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Most natural and artificial materials have crystalline structures from which abundant topological phases emerge1-6. However, the bulk-edge correspondence-which has been widely used in experiments to determine the band topology from edge properties-is inadequate in discerning various topological crystalline phases7-16, leading to challenges in the experimental classification of the large family of topological crystalline materials4-6. It has been theoretically predicted that disclinations-ubiquitous crystallographic defects-can provide an effective probe of crystalline topology beyond edges17-19, but this has not yet been confirmed in experiments. Here we report an experimental demonstration of bulk-disclination correspondence, which manifests as fractional spectral charge and robust bound states at the disclinations. The fractional disclination charge originates from the symmetry-protected bulk charge patterns-a fundamental property of many topological crystalline insulators (TCIs). Furthermore, the robust bound states at disclinations emerge as a secondary, but directly observable, property of TCIs. Using reconfigurable photonic crystals as photonic TCIs with higher-order topology, we observe these hallmark features via pump-probe and near-field detection measurements. It is shown that both the fractional charge and the localized states emerge at the disclination in the TCI phase but vanish in the trivial phase. This experimental demonstration of bulk-disclination correspondence reveals a fundamental phenomenon and a paradigm for exploring topological materials.
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Aromatic polyketides are renowned for their wide-ranging pharmaceutical activities. Their structural diversity is mainly produced via modification of limited types of basic frameworks. In this study, we characterized the biosynthesis of a unique basic aromatic framework, phenyldimethylanthrone (PDA) found in (+)/(-)-anthrabenzoxocinones (ABXs) and fasamycin (FAS). Its biosynthesis employs a methyltransferase (Abx(+)M/Abx(-)M/FasT) and an unusual TcmI-like aromatase/cyclase (ARO/CYC, Abx(+)D/Abx(-)D/FasL) as well as a nonessential helper ARO/CYC (Abx(+)C/Abx(-)C/FasD) to catalyze the aromatization/cyclization of polyketide chain, leading to the formation of all four aromatic rings of the PDA framework, including the C9 to C14 ring and a rare angular benzene ring. Biochemical and structural analysis of Abx(+)D reveals a unique loop region, giving rise to its distinct acyl carrier protein-dependent specificity compared to other conventional TcmI-type ARO/CYCs, all of which impose on free molecules. Mutagenic analysis discloses critical residues of Abx(+)D for its catalytic activity and indicates that the size and shape of its interior pocket determine the orientation of aromatization/cyclization. This study unveils the tetracyclic and non-TcmN type C9 to C14 ARO/CYC, significantly expanding our cognition of ARO/CYCs and the biosynthesis of aromatic polyketide framework.
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Aromatasa , Policétidos , Ciclización , Proteína Transportadora de Acilo , CatálisisRESUMEN
How receptors juggle their interactions with multiple downstream effectors remains poorly understood. Here we show that the outcome of death receptor p75NTR signaling is determined through competition of effectors for interaction with its intracellular domain, in turn dictated by the nature of the ligand. While NGF induces release of RhoGDI through recruitment of RIP2, thus decreasing RhoA activity in favor of NFkB signaling, MAG induces PKC-mediated phosphorylation of the RhoGDI N-terminus, promoting its interaction with the juxtamembrane domain of p75NTR, disengaging RIP2, and enhancing RhoA activity in detriment of NF-kB. This results in stunted neurite outgrowth and apoptosis in cerebellar granule neurons. If presented simultaneously, MAG prevails over NGF. The NMR solution structure of the complex between the RhoGDI N-terminus and p75NTR juxtamembrane domain reveals previously unknown structures of these proteins and clarifies the mechanism of p75NTR activation. These results show how ligand-directed competition between RIP2 and RhoGDI for p75NTR engagement determine axon growth and neuron survival. Similar principles are likely at work in other receptors engaging multiple effectors and signaling pathways.
