α-syn arginylation in human brain pathology using newly derived antibodies in combination with Western blotting, biochemical assays, and experiments in live neurons. RESULTS: We found that α-syn was arginylated in the human brain on E46 and E83, two sites previously implicated in α-syn pathology and familial cases of Parkinson's disease. The levels of arginylation in different brain samples ranged between ~ 3% and ~ 50% of the total α-syn pool, and this arginylation nearly exclusively concentrated in the subcellular α-syn fraction that sedimented at low centrifugation speeds and appeared to be simultaneously targeted by multiple posttranslational modifications. Arginylated α-syn was less susceptible to S129 phosphorylation and pathological aggregation in neurons. The arginylation level inversely correlated with the overall α-syn levels and with patient age, suggesting a possible causal relationship between arginylation decline and α-syn-dependent neuropathology. CONCLUSION: We propose that α-syn arginylation constitutes a potential neuroprotective mechanism that prevents its abnormal accumulation during neurodegeneration and aging in the human brain.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Sinucleinopatias , Animais , Encéfalo/metabolismo , Humanos , Camundongos , Doença de Parkinson/patologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
10.
Clin Transl Med ; 12(4): e807, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35389568

Assuntos
Luz , Optogenética
11.
Front Endocrinol (Lausanne) ; 13: 818888, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35250874

RESUMO

Female fertility declines with age, and this natural variation culminates in reproductive senescence. Human follicular fluids are rich in low-molecular weight metabolites which are responsible for the maturation of oocytes. The metabolomic approaches are powerful tools to study biochemical markers of oocyte quality in the follicular fluids. It is necessary to identify and quantify the reliable metabolites in follicular fluids reflecting oocyte developmental potential. The goal of this study is to conduct a metabolomic analysis of the follicular fluids in women of different ages and study the metabolomic profile of the follicular fluids in relationship with oocyte quality in assisted reproductive technology (ART) treatment. A total of 30 women seeking for ART treatment at the Women's Hospital, Zhejiang University School of Medicine from October 2014 to April 2015 were recruited for the present study. Fifteen women aged from 39 to 47 were grouped as advanced maternal age, and the other 15 women aged from 27 to 34, as young controls. Ovarian stimulation and oocyte retrieval were conducted using a regular protocol involving mid-luteal pituitary down-regulation and controlled ovarian stimulation. Follicular fluids from mature follicles were collected and centrifuged for analyses. Liquid Chromatography-Mass Spectrometry (LC-MS) and Gas Chromatography-Mass Spectroscopy (GC-MS) were used to perform the quantitative metabolomic analysis. The follicular fluid levels of 311 metabolites and the metabolic significance were assessed. 70 metabolites showed significant differences between women with young and advanced ages. Follicular fluids from women with advanced age showed significantly higher levels of creatine, histidine, methionine, trans-4-hydroxyproline, choline, mevalonate, N2,N2-dimethylguanosine and gamma-glutamylvaline, as compared to those from the young age group. 8 metabolites were found significantly correlated with maternal age positively. Moreover, 3 metabolites were correlated with the number of oocytes retrieved, and 5 metabolites were correlated with cleaved embryo numbers, both negatively. The follicular fluids from women undergoing ART treatment exhibited age-dependent metabolomic profile. Metabolites associated with oocyte quality were identified, suggesting them as potential biomarkers for oocyte maturation and ART outcomes.


Assuntos
Líquido Folicular , Recuperação de Oócitos , Feminino , Líquido Folicular/metabolismo , Humanos , Masculino , Metabolômica , Oócitos/fisiologia , Técnicas de Reprodução Assistida
12.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1867(6): 159120, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35231606

