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The endosomal sorting complex required for transport (ESCRT) machinery constitutes multisubunit protein complexes that play an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, including cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair, and autophagy. Given the versatile functionality of ESCRTs, and the intricate organizational structure of the ESCRT machinery, the targeted modulation of distinct ESCRT complexes is considerably challenging. This study presents a pseudonatural product targeting IST1-CHMP1B within the ESCRT-III complexes. The compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1-CHMP1B copolymers essential for normal-topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting, or biogenesis of extracellular vesicles, it rapidly inhibits transferrin receptor recycling in cells, resulting in the accumulation of transferrin in stalled sorting endosomes. Stalled endosomes become decorated by lipidated LC3, suggesting a link between noncanonical LC3 lipidation and inhibition of the IST1-CHMP1B complex.
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Complexos Endossomais de Distribuição Requeridos para Transporte , Endossomos , Endossomos/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Transporte Proteico , Corpos Multivesiculares/metabolismoRESUMO
Non-canonical peptides (NCPs) are a class of peptides generated from regions previously thought of as non-coding, such as introns, 5' untranslated regions (UTRs), 3' UTRs, and intergenic regions. In recent years, the significance and diverse functions of NCPs have come to light, yet a systematic and comprehensive NCP database remains absent. Here, we developed NCPbook (https://ncp.wiki/ncpbook/), a database of evidence-supported NCPs, which aims to provide a resource for efficient exploration, analysis, and manipulation of NCPs. NCPbook incorporates data from diverse public databases and scientific literature. The current version of NCPbook includes 180,676 NCPs across 29 different species, evidenced by mass spectrometry (MS), ribosome profiling (Ribo-seq), or molecular experiments (ME). These NCPs are distributed across kingdoms, comprising 123,408 from 14 plant species, 56,999 from seven animal species, and 269 from eight microbial species. Furthermore, NCPbook encompasses 9,166 functionally characterized NCPs playing important roles in immunity, stress resistance, growth, and development. Equipped with a user-friendly interface, NCPbook allows users to search, browse, visualize, and retrieve data, making it an indispensable platform for researching NCPs in various plant, animal, and microbial species.
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Lysosomal membrane damage represents a threat to cell viability. As such, cells have evolved sophisticated mechanisms to maintain lysosomal integrity. Small membrane lesions are detected and repaired by the endosomal sorting complex required for transport (ESCRT) machinery while more extensively damaged lysosomes are cleared by a galectin-dependent selective macroautophagic pathway (lysophagy). In this study, we identify a novel role for the autophagosome-lysosome tethering factor, TECPR1, in lysosomal membrane repair. Lysosomal damage promotes TECPR1 recruitment to damaged membranes via its N-terminal dysferlin domain. This recruitment occurs upstream of galectin and precedes the induction of lysophagy. At the damaged membrane, TECPR1 forms an alternative E3-like conjugation complex with the ATG12-ATG5 conjugate to regulate ATG16L1-independent unconventional LC3 lipidation. Abolishment of LC3 lipidation via ATG16L1/TECPR1 double knockout impairs lysosomal recovery following damage.
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Autofagia , Proteínas Associadas aos Microtúbulos , Proteínas Associadas aos Microtúbulos/metabolismo , Macroautofagia , Galectinas/metabolismo , Lisossomos/metabolismo , Proteínas Relacionadas à Autofagia/metabolismoRESUMO
Sugar Will Eventually be Exported Transporter (SWEET) proteins are highly conserved in various organisms and play crucial roles in sugar transport processes. However, SWEET proteins in peanuts, an essential leguminous crop worldwide, remain lacking in systematic characterization. Here, we identified 94 SWEET genes encoding the conservative MtN3/saliva domains in three peanut species, including 47 in Arachis hypogea, 23 in Arachis duranensis, and 24 in Arachis ipaensis. We observed significant variations in the exon-intron structure of these genes, while the motifs and domain structures remained highly conserved. Phylogenetic analysis enabled us to categorize the predicted 286 SWEET proteins from eleven species into seven distinct groups. Whole genome duplication/segment duplication and tandem duplication were the primary mechanisms contributing to the expansion of the total number of SWEET genes. In addition, an investigation of cis-elements in the potential promoter regions and expression profiles across 22 samples uncovered the diverse expression patterns of AhSWEET genes in peanuts. AhSWEET24, with the highest expression level in seeds from A. hypogaea Tifrunner, was observed to be localized on both the plasma membrane and endoplasmic reticulum membrane. Moreover, qRT-PCR results suggested that twelve seed-expressed AhSWEET genes were important in the regulation of seed development across four different peanut varieties. Together, our results provide a foundational basis for future investigations into the functions of SWEET genes in peanuts, especially in the process of seed development.
