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Alternative polyadenylation (APA) produces mRNA isoforms with different 3' UTR lengths. Previous studies indicated that 3' end processing and mRNA export are intertwined in gene regulation. Here, we show that mRNA export factors generally facilitate usage of distal cleavage and polyadenylation sites (PASs), leading to long 3' UTR isoform expression. By focusing on the export receptor NXF1, which exhibits the most potent effect on APA in this study, we reveal several gene features that impact NXF1-dependent APA, including 3' UTR size, gene size, and AT content. Surprisingly, NXF1 downregulation results in RNA polymerase II (Pol II) accumulation at the 3' end of genes, correlating with its role in APA regulation. Moreover, NXF1 cooperates with CFI-68 to facilitate nuclear export of long 3' UTR isoform with UGUA motifs. Together, our work reveals important roles of NXF1 in coordinating transcriptional dynamics, 3' end processing, and nuclear export of long 3' UTR transcripts, implicating NXF1 as a nexus of gene regulation.
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Núcleo Celular/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Poliadenilación , ARN Mensajero/biosíntesis , Proteínas de Unión al ARN/metabolismo , Transcripción Genética , Regiones no Traducidas 3' , Transporte Activo de Núcleo Celular , Sitios de Unión , Núcleo Celular/genética , Células HEK293 , Células HeLa , Humanos , Cinética , Proteínas de Transporte Nucleocitoplasmático/genética , Unión Proteica , ARN Polimerasa II/metabolismo , ARN Mensajero/genética , Proteínas de Unión al ARN/genéticaRESUMEN
The exosome functions in the degradation of diverse RNA species, yet how it is negatively regulated remains largely unknown. Here, we show that NRDE2 forms a 1:1 complex with MTR4, a nuclear exosome cofactor critical for exosome recruitment, via a conserved MTR4-interacting domain (MID). Unexpectedly, NRDE2 mainly localizes in nuclear speckles, where it inhibits MTR4 recruitment and RNA degradation, and thereby ensures efficient mRNA nuclear export. Structural and biochemical data revealed that NRDE2 interacts with MTR4's key residues, locks MTR4 in a closed conformation, and inhibits MTR4 interaction with the exosome as well as proteins important for MTR4 recruitment, such as the cap-binding complex (CBC) and ZFC3H1. Functionally, MID deletion results in the loss of self-renewal of mouse embryonic stem cells. Together, our data pinpoint NRDE2 as a nuclear exosome negative regulator that ensures mRNA stability and nuclear export.
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Exosomas/genética , Exosomas/metabolismo , Proteínas Nucleares/fisiología , ARN Helicasas/metabolismo , Animales , Núcleo Celular/metabolismo , Células Madre Embrionarias , Células HEK293 , Células HeLa , Humanos , Ratones , Proteínas Nucleares/genética , Unión Proteica , Dominios Proteicos , Transporte de Proteínas/genética , Estabilidad del ARN/genéticaRESUMEN
Zinc-iodine batteries (ZIBs) are promising candidates for ecofriendly, safe, and low-cost energy storage systems, but polyiodide shuttling and the complex cathode fabrication procedures have severely hindered their broader commercial usage. Herein, a protocol is developed using phospholipid-like oleylamine molecules for scalable production of Langmuir-Blodgett films, which allows the facile preparation of ZIB cathodes in less than 1 min. The resulting inhomogeneous cathode allows for the continuous conversion of iodine. Moreover, the amine group of the oleylamine molecule at the cathode is capable of producing [OA*I+]I3- charge-transfer complexes with iodine, which facilitates the rapid migration of iodine and results in a highly reversible iodine conversion process. Consequently, the as-prepared ZIBs can deliver over 2000 cycles at 0.5 mA cm-2 with a capacity retention of 75.3%. This work presents a novel, straightforward, and efficient method for the rapid construction of ZIBs.