RESUMO

An AMP-activated kinase (AMPK) signaling pathway is activated during myocardial ischemia and promotes cardiac fatty acid (FA) uptake and oxidation. Similarly, the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is also triggered by myocardial ischemia, but its function in FA metabolism remains unclear. Here, we explored the role of CaMKII in FA metabolism during myocardial ischemia by investigating the effects of cardiac CaMKII on AMPK-acetyl-CoA carboxylase (ACC), malonyl CoA decarboxylase (MCD), and FA translocase cluster of differentiation 36 (FAT/CD36), as well as cardiac FA uptake and oxidation. Moreover, we tested whether CaMKII and AMPK are binding partners. We demonstrated that diseased hearts from patients with terminal ischemic heart disease displayed increased phosphorylation of CaMKII, AMPK, and ACC and increased expression of MCD and FAT/CD36. AC3-I mice, which have a genetic myocardial inhibition of CaMKII, had reduced gene expression of cardiac AMPK. In post-MI (myocardial infarction) AC3-I hearts, AMPK-ACC phosphorylation, MCD and FAT/CD36 levels, cardiac FA uptake, and FA oxidation were significantly decreased. Notably, we demonstrated that CaMKII interacted with AMPK α1 and α2 subunits in the heart. Additionally, AC3-I mice displayed significantly less cardiac hypertrophy and apoptosis 2 weeks post-MI. Overall, these findings reveal a unique role for CaMKII inhibition in repressing FA metabolism by interacting with AMPK signaling pathways, which may represent a novel mechanism in ischemic heart disease.


Assuntos
Infarto do Miocárdio , Isquemia Miocárdica , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Antígenos CD36/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ácidos Graxos/metabolismo , Humanos , Camundongos
13.
Neural Regen Res ; 17(10): 2286-2292, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35259851

RESUMO

Extracellular aggregation of amyloid-beta (Aß) and intracellular tau tangles are two major pathogenic hallmarks and critical factors of Alzheimer's disease. A linear interaction between Aß and tau protein has been characterized in several models. Aß induces tau hyperphosphorylation through a complex mechanism; however, the master regulators involved in this linear process are still unclear. In our study with Drosophila melanogaster, we found that Aß regulated tau hyperphosphorylation and toxicity by activating c-Jun N-terminal kinase. Importantly, Aß toxicity was dependent on tau hyperphosphorylation, and flies with hypophosphorylated tau were insulated against Aß-induced toxicity. Strikingly, tau accumulation reciprocally interfered with Aß degradation and correlated with the reduction in mRNA expression of genes encoding Aß-degrading enzymes, including dNep1, dNep3, dMmp2, dNep4, and dIDE. Our results indicate that Aß and tau protein work synergistically to further accelerate Alzheimer's disease progression and may be considered as a combined target for future development of Alzheimer's disease therapeutics.

14.
Micromachines (Basel) ; 13(3)2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35334758

RESUMO

In this paper, thermoreflectance microscopy was used to measure the high spatial resolution temperature distribution of the p-GaN HEMT under high power density. The maximum temperature along the GaN channel was located at the drain-side gate edge region. It was found that the thermal resistance (Rth) of the p-GaN HEMT device increased with the increase of channel temperature. The Rth dependence on the temperature was well approximated by a function of Rth~Ta (a = 0.2). The three phonon Umklapp scattering, point mass defects and dislocations scattering mechanisms are suggested contributors to the heat transfer process for the p-GaN HEMT. The impact of bias conditions and gate length on the thermal characteristics of the device was investigated. The behaviour of temperature increasing in the time domain with 50 µs pulse width and different drain bias voltage was analysed. Finally, a field plate structure was demonstrated for improving the device thermal performance.