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FN-kappa B , Neuronas , Inhibidores de la Disociación del Nucleótido Guanina rho-Específico/metabolismo , Ligandos , Fosforilación , FN-kappa B/metabolismo , Neuronas/metabolismo , Receptores de Muerte Celular/metabolismo , Axones/metabolismo , Receptor de Factor de Crecimiento Nervioso/metabolismoRESUMEN
Small-molecule carboxyl methyltransferases (CbMTs) constitute a small proportion of the reported methyltransferases, but they have received extensive attention due to their important physiological functions. Most of the small-molecule CbMTs isolated to date originate from plants and are members of the SABATH family. In this study, we identified a type of CbMT (OPCMT) from a group of Mycobacteria, which has a distinct catalytic mechanism from the SABATH methyltransferases. The enzyme contains a large hydrophobic substrate-binding pocket (~400 Å3) and utilizes two conserved residues, Thr20 and Try194, to retain the substrate in a favorable orientation for catalytic transmethylation. The OPCMT_like MTs have a broad substrate scope and can accept diverse carboxylic acids enabling efficient production of methyl esters. They are widely (more than 10,000) distributed in microorganisms, including several well-known pathogens, whereas no related genes are found in humans. In vivo experiments implied that the OPCMT_like MTs was indispensable for M. neoaurum, suggesting that these proteins have important physiological functions.
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Metiltransferasas , Plantas , Humanos , Metiltransferasas/metabolismo , Secuencia de Aminoácidos , Plantas/metabolismoRESUMEN
Recent studies have revealed that long noncoding RNAs (lncRNAs) are closely linked to several human diseases, providing new opportunities for their use in detection and therapy. Many graph propagation and similarity fusion approaches can be used for predicting potential lncRNA-disease associations. However, existing similarity fusion approaches suffer from noise and self-similarity loss in the fusion process. To address these problems, a new prediction approach, termed SSMF-BLNP, based on organically combining selective similarity matrix fusion (SSMF) and bidirectional linear neighborhood label propagation (BLNP), is proposed in this paper to predict lncRNA-disease associations. In SSMF, self-similarity networks of lncRNAs and diseases are obtained by selective preprocessing and nonlinear iterative fusion. The fusion process assigns weights to each initial similarity network and introduces a unit matrix that can reduce noise and compensate for the loss of self-similarity. In BLNP, the initial lncRNA-disease associations are employed in both lncRNA and disease directions as label information for linear neighborhood label propagation. The propagation was then performed on the self-similarity network obtained from SSMF to derive the scoring matrix for predicting the relationships between lncRNAs and diseases. Experimental results showed that SSMF-BLNP performed better than seven other state of-the-art approaches. Furthermore, a case study demonstrated up to 100% and 80% accuracy in 10 lncRNAs associated with hepatocellular carcinoma and 10 lncRNAs associated with renal cell carcinoma, respectively. The source code and datasets used in this paper are available at: https://github.com/RuiBingo/SSMF-BLNP.
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ARN Largo no Codificante , Humanos , Algoritmos , Biología Computacional/métodos , ARN Largo no Codificante/genética , Programas Informáticos , Carcinoma Hepatocelular/genética , Carcinoma de Células Renales/genética , Neoplasias Hepáticas/genética , Neoplasias Renales/genéticaRESUMEN
Although the use of Doxorubicin (Dox) is extensive in the treatment of malignant tumor, the toxic effects of Dox on the heart can cause myocardial injury. Therefore, it is necessary to find an alternative drug to alleviate the Dox-induced cardiotoxicity. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, which is an active ingredient of Artemisia annua. The study investigates the effects of DHA on doxorubicin-induced cardiotoxicity and ferroptosis, which are related to the activation of Nrf2 and the regulation of autophagy. Different concentrations of DHA were administered by gavage for 4 weeks in mice. H9c2 cells were pretreated with different concentrations of DHA for 24 h in vitro. The mechanism of DHA treatment was explored through echocardiography, biochemical analysis, real-time quantitative PCR, western blotting analysis, ROS/DHE staining, immunohistochemistry, and immunofluorescence. In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes. In vitro, DHA attenuated oxidative stress and cardiomyocyte ferroptosis, activated Nrf2, promoted clearance of autophagosomes, and reduced lysosomal destruction. The changes of ferroptosis and Nrf2 depend on selective degradation of keap1 and recovery of lysosome. We found for the first time that DHA could protect the heart from the toxic effects of Dox-induced cardiotoxicity. In addition, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.
