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1.
Neurol Ther ; 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38625649

RESUMO

INTRODUCTION: Pseudobulbar palsy is a common symptom in patients with amyotrophic lateral sclerosis (ALS), but it is often underdiagnosed or misdiagnosed as other diseases. The Center for Neurologic Study Lability Scale (CNS-LS) is a self-report scale consisting of seven questions designed for evaluating pseudobulbar affect (PBA). The current study aimed to validate a Chinese version of the CNS-LS. METHODS: The Chinese version of the CNS-LS was obtained through a standardized forward-backward translation and cultural adaptation. A total of 105 patients with ALS were recruited from the ALS database of Peking University Third Hospital in Beijing, China, to complete the CNS-LS. The reliability of the Chinese version was determined by the test-retest method, and receiver operating characteristic (ROC) analysis was performed for criterion validity. RESULTS: Of 105 patients with ALS, 37 had symptoms of PBA and were diagnosed with that condition by neurologists. Forty-two patients completed the CNS-LS twice, and there was no statistically significant difference between the scores (Z = -0.896, p = 0.37). The Spearman correlation coefficient between the test and retest scores was 0.940 (p < 0.0005), and the Cronbach alpha coefficient was high (α = 0.905, n = 105). Scores of 12 or higher on the CNS-LS identified PBA with sensitivity of 0.919 and specificity of 0.882. The area under the ROC curve was 0.924. CONCLUSION: The Chinese version of the CNS-LS demonstrated good sensitivity and specificity in the group of patients with ALS enrolled in this study. The CNS-LS should be a useful instrument for clinical and research purposes for patients in this language group.

2.
Psychol Res Behav Manag ; 17: 1477-1485, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38606089

RESUMO

Objective: Non-suicidal self-injury (NSSI) behavior is very common in adolescents with depression, and childhood trauma is considered one of the distal risk factors for its exacerbation. Rumination caused by adverse traumatic experiences, which can be transferred through NSSI behavior, can alleviate symptoms of depression in adolescents. The current research focuses on the relationship between the three, further exploring whether rumination is a mediator in the relationship between childhood trauma and NSSI behavior on the basis of previous studies, and provides some suggestions for future early intervention for adolescents with depression. Methods: A total of 833 adolescent patients with depression who met the DSM-5 criteria for depressive episode were recruited from 12 hospitals in China. The Chinese version of the Function Assessment of Self-mutilation, Childhood Trauma Questionnaire, and Rumination Inventory were used as research tools. Results: The scores of childhood trauma and rumination in adolescents with depression in the NSSI group were higher than those in the non-NSSI group. A Pearson's correlation analysis showed that childhood trauma was positively correlated with rumination (r=0.165, P<0.01), different types of childhood trauma were significantly positively correlated with rumination and its three factors, and these results were statistically significant. Rumination partially mediated the relationship between childhood trauma and NSSI behavior in depressed adolescent patients (effect size=0.002), and the effect in female participants (effect size=0.003), was greater than that in male participants (effect size=0.002). Conclusion: Childhood trauma and rumination were key factors for NSSI behavior in adolescents with depression. Childhood trauma not only has a direct effect on NSSI behavior in adolescent depression, but also plays an indirect effect on NSSI behavior through rumination.