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The RNA-binding protein ALYREF plays key roles in nuclear export and also 3'-end processing of polyadenylated mRNAs, but whether such regulation also extends to non-polyadenylated RNAs is unknown. Replication-dependent (RD)-histone mRNAs are not polyadenylated, but instead end in a stem-loop (SL) structure. Here, we demonstrate that ALYREF prevalently binds a region next to the SL on RD-histone mRNAs. SL-binding protein (SLBP) directly interacts with ALYREF and promotes its recruitment. ALYREF promotes histone pre-mRNA 3'-end processing by facilitating U7-snRNP recruitment through physical interaction with the U7-snRNP-specific component Lsm11. Furthermore, ALYREF, together with other components of the TREX complex, enhances histone mRNA export. Moreover, we show that 3'-end processing promotes ALYREF recruitment and histone mRNA export. Together, our results point to an important role of ALYREF in coordinating 3'-end processing and nuclear export of non-polyadenylated mRNAs.
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Histonas/metabolismo , Proteínas Nucleares/metabolismo , Procesamiento Postranscripcional del ARN , Transporte de ARN , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Ribonucleoproteína Nuclear Pequeña U7/metabolismo , Factores de Transcripción/metabolismo , Transporte Activo de Núcleo Celular , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/metabolismo , Histonas/genética , Humanos , Proteínas Nucleares/genética , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Ribonucleoproteína Nuclear Pequeña U7/genética , Factores de Transcripción/genéticaRESUMEN
All-solid-state sodium metal batteries paired with solid polymer electrolytes (SPEs) are considered a promising candidate for high energy-density, low-cost, and high-safety energy storage systems. However, the low ionic conductivity and inferior interfacial stability with Na metal anode of SPEs severely hinder their practical applications. Herein, an anion-trapping 3D fiber network enhanced polymer electrolyte (ATFPE) is developed by infusing poly(ethylene oxide) matrix into an electrostatic spun fiber framework loading with an orderly arranged metal-organic framework (MOF). The 3D continuous channel provides a fast Na+ transport path leading to high ionic conductivity, and simultaneously the rich coordinated unsaturated cation sites exposed on MOF can effectively trap anions, thus regulating Na+ concentration distribution for constructing stable electrolyte/Na anode interface. Based on such advantages, the ATFPE exhibits high ionic conductivity and considerable Na+ transference number, as well as enhanced interfacial stability. Consequently, Na/Na symmetric cells using this ATFPE possess cyclability over 600 h at 0.1 mA cm-2 without discernable Na dendrites. Cooperated with Na3 V2 (PO4 )3 cathode, the all-solid-state sodium metal batteries (ASSMBs) demonstrate significantly improved rate and cycle performances, delivering a high discharge capacity of 117.5 mAh g-1 under 0.1 C and rendering high capacity retention of 78.2% after 1000 cycles even at 1 C.
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To ensure efficient and accurate gene expression, pre-mRNA processing and mRNA export need to be balanced. However, how this balance is ensured remains largely unclear. Here, we found that SF3b, a component of U2 snRNP that participates in splicing and 3' processing of pre-mRNAs, interacts with the key mRNA export adaptor THO in vivo and in vitro. Depletion of SF3b reduces THO binding with the mRNA and causes nuclear mRNA retention. Consistently, introducing SF3b binding sites into the mRNA enhances THO recruitment and nuclear export in a dose-dependent manner. These data demonstrate a role of SF3b in promoting mRNA export. In support of this role, SF3b binds with mature mRNAs in the cells. Intriguingly, disruption of U2 snRNP by using a U2 antisense morpholino oligonucleotide does not inhibit, but promotes, the role of SF3b in mRNA export as a result of enhanced SF3b-THO interaction and THO recruitment to the mRNA. Together, our study uncovers a U2-snRNP-independent role of SF3b in mRNA export and suggests that SF3b contributes to balancing pre-mRNA processing and mRNA export.