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Artemisininas , Autofagia , Cardiotoxicidad , Doxorrubicina , Ferroptosis , Miocitos Cardíacos , Factor 2 Relacionado con NF-E2 , Artemisininas/farmacología , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Autofagia/efectos de los fármacos , Doxorrubicina/efectos adversos , Doxorrubicina/toxicidad , Ratones , Ferroptosis/efectos de los fármacos , Cardiotoxicidad/etiología , Cardiotoxicidad/prevención & control , Cardiotoxicidad/metabolismo , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratones Endogámicos C57BL , Línea Celular , RatasRESUMEN
Twin and family studies have established the genetic contribution to idiopathic generalized epilepsy (IGE). The genetic architecture of IGE is generally complex and heterogeneous, and the majority of the genetic burden in IGE remains unsolved. We hypothesize that gene-gene interactions contribute to the complex inheritance of IGE. CNTN2 (OMIM* 615,400) variants have been identified in cases with familial adult myoclonic epilepsy and other epilepsies. To explore the gene-gene interaction network in IGE, we took the CNTN2 gene as an example and investigated its co-occurrent genetic variants in IGE cases. We performed whole-exome sequencing in 114 unrelated IGE cases and 296 healthy controls. Variants were qualified with sequencing quality, minor allele frequency, in silico prediction, genetic phenotype, and recurrent case numbers. The STRING_TOP25 gene interaction network analysis was introduced with the bait gene CNTN2 (denoted as A). The gene-gene interaction pair mode was presumed to be A + c, A + d, A + e, with a leading gene A, or A + B + f, A + B + g, A + B + h, with a double-gene A + B, or other combinations. We compared the number of gene interaction pairs between the case and control groups. We identified three pairs in the case group, CNTN2 + PTPN18, CNTN2 + CNTN1 + ANK2 + ANK3 + SNTG2, and CNTN2 + PTPRZ1, while we did not discover any pairs in the control group. The number of gene interaction pairs in the case group was much more than in the control group (p = 0.021). Taking together the genetic bioinformatics, reported epilepsy cases, and statistical evidence in the study, we supposed CNTN2 as a candidate pathogenic gene for IGE. The gene interaction network analysis might help screen candidate genes for IGE or other complex genetic disorders.
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Contactinas , Epilepsia Generalizada , Epistasis Genética , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Adulto Joven , Estudios de Casos y Controles , Contactinas/genética , Epilepsia Generalizada/genética , Secuenciación del Exoma , Frecuencia de los GenesRESUMEN
We conducted a thorough genome-wide investigation of protein phosphorylation in the halotolerant bacterium Mangrovibacter phragmitis (MPH) ASIOC01, using the Fe-IMAC enrichment method combined with tandem mass spectrometry under low- and high-salinity conditions. The phosphoproteome comprises 86 unique phosphorylated proteins, crucially involving pathways such as glycolysis/gluconeogenesis, the citrate cycle, chaperones, ribosomal proteins, and cell division. This study represents the first and most extensive investigation to-date comparing the bacterial phosphoproteome under different osmotic conditions using a gel-free approach. We identified 45 unique phosphoproteins in MPH cultured in media containing 1 % NaCl, and 33 exclusive phosphoproteins in MPH cultured in media containing 5 % NaCl. Eight phosphoproteins were detected in both growth conditions. Analysis of high-confidence phosphosites reveals that phosphorylation predominantly occurs on serine residues (52.3 %), followed by threonine (35.1 %) and tyrosine (12.6 %) residues. Interestingly, 34 % of the phosphopeptides display multiple phosphosites. Currently, prokaryotic phosphorylation site prediction platforms like MPSite and NetPhosBac 1.0 demonstrate an average prediction accuracy of only 21 % when applied to our dataset. Fourteen phosphoproteins did not yield matches when compared against dbPSP 2.0 (database of Phosphorylation Sites in Prokaryotes), indicating that these proteins may be novel phosphoproteins. These unique proteins undergoing phosphorylation under high salinity growth conditions potentially enhance their adaptive capabilities to environmental challenges.