3.
J Exp Clin Cancer Res ; 43(1): 114, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627815

RESUMO

BACKGROUND: The efficacy of anti-PD-1 therapy is primarily hindered by the limited T-cell immune response rate and immune evasion capacity of tumor cells. Autophagy-related protein 7 (ATG7) plays an important role in autophagy and it has been linked to cancer. However, the role of ATG7 in the effect of immune checkpoint blockade (ICB) treatment on high microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) CRC is still poorly understood. METHODS: In this study, patients from the cancer genome altas (TCGA) COAD/READ cohorts were used to investigate the biological mechanism driving ATG7 development. Several assays were conducted including the colony formation, cell viability, qRT-PCR, western blot, immunofluorescence, flow cytometry, ELISA, immunohistochemistry staining and in vivo tumorigenicity tests. RESULTS: We found that ATG7 plays a crucial role in MSI-H CRC. Its knockdown decreased tumor growth and caused an infiltration of CD8+ T effector cells in vivo. ATG7 inhibition restored surface major histocompatibility complex I (MHC-I) levels, causing improved antigen presentation and anti-tumor T cell response by activating reactive oxygen species (ROS)/NF-κB pathway. Meanwhile, ATG7 inhibition also suppressed cholesterol accumulation and augmentation of anti-tumor immune responses. Combining ATG7 inhibition and statins improved the therapeutic benefit of anti-PD-1 in MSI-H CRC. Importantly, CRC patients with high expression of both ATG7 and recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) experienced worse prognosis compared to those with low ATG7 and HMGCR expression. CONCLUSIONS: Inhibition of ATG7 leads to upregulation of MHC-I expression, augments immune response and suppresses cholesterol accumulation. These findings demonstrate that ATG7 inhibition has therapeutic potential and application of statins can increase the sensitivity to immune checkpoint inhibitors.


Assuntos
Neoplasias Encefálicas , Neoplasias Colorretais , Inibidores de Hidroximetilglutaril-CoA Redutases , Síndromes Neoplásicas Hereditárias , Humanos , Instabilidade de Microssatélites , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteína 7 Relacionada à Autofagia/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Imunidade , Colesterol , Reparo de Erro de Pareamento de DNA
4.
J Phys Chem Lett ; : 4486-4493, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38634523

RESUMO

Two-dimensional (2D) MXene materials with innovative properties and versatile applications have gained immense popularity among scientists. The green and environmentally friendly Lewis acid salt etching route has opened up immense possibilities for the advancement of 2D MXene materials. In this study, we precisely etched the Al element from the double A-element MAX phases Ti2(SnyAl1-y)C by employing Lewis molten salt guided by redox potentials. This approach led to the discovery of a novel Ti2SnyCClx dual-phase structure consisting of Ti2SnC and Ti2CClx. We then established that the etching of the MAX phase via Lewis acid salt is facilitated by the oxidation of M-site elements, with the MX sublayer acting as an electron transmission conduit to enable the oxidation of A-site elements. This work is dedicated to unraveling the underlying mechanisms governing the etching processes using Lewis molten salt, thereby contributing to a more profound comprehension of these innovative etching routes.

5.
Proc Natl Acad Sci U S A ; 121(16): e2317978121, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38593069

RESUMO

Mosquito-borne flaviviruses such as dengue (DENV) and Zika (ZIKV) cause hundreds of millions of infections annually. The single-stranded RNA genome of flaviviruses is translated into a polyprotein, which is cleaved equally into individual functional proteins. While structural proteins are packaged into progeny virions and released, most of the nonstructural proteins remain intracellular and could become cytotoxic if accumulated over time. However, the mechanism by which nonstructural proteins are maintained at the levels optimal for cellular fitness and viral replication remains unknown. Here, we identified that the ubiquitin E3 ligase HRD1 is essential for flaviviruses infections in both mammalian hosts and mosquitoes. HRD1 directly interacts with flavivirus NS4A and ubiquitylates a conserved lysine residue for ER-associated degradation. This mechanism avoids excessive accumulation of NS4A, which otherwise interrupts the expression of processed flavivirus proteins in the ER. Furthermore, a small-molecule inhibitor of HRD1 named LS-102 effectively interrupts DENV2 infection in both mice and Aedes aegypti mosquitoes, and significantly disturbs DENV transmission from the infected hosts to mosquitoes owing to reduced viremia. Taken together, this study demonstrates that flaviviruses have evolved a sophisticated mechanism to exploit the ubiquitination system to balance the homeostasis of viral proteins for their own advantage and provides a potential therapeutic target to interrupt flavivirus infection and transmission.