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Fosfoproteínas , Precursores del ARN , Factores de Empalme de ARN , ARN Mensajero , Ribonucleoproteína Nuclear Pequeña U2 , Sitios de Unión/genética , Células HeLa , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Precursores del ARN/genética , Precursores del ARN/metabolismo , Empalme del ARN/genética , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribonucleoproteína Nuclear Pequeña U2/genética , Ribonucleoproteína Nuclear Pequeña U2/metabolismoRESUMEN
Seedling establishment is inhibited on media containing high levels (â¼ 6%) of glucose or fructose. Genetic loci that overcome the inhibition of seedling growth on high sugar have been identified using natural variation analysis and mutant selection, providing insight into sugar signaling pathways. In this study, a quantitative trait locus (QTL) analysis was performed for seedling sensitivity to high sugar in a Col/C24 F2 population of Arabidopsis thaliana. A glucose and fructose-sensing QTL, GSQ11, was mapped through selective genotyping and confirmed in near-isogenic lines in both Col and C24 backgrounds. Allelism tests and transgenic complementation showed that GSQ11 lies within the ANAC060 gene. The Col ANAC060 allele confers sugar insensitivity and was dominant over the sugar-sensitive C24 allele. Genomic and mRNA analyses showed that a single-nucleotide polymorphism (SNP) in Col ANAC060 affects the splicing patterns of ANAC060 such that 20 additional nucleotides are present in the mRNA. The insertion created a stop codon, resulting in a truncated ANAC60 protein lacking the transmembrane domain (TMD) that is present in the C24 ANAC060 protein. The absence of the TMD results in the nuclear localization of ANAC060. The short version of the ANAC060 protein is found in â¼ 12% of natural Arabidopsis accessions. Glucose induces GSQ11/ANAC060 expression in a process that requires abscisic acid (ABA) signaling. Chromatin immunoprecipitation-qPCR and transient expression analysis showed that ABI4 directly binds to the GSQ11/ANAC060 promoter to activate transcription. Interestingly, Col ANAC060 reduced ABA sensitivity and Glc-induced ABA accumulation, and ABI4 expression was also reduced in Col ANAC060 lines. Thus, the sugar-ABA signaling cascade induces ANAC060 expression, but the truncated Col ANAC060 protein attenuates ABA induction and ABA signaling. This negative feedback from nuclear ANAC060 on ABA signaling results in sugar insensitivity.
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Proteínas de Arabidopsis/genética , Sitios de Carácter Cuantitativo/genética , Plantones/genética , Transducción de Señal/genética , Factores de Transcripción/genética , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Proteínas de Arabidopsis/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Fructosa/metabolismo , Regulación de la Expresión Génica de las Plantas , Prueba de Complementación Genética , Genotipo , Glucosa/metabolismo , Mutación , Factores de Transcripción/metabolismoRESUMEN
Objective: To prospectively determine the median effective dose (ED50) of propofol for inhibiting a response to laryngeal mask airway (LMA) insertion when combined with different doses of esketamine in female patients. Methods: A total of 58 female patients (aged 20-60 years, ASAâ -â ¡) scheduled for elective hysteroscopy were enrolled and randomly divided into 2 groups, one of which was administered 0.2 mg/kg of esketamine (K1 group, n = 28) and the other 0.3 mg/kg of esketamine (K2 group, n = 30). The 2 groups received the corresponding doses of esketamine intravenously, followed by an intravenous injection of propofol (injection time was 30 s). The initial dose of propofol was 2 mg/kg, and the dose ratio of propofol in the adjacent patients was 0.9. If a positive reaction occurred due to LMA insertion, the dose ratio in the next patient was increased by 1 gradient; if not, the dose ratio was decreased by 1 gradient. The ED50, 95 % effective dose (ED95) and 95 % confidence interval (CI) of propofol for inhibiting a response to LMA insertion in the 2 esketamine groups were calculated using probit analysis. Results: The ED50 of propofol for inhibiting a response to LMA insertion in female patients was 1.95 mg/kg (95 % CI, 1.82-2.08 mg/kg) in the K1 group and 1.60 mg/kg (95 % CI, 1.18-1.83 mg/kg) in the K2 group. The ED95 of propofol for inhibiting a response to LMA insertion in female patients was 2.22 mg/kg (95 % CI, 2.09-2.86 mg/kg) in the K1 group and 2.15 mg/kg (95 % CI, 1.88-3.09 mg/kg) in the K2 group. Conclusion: Propofol combined with 0.3 mg/kg of esketamine has low ED50 and ED95 effective doses for inhibiting an LMA insertion response in female patients undergoing hysteroscopy and surgery. There were no significant adverse effects, but the additional dose of propofol and airway pressure were significantly higher than those in the group administered 0.2 mg/kg of esketamine. Based on the results, we recommend the combination of propofol with 0.2 mg/kg esketamine for optimal conditions during LMA insertion in women undergoing hysteroscopy.
