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Selective autophagy of organelles is critical for cellular differentiation, homeostasis, and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathy but is poorly understood beyond a few autophagosomal receptors and remodelers. By using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence human ER-phagy factors. Two pathways were unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ER-phagy, which is opposite of general autophagy and is independent of AMPK. Second, ER-localized UFMylation is required for ER-phagy to repress the unfolded protein response via IRE1α. The UFL1 ligase is brought to the ER surface by DDRGK1 to UFMylate RPN1 and RPL26 and preferentially targets ER sheets for degradation, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the cellular logic of ER-phagy, reveal parallels between organelle autophagies, and provide an entry point to the relatively unexplored process of degrading the ER network.
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Autofagia/fisiología , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Autofagia/genética , Estrés del Retículo Endoplásmico/fisiología , Endorribonucleasas/metabolismo , Estudio de Asociación del Genoma Completo/métodos , Células HCT116 , Células HEK293 , Células HeLa , Homeostasis , Humanos , Proteínas de la Membrana/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas/metabolismo , Proteínas Ribosómicas/metabolismo , Respuesta de Proteína Desplegada/fisiologíaRESUMEN
Neonicotinoid insecticides, which target insect nicotinic acetylcholine receptors (nAChRs), have been widely and intensively used to control the whitefly, Bemisia tabaci, a highly damaging, globally distributed, crop pest. This has inevitably led to the emergence of populations with resistance to neonicotinoids. However, to date, there have been no reports of target-site resistance involving mutation of B. tabaci nAChR genes. Here we characterize the nAChR subunit gene family of B. tabaci and identify dual mutations (A58T&R79E) in one of these genes (BTß1) that confer resistance to multiple neonicotinoids. Transgenic D. melanogaster, where the native nAChR Dß1 was replaced with BTß1A58T&R79E, were significantly more resistant to neonicotinoids than flies where Dß1 were replaced with the wildtype BTß1 sequence, demonstrating the causal role of the mutations in resistance. The two mutations identified in this study replace two amino acids that are highly conserved in >200 insect species. Three-dimensional modelling suggests a molecular mechanism for this resistance, whereby A58T forms a hydrogen bond with the R79E side chain, which positions its negatively-charged carboxylate group to electrostatically repulse a neonicotinoid at the orthosteric site. Together these findings describe the first case of target-site resistance to neonicotinoids in B. tabaci and provide insight into the molecular determinants of neonicotinoid binding and selectivity.
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Hemípteros , Insecticidas , Receptores Nicotínicos , Animales , Receptores Nicotínicos/genética , Insecticidas/farmacología , Hemípteros/genética , Drosophila melanogaster , Neonicotinoides/farmacología , MutaciónRESUMEN
USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14âE16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12â20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.
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Chiral 3D perovskites pose challenges compared to lower-dimensional variants due to limited chiral organic cation options. Here, we present a universal and controlled method for synthesizing chiral 3D lead halide perovskites using organic amines or alcohols as chiral templates. Introducing these templates to PbCl2 in N,N-dimethylformamide (DMF) under acidic conditions induces the crystallization of R/S [DMA]PbCl3 (DMA = dimethylamine). The resulting structure aligns with the templates used, stemming from the helical Pb2Cl95- chain as verified by single-crystal X-ray diffraction. Furthermore, the chiral perovskite exhibits absorption and circular dichroism (CD) signals in the high-energy band, enabling the circularly polarized light (CPL) detection in the UV spectrum. A CPL detector constructed by this chiral perovskite demonstrates excellent performance, boasting an anisotropy factor for photocurrent (gIph) of 0.296. Our work not only introduces a novel and controllable method for crafting chiral perovskites but also opens new avenues for circularly polarized light detection.