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The oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC) products in human high-density lipoproteins (HDLs) were investigated by low-flow capillary electrophoresis-mass spectrometry (low-flow CE-MS). To accelerate the optimization, native PAPC (n-PAPC) standard was first analyzed by a commercial CE instrument with a photodiode array detector. The optimal separation buffer contained 60% (v/v) acetonitrile, 40% (v/v) methanol, 20 mM ammonium acetate, 0.5% (v/v) formic acid, and 0.1% (v/v) water. The selected separation voltage and capillary temperature were 20 kV and 23°C. The optimal CE separation buffer was then used for the low-flow CE-MS analysis. The selected MS conditions contained heated capillary temperature (250°C), capillary voltage (10 V), and injection time (1 s). No sheath gas was used for MS. The linear range for n-PAPC was 2.5-100.0 µg/mL. The coefficient of determination (R2 ) was 0.9918. The concentration limit of detection was 1.52 µg/mL, and the concentration limit of quantitation was 4.60 µg/mL. The optimal low-flow CE-MS method showed good repeatability and sensitivity. The ox-PAPC products in human HDLs were determined based on the in vitro ox-PAPC products of n-PAPC standard. Twenty-one ox-PAPC products have been analyzed in human HDLs. Uremic patients showed significantly higher levels of 15 ox-PAPC products than healthy subjects.
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Lipoproteínas HDL , Fosfolípidos , Humanos , Células Cultivadas , Espectrometría de Masas , Electroforesis CapilarRESUMEN
DNA 4 mC plays a crucial role in the genetic expression process of organisms. However, existing deep learning algorithms have shortcomings in the ability to represent DNA sequence features. In this paper, we propose a 4 mC site identification algorithm, DNABert-4mC, based on a fusion of the pruned pre-training DNABert-Pruning model and artificial feature encoding to identify 4 mC sites. The algorithm prunes and compresses the DNABert model, resulting in the pruned pre-training model DNABert-Pruning. This model reduces the number of parameters and removes redundancy from output features, yielding more precise feature representations while upholding accuracy.Simultaneously, the algorithm constructs an artificial feature encoding module to assist the DNABert-Pruning model in feature representation, effectively supplementing the information that is missing from the pre-trained features. The algorithm also introduces the AFF-4mC fusion strategy, which combines artificial feature encoding with the DNABert-Pruning model, to improve the feature representation capability of DNA sequences in multi-semantic spaces and better extract 4 mC sites and the distribution of nucleotide importance within the sequence. In experiments on six independent test sets, the DNABert-4mC algorithm achieved an average AUC value of 93.81%, outperforming seven other advanced algorithms with improvements of 2.05%, 5.02%, 11.32%, 5.90%, 12.02%, 2.42% and 2.34%, respectively.
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Algoritmos , ADN , ADN/genética , NucleótidosRESUMEN
Surgical adhesives play a crucial role in tissue integration and repair, yet their application in wet conditions has been severely limited by inadequate adhesive strength and subpar biocompatibility. Furthermore, tissue adhesives have rarely been reported in cartilage tissue repair. In this study, a three-armed dopamine-modified hyaluronic acid derivative adhesive was prepared to function as a bio-inspired adhesive in moist environments. To meet the clinical requirements for cartilage tissue adhesion, we studied its chemical structure, including microscopic morphology, adhesion properties with materials and tissues, in vivo degradation rules, and biological evaluation. The OGMHA8-DOPA adhesive with the optimal aldehyde substitution degree and dopamine-grafting rate was determined by analyzing the experimental conditions. SEM results revealed that the cartilage tissue adhered to a porous interconnected structure. The excellent biocompatibility of the material not only facilitated chondrocyte adhesion but also supported their proliferation on its surface. Animal experiments have demonstrated that this material has no observable inflammatory response or incidence of fibrous capsule formation. The degradation timeline of the material extends beyond the duration of two weeks. The dopamine-modified adhesive exhibited a tight interfacial binding force between the biomaterial and cartilage tissue and excellent biocompatibility in watery tissue, revealing its potential for application in cartilage tissue repair and minimally invasive surgery.