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Anesthetic management of patients with renal cell carcinoma with tumor thrombus in the inferior vena cava (IVC) is challenging. This paper reports the experience of anesthesia management in a patient with advanced renal cell carcinoma with thrombus accumulation in the IVC, right atrium, and pulmonary artery who underwent radical nephrectomy and tumor thrombus removal assisted by cardiopulmonary bypass. The emboli, measuring approximately 3 × 6 cm in the left inferior pulmonary artery and 4 × 13 cm in the right main pulmonary artery, were removed completely. During incision of the IVC under systemic heparinization, significant blood loss occurred in the surgical field. The surgery took 724 min, and cardiopulmonary bypass took 396 min. Intraoperative blood loss was 22,000 ml. The patient was extubated 39 hours after surgery and stayed in intensive care unit for 3 days. At 1 year follow-up, the patient was in good health and leading a normal life.
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[This retracts the article DOI: 10.3892/etm.2014.1501.].
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Poor compatibility limits the wide application of biodegradable poly (lactic acid)/poly (butylene adipate-terephthalate) (PLA/PBAT) blends in packaging industry. How to prepare compatibilizers with high efficiency and low cost by simple methods is a challenge. In this work, methyl methacrylate-co-glycidyl methacrylate (MG) copolymer with different epoxy group content are synthesized as reactive compatibilizers to resolve this issue. The effects of glycidyl methacrylate and MG contents on phase morphology and physical properties of the PLA/PBAT blends are systematically investigated. During melt blending, MG migrates to the phase interface, and then grafts with PBAT to form PLA-g-MG-g-PBAT terpolymers. When the molar ratio of MMA and GMA in MG is 3:1, the reaction activity of MG with PBAT is the highest and the compatibilization effect is the best. When the M3G1 content is 1 wt%, the tensile strength and the fracture toughness are increased to 37. 1 MPa and 120 MJ/m3, which increase by 34 % and 87 %, respectively. The size of PBAT phase decreases from 3.7 µm to 0.91 µm. Therefore, this work provides a low-cost and simple method to prepare the compatibilizers with high efficiency for the PLA/PBAT blend, and provides a new basis for the design of epoxy compatibilizers.
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Poliésteres , Polímeros , Resinas Epoxi , Adipatos , Poli A , Ácido LácticoRESUMEN
Uncontrolled dendrite growth and water-related side reactions in mild electrolytes are the main causes of poor cycling stability of zinc anodes, resulting in the deterioration of aqueous zinc-based batteries. Herein, a multifunctional fluorapatite (Ca5(PO4)3F) aerogel (FAG) interface layer is proposed to realize highly stable zinc anodes via the integrated regulation of Zn2+ migration kinetics and Zn (002) orientation deposition. Owing to the well-defined aerogel nanochannels and the rich Zn2+ adsorption sites resulting from the ion exchange between Ca2+ and Zn2+, the FAG interface layer could significantly accelerate the Zn2+ migration and effectively homogenize the Zn2+ flux and nucleation sites, thus promoting rapid and uniform Zn2+ migration at the electrode/electrolyte interface. Additionally, during the cycling process, the F atoms from FAG promote the in situ generation of ZnF2, which facilitates the manipulation of the preferred Zn (002) orientation deposition, thus efficiently suppressing dendrite growth and side reactions by combining with the above synergistic effects. Consequently, the FAG-modified Zn anode displays a stable cycle life of over 4000 h at 1 mA cm-2 and exhibits highly reversible Zn plating/stripping behavior. Meanwhile, the Zn||MnO2 full cells exhibit improved cycle stability over 2000 cycles compared with that of the bare Zn, highlighting the virtues of the FAG protective layer for highly reversible Zn anodes. Our work brings the insight in to stabilize Zn anodes and power the commercial applications of aqueous zinc-based batteries.