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0D organic-inorganic metal halides (OIMHs) provide unprecedented versatility in structures and photoluminescence properties. Here, a series of bluish-white emissive 0D OIMHs, (TPE-TPP)2Sb2BrxCl8-x (x = 1.16 to 8), are prepared by assembling the 1-triphenylphosphonium-4-(1,2,2-triphenylethenyl)benzene cation (TPE-TPP)+ with antimony halides anions. Based on experimental characterizations and theoretical calculations, the emission of the 0D OIMHs are attributed to the fluorescence of the organic cations with aggregation-induced emission (AIE) properties. The 0D structure minimized the molecular motion and intermolecular interactions between (TPE-TPP)+ cations, effectively suppressing the non-radiative recombination processes. Consequently, the photoluminescence quantum efficiency (PLQE) of (TPE-TPP)2Sb2Br1.16Cl6.84 is significantly enhanced to 55.4% as compared to the organic salt (TPE-TPP)Br (20.5%). The PLQE of (TPE-TPP)2Sb2BrxCl8-x can also be readily manipulated by halide substitution, due to the competitive processes between non-radiative recombination on the inorganic moiety and the energy transfer from inorganic to organic. In addition, electrically driven light-emitting diodes (LEDs) are fabricated based on (TPE-TPP)2Sb2Br1.16Cl6.84 emitter, which exhibited bluish-white emission with a maximum external quantum efficiency (EQE) of 1.1% and luminance of 335 cd m-2. This is the first report of electrically driven LED based on 0D OIMH with bluish-white emission.
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Root architecture and function are critical for plants to secure water and nutrient supply from the soil, but environmental stresses alter root development. The phytohormone jasmonic acid (JA) regulates plant growth and responses to wounding and other stresses, but its role in root development for adaptation to environmental challenges had not been well investigated. We discovered a novel JA Upregulated Protein 1 gene (JAUP1) that has recently evolved in rice and is specific to modern rice accessions. JAUP1 regulates a self-perpetuating feed-forward loop to activate the expression of genes involved in JA biosynthesis and signalling that confers tolerance to abiotic stresses and regulates auxin-dependent root development. Ectopic expression of JAUP1 alleviates abscisic acid- and salt-mediated suppression of lateral root (LR) growth. JAUP1 is primarily expressed in the root cap and epidermal cells (EPCs) that protect the meristematic stem cells and emerging LRs. Wound-activated JA/JAUP1 signalling promotes crosstalk between the root cap of LR and parental root EPCs, as well as induces cell wall remodelling in EPCs overlaying the emerging LR, thereby facilitating LR emergence even under ABA-suppressive conditions. Elevated expression of JAUP1 in transgenic rice or natural rice accessions enhances abiotic stress tolerance and reduces grain yield loss under a limited water supply. We reveal a hitherto unappreciated role for wound-induced JA in LR development under abiotic stress and suggest that JAUP1 can be used in biotechnology and as a molecular marker for breeding rice adapted to extreme environmental challenges and for the conservation of water resources.
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Ciclopentanos , Oryza , Oxilipinas , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fitomejoramiento , Reguladores del Crecimiento de las Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas/genéticaRESUMEN
Isthmin is a polypeptide secreted by adipocytes that was first detected in Xenopus gastrula embryos. Recent studies have focused on the biological functions of isthmin in growth and development, angiogenesis, and metabolism. Distinct spatiotemporal expression of isthmin-1 (ISM-1) was observed during growth and development. ISM-1 plays an important role in the occurrence and development of cancer by regulating cell proliferation, migration, angiogenesis, and immune microenvironments. Moreover, ISM-1, as a newly identified insulin-like adipokine, increases adipocyte glucose uptake and inhibits hepatic lipid synthesis. However, the biological function of ISM-1 remains largely unknown. In this review, we highlight the structure and physiological functions of isthmin and explore its application potential, contributing to a better understanding of its function and providing prevention and treatment strategies for various diseases.
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Trombospondinas , Proliferación Celular , Glucosa , Insulina , Hígado/metabolismo , Humanos , Animales , Trombospondinas/fisiologíaRESUMEN
Chronic lymphocytic leukemia (CLL) patients with hepatitis B virus (HBV) infection have a poor prognosis, underlying mechanism remains unclear. NOTCH mutations are frequent in CLL and associated with disease progression and drug resistance. It is also reported to be associated with hepatitis infection in lymphoid malignancies. In order to investigate the relation between the NOTCH pathway and HBV-associated CLL, we studied 98 previously untreated HBV-positive CLL patients and 244 HBV-negative CLL. NOTCH mutations were more frequent in HBV-positive CLL subgroup (p = 0.033). By survival analysis, HBV infection was associated with disease progression and poor survival (p = 0.0099 for overall survival (OS) and p = 0.0446 for time-to-treatment (TTT)). Any lesions of the NOTCH pathway (NOTCH1, NOTCH2, and SPEN) aggravated prognosis. In multivariate analysis, NOTCH mutation retained an independent significance for HBV-infected patients (p = 0.016 for OS and p = 0.023 for TTT). However, HBV positive with NOTCH unmutated had no statistical difference in prognosis compared with HBV-negative patients (p = 0.1706 for OS and p = 0.2387 for TTT), which indicated that NOTCH pathway mutation contributed to inferior prognosis in HBV-infected CLL. In conclusion, a cohort of CLL patients with HBV positive displayed a worse clinical outcome and the status of the NOTCH signaling pathway might play a crucial role.