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Adhesivos , Materiales Biocompatibles , Animales , Materiales Biocompatibles/farmacología , Adhesivos/química , Dopamina/química , Cartílago , CondrocitosRESUMEN
Bivalves are often employed for biomonitoring contaminants in marine environments; however, in these large-scale programs, unavoidably, using multiple species presents a significant challenge. Interspecies differences in contaminant bioaccumulation can complicate data interpretation, and direct comparisons among species may result in misleading conclusions. Here, we propose a robust framework based on toxicokinetic measurements that accounts for interspecies differences in bioaccumulation. Specifically, via a recently developed double stable isotope tracer technique, we determined the toxicokinetics of cadmium (Cd)âa metal known for its high concentrations in bivalves and significant interspecies bioaccumulation variabilityâin six widespread bivalve species including mussels (Perna viridis, Mytilus unguiculatus, Mytilus galloprovincialis) and oysters (Magallana gigas, Magallana hongkongensis, Magallana angulata). Results show that oysters generally have higher Cd uptake rate constants (ku: 1.18-3.09 L g-1 d-1) and lower elimination rate constants (ke: 0.008-0.017 d-1) than mussels (ku: 0.21-0.64 L g-1 d-1; ke: 0.018-0.037 d-1). The interspecies differences in tissue Cd concentrations are predominantly due to Cd uptake rather than elimination. Utilizing toxicokinetic parameters to back-calculate Cd concentrations in seawater, we found that the ranking of Cd contamination levels at the six sites markedly differs from those based on tissue Cd concentrations. We propose that this approach will be useful for interpreting data from past and future biomonitoring programs.
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Bivalvos , Cadmio , Toxicocinética , Contaminantes Químicos del Agua , Animales , Cadmio/metabolismo , Cadmio/farmacocinética , Cadmio/toxicidad , Bivalvos/metabolismo , Monitoreo del Ambiente/métodos , Mytilus/metabolismo , Monitoreo Biológico , Especificidad de la EspecieRESUMEN
Endophytic fungus Serendipita indica can bolster plant growth and confer protection against various biotic and abiotic stresses. However, S. indica-reshaped rhizosphere microecology interactions and root-soil interface processes in situ at the submicrometer scale remain poorly understood. We combined amplicon sequencing and high-resolution nano X-ray fluorescence (nano-XRF) imaging of the root-soil interface to reveal cadmium (Cd) rhizosphere processes. S. indica can successfully colonize the roots of Sedum alfredii Hance, which induces a remarkable increase in shoot biomass by 211.32% and Cd accumulation by 235.72%. Nano-XRF images showed that S. indica colonization altered the Cd distribution in the rhizosphere and facilitated the proximity of more Cd and sulfur (S) to enter the roots and transport to the shoot. Furthermore, the rhizosphere-enriched microbiota demonstrated a more stable network structure after the S. indica inoculation. Keystone species were strongly associated with growth promotion and Cd absorption. For example, Comamonadaceae are closely related to the organic acid cycle and S bioavailability, which could facilitate Cd and S accumulation in plants. Meanwhile, Sphingomonadaceae could release auxin and boost plant biomass. In summary, we construct a mutualism system for beneficial fungi and hyperaccumulation plants, which facilitates high-efficient remediation of Cd-contaminated soils by restructuring the rhizosphere microbiota.