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Arachis , Família Multigênica , Arachis/genética , Arachis/metabolismo , Filogenia , Sementes , Açúcares/metabolismo , Proteínas de Plantas/metabolismoRESUMO
OBJECTIVE: Reports of tuberculosis (TB) during anticancer treatment with immune checkpoint inhibitors (ICIs) are increasing. However, it is not clear whether the use of ICIs is a significant risk factor for TB, including reactivation or latent TB infection (LTBI). METHODS: To determine the risk of TB reactivation in patients with lung cancer who use ICIs or tyrosine kinase inhibitors (TKIs), we conducted a retrospective study using a hospital-based cancer registry. In addition, we monitored patients with cancer using ICI or TKI in a multicenter prospective study to check the incidence of LTBI. RESULTS: In the retrospective study, several demographic factors were imbalanced between the ICI and TKI groups: the ICI group was younger, had more males, exhibited more squamous cell carcinoma in histology rather than adenocarcinoma, had fewer EGFR mutations, and received more chemotherapy. Propensity score matching was used to control for confounding factors, and we found that the incidence of TB was higher among patients with lung cancer who received ICIs than among those who received TKIs (2298 vs 412 per 100 000 person-years, Pâ =â .0165). Through multivariable analysis, group (ICI vs TKI) was the independent risk factor for TB development (adjusted hazard ratio (aHR): 6.29, 95% CI, 1.23-32.09, Pâ =â .0269). In the prospective cohort, which included 72 patients receiving ICIs and 50 receiving TKIs, we found that the incidence of positive seroconversion of LTBI by interferon gamma release assay (IGRA) was significantly higher in patients receiving ICIs (18% vs 0%, aHR: 9.88, Pâ =â 0.035) under multivariable Cox regression. CONCLUSION: The use of ICIs may be linked to a higher likelihood of TB reactivation and LTBI than individuals solely receiving TKIs as anticancer therapy. Consequently, the implementation of a screening program for TB reactivation and LTBI among patients undergoing ICI treatment could prove advantageous by enabling early detection and prompt treatment of the infection.
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Neoplasias Pulmonares , Tuberculose , Humanos , Masculino , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Tuberculose/induzido quimicamente , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , FemininoRESUMO
BACKGROUND: To assess the association of cirrhosis and hepatocellular carcinoma (HCC) with the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs), which are the two commonly prescribed injectable glucose-lowering agents (GLAs) for patients with type 2 diabetes (T2D) after the failure of multiple oral GLAs. METHODS: We emulated a target trial using the nationwide data of a Taiwanese cohort with T2D. Incident new users of GLP-1RAs and LAIs during 2013-2018 were identified, and propensity score (PS) matching was applied to ensure between-group comparability in baseline patient characteristics. The primary outcome was the composite liver disease including cirrhosis or HCC. Each patient was followed until the occurrence of a study outcome, death, or the end of 2019, whichever came first. Subdistribution hazard models were employed to assess the treatment-outcome association. Sensitivity (e.g., stabilized inverse probability of treatment weighting analysis, time-dependent analysis), E-value, and negative control outcome analyses were performed to examine the robustness of study findings. RESULTS: We included 7171 PS-matched pairs of GLP-1RA and LAI users with no significant between-group differences at baseline. Compared with LAIs, the use of GLP-1RAs was associated with significantly reduced risks of composite liver disease (subdistribution hazard ratio [95% confidence interval]: 0.56 [0.42-0.76]), cirrhosis (0.59 [0.43-0.81]), and HCC (0.47 [0.24-0.93]). Results were consistent across sensitivity analyses and among patients with different baseline characteristics. CONCLUSION: Among T2D patients who require injectable GLAs, the use of GLP-1RAs versus LAIs was associated with lower risks of cirrhosis and HCC.