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Hepatitis B , Leucemia Linfocítica Crónica de Células B , Humanos , Virus de la Hepatitis B , Leucemia Linfocítica Crónica de Células B/patología , Pronóstico , Mutación , Progresión de la Enfermedad , Receptor Notch1/genéticaRESUMEN
The aim of the study was to explore the significance and prognostic value of 25-hydroxy vitamin D (25-(OH) D) deficiency in peripheral T-cell lymphomas (PTCLs). One hundred fifty-six patients of newly diagnosed PTCLs were enrolled in the study. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curves were plotted, and corresponding areas under the curve (AUC) were calculated to estimate the accuracy of International Prognostic Index (IPI) plus 25-(OH) D deficiency and Prognostic Index for T-cell lymphoma (PIT) plus 25-(OH) D deficiency respectively in PTCL risk stratification. Our results showed that the 25-(OH) D deficiency was an independent inferior prognostic factor for both PFS (P = 0.0019) and OS (P = 0.005) for PTCLs, especially for AITL and PTCL-not otherwise specified (PTCL-NOS). Additionally, adding 25-(OH) D deficiency to PIT indeed has a superior prognostic significance than PIT alone for PFS (P = 0.043) and OS (P = 0.036). Multivariate COX regression analysis revealed that PIT 2â4, albumin (ALB) ≤ 35 g/L, and 25-(OH) D deficiency were regarded as independent risk factors of PFS and OS. Our results showed that 25-(OH) D deficiency was associated with inferior survival outcome of PTCLs, especially for AITL and PTCL-NOS. PIT plus 25-(OH) D deficiency could better indicate the prognosis for PFS and OS of PTCLs than PIT.
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Linfoma de Células T Periférico , Deficiencia de Vitamina D , Humanos , Pronóstico , Vitamina D , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
Diffuse large B-cell lymphoma (DLBCL), accounts for 30-40% of newly diagnosed lymphomas, has an overall cure rate of approximately 60%. Despite previous reports suggesting a negative prognostic association between CCND3 mutations and Burkitt lymphoma, their prognostic implications in DLBCL remain controversial. To investigate this, we evaluated CCND3 mutation status in 2059 DLBCL patient samples from four database (integrated cohort) and additional 167 DLBCL patient samples in our center (JSPH cohort). The mutation was identified in 5.5% (113/2059) of the cases in the integrated cohort, with 86% (97/113) found in exon 5. Furthermore, P284, R271, I290 and Q276 are described as CCND3 mutation hotspots. CCND3 mutation was associated with decreased overall survival (OS) in the integrated cohort (P = 0.0407). Further subgroup analysis revealed that patients diagnosed as EZB subtype DLBCL by LymphGen algorithm with CCND3 mutations had poorer OS than patients diagnosed as EZB subtype without CCND3 mutations (P = 0.0140). Using the next-generation sequencing (NGS) in the JSPH cohort, it was found that both cell cycle and DNA replication pathways were highly upregulated in patients with CCND3 mutations. Our results suggest that CCND3 mutations can serve as a novel prognostic factor in DLBCL pathogenesis. Consequently, the development of personalized therapeutic strategies for DLBCL patients with CCND3 mutations might enhance their prognosis.