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Cadmio , Microbiota , Rizosfera , Sedum , Contaminantes del Suelo , Azufre , Cadmio/metabolismo , Sedum/metabolismo , Contaminantes del Suelo/metabolismo , Azufre/metabolismo , Basidiomycota , Suelo/química , Biodegradación Ambiental , Raíces de Plantas/metabolismo , Raíces de Plantas/microbiologíaRESUMEN
A key limitation of the use of the CRISPR-Cas9 system for genome editing and other applications is the requirement that a protospacer adjacent motif (PAM) be present at the target site. For the most commonly used Cas9 from Streptococcus pyogenes (SpCas9), the required PAM sequence is NGG. No natural or engineered Cas9 variants that have been shown to function efficiently in mammalian cells offer a PAM less restrictive than NGG. Here we use phage-assisted continuous evolution to evolve an expanded PAM SpCas9 variant (xCas9) that can recognize a broad range of PAM sequences including NG, GAA and GAT. The PAM compatibility of xCas9 is the broadest reported, to our knowledge, among Cas9 proteins that are active in mammalian cells, and supports applications in human cells including targeted transcriptional activation, nuclease-mediated gene disruption, and cytidine and adenine base editing. Notably, despite its broadened PAM compatibility, xCas9 has much greater DNA specificity than SpCas9, with substantially lower genome-wide off-target activity at all NGG target sites tested, as well as minimal off-target activity when targeting genomic sites with non-NGG PAMs. These findings expand the DNA targeting scope of CRISPR systems and establish that there is no necessary trade-off between Cas9 editing efficiency, PAM compatibility and DNA specificity.
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Proteínas Asociadas a CRISPR/genética , Proteínas Asociadas a CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , ADN/genética , ADN/metabolismo , Edición Génica/métodos , Mutación , Especificidad por Sustrato/genética , División del ADN , Desoxirribonucleasas/metabolismo , Evolución Molecular Dirigida , Genoma Humano/genética , Células HEK293 , Humanos , Motivos de Nucleótidos , Streptococcus pyogenes/enzimología , Streptococcus pyogenes/genética , Activación TranscripcionalRESUMEN
BACKGROUND: Esculentin-1, initially discovered in the skin secretions of pool frogs (Pelophylax lessonae), has demonstrated broad-spectrum antimicrobial activity; however, its immunomodulatory properties have received little attention. RESULTS: In the present study, esculentin-1 cDNA was identified by analysing the skin transcriptome of the dark-spotted frog (Pelophylax nigromaculatus). Esculentin-1 from this species (esculentin-1PN) encompasses a signal peptide, an acidic spacer peptide, and a mature peptide. Sequence alignments with other amphibian esculentins-1 demonstrated conservation of the peptide, and phylogenetic tree analysis revealed its closest genetic affinity to esculentin-1P, derived from the Fukien gold-striped pond frog (Pelophylax fukienensis). Esculentin-1PN transcripts were observed in various tissues, with the skin exhibiting the highest mRNA levels. Synthetic esculentin-1PN demonstrated antibacterial activity against various pathogens, and esculentin-1PN exhibited bactericidal activity by disrupting cell membrane integrity and hydrolyzing genomic DNA. Esculentin-1PN did not stimulate chemotaxis in RAW264.7, a murine leukemic monocyte/macrophage cell line. However, it amplified the respiratory burst and augmented the pro-inflammatory cytokine gene (TNF-α and IL-1ß) expression in RAW264.7 cells. CONCLUSIONS: This novel finding highlights the immunomodulatory activity of esculentin-1PN on immune cells.