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Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Estudos de Coortes , Neoplasias Hepáticas/epidemiologia , Cirrose Hepática/tratamento farmacológicoRESUMO
Development of interactive web applications to deposit, visualize and analyze biological datasets is a major subject of bioinformatics. R is a programming language for data science, which is also one of the most popular languages used in biological data analysis and bioinformatics. However, building interactive web applications was a great challenge for R users before the Shiny package was developed by the RStudio company in 2012. By compiling R code into HTML, CSS and JavaScript code, Shiny has made it incredibly easy to build web applications for the large R community in bioinformatics and for even non-programmers. Over 470 biological web applications have been developed with R/Shiny up to now. To further promote the utilization of R/Shiny, we reviewed the development of biological web applications with R/Shiny, including eminent biological web applications built with R/Shiny, basic steps to build an R/Shiny application, commonly used R packages to build the interface and server of R/Shiny applications, deployment of R/Shiny applications in the cloud and online resources for R/Shiny.
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Biologia Computacional , Software , Linguagens de ProgramaçãoRESUMO
BACKGROUND AND PURPOSE: Liver fibrosis is a wound-healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. METHODS: The delivery system of HCQ@retinol-liposome nanoparticles (HCQ@ROL-LNPs) targeting aHSC was constructed by the film dispersion and pH-gradient method. TGF-ß-induced HSC activation and thioacetamide (TAA)-induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL-LNPs in liver fibrosis were studied subsequently in vitro and in vivo. RESULTS: HCQ@ROL-LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL-LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. CONCLUSION: Construction of HCQ@ROL-LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases.
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Autofagia , Células Estreladas do Fígado , Hidroxicloroquina , Cirrose Hepática , Hidroxicloroquina/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Animais , Autofagia/efeitos dos fármacos , Camundongos , Cirrose Hepática/tratamento farmacológico , Lipossomos , Nanopartículas , Masculino , Modelos Animais de Doenças , Humanos , Tioacetamida , Camundongos Endogâmicos C57BLRESUMO
AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/efeitos adversos , Voluntários Saudáveis , Área Sob a Curva , Teste de Tolerância a Glucose , Método Duplo-Cego , Relação Dose-Resposta a DrogaRESUMO
PURPOSE: The aim of this study was to elucidate the factors associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may initiate cytokine cascades and correlate the clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with their serum cytokine profiles. METHODS: Recombinant baculoviruses displaying SARS-CoV-2 spike or nucleocapsid protein were constructed and transfected into A549 cells and THP-1-derived macrophages, to determine which protein initiate cytokine release. SARS-CoV-2-specific antibody titers and cytokine profiles of patients with COVID-19 were determined, and the results were associated with their clinical characteristics, such as development of pneumonia or length of hospital stay. RESULTS: The SARS-CoV-2 nucleocapsid protein, rather than the spike protein, triggers lung epithelial A549 cells to express IP-10, RANTES, IL-16, MIP-1α, basic FGF, eotaxin, IL-15, PDGF-BB, TRAIL, VEGF-A, and IL-5. Additionally, serum CTACK, basic FGF, GRO-α, IL-1α, IL-1RA, IL-2Rα, IL-9, IL-15, IL-16, IL-18, IP-10, M-CSF, MIF, MIG, RANTES, SCGF-ß, SDF-1α, TNF-α, TNF-ß, VEGF, PDGF-BB, TRAIL, ß-NGF, eotaxin, GM-CSF, IFN-α2, INF-γ, and MCP-1 levels were considerably increased in patients with COVID-19. Among them, patients with pneumonia had higher serum IP-10 and M-CSF levels than patients without. Patients requiring less than 3 weeks to show negative COVID-19 tests after contracting COVID-19 had higher serum IP-10 levels than the remaining patients. CONCLUSION: Our study revealed that nucleocapsid protein, lung epithelial cells, and IP-10 may be potential targets for the development of new strategies to prevent, or control, severe COVID-19.
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COVID-19 , Proteínas do Nucleocapsídeo de Coronavírus , Citocinas , Células Epiteliais , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , COVID-19/imunologia , COVID-19/sangue , Glicoproteína da Espícula de Coronavírus/imunologia , SARS-CoV-2/imunologia , Citocinas/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Células Epiteliais/virologia , Células Epiteliais/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Idoso , Células A549 , Pulmão/patologia , Pulmão/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/sangue , Adulto , Anticorpos Antivirais/sangue , FosfoproteínasRESUMO
Designing short-wavelength nonlinear-optical (NLO) crystals is of vital importance for laser applications. Here, the combination of alkaline-earth metals, d0 transition metals, and F atom has generated two new and isostructural fluorides, CaBaZr2F12 (CBZF) and CaBaHf2F12 (CBHF), which adopt centrosymmetric space group I4/mmm. Taking CBZF and CBHF as the parents, two new fluorides, K2BaZr2F12 (KBZF) and K2BaHf2F12 (KBHF), with an Imm2 polar structure were obtained via a heterovalent cation substitution strategy. All four compounds feature ZrF8-dodecahedra-built {[Zr2F12]4-}∞ chains and show short ultraviolet cutoff edges (<200 nm). KBZF and KBHF show phase-matchable behavior with moderate second-harmonic-generation responses [0.6 and 0.35 × KH2PO4 (KDP)] under 1064 nm laser radiation. This work enriches fluorides as promising short-wavelength NLO materials.