Assuntos
Aedes , Infecções por Flavivirus , Flavivirus , Infecção por Zika virus , Zika virus , Animais , Camundongos , Flavivirus/genética , Zika virus/genética , Ubiquitina/metabolismo , Ligases/metabolismo , Proteínas Virais/metabolismo , Mamíferos
6.
Vision Res ; 220: 108388, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38593635

RESUMO

The function of exosomal miRNAs (miRs) in retinal degeneration is largely unclear. We were aimed to investigate the functions of exosomes as well as their miRs derived from retinal pigment epithelial (RPE) cells following exposure to oxidative stress (OS). After the OS by lipopolysaccharide and rotenone on RPE cells, interleukin-1 beta (IL-1ß), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α) were upregulated, along with the decreased mitochondrial membrane potential and upregulated oxidative damage marker 8-OH-dG in RPE cells. RPE-derived exosomes were then isolated, identified, injected into the subretinal space in mice. After subretinal injection, RPE-exosomes after OS not only induced higher ROS level and apoptotic retinal cells, but also elevated IL-1ß, IL-6 alongside TNF-α expressions among retina/RPE/choroidal complex. Next, miRs inside the exosomes were sequenced by the next generation sequencing (NGS) technology. NGS revealed that certain miRs were abundant in exosomes, while others were selectively kept by RPE cells. Further, downregulated miRs, like miR-125b-5p, miR-125a-5p, alongside miR-128-3p, and upregulated miR, such as miR-7-5p were validated byRT-qPCR. Finally, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to find the possible target genes of those selective exosomal miRs. Our results proved that the RPE-derived exosomes after OS selectively express certain miRs, providing novel insights into the pathogenesis of age-related macular degeneration (AMD) in future.

7.
MedComm (2020) ; 5(4): e543, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38585233

RESUMO

High metastatic propensity of osteosarcoma leads to its therapeutic failure and poor prognosis. Although nuclear activation miRNAs (NamiRNAs) are reported to activate gene transcription via targeting enhancer and further promote tumor metastasis, it remains uncertain whether NamiRNAs regulate osteosarcoma metastasis and their exact mechanism. Here, we found that extracellular vesicles of the malignant osteosarcoma cells (143B) remarkably increased the migratory abilities of MNNG cells representing the benign osteosarcoma cells by two folds, which attributed to their high miR-1246 levels. Specially, miR-1246 located in nucleus could activate the migration gene expression (such as MMP1) to accelerate MNNG cell migration through elevating the enhancer activities via increasing H3K27ac enrichment. Instead, MMP1 expression was dramatically inhibited after Argonaute 2 (AGO2) knockdown. Notably, in vitro assays demonstrated that AGO2 recognized the hybrids of miR-1246 and its enhancer DNA via PAZ domains to prevent their degradation from RNase H and these protective roles of AGO2 may favor the gene activation by miR-1246 in vivo. Collectively, our findings suggest that miR-1246 could facilitate osteosarcoma metastasis through interacting with enhancer to activate gene expression dependent on AGO2, highlighting the nuclear AGO2 as a guardian for NamiRNA-targeted gene activation and the potential of miR-1246 for osteosarcoma metastasis therapy.

8.
Mol Biol Rep ; 51(1): 484, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578353

RESUMO

BACKGROUND: Mitochondrial Ts translation elongation factor (TSFM) is an enzyme that catalyzes exchange of guanine nucleotides. By forming a complex with mitochondrial Tu translation elongation factor (TUFM), TSFM participates in mitochondrial protein translation. We have previously reported that TUFM regulates translation of beta-site APP cleaving enzyme 1 (BACE1) via ROS (reactive oxygen species)-dependent mechanism, suggesting a potential role in amyloid precursor protein (APP) processing associated with Alzheimer's disease (AD), which led to the speculation that TSFM may regulate APP processing in a similar way to TUFM. METHODS AND RESULTS: Here, we report that in cultured cells, knockdown or overexpression TSFM did not change protein levels in BACE1 and APP. Besides, the levels of cytoplasmic ROS and mitochondrial superoxide, in addition to ATP level, cell viability and mitochondrial membrane potential were not significantly altered by TSFM knockdown in the short term. Further transcriptome analysis revealed that expression of majority of mitochondrial genes were not remarkably changed by TSFM silencing. The possibility of TSFM involved in cardiomyopathy and cancer development was uncovered using bioinformatics analysis. CONCLUSIONS: Collectively, short-term regulation of TSFM level in cultured cells does not cause a significant change in proteins involved in APP processing, levels in ROS and ATP associated with mitochondrial function. Whereas our study could contribute to comprehend certain clinical features of TSFM mutations, the roles of TSFM in cardiomyopathy and cancer development might deserve further investigation.