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Proteínas Anfibias , Antibacterianos , Filogenia , Ranidae , Animales , Proteínas Anfibias/farmacología , Proteínas Anfibias/química , Proteínas Anfibias/genética , Ratones , Antibacterianos/farmacología , Antibacterianos/química , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Catiónicos Antimicrobianos/genética , Secuencia de Aminoácidos , Piel/metabolismo , Factores Inmunológicos/farmacología , Factores Inmunológicos/química , Células RAW 264.7 , Alineación de SecuenciaRESUMEN
MASH is a prevalent liver disease that can progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and ultimately death, but there are no approved therapies. Leukotriene B4 (LTB4) is a potent pro-inflammatory chemoattractant that drives macrophage and neutrophil chemotaxis, and genetic loss or inhibition of its high affinity receptor, leukotriene B4 receptor 1 (BLT1), results in improved insulin sensitivity and decreased hepatic steatosis. To validate the therapeutic efficacy of BLT1 inhibition in an inflammatory and pro-fibrotic mouse model of MASH and fibrosis, mice were challenged with a choline-deficient, L-amino acid defined high fat diet and treated with a BLT1 antagonist at 30 or 90 mg/kg for 8 weeks. Liver function, histology, and gene expression were evaluated at the end of the study. Treatment with the BLT1 antagonist significantly reduced plasma lipids and liver steatosis but had no impact on liver injury biomarkers or histological endpoints such as inflammation, ballooning, or fibrosis compared to control. Artificial intelligence-powered digital pathology analysis revealed a significant reduction in steatosis co-localized fibrosis in livers treated with the BLT1 antagonist. Liver RNA-seq and pathway analyses revealed significant changes in fatty acid, arachidonic acid, and eicosanoid metabolic pathways with BLT1 antagonist treatment, however, these changes were not sufficient to impact inflammation and fibrosis endpoints. Targeting this LTB4-BLT1 axis with a small molecule inhibitor in animal models of chronic liver disease should be considered with caution, and additional studies are warranted to understand the mechanistic nuances of BLT1 inhibition in the context of MASH and liver fibrosis.
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BACKGROUND: We compared total arterial revascularization (TAR) versus conventional revascularization (CR) in terms of left ventricular function recovery in patients with multivessel coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF). METHODS: We conducted a retrospective cohort study of 162 consecutive patients with multivessel CAD and reduced LVEF who underwent isolated coronary artery bypass grafting at our institution between January 2013 and July 2022. We assessed left ventricular function by transthoracic echocardiography at admission, before discharge, and at follow-up of 3, 6, and 12 months, using LVEF, global longitudinal peak strain, end-diastolic volume index, and end-systolic volume index. We also evaluated mitral valve regurgitation and graft patency rate at 1 year. RESULTS: The TAR group had a significantly higher increase in LVEF and global longitudinal peak strain, and a significantly lower decrease in end-diastolic volume index and end-systolic volume index than the CR group at 6 and 12 months after surgery. The TAR group also had a significantly lower degree of mitral valve regurgitation than the CR group at all-time points within 12 months after surgery. The TAR group had a significantly higher graft patency rate than the CR group at 12 months. There was no significant difference in hospital mortality or repeat revascularization between the groups. CONCLUSIONS: TAR was associated with better recovery of left ventricular function than CR in patients with multivessel CAD and reduced LVEF. Further studies are needed to confirm these findings in this high-risk population.
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Puente de Arteria Coronaria , Enfermedad de la Arteria Coronaria , Ecocardiografía , Volumen Sistólico , Humanos , Masculino , Femenino , Enfermedad de la Arteria Coronaria/cirugía , Enfermedad de la Arteria Coronaria/fisiopatología , Puente de Arteria Coronaria/métodos , Estudios Retrospectivos , Volumen Sistólico/fisiología , Persona de Mediana Edad , Anciano , Función Ventricular Izquierda/fisiología , Recuperación de la Función , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/cirugía , Disfunción Ventricular Izquierda/diagnóstico por imagen , Resultado del Tratamiento , Insuficiencia de la Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/fisiopatología , Insuficiencia de la Válvula Mitral/diagnóstico por imagenRESUMEN
Natural spider silk with extraordinary mechanical properties is typically spun from more than one type of spidroin. Although the main components of various spider silks have been widely studied, little is known about the molecular role of the minor silk components in spidroin self-assembly and fiber formation. Here, we show that the minor component of spider eggcase silk, TuSp2, not only accelerates self-assembly but remarkably promotes molecular chain alignment of spidroins upon physical shearing. NMR structure of the repetitive domain of TuSp2 reveals that its dimeric structure with unique charged surface serves as a platform to recruit different domains of the main eggcase component TuSp1. Artificial fiber spun from the complex between TuSp1 and TuSp2 minispidroins exhibits considerably higher strength and Young's modulus than its native counterpart. These results create a framework for rationally designing silk biomaterials based on distinct roles of silk components.