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As one of the potential candidates of nonlinear-optical (NLO) materials, rare-earth chalcophosphates have demonstrated promising properties. Here, KREP2S6 (RE = Sm, Gd, Tb, Dy) were synthesized using the facile RE2O3-B-S solid-state method. They crystallize with a monoclinic chiral P21 structure, and their layer structures are built by isolated ethane-like P2S6 dimers and RES8 bicapped trigonal prisms built {[RE2S15]24-}∞ layers. By comparing the structures with related ones, the change of the alkali metal or RE3+ ions can cause structural transformation. Their band gaps are tunable between 2.58 and 3.79 eV, and their powder samples exhibit good NLO properties. Theoretical calculations suggest that the NLO properties are mainly contributed by P2S6 units and {[RE2S15]24-}∞ layers synergistically, in which {[RE2S15]24-}∞ layers and P2S6 units dominate the contribution to the band gap and second-harmonic-generation response, respectively. This work enriches the application of rare-earth chalcophosphates as NLO materials.
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Oxychalcogenides are increasingly attracting wide attention because they contain multiple anions that may combine the advantages of oxides and chalcogenides. In this work, two new pentanary oxythiogermanates, Ba3MGe3O2S8 [M = Ca (1), Zn (2)], were synthesized by a high-temperature solid-state reaction. They crystallize in the orthorhombic space group Pnma, and their structures contain isolated [Ge3O2S8]8- units constructed by one [GeO2S2] and two [GeOS3] tetrahedra that link with M2+ ions to build the {[MGe3O2S8]6-}∞ chain, representing a new type of oxythiogermanate. Notably, a [ZnS5] square pyramid exists in 2. Their structural chemistry and relationship with relevant structures are analyzed. 1 and 2 exhibit wide band gaps of 3.93 and 2.63 eV, birefringences of 0.100 and 0.089 at 2100 nm, respectively, and also obvious photocurrent responses. This work may be extended to a family of AE3MIIMIV3O2Q8 (AE = alkali-earth metal; MII = Ca, Zn, Cd, Hg; MIV = Si, Ge, Sn; Q = S, Se), and further systematic survey on them can be performed to enrich the study of multifunctional oxychalcogenides.
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Noncentrosymmetric chalcogenides are promising candidates for infrared nonlinear-optical (NLO) crystals, and exploring high-performance ones is a hot topic and challengeable. Herein, the combination of AgQ4, InQ4, and SiQ4 (Q = S, Se) units with different S/Se ratios resulted in the discovery of the tetrahedral chalcogenides Ag2In2SiS4Se2 (1) and Ag2In2SiS5Se (2). They both crystallize in the monoclinic Cc space group with different local structures. Co-occupied S/Se sites only exist in 2, and the arrangement of [In2SiQ3] six-membered rings builds different helical chains and 3D [(In2SiQ6)2-]n polyanionic frameworks in 1 and 2. They show balanced NLO performances, including phase-matchable moderate NLO responses (0.7 and 0.5 × AGS) and enhanced laser-induced damage thresholds (4.5 and 5.1 × AGS). Theoretical calculations reveal that their NLO responses are predominantly contributed by the AgQ4 and InQ4 units.