Assuntos
Doença de Alzheimer , Cardiomiopatias , Neoplasias , Humanos , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ácido Aspártico Endopeptidases/genética , Doença de Alzheimer/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Cardiomiopatias/metabolismo , Fatores de Alongamento de Peptídeos/metabolismo , Trifosfato de Adenosina , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo
9.
World J Microbiol Biotechnol ; 40(5): 163, 2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38613659

RESUMO

Biotin, also known as vitamin H or B7, acts as a crucial cofactor in the central metabolism processes of fatty acids, amino acids, and carbohydrates. Biotin has important applications in food additives, biomedicine, and other fields. While the ability to synthesize biotin de novo is confined to microorganisms and plants, humans and animals require substantial daily intake, primarily through dietary sources and intestinal microflora. Currently, chemical synthesis stands as the primary method for commercial biotin production, although microbial biotin production offers an environmentally sustainable alternative with promising prospects. This review presents a comprehensive overview of the pathways involved in de novo biotin synthesis in various species of microbes and insights into its regulatory and transport systems. Furthermore, diverse strategies are discussed to improve the biotin production here, including mutation breeding, rational metabolic engineering design, artificial genetic modification, and process optimization. The review also presents the potential strategies for addressing current challenges for industrial-scale bioproduction of biotin in the future. This review is very helpful for exploring efficient and sustainable strategies for large-scale biotin production.


Assuntos
Aminoácidos , Biotina , Animais , Humanos , Biotecnologia , Ácidos Graxos , Aditivos Alimentares
10.
Carbohydr Res ; 538: 109094, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38564900

RESUMO

Human diseases often correlate with changes in protein glycosylation, which can be observed in serum or plasma samples. N-glycosylation, the most common form, can provide potential biomarkers for disease prognosis and diagnosis. However, glycoproteins constitute a relatively small proportion of the total proteins in human serum and plasma compared to the non-glycosylated protein albumin, which constitutes the majority. The detection of microheterogeneity and low glycan abundance presents a challenge. Mass spectrometry facilitates glycoproteomics research, yet it faces challenges due to interference from abundant plasma proteins. Therefore, methods have emerged to enrich N-glycans and N-linked glycopeptides using glycan affinity, chemical properties, stationary phase chemical coupling, bioorthogonal techniques, and other alternatives. This review focuses on N-glycans and N-glycopeptides enrichment in human serum or plasma, emphasizing methods and applications. Although not exhaustive, it aims to elucidate principles and showcase the utility and limitations of glycoproteome characterization.


Assuntos
Glicopeptídeos , Glicoproteínas , Humanos , Glicopeptídeos/química , Glicoproteínas/química , Glicosilação , Espectrometria de Massas/métodos , Polissacarídeos
11.
J Chromatogr A ; 1721: 464861, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38564931

RESUMO

The covalent attachment of polyoxometalates (POMs) to polymers has been developed as a strategic approach for the advancement of POM-based hybrid materials with versatile applications. In this study, we utilized thiol-maleimide Michael addition to investigate the kinetics and efficacy of the "one-to-one" conjugation between Keggin type POM and polystyrene. We explored the effects of solvent polarity, catalyst, molecular weight of PS and synthetic strategies on the reaction kinetics and efficiency, by means of reverse-phase high-performance liquid chromatography (RP-HPLC). A series of comparative analysis affirmed the superior efficiency of the one-pot method, particularly when facilitated by the addition of a high-polarity solvent and an excess of maleimide. These findings offer valuable insights into the intricate interplay between reaction conditions, kinetics, and selectivity in thiol-maleimide reactions of POMs and polymers. They hold profound implications for advancing the study of POM-based multifunctional materials and the synthesis of complex hybrid molecules.