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PURPOSE: This study mainly exams a novel treatment for infective segmental femoral defect, and we combined the 3D printed porous tantalum prosthesis and Masquelet's induce membrane technique to reconstruct bone defect and discussed the clinical effect. METHOD: The clinical research included 9 observational cases series, as a permanently implantation, the customized 3D-printed scaffolds that connected with an anatomical plate was implanted into the bone defect segment after successful formation of induced membrane, the clinical effect was evaluated by radiological exams and Paley's bone union criteria. RESULT: The personalized 3D-printed porous tantalum was, respectively, manufactured and used in 9 consecutive patients to reconstruct the infective segmental bone defect of femur, the mean defect length was 16.1 ± 2.8 cm, the mean length of follow-up was 16.9 ± 4.0 months, after 2 stage operation, there was no deep infections, refractures, sensorimotor disorder, vascular injury, ankylosis and recurrence of infection occurred in all cases. postoperative radiological exams shown stable internal fixation and osseointegration, and all these results were invariable during the follow-up time in all cases. All patients significantly obtained deformity correction and length of limb. CONCLUSION: The customized 3D-printed porous tantalum prosthesis was an acceptable alternative treatment to the autogenous or allograft bone graft, the combination of the two techniques could achieve satisfactory reconstruct to infective broad bone defect in femur when other biological techniques were not suitable.
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Fémur , Tantalio , Humanos , Porosidad , Fémur/diagnóstico por imagen , Fémur/cirugía , Oseointegración , Impresión TridimensionalRESUMEN
The aqueous zinc-ion battery (AZIB) has been widely investigated in recent years because it has the advantages of being green, safe, and made from abundant raw materials. It is necessary to continue to study how to prepare cathode materials with excellent performance and high cycling stability for future commercialization. In this work, a strategy was proposed that uses sustainable sodium lignosulfonate as both carbon and sodium sources to obtain a sodium pre-intercalated vanadium oxide/carbon (VO/LSC) composite as the cathode of AZIB. The carbon matrix could improve the electronic conductivity of vanadium oxide, while the sodium lignosulfonate could provide sodium ions pre-intercalated into the layered vanadium oxide simultaneously. Through this strategy, vanadium-based cathode materials with high stability and excellent rate capability were obtained. The VO/LSC cathode delivered high capacities of 350 and 112.8â mAh g-1 at 0.1 and 4.0â A g-1 , respectively. Zinc sulfate and zinc trifluoromethyl sulfonate were selected as electrolytes, and the influence of electrolytes on the performance of VO/LSC was analyzed. The oxygen in the environment was used to oxidize the low-priced vanadium oxide to achieve a self-charging AZIB. This paper provides a valuable strategy for the design of vanadium-based cathode material for AZIB, which can broaden the research and application of AZIB.
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In recent years, micropeptides have been increasingly identified as important regulators in various biological processes. However, whether micropeptides are functionally conserved remains largely unknown. Here, we uncovered a micropeptide with evolutionarily conserved roles in myogenesis. RNA-seq data analysis of proliferating mouse satellite cells (SCs) and differentiated myotubes identified a previously annotated lncRNA, MyolncR4 (1500011K16RIK), which is upregulated during muscle differentiation. Significantly, MyolncR4 is highly conserved across vertebrate species. Multiple lines of evidence demonstrate that MyolncR4 encodes a 56-aa micropeptide, which was named as LEMP (lncRNA encoded micropeptide). LEMP promotes muscle formation and regeneration in mouse. In zebrafish, MyolncR4 is enriched in developing somites and elimination of LEMP results in impaired muscle development, which could be efficiently rescued by expression of the mouse LEMP. Interestingly, LEMP is localized at both the plasma membrane and mitochondria, and associated with multiple mitochondrial proteins, suggestive of its involvement in mitochondrial functions. Together, our work uncovers a micropeptide that plays an evolutionarily conserved role in skeletal muscle differentiation, pinpointing the functional importance of this growing family of small peptides.