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Obtaining compounds with large nonlinear-optical (NLO) coefficients and wide band gaps is challenging due to their competitive requirements for chemical bonds. Herein, the first member with mixed cations on the A site in the A-M3-Q5 or A-Ag-M6-Q10 (A = alkali metal; M = Ga, In; Q = S, Se, Te) family, viz. Na0.45Ag0.55Ga3Se5 (NAGSe), was obtained by a solid-state reaction. Its structure features [GaSe4] tetrahedra built three-dimensional {[Ga3Se5]-}∞ network, with Na and Na/Ag cations located at the octahedral cavities. Noncentrosymmetric (R32) NAGSe can also be transformed from centrosymmetric RbGa3S5 (P21/c) via multiple-site cosubstitution. NAGSe exhibits the highest NLO response (1.9 × AGS) in the A-Ag-M-Q family. Crystal structure analysis and theoretical calculations suggest that the NLO response is mainly contributed by the regularly arranged [GaSe4] units. This work enriches the exploration of the undeveloped A-M3-Q5 or A-Ag-M6-Q10 family as potential infrared NLO materials.
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Designing new compounds based on anion regulation has been widely favored due to the production of diverse crystal structures and excellent optical properties. Here, a new nitrate oxyfluoride, Hg16O12(NO3)6F2(H2O), has been obtained through a hydrothermal reaction. It crystallizes in the centric Ibca space group and shows a novel three-dimensional [(Hg16O12F2(H2O))6+]∞ cationic framework composed of interconnected HgO2F, HgO3, and HgO2(H2O) units, with isolated NO3- groups as balanced anions to build the whole structure. Notably, the HgO2F and HgO2(H2O) units are first presented here among mercury (Hg)-based compounds. Additionally, Hg16O12(NO3)6F2(H2O) exhibits a large birefringence of 0.17 at 546 nm. This work enriches the multiformity of Hg-based compounds and provides a route for developing promising birefringent materials.
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OBJECTIVE: To explore characteristics of tongue pressure changes in nasopharyngeal carcinoma (NPC) patients with dysphagia after radiotherapy using a novel system with multisite flexible sensors. DESIGN: Prospective observational study. SETTING: Inpatient rehabilitation centers and community dwellings. PARTICIPANTS: Nineteen patients with dysphagia after radiotherapy for NPC and 19 healthy participants were recruited for this study (N=38). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: A new 9-site (3 × 3) flexible tongue pressure sensor was used to measure tongue-to-palate pressure across different parts of the tongue. The oral tongue was divided into 3 parts: anterior tongue region (TAR), central tongue region (TCR), and posterior tongue region (TPR); 3 sensors were placed on each part. The mean tongue pressure and endurance time at the 3 sites in the TAR, TCR, and TPR were analyzed. The ratios of the mean TAR, TCR, and TPR values were calculated. RESULTS: Pressures of TAR, TCR, and TPR in NPC patients with dysphagia were significantly lower than those in healthy participants (P<.05). The pressure in TPR decreased most significantly, followed by that in TCR. The endurance times of TAR and TCR were longer than those of healthy participants (P<.05). The endurance time of TPR was not significantly different between the patients and healthy participants (P>.05). Ratios of pressure between TAR and TCR and TAR and TPR in patients were lower than that in healthy participants (P<.05). There was no significant difference in the TCR to TPR pressure ratio between patients and healthy participants (P>.05). CONCLUSIONS: Tongue pressure significantly decreased in NPC patients with dysphagia, and the drop in pressure was most pronounced in the TPR area. The results of our study indicate that we should pay attention to the pressure training of the TPR during treatments. The endurance time of the TAR and TCR increased significantly, which may be due to bolus transport compensation. Therefore, clinical rehabilitation strategies should aim to increase the endurance time training in NPC patients after radiotherapy to help increase the effectiveness of the swallowing process in patients.
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Transtornos de Deglutição , Neoplasias Nasofaríngeas , Humanos , Transtornos de Deglutição/etiologia , Carcinoma Nasofaríngeo/radioterapia , Pressão , Língua , Neoplasias Nasofaríngeas/radioterapia , Receptores de Antígenos de Linfócitos TRESUMO
Small RNAs (sRNAs) constitute a large portion of functional elements in eukaryotic genomes. Long inverted repeats (LIRs) can be transcribed into long hairpin RNAs (hpRNAs), which can further be processed into small interfering RNAs (siRNAs) with vital biological roles. In this study, we systematically identified a total of 6 619 473 LIRs in 424 eukaryotic genomes and developed LIRBase (https://venyao.xyz/lirbase/), a specialized database of LIRs across different eukaryotic genomes aiming to facilitate the annotation and identification of LIRs encoding long hpRNAs and siRNAs. LIRBase houses a comprehensive collection of LIRs identified in a wide range of eukaryotic genomes. In addition, LIRBase not only allows users to browse and search the identified LIRs in any eukaryotic genome(s) of interest available in GenBank, but also provides friendly web functionalities to facilitate users to identify LIRs in user-uploaded sequences, align sRNA sequencing data to LIRs, perform differential expression analysis of LIRs, predict mRNA targets for LIR-derived siRNAs, and visualize the secondary structure of candidate long hpRNAs encoded by LIRs. As demonstrated by two case studies, collectively, LIRBase bears the great utility for systematic investigation and characterization of LIRs and functional exploration of potential roles of LIRs and their derived siRNAs in diverse species.