Assuntos
Ânions , Polieletrólitos , Polímeros , Compostos de Sulfidrila , Polímeros/química , Maleimidas/química , Solventes
12.
Adv Sci (Weinh) ; : e2401710, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38582513

RESUMO

Corneal neovascularization (CNV) is a common clinical finding seen in a range of eye diseases. Current therapeutic approaches to treat corneal angiogenesis, in which vascular endothelial growth factor (VEGF) A plays a central role, can cause a variety of adverse side effects. The technology of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 can edit VEGFA gene to suppress its expression. CRISPR offers a novel opportunity to treat CNV. This study shows that depletion of VEGFA with a novel CRISPR/Cas9 system inhibits proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Importantly, subconjunctival injection of this dual AAV-SpCas9/sgRNA-VEGFA system is demonstrated which blocks suture-induced expression of VEGFA, CD31, and α-smooth muscle actin as well as corneal neovascularization in mice. This study has established a strong foundation for the treatment of corneal neovascularization via a gene editing approach for the first time.

13.
Genes Dis ; 11(4): 100987, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38560498

RESUMO

Cancer occurrence and development are closely related to increased lipid production and glucose consumption. Lipids are the basic component of the cell membrane and play a significant role in cancer cell processes such as cell-to-cell recognition, signal transduction, and energy supply, which are vital for cancer cell rapid proliferation, invasion, and metastasis. Sterol regulatory element-binding transcription factor 1 (SREBP1) is a key transcription factor regulating the expression of genes related to cholesterol biosynthesis, lipid homeostasis, and fatty acid synthesis. In addition, SREBP1 and its upstream or downstream target genes are implicated in various metabolic diseases, particularly cancer. However, no review of SREBP1 in cancer biology has yet been published. Herein, we summarized the roles and mechanisms of SREBP1 biological processes in cancer cells, including SREBP1 modification, lipid metabolism and reprogramming, glucose and mitochondrial metabolism, immunity, and tumor microenvironment, epithelial-mesenchymal transition, cell cycle, apoptosis, and ferroptosis. Additionally, we discussed the potential role of SREBP1 in cancer prognosis, drug response such as drug sensitivity to chemotherapy and radiotherapy, and the potential drugs targeting SREBP1 and its corresponding pathway, elucidating the potential clinical application based on SREBP1 and its corresponding signal pathway.

14.
PeerJ ; 12: e17131, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38563000

RESUMO

Global warming continues to exert unprecedented impacts on marine habitats. Species distribution models (SDMs) are proven powerful in predicting habitat distribution for marine demersal species under climate change impacts. The Antarctic toothfish, Dissostichus mawsoni (Norman 1937), an ecologically and commercially significant species, is endemic to the Southern Ocean. Utilizing occurrence records and environmental data, we developed an ensemble model that integrates various modelling techniques. This model characterizes species-environment relationships and predicts current and future fishable habitats of D. mawsoni under four climate change scenarios. Ice thickness, depth and mean water temperature were the top three important factors in affecting the distribution of D. mawsoni. The ensemble prediction suggests an overall expansion of fishable habitats, potentially due to the limited occurrence records from fishery-dependent surveys. Future projections indicate varying degrees of fishable habitat loss in large areas of the Amery Ice Shelf's eastern and western portions. Suitable fishable habitats, including the spawning grounds in the seamounts around the northern Ross Sea and the coastal waters of the Bellingshausen Sea and Amundsen Sea, were persistent under present and future environmental conditions, highlighting the importance to protect these climate refugia from anthropogenic disturbance. Though data deficiency existed in this study, our predictions can provide valuable information for designing climate-adaptive development and conservation strategies in maintaining the sustainability of this species.