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Diffuse large B-cell lymphoma (DLBCL) is a severe non-Hodgkin's lymphoma. Life expectancy has improved with rituximab, but cause-specific mortality data is lacking. Using the Surveillance, Epidemiology, and End Results (SEER) database to study 27,449 individuals aged 20-74 years diagnosed with primary DLBCL who received chemotherapy between 2000 and 2019, we calculated standardized mortality rate (SMR) and excess absolute risk (EAR) and examined the connection between age, sex, time after diagnosis, and cause of death. Based on 12,205 deaths, 68.7% were due to lymphoma, 20.1% non-cancer causes, and 11.2% other cancers. Non-cancer mortality rates (SMR 1.2; EAR, 21.5) increased with DLBCL compared to the general population. The leading non-cancer death causes were cardiovascular (EAR, 22.6; SMR, 1.6) and infectious (EAR, 9.0; SMR, 2.9) diseases with DLBCL. Risks for non-cancer death and solid neoplasms are highest within the first diagnosis year, then decrease. Among socioeconomic factors, being white, being married, and having a higher income were favorable factors for reducing non-cancer mortality. To improve survival, close surveillance, assessment of risk factors, and early intervention are needed.
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Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Humanos , Causas de Muerte , Programa de VERF , Linfoma de Células B Grandes Difuso/patología , Linfoma no Hodgkin/epidemiología , Rituximab/uso terapéuticoRESUMEN
TP53 mutation (TP53-mut) correlates with inferior survival in many cancers, whereas its prognostic role in diffuse large B-cell lymphoma (DLBCL) is still in controversy. Therefore, more precise risk stratification needs to be further explored for TP53-mut DLBCL patients. A set of 2637 DLBCL cases from multiple cohorts, was enrolled in our analysis. Among the 2637 DLBCL patients, 14.0% patients (370/2637) had TP53-mut. Since missense mutations account for the vast majority of TP53-mut DLBCL patients, and most non-missense mutations affect the function of the P53 protein, leading to worse survival rates, we distinguished patients with missense mutations. A TP53 missense mutation risk model was constructed based on a 150-combination machine learning computational framework, demonstrating excellent performance in predicting prognosis. Further analysis revealed that patients with high-risk missense mutations are significantly associated with early progression and exhibit dysregulation of multiple immune and metabolic pathways at the transcriptional level. Additionally, the high-risk group showed an absolutely suppressed immune microenvironment. To stratify the entire cohort of TP53-mut DLBCL, we combined clinical characteristics and ultimately constructed the TP53 Prognostic Index (TP53PI) model. In summary, we identified the truly high-risk TP53-mut DLBCL patients and explained this difference at the mutation and transcriptional levels.
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Linfoma de Células B Grandes Difuso , Proteína p53 Supresora de Tumor , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Humanos , Proteína p53 Supresora de Tumor/genética , Pronóstico , Mutación Missense/genética , Mutación/genética , Microambiente Tumoral/genética , Masculino , Femenino , Factores de Riesgo , Persona de Mediana EdadRESUMEN
The asymmetric cycloaddition between N-2,2,2-trifluoroethylisatin ketimines and unsymmetrical dicarbonyl-activated alkenes catalyzed by a bifunctional squaramide has been discovered. The present study demonstrates an efficient approach for the regio-, diastereo-, and enantioselective synthesis of densely functionalized 5'-trifluoromethylated 3,2'-pyrrolidinyl spirooxindoles featuring three different types of carbonyl groups.
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Influenza A virus (IAV) is a widespread pathogen that poses a significant threat to human health, causing pandemics with high mortality and pathogenicity. Given the emergence of increasingly drug-resistant strains of IAV, currently available antiviral drugs have been reported to be inadequate to meet clinical demands. Therefore, continuous exploration of safe, effective and broad-spectrum antiviral medications is urgently required. Here, we found that the small molecule compound J1 exhibited low toxicity both in vitro and in vivo. Moreover, J1 exhibits broad-spectrum antiviral activity against enveloped viruses, including IAV, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human coronavirus OC43 (HCoV-OC43), herpes simplex virus type 1 (HSV-1) and HSV-2. In this study, we explored the inhibitory effects and mechanism of action of J1 on IAV in vivo and in vitro. The results showed that J1 inhibited infection by IAV strains, including H1N1, H7N9, H5N1 and H3N2, as well as by oseltamivir-resistant strains. Mechanistic studies have shown that J1 blocks IAV infection mainly through specific interactions with the influenza virus hemagglutinin HA2 subunit, thereby blocking membrane fusion. BALB/c mice were used to establish a model of acute lung injury (ALI) induced by IAV. Treatment with J1 increased survival rates and reduced viral titers, lung index and lung inflammatory damage in virus-infected mice. In conclusion, J1 possesses significant anti-IAV effects in vitro and in vivo, providing insights into the development of broad-spectrum antivirals against future pandemics.