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Bases de Dados Genéticas , Eucariotos/genética , Genoma/genética , Sequências Repetidas Invertidas/genética , Eucariotos/classificação , HumanosRESUMO
Heat stress (HS) disrupts intestinal microbiota, glycolipid metabolism, and hepatic mitochondrial function in late gestational mice. Baicalin (BAI), a Chinese herbal medicine known for its heat-clearing and anti-inflammatory properties, has shown promise in modulating intestinal microecology and mitigating inflammation in various organs. This study investigates whether baicalin attenuates HS-induced intestinal microbial dysbiosis and liver damage in pregnant mice during late gestation. Twenty-four pregnant mice were randomly assigned to four groups, including thermoneutral (TN) (24 ± 1 â), HS (35 ± 1 â), HS+BAI200 (oral gavaged with 200â¯mg/kg BW of BAI), and HS+BAI400 (oral gavaged with 400â¯mg/kg BW of BAI). 400â¯mg/kg BAI treatment markedly decreased the rectal temperature and increased fetal weight in HS pregnant mice. Furthermore, 400â¯mg/kg BAI administration effectively ameliorated HS-induced hepatic damage and lipid disorders, reducing HSP70, AST, and ALT levels while increasing TG concentration. Notably, it activated a network of genes involved in lipid synthesis, including fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and oxidation, such as peroxisome proliferator-activated receptor alpha (PPARα), carnitine palmityl transferase 1 beta (CPT1ß). Moreover, BAI intervention restored the intestinal morphology and barrier function, evidenced by increased intestinal villus height, the ratio of villus height to crypt depth, and colonic goblet cells numbers. 400â¯mg/kg of BAI treatment up-regulated the expression of tight junction proteins, such as claudin-1 and Zonula Occludens-1 (ZO-1), in the jejunum and ileum, counteracting HS-induced downregulation. High-throughput sequencing showed that BAI treatment altered cecal microbial composition, increasing the relative abundance of beneficial Bacteroidota and decreasing Deferribacterota, Turicibacter, and Akkermansia. Spearman's correlation analysis highlighted significant correlations between differential cecal microbiota and physiological indexes. In conclusion, BAI administration alleviated adverse impacts in heat-exposed mice during late gestation, improving maternal physiological parameters, and ameliorating hepatic damage with altered cecal microbial composition. The findings suggest that BAI may regulate the gut-liver axis by modulating intestinal morphology, microecology, and hepatic function.
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Di(2-ethylhexyl) phthalate (DEHP) is a widely recognized environmental endocrine disruptor that potentially impacts female reproductive function, although the specific mechanisms leading to such impairment remain unclear. A growing body of research has revealed that the endoplasmic reticulum and mitochondrial function significantly influence oocyte quality. The structure of mitochondria-associated endoplasmic reticulum membranes (MAMs) is crucial for facilitating the exchange of Ca2+, lipids, and metabolites. This study aimed to investigate the alterations in the composition and function of MAMs after DEHP exposure and to elucidate the underlying mechanisms of ovarian toxicity. The female mice were exposed to DEHP at doses of 5 and 500â¯mg/kg/day for one month. The results revealed that DEHP exposure led to reduced serum anti-Müllerian hormone levels and increased atretic follicles in mice. DEHP induced endoplasmic reticulum stress and disrupted calcium homeostasis in oocytes. Furthermore, DEHP impaired the mitochondrial function of oocytes and reduced their membrane potential, and promoting apoptosis. Similar results were observed in human granulosa cells after exposure to mono-(2-ethylhexyl) phthalate (MEHP, metabolites of DEHP) in vitro. Proteomic analysis and transmission electron microscopy revealed modifications in the functional proteins and structure of the MAMs, and the suppression of oxidative phosphorylation pathways. The findings of this investigation provide a new perspective on the mechanism underlying the reproductive toxicity of DEHP in females.