15.
Poult Sci ; 101(5): 101809, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35358924

RESUMO

Stocking density critically affects the growth and subsequent performance of animals in modern poultry production. This study investigated the effects of stocking density on ovarian development, ovarian maturation, and the mRNA expression of key genes in the reproductive axis during the rearing period of Shan-ma ducks. The experiments involved 180 healthy 7-wk-old Shan-ma ducks and randomly divided into low stocking density (LSD; n = 30, density = 5 birds/m2), medium stocking density (MSD; n = 60, density = 10 birds/m2) and high stocking density groups (HSD; n = 90, density = 15 birds/m2), for rearing. After examining ovarian development and measuring hormone levels in the plasma and expression levels of key regulatory genes in the reproductive axis at 19 wk of rearing, analysis of the gonad index analysis, reflecting stocking density, uncovered statistically significant differences. The gonad index of the LSD group was significantly higher than those of the MSD and HSD groups (P < 0.01), while no significant difference was observed between the MSD and HSD groups. pre-ovulatory follicles (POFs) and small yellow follicles (SYFs) development was only apparent in the LSD group, with the large white follicles (LWFs) number of this group being significantly higher than that of the MSD group (P < 0.05). The blood levels of E2 (estradiol), P4 (progesterone), and T (testosterone) were significantly higher in the LSD group than in the MSD and HSD groups (P < 0.05 or 0.01). Also, the levels of both P4 and T were significantly higher in the MSD group than in the HSD group (P < 0.01). The gene expression levels of GnRHR, FSH, AMHR, and FSHR were significantly increased in the LSD group compared to the MSD and HSD groups (P < 0.05 or 0.01), while the expression levels of GnIHR and GDF9 were significantly decreased in the LSD and MSD groups compared to the HSD group (P < 0.05 or 0.01). Steroid biosynthesis pathway genes such as StAR, CYP11A1, 3ß-HSD, CYP19A1, and BMP15 were significantly downregulated at greater stocking densities (P < 0.05 or 0.01). Likewise, the protein expression of StAR, 3ß-HSD, and CYP19A1 was also significantly decreased (P < 0.05 or 0.01). These results demonstrate that both medium and high stocking densities suppressed the expression of the key reproduction-promoting factors, while the expression level of the key reproductive inhibitory factors was enhanced. Therefore, rates of ovarian development and maturation could be reduced by a high stocking density leading to a delay in reproduction performance during the rearing period of Shan-ma ducks.


Assuntos
Galinhas , Patos , Animais , Patos/genética , Estradiol , Dietilamida do Ácido Lisérgico , Progesterona
16.
Front Oncol ; 12: 851091, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35311068

RESUMO

Objective: Malnutrition is recognized as a risk factor for poor outcome in patients with gastric cancer (GC). In 2018, the Global Leadership Initiative on Malnutrition (GLIM) published standardized criteria for the diagnosis of malnutrition. Our aim was to investigate whether any of the components of the GLIM diagnostic criteria were related to worse clinical outcomes in patients with GC. Methods: This study analyzed patients with GC who underwent radical gastrectomy in our hospital between 2014 and 2019. A preoperative nutritional assessment was performed for each patient. Matching was based on the presence of three GLIM components: high weight loss (WL), low body mass index (BMI), and low skeletal muscle index (SMI). Results: The analysis included 1,188 patients, including 241 (20.3%) with high WL, 156 (13.1%) with low BMI, and 355 (29.9%) with low SMI. Before matching, patients who met the GLIM component criteria were mostly associated with older age, low nutritional reserves, and late tumor progression. After matching, the clinical characteristics of the three cohorts were balanced. In the matched queue, the survival prognosis of the high WL group was worse than that of the non-WL group, and the postoperative complication rate was higher in the low SMI group than in the normal SMI group (P <0.05). In addition, the clinical outcomes in the low and normal BMI groups were similar (P >0.05). Conclusion: Of the GLIM criteria, high WL and low SMI may be associated with poor clinical outcomes in patients with GC, while a low BMI may not be associated with outcome.

17.
ACS Appl Mater Interfaces ; 14(12): 14226-14234, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35294166

RESUMO

The electrode deterioration and capacity decay caused by the dissolution of transition metal ions have been criticized for a long time. The branched polyethyleneimine (PEI) was employed as a functional binder for spinel lithium manganese oxide (LiMn2O4, LMO) and layer structure lithium cobalt oxide (LiCoO2, LCO) to resolve the problem. Due to the chelation reaction of amine groups, PEI polymer binder can effectively absorb soluble transition metal ions, which is beneficial to reduce the loss of active materials. For PEI-based cathode, the uniform distribution of key components is achieved by the rapid curing process of water, which endow PEI-based cathode with a higher Li+ diffusion coefficient and improved electrochemical reaction kinetics. In addition, the fixed binder coating is favorable to protecting the active materials from parasitic reaction with the lithium hexafluorophosphate (LiPF6)-based electrolyte. Therefore, the PEI-based cell shows superior rate capability and long-term cycle performance. Functional binders of this study provide a simple and effective strategy to achieve higher capacity and longer cycle stability for transition metal oxide electrodes.