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Hepatic glucose and lipid metabolism disorders promote the development and progression of type 2 diabetes mellitus (T2DM), yet the underlying mechanisms are not fully understood. Here, we identify tripartite motif-containing protein 21 (TRIM21), a class IV TRIM family member, as a pivotal regulator of hepatic metabolism in T2DM for the first time. Bioinformatic analysis suggests that TRIM21 expression is significantly reduced in T2DM patients. Intriguingly, in a mouse model of obese diabetes, TRIM21 expression is predominantly reduced in the liver rather than in other metabolic organs. It is further demonstrated that hepatic overexpression of TRIM21 significantly ameliorates glucose intolerance, insulin resistance, hepatic steatosis, and dyslipidemia in obese diabetic mice. In contrast, the knockdown of TRIM21 promotes glucose intolerance, insulin resistance, and triglyceride accumulation. Mechanistically, both phosphoenolpyruvate carboxykinase 1 (PEPCK1) and fatty acid synthase (FASN) are the hepatic targets of TRIM21. We revealed that TRIM21 promotes the degradation of PEPCK1 and FASN through a direct protein-protein interaction mediated K48-linked ubiquitination. Notably, overexpression of PEPCK1 and FASN essentially abolished the beneficial effects achieved by TRIM21 overexpression in obese diabetic mice. Overall, our data demonstrate that TRIM21 is a novel regulator of hepatic metabolic disorder, and suggest TRIM21 as a promising therapeutic target for T2DM.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Intolerancia a la Glucosa , Resistencia a la Insulina , Trastornos del Metabolismo de los Lípidos , Animales , Ratones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/uso terapéutico , Glucosa/metabolismo , Intolerancia a la Glucosa/metabolismo , Trastornos del Metabolismo de los Lípidos/metabolismo , Lípidos , Hígado/metabolismo , Obesidad/metabolismo , Ubiquitinación , HumanosRESUMEN
The aim of this article is to review the application progress of proteomics technology in brain injury research in recent years, point out the current problems that need to be overcome, and explore the application prospects of proteomics analysis in brain injury. This study also aims to retrieve all literature on brain injury and proteomics and summarize it. Through searching and screening, the widespread application of proteomics technology in the treatment of traumatic brain injury (TBI) and the use of a large number of TBI biomarkers were discovered. The pathways mediated by some biomarkers and the physiological and pathological mechanisms of occurrence were elucidated. The current classification of brain injury is mainly based on subjective evaluation of clinical symptoms, combined with objective imaging. However, its practical value is often limited when applied to prognosis evaluation in brain injury. Proteomics technology can make up for this deficiency and provide a reference for the prevention and treatment of brain injury.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Humanos , Proteómica/métodos , Lesiones Encefálicas/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , BiomarcadoresRESUMEN
Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.
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Podofilotoxina , Animales , Podofilotoxina/toxicidad , Ratas , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Ratas Sprague-Dawley , Receptores Activados del Proliferador del Peroxisoma/metabolismo , PPAR gamma/metabolismo , Microbiota/efectos de los fármacosRESUMEN
AIMS: To identify and reach consensus on dimensions and criteria of a competence assessment instrument for health professionals in relation to the process of evidence-based healthcare. DESIGN: A two-round Delphi survey was carried out from April to June 2023. METHODS: Consensus was sought from an expert panel on the instrument preliminarily established based on the JBI Model of Evidence-Based Healthcare and a rapid review of systematic reviews of relevant literature. The level of consensus was reflected by the concentration and coordination of experts' opinions and percentage of agreement. The instrument was revised significantly based on the combination of data analysis, the experts' comments and research group discussions. RESULTS: Sixteen national and three international experts were involved in the first-round Delphi survey and 17 experts participated in the second-round survey. In both rounds, full consensus was reached on the four dimensions of the instrument, namely evidence-generation, evidence-synthesis, evidence-transfer and evidence-implementation. In round-one, the instrument was revised from 77 to 61 items. In round-two, the instrument was further revised to have 57 items under the four dimensions in the final version. CONCLUSION: The Delphi survey achieved consensus on the instrument. The validity and reliability of the instrument needs to be tested in future research internationally. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Systematic assessment of nurses and other health professionals' competencies in different phases of evidence-based healthcare process based on this instrument provides implications for their professional development and multidisciplinary team collaboration in evidence-based practice and better care process and outcomes. IMPACT: This study addresses a research gap of lacking an instrument to systematically assess interprofessional competencies in relation to the process of EBHC. The instrument covers the four phases of EBHC process with minimal criteria, highlighting essential aspects of ability to be developed. Identification of health professionals' level of competence in these aspects helps strengthen their capacity accordingly so as to promote virtuous EBHC ecosystem for the ending purpose of improving global healthcare outcomes. REPORTING METHOD: This study was reported in line with the Conducting and REporting of DElphi studies (CREDES) guidance on Delphi studies. PATIENT AND PUBLIC CONTRIBUTION: No patient or public contribution.