Assuntos
Mudança Climática , Perciformes , Animais , Regiões Antárticas , Ecossistema , Oceanos e Mares
15.
Mol Cell Biochem ; 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38564125

RESUMO

Osteosarcoma (OS) is a malignant bone sarcoma arising from mesenchymal stem cells. The biological role of Acyl-CoA synthetase long-chain family member 4 (ACSL4), recently identified as an oncogene in numerous tumor types, remains largely unclear in OS. In this study, we investigated the expression of ACSL4 in OS tissues using immunohistochemistry staining (IHC) staining of a human tissue microarray and in OS cells by qPCR assay. Our findings revealed a significant up-regulation of ACSL4 in both OS tissues and cells. To further understand its biological effects, we conducted a series of loss-of-function experiments using ACSL4-depleted MNNG/HOS and U-2OS cell lines, focusing on OS cell proliferation, migration, and apoptosis in vitro. Our results demonstrated that ACSL4 knockdown remarkably suppressed OS cell proliferation, arrested cells in the G2 phase, induced cell apoptosis, and inhibited cell migration. Additionally, a subcutaneous xenograft mice model was established to validate the in vivo impact of ACSL4, revealing ACSL4 silencing impaired tumor growth in the OS xenograft mice. Additionally, we discovered that ACSL4 could regulate the phosphorylation level of Smad2 through cooperative interactions, and treatment with a TGF-ß inhibitor weakened the promoting effects of ACSL4 overexpression. In short, ACSL4 regulated OS progression by modulating TGF-ß/Smad2 signaling pathway. These findings underscore ACSL4 as a promising therapeutic target for OS patients and contribute novel insights into the pathogenesis of OS.

16.
J Physiol ; 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38568869

RESUMO

We are studying the mechanisms of H-reflex operant conditioning, a simple form of learning. Modelling studies in the literature and our previous data suggested that changes in the axon initial segment (AIS) might contribute. To explore this, we used blinded quantitative histological and immunohistochemical methods to study in adult rats the impact of H-reflex conditioning on the AIS of the spinal motoneuron that produces the reflex. Successful, but not unsuccessful, H-reflex up-conditioning was associated with greater AIS length and distance from soma; greater length correlated with greater H-reflex increase. Modelling studies in the literature suggest that these increases may increase motoneuron excitability, supporting the hypothesis that they may contribute to H-reflex increase. Up-conditioning did not affect AIS ankyrin G (AnkG) immunoreactivity (IR), p-p38 protein kinase IR, or GABAergic terminals. Successful, but not unsuccessful, H-reflex down-conditioning was associated with more GABAergic terminals on the AIS, weaker AnkG-IR, and stronger p-p38-IR. More GABAergic terminals and weaker AnkG-IR correlated with greater H-reflex decrease. These changes might potentially contribute to the positive shift in motoneuron firing threshold underlying H-reflex decrease; they are consistent with modelling suggesting that sodium channel change may be responsible. H-reflex down-conditioning did not affect AIS dimensions. This evidence that AIS plasticity is associated with and might contribute to H-reflex conditioning adds to evidence that motor learning involves both spinal and brain plasticity, and both neuronal and synaptic plasticity. AIS properties of spinal motoneurons are likely to reflect the combined influence of all the motor skills that share these motoneurons. KEY POINTS: Neuronal action potentials normally begin in the axon initial segment (AIS). AIS plasticity affects neuronal excitability in development and disease. Whether it does so in learning is unknown. Operant conditioning of a spinal reflex, a simple learning model, changes the rat spinal motoneuron AIS. Successful, but not unsuccessful, H-reflex up-conditioning is associated with greater AIS length and distance from soma. Successful, but not unsuccessful, down-conditioning is associated with more AIS GABAergic terminals, less ankyrin G, and more p-p38 protein kinase. The associations between AIS plasticity and successful H-reflex conditioning are consistent with those between AIS plasticity and functional changes in development and disease, and with those predicted by modelling studies in the literature. Motor learning changes neurons and synapses in spinal cord and brain. Because spinal motoneurons are the final common pathway for behaviour, their AIS properties probably reflect the combined impact of all the behaviours that use these motoneurons.