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Fibroínas/química , Animales , Materiales Biocompatibles , Fibroínas/metabolismo , Seda/química , Seda/metabolismo , Arañas/metabolismoRESUMEN
BACKGROUND: The systemic inflammatory response index (SIRI), served as a novel inflammatory biomarker, is the synthesis of neutrophils, monocytes and lymphocytes. AIMS: We hypothesized that SIRI has predictive value for contrast-associated acute kidney injury (CA-AKI) and long-term mortality in patients undergoing elective percutaneous coronary intervention (PCI). METHODS: We retrospectively observed 5685 patients undergoing elective PCI from January 2012 to December 2018. Venous blood samples were collected to obtain the experimental data on the day of admission or the morning of the next day. SIRI = neutrophil count × monocyte count/lymphocyte count. CA-AKI was defined as an increase of 50% or 0.3 mg/dl in SCr from baseline within 48 h after contrast exposure. RESULTS: The incidence of CA-AKI was 6.1% (n = 352). The best cutoff value of SIRI for predicting CA-AKI was 1.39, with a sensitivity of 52.3% and a specificity of 67.3%. [AUC: 0.620, 95% confidence interval (CI): 0.590-0.651, p < 0.001]. After adjusting for potential confounders, multivariate analysis showed that the high SIRI group (SIRI > 1.39) was a strong independent predictor of CA-AKI in patients undergoing elective PCI compared with the low SIRI group (SIRI ≤ 1.39) (odds ratio = 1.642, 95% CI: 1.274-2.116, p < 0.001). Additionally, COX regression analysis showed that SIRI > 1.39 was significantly associated with long-term mortality at a median follow-up of 2.8 years. [Hazard ratio (HR)=1.448, 95%CI: 1.188-1.765; p < 0.001]. Besides, Kaplan-Meier survival curve also indicated that the cumulative rate of mortality was considerably higher in the high SIRI group. CONCLUSIONS: High levels of SIRI are independent predictors of CA-AKI and long-term mortality in patients undergoing elective PCI.
Asunto(s)
Lesión Renal Aguda , Intervención Coronaria Percutánea , Humanos , Intervención Coronaria Percutánea/efectos adversos , Estudios Retrospectivos , Medios de Contraste/efectos adversos , Factores de Riesgo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Síndrome de Respuesta Inflamatoria SistémicaRESUMEN
In the context of the rapid development of the Internet of Vehicles, virtual reality, automatic driving and the industrial Internet, the terminal devices in the network show explosive growth. As a result, more and more information is generated from the edge of the network, which makes the data throughput increase dramatically in the mobile communication network. As the key technology of the fifth-generation mobile communication network, mobile edge caching technology which caches popular data to the edge server deployed at the edge of the network avoids the data transmission delay of the backhaul link and the occurrence of network congestion. With the growing scale of the network, distributing hot data from cloud servers to edge servers will generate huge energy consumption. To realize the green and sustainable development of the communication industry and reduce the energy consumption of distribution of data that needs to be cached in edge servers, we make the first attempt to propose and solve the problem of edge caching data distribution with minimum energy consumption (ECDDMEC) in this paper. First, we model and formulate the problem as a constrained optimization problem and then prove its NP-hardness. Subsequently, we design a greedy algorithm with computational complexity of O(n2) to solve the problem approximately. Experimental results show that compared with the distribution strategy of each edge server directly requesting data from the cloud server, the strategy obtained by the algorithm can significantly reduce the energy consumption of data distribution.