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Diferenciación Celular , Evolución Molecular , Desarrollo de Músculos , Péptidos/metabolismo , Células Satélite del Músculo Esquelético/metabolismo , Proteínas de Pez Cebra/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Secuencia Conservada , Ratones Noqueados , Péptidos/deficiencia , Péptidos/genética , Transducción de Señal , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
Solid-state rechargeable batteries using polymer electrolytes have been considered, which can avoid safety issues and enhance energy density. However, commercial application of the polymer electrolyte solid-state battery is still significantly limited by the low room-temperature ionic conductivity, poor mechanical properties, and weak interfacial compatibility between the electrolyte and electrode, especially for the room-temperature solid-state rechargeable battery. In this work, a poly(vinylene carbonate)-based composite polymer electrolyte (PVC-CPE) is reported for the first time to realize room-temperature solid-state sodium batteries with high performances. This in situ solidified PVC-CPE possesses superior ionic conductivity (0.12 mS cm-1 at 25 °C), high Na+ transference number (tNa+ = 0.60), as well as enhanced electrode/electrolyte interfacial stability. Notably, the composite cathode NaNi1/3Fe1/3Mn1/3O2 (c-NFM) is designed through the in situ growth of the polymer electrolyte inside the electrode to decrease interfacial resistance and facilitate effective ion transport in electrode/electrolyte interfaces. It is demonstrated that the solid-state c-NFM/PVC-CPE/Na battery assembled by a one-step in situ solidification method exhibits remarkably enhanced cell performances at room temperature compared with a reference NFM/PVC-CPE/Na assembled through a conventional ex situ method. The battery presents a high initial specific capacity of 104.2 mA h g-1 at 0.2 C with a capacity retention of 86.8% over 250 cycles and â¼80.2 mA h g-1 at 1 C. This study suggests that PVC-CPE is a very promising electrolyte for solid-state sodium batteries. This study also suggests a new method to design high-performance polymer electrolytes for other solid-state rechargeable batteries to realize high safety and considerable electrochemical performance at room temperature.
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Nuclear speckles (NSs) serve as splicing factor storage sites. In this study, we unexpectedly found that many endogenous intronless mRNAs, which do not undergo splicing, associate with NSs. These associations do not require transcription, polyadenylation, or the polyA tail. Rather, exonic splicing enhancers present in intronless mRNAs and their binding partners, SR proteins, promote intronless mRNA localization to NSs. Significantly, speckle targeting of mRNAs promotes the recruitment of the TREX export complex and their TREX-dependent nuclear export. Furthermore, TREX, which accumulates in NSs, is required for releasing intronless mRNAs from NSs, whereas NXF1, which is mainly detected at nuclear pores, is not. Upon NXF1 depletion, the TREX protein UAP56 loses speckle concentration but coaccumulates with intronless mRNAs and polyA RNAs in the nucleoplasm, and these RNAs are trapped in NSs upon UAP56 codepletion. We propose that the export-competent messenger RNP assembly mainly occurs in NSs for intronless mRNAs and that entering NSs serves as a quality control step in mRNA export.
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ARN Helicasas DEAD-box/metabolismo , Espacio Intranuclear/metabolismo , Poro Nuclear/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Transporte Activo de Núcleo Celular/fisiología , ARN Helicasas DEAD-box/genética , Células HeLa , Humanos , Poro Nuclear/genética , Proteínas de Transporte Nucleocitoplasmático/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/genéticaRESUMEN
Postoperative cognitive dysfunction (POCD) is common in elderly patients. Senegenin, an active component of extracts from Polygala tenuifolia root, a traditional Chinese medicine, has neuroprotective and neuroregenerative effects. However, the mechanism underlying the effects of senegenin against postoperative cognitive impairment in elderly individuals has yet to be elucidated. The aim of this study was to investigate the protective effects of senegenin on the cognitive functions of elderly rats with splenectomy-induced POCD. Results from a Morris water maze test suggested that splenectomy induced a transient cognitive deficiency in the elderly rats; however, when the rats were treated with senegenin, the cognitive impairment was notably attenuated. Further experiments showed that senegenin significantly inhibited the mRNA and protein expression of several key pro-inflammatory cytokines, specifically, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6 and IL-8, in the hippocampal tissues of elderly rats following splenectomy. In order to investigate the molecular mechanism involved, the expression and activity of the Toll-like receptor 4 (TLR4) signaling pathway was assessed. On day 1 postoperatively, it was observed that senegenin markedly suppressed the mRNA and protein expression of TLR4, myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor-inducing interferon-ß (TRIF). Furthermore, the phosphorylation levels of nuclear factor-κB (NF-κB) p65 and inhibitor of NF-κB (IκBα) were also decreased following senegenin treatment on the first day subsequent to surgery. These results suggest that senegenin suppressed splenectomy-induced transient cognitive impairment in elderly rats, possibly by downregulating two signaling pathways involved in inflammation, TLR4/MyD88/NF-κB and TLR4/TRIF/NF-κB, to further inhibit the expression of key pro-inflammatory cytokines, specifically, TNF-α, IL-1ß, IL-6 and IL-8, and ultimately the neuroinflammation in the hippocampal tissues. In conclusion, the present study revealed that senegenin exhibited neuroprotective effects against splenectomy-induced transient cognitive impairment in elderly rats, which indicated that senegenin may be a promising agent for the treatment of POCD.