17.
Adv Sci (Weinh) ; : e2309002, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38569496

RESUMO

Preeclampsia (PE) is considered as a disease of placental origin. However, the specific mechanism of placental abnormalities remains elusive. This study identified thrombospondin-1 (THBS1) is downregulated in preeclamptic placentae and negatively correlated with blood pressure. Functional studies show that THBS1 knockdown inhibits proliferation, migration, and invasion and increases the cycle arrest and apoptosis rate of HTR8/SVneo cells. Importantly, THBS1 silencing induces necroptosis in HTR8/SVneo cells, accompanied by the release of damage-associated molecular patterns (DAMPs). Necroptosis inhibitors necrostatin-1 and GSK'872 restore the trophoblast survival while pan-caspase inhibitor Z-VAD-FMK has no effect. Mechanistically, the results show that THBS1 interacts with transforming growth factor B-activated kinase 1 (TAK1), which is a central modulator of necroptosis quiescence and affects its stability. Moreover, THBS1 silencing up-regulates the expression of neuronal precursor cell-expressed developmentally down-regulated 4 (NEDD4), which acts as an E3 ligase of TAK1 and catalyzes K48-linked ubiquitination of TAK1 in HTR8/SVneo cells. Besides, THBS1 attenuates PE phenotypes and improves the placental necroptosis in vivo. Taken together, the down-regulation of THBS1 destabilizes TAK1 by activating NEDD4-mediated, K48-linked TAK1 ubiquitination and promotes necroptosis and DAMPs release in trophoblast cells, thus participating in the pathogenesis of PE.

18.
J Formos Med Assoc ; 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38570237

RESUMO

In the wake of the COVID-19 pandemic, the fluctuating nurse resignation rates highlighted an understudied area in healthcare: post-pandemic challenges in clinical settings. This study, conducted from May to November 2023, employed a qualitative inquiry using focus groups to delve into these challenges. Six focus group sessions, involving 33 nurse participants recruited through snowball sampling from various hospital settings were conducted to explore their clinical experiences during and after the pandemic. Thematic analysis revealed two primary themes: the 'Invisibility of Nurses' within the healthcare system and the 'Moral Duty of Nursing Practice'. These findings illuminate a tension between the overlooked role of nurses and their ethical obligations, underscoring a critical need for policy reassessment. The study advocates for systemic changes, particularly in the undervaluation of the nursing profession and the National Health Insurance system, to address the poor working environment and mitigate long-term nursing shortages. This research deepens understanding of post-pandemic nursing workforce challenges in Taiwan, highlighting the need for policy evolution to enhance recognition and support for the nursing industry. It is suggested to provide tangible compensation to acknowledge nurses' daily care and health education for patients. A healthier working environment can be enhanced by collaborative efforts between healthcare institutions and nurses.

19.
Signal Transduct Target Ther ; 9(1): 79, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38565886

RESUMO

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Oxaloacetatos , Humanos , Bevacizumab/uso terapêutico , Capecitabina/uso terapêutico , Oxaliplatina , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Imunoterapia
20.
EMBO J ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600242

RESUMO

The centromeric histone H3 variant CENP-A is overexpressed in many cancers. The mislocalization of CENP-A to noncentromeric regions contributes to chromosomal instability (CIN), a hallmark of cancer. However, pathways that promote or prevent CENP-A mislocalization remain poorly defined. Here, we performed a genome-wide RNAi screen for regulators of CENP-A localization which identified DNAJC9, a J-domain protein implicated in histone H3-H4 protein folding, as a factor restricting CENP-A mislocalization. Cells lacking DNAJC9 exhibit mislocalization of CENP-A throughout the genome, and CIN phenotypes. Global interactome analysis showed that DNAJC9 depletion promotes the interaction of CENP-A with the DNA-replication-associated histone chaperone MCM2. CENP-A mislocalization upon DNAJC9 depletion was dependent on MCM2, defining MCM2 as a driver of CENP-A deposition at ectopic sites when H3-H4 supply chains are disrupted. Cells depleted for histone H3.3, also exhibit CENP-A mislocalization. In summary, we have defined novel factors that prevent mislocalization of CENP-A, and demonstrated that the integrity of H3-H4 supply chains regulated by histone chaperones such as DNAJC9 restrict CENP-A mislocalization and CIN.

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