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The theory of kidney storing essence storage, an important part of the basic theory of traditional Chinese medicine(TCM), comes from the Chapter 9 Discussion on Six-Plus-Six System and the Manifestations of the Viscera in the Plain Questions, which says that "the kidney manages closure and is the root of storage and the house of Jing(Essence)". According to this theory, essence is the fundamental substance of human life activities and it is closely related to the growth and development of the human body. Alzheimer's disease(AD) is one of the common neurodegenerative diseases, with the main pathological features of Aß deposition and Tau phosphorylation, which activate neurotoxic reactions and eventually lead to neuronal dysfunction and cell death, severely impairing the patient's cognitive and memory functions. Although research results have been achieved in the TCM treatment of AD, the complex pathogenesis of AD makes it difficult to develop the drugs capable of curing AD. The stem cell therapy is an important method to promote self-repair and regeneration, and bone marrow mesenchymal stem cells(BMSCs) as adult stem cells have the ability of multi-directional differentiation. By reviewing the relevant literature, this paper discusses the association between BMSCs and the TCM theory of kidney storing essence, and expounds the material basis of this theory from the perspective of molecular biology. Studies have shown that TCM with the effect of tonifying the kidney in the treatment of AD are associated with BMSCs. Exosomes produced by such cells are one of the main substances affecting AD. Exosomes containing nucleic acids, proteins, and lipids can participate in intercellular communication, regulate cell function, and affect AD by reducing Aß deposition, inhibiting Tau protein phosphorylation and neuroinflammation, and promoting neuronal regeneration. Therefore, discussing the prevention and treatment of exosomes and AD based on the theory of kidney storing essence will provide a new research idea for the TCM treatment of AD.
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Enfermedad de Alzheimer , Exosomas , Adulto , Humanos , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/tratamiento farmacológico , Exosomas/metabolismo , Exosomas/patología , Riñón/patología , Medicina Tradicional China , NeuronasRESUMEN
Lymphocyte proliferation and tumourigenesis are dependent on nucleotide synthesis to support DNA, RNA and phospholipid synthesis. Here, we identified that reprogramming of nucleotide metabolism as an important factor divides mantle cell lymphoma (MCL) into two groups with different transcriptional signalling pathways and varying prognoses. We establish a nucleotide metabolism-related prognostic model that includes six genes with different regression coefficients, which significantly predicts prognosis for MCL patients (p < 0.0001). Of these six genes, de novo CTP synthesis pathway enzyme CTPS1 whose inhibitor (STP938) is already in clinical trials for relapsed/refractory lymphomas (NCT05463263) has the highest regression coefficient. An increase in CTPS1 expression predicts adverse overall survival and progression-free survival with independent prognostic significance in 105 primary MCL samples and GEO database (GSE93291). CRISPR CTPS1 knockout causes DNA damage and proliferation defects in MCL. Additionally, MYC positively regulates CTPS1 expression, and TP53-aberrant and ibrutinib-resistant MCL cells also rely on cytidine metabolism. Furthermore, besides the obvious decreased CTP pool caused by CTPS1 deficiency, CTPS1 inhibition may also induce immune-related responses via activating dsDNA-cGAS-STING pathway, which plays a crucial role in impeding tumour growth in MCL patients.