18.
Nucleic Acids Res ; 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35325178

RESUMO

The nucleolus is a subnuclear membraneless compartment intimately involved in ribosomal RNA synthesis, ribosome biogenesis and stress response. Multiple optogenetic devices have been developed to manipulate nuclear protein import and export, but molecular tools tailored for remote control over selective targeting or partitioning of cargo proteins into subnuclear compartments capable of phase separation are still limited. Here, we report a set of single-component photoinducible nucleolus-targeting tools, designated pNUTs, to enable rapid and reversible nucleoplasm-to-nucleolus shuttling, with the half-lives ranging from milliseconds to minutes. pNUTs allow both global protein infiltration into nucleoli and local delivery of cargoes into the outermost layer of the nucleolus, the granular component. When coupled with the amyotrophic lateral sclerosis (ALS)-associated C9ORF72 proline/arginine-rich dipeptide repeats, pNUTs allow us to photomanipulate poly-proline-arginine nucleolar localization, perturb nucleolar protein nucleophosmin 1 and suppress nascent protein synthesis. pNUTs thus expand the optogenetic toolbox by permitting light-controllable interrogation of nucleolar functions and precise induction of ALS-associated toxicity in cellular models.

19.
iScience ; 25(4): 104042, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35330682

RESUMO

Extracellular vesicles (EVs) participate in intercellular communication and contribute to the angiogenesis. However, the understanding of the mechanisms underlying EVs secretion by neurons and their action on the vascular system of the central nervous system (CNS) remain rudimentary. Here, we show that vacuolar protein sorting 28 (Vps28) is essential for the sprouting of brain central arteries (CtAs) and for the integrity of blood-brain barrier (BBB) in zebrafish. Disruption of neuron-enriched Vps28 significantly decreased EVs secretion by regulating the formation of intracellular multivesicular bodies (MVBs). EVs derived from zebrafish embryos or mouse cortical neurons partially rescued the brain vasculature defect and brain leakage. Further investigations revealed that neuronal EVs containing vascular endothelial growth factor A (VEGF-A) are key regulators in neurovascular communication. Our results indicate that Vps28 acts as an intercellular endosomal regulator mediating the secretion of neuronal EVs, which in turn communicate with endothelial cells to mediate angiogenesis through VEGF-A trafficking.

20.
Cereb Cortex ; 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35253853

RESUMO

The social brain hypothesis posits that a disproportionate encephalization in primates enabled to adapt behavior to a social context. Also, it has been proposed that phylogenetically recent brain areas are disproportionally affected by neurodegeneration. Using structural and functional magnetic resonance imaging, the present study investigates brain-behavior associations and neural integrity of hyperspecialized and domain-general cortical social brain areas in behavioral variant frontotemporal dementia (bvFTD). The results revealed that both structure and function of hyperspecialized social areas in the middle portion of the superior temporal sulcus (STS) are compromised in bvFTD, while no deterioration was observed in domain general social areas in the posterior STS. While the structural findings adhered to an anterior-posterior gradient, the functional group differences only occurred in the hyperspecialized locations. Activity in specialized regions was associated with structural integrity of the amygdala and with social deficits in bvFTD. In conclusion, the results are in line with the paleo-neurology hypothesis positing that neurodegeneration primarily hits cortical areas showing increased specialization, but also with the compatible alternative explanation that anterior STS regions degenerate earlier, based on stronger connections to and trans-neuronal spreading from regions affected early in bvFTD.

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