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Toll-like receptors (TLRs) and cytokines play key roles in innate and adaptive immunity against Mycobacterium tuberculosis (M.TB). The aim of this study was to investigate whether the functional genetic variations at position 1805 G/T in TLR1, 2258 A/G in TLR2, -857 C/T, and -863 A/C in tumor necrosis factor-α (TNF-α), as well as -819 C/T in interleukin-10 (IL-10) confer susceptibility to pulmonary tuberculosis (PTB). We performed a hospital-based case-control study using 543 case patients and 544 controls. Multivariate logistic regression analysis revealed that the TT genotype of -857 C/T in TNF-α gene was significantly associated with lower risk of PTB, in comparison with other genotypes (odds ratios [OR] = 0.68, 95% confidence interval [CI] = 0.53-0.86, p = 0.001). Conversely, the genetic variants of -863 A/C in TNF-α gene was associated with susceptibility to PTB (OR = 2.42%, 95% CI = 1.28-4.59, p = 0.007) and clinical severity of disease (OR = 3.59%, 95% CI = 1.41-9.11, p = 0.007). Our results indicated that the variants in TNF-α gene were associated with susceptibility to PTB and clinical severity of disease, whereas no significance could be inferred from TLRs and IL-10 genes polymorphisms.
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Interleucina-10/genética , Mycobacterium tuberculosis/inmunología , Receptores Toll-Like/genética , Tuberculosis Pulmonar/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , China , Progresión de la Enfermedad , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/patogenicidad , Polimorfismo Genético , Riesgo , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/fisiopatologíaRESUMEN
OBJECTIVE: To evaluate the tissue response induced by three kinds of bone transplantation materials implanted in rat so as to provide proper evidence for their clinical application. METHODS: Thirty-six healthy mature Sprague-Dawley rat, weighing from 229 g to 358 g, were randomly assigned to groups A and B (n=18). Three kinds of materials were implanted into muscles of rats. Calcium sulfate (CS) granular preparations and allogeneic demineralized bone matrix (DBM) were transplanted into the left (group A1) and right (group A2) thigh muscle pouches of group A. Respectively, whereas xenogenic DBM were transplanted into the left (group B1) thigh muscle pouches of group B and the right (group B2) sites were taken as control without implant. The samples (n=6) were collected to make the observation of gross and histology and to analyze histological score after 2, 4, and 6 weeks. RESULTS: The gross observation: implanted materials were gradually absorbed at late stage in group A1. No obvious degradation and absorption, but fibrosis of tissues were observed in group A2 and B1. The inflammatory reactions were more severe in groups A2 and B1. In group B2, only the changes of scar were seen at operative site. The histological observation: no obvious inflammatory reactions were seen in group A1, CS were gradually absorbed and completely absorbed at 6 weeks, while fibrosis of tissues increased at late stage. Inflammatory reactions in group A2 and group B1 were alleviated gradually, no obvious absorption and degradation were observed. The different two DBM could induce granulation tissues and bone formation at different sites and secondary fibrosis with no obvious immune response was observed. In group B2, there was an increase in collagen fiber density and angiogenesis at late stage. The scores of inflammatory infiltration were significantly higher in groups A2, B1 than in groups A1, B2 (P < 0.05), and the scores of fibrosis was larger in groups A1, A2 and B1 than in group B2 (P < 0.05). CONCLUSION: CS has rapid dissolution and good biocompatibility. It is a good replaceable packing materials of bone defects in some upper limb's or acute bone fracture. Both of two DBM have biocompatibility and osteoinductive potential, which dissolution are very slow. Due to these capacity, they can be served as an ideal materials in treatment of lower limb's bone defect and nonunion.