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1.
Nature ; 608(7922): 405-412, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35922506

RESUMEN

After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death1,2. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology3. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.


Asunto(s)
Supervivencia Celular , Citoprotección , Perfusión , Porcinos , Isquemia Tibia , Animales , Muerte Celular , Perfilación de la Expresión Génica , Isquemia/metabolismo , Isquemia/patología , Isquemia/prevención & control , Especificidad de Órganos , Perfusión/métodos , Porcinos/anatomía & histología
2.
Proc Natl Acad Sci U S A ; 121(9): e2316922121, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38381790

RESUMEN

The self-assembly of proteins into curved structures plays an important role in many cellular processes. One good example of this phenomenon is observed in the septum-forming protein (SepF), which forms polymerized structures with uniform curvatures. SepF is essential for regulating the thickness of the septum during bacteria cell division. In Bacillus subtilis, SepF polymerization involves two distinct interfaces, the ß-ß and α-α interfaces, which define the assembly unit and contact interfaces, respectively. However, the mechanism of curvature formation in this step is not yet fully understood. In this study, we employed solid-state NMR (SSNMR) to compare the structures of cyclic wild-type SepF assemblies with linear assemblies resulting from a mutation of G137 on the ß-ß interface. Our results demonstrate that while the sequence differences arise from the internal assembly unit, the dramatic changes in the shape of the assemblies depend on the α-α interface between the units. We further provide atomic-level insights into how the angular variation of the α2 helix on the α-α interface affects the curvature of the assemblies, using a combination of SSNMR, cryo-electron microscopy, and simulation methods. Our findings shed light on the shape control of protein assemblies and emphasize the importance of interhelical contacts in retaining curvature.


Asunto(s)
Citocinesis , Microscopía por Crioelectrón , Polimerizacion , División Celular , Mutación
3.
Plant J ; 117(4): 1264-1280, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37964640

RESUMEN

Rosa roxburghii and Rosa sterilis, two species belonging to the Rosaceae family, are widespread in the southwest of China. These species have gained recognition for their remarkable abundance of ascorbate in their fresh fruits, making them an ideal vitamin C resource. In this study, we generated two high-quality chromosome-scale genome assemblies for R. roxburghii and R. sterilis, with genome sizes of 504 and 981.2 Mb, respectively. Notably, we present a haplotype-resolved, chromosome-scale assembly for diploid R. sterilis. Our results indicated that R. sterilis originated from the hybridization of R. roxburghii and R. longicuspis. Genome analysis revealed the absence of recent whole-genome duplications in both species and identified a series of duplicated genes that possibly contributing to the accumulation of flavonoids. We identified two genes in the ascorbate synthesis pathway, GGP and GalLDH, that show signs of positive selection, along with high expression levels of GDP-d-mannose 3', 5'-epimerase (GME) and GDP-l-galactose phosphorylase (GGP) during fruit development. Furthermore, through co-expression network analysis, we identified key hub genes (MYB5 and bZIP) that likely regulate genes in the ascorbate synthesis pathway, promoting ascorbate biosynthesis. Additionally, we observed the expansion of terpene synthase genes in these two species and tissue expression patterns, suggesting their involvement in terpenoid biosynthesis. Our research provides valuable insights into genome evolution and the molecular basis of the high concentration of ascorbate in these two Rosa species.


Asunto(s)
Rosa , Rosa/genética , Rosa/metabolismo , Ácido Ascórbico/metabolismo , Genes de Plantas , Cromosomas , Evolución Molecular
4.
Brain ; 147(4): 1553-1570, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38128548

RESUMEN

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.


Asunto(s)
Trastorno del Espectro Autista , Acueducto del Mesencéfalo/anomalías , Enfermedades Genéticas Ligadas al Cromosoma X , Hidrocefalia , Niño , Humanos , Trastorno del Espectro Autista/genética , Factores de Transcripción/genética , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/genética , Epigénesis Genética , Proteínas del Ojo/genética , Péptidos y Proteínas de Señalización Intracelular/genética
5.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-35078933

RESUMEN

Protein nanocages (PNCs) in cells and viruses have inspired the development of self-assembling protein nanomaterials for various purposes. Despite the successful creation of artificial PNCs, the de novo design of PNCs with defined permeability remains challenging. Here, we report a prototype oxygen-impermeable PNC (OIPNC) assembled from the vertex protein of the ß-carboxysome shell, CcmL, with quantum dots as the template via interfacial engineering. The structure of the cage was solved at the atomic scale by combined solid-state NMR spectroscopy and cryoelectron microscopy, showing icosahedral assembly of CcmL pentamers with highly conserved interpentamer interfaces. Moreover, a gating mechanism was established by reversibly blocking the pores of the cage with molecular patches. Thus, the oxygen permeability, which was probed by an oxygen sensor inside the cage, can be completely controlled. The CcmL OIPNC represents a PNC platform for oxygen-sensitive or oxygen-responsive storage, catalysis, delivery, sensing, etc.


Asunto(s)
Oxígeno/metabolismo , Proteínas/metabolismo , Microscopía por Crioelectrón/métodos , Espectroscopía de Resonancia Magnética/métodos , Permeabilidad
6.
Analyst ; 149(5): 1579-1585, 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38288594

RESUMEN

A semi-packed gas chromatographic column has the advantages of high specific surface area and low column pressure. We report that the stagnation regions formed in the adjacent posts along the channel of the semi-packed columns can decrease the area and height of chromatographic peaks, which makes it difficult to detect low-concentration mixed gases. A semi-packed column with staggered elliptic cylindrical post arrays (SC-S) made using a micro-electro-mechanical system technique is presented, and the separation performance of SC-S is compared with that of a semi-packed column with aligned elliptic cylindrical post arrays (SC-A). The simulation results show that the width of stagnation regions in SC-S is 86.89% smaller than that in SC-A. The experimental results indicate that the area and height of chromatographic peaks increased as stagnation regions reduced. In the separation of the alkane mixture from C8 through C10 with 10 ppm concentration, the chromatographic peak of decane was hardly identified in SC-A while the chromatographic peak in SC-S was still clearly visible. The chromatographic peak heights of octane and nonane were increased by 65.06% and 130.00%, respectively, in SC-S. The peak areas of octane and nonane were increased by 120.45% and 168.18%, respectively.

7.
Int J Mol Sci ; 25(10)2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38791136

RESUMEN

DNA methylation is an important mechanism for epigenetic modifications that have been shown to be associated with responses to plant development. Previous studies found that inverted Populus yunnanensis cuttings were still viable and could develop into complete plants. However, the growth status of inverted cuttings was weaker than that of upright cuttings, and the sprouting time of inverted cuttings was later than that of upright cuttings. There is currently no research on DNA methylation patterns in inverted cuttings of Populus yunnanensis. In this study, we detected genome-wide methylation patterns of stem tips of Populus yunnanensis at the early growth stage and the rapid growth stage by Oxford Nanopore Technologies (ONT) methylation sequencing. We found that the methylation levels of CpG, CHG, CHH, and 6mA were 41.34%, 33.79%, 17.27%, and 12.90%, respectively, in the genome of inverted poplar cuttings, while the methylation levels of the four methylation types were higher in the genome of upright poplar cuttings than in inverted cuttings, 41.90%, 34.57%, 18.09%, and 14.11%, suggesting important roles for DNA methylation in poplar cells. In all comparison groups, CpG-type methylation genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were annotated to pathways associated with carbon metabolism, ribosome biogenesis in eukaryotes, glycolysis/gluconeogenesis, pyruvate metabolism, and mRNA detection pathways, suggesting that different biological processes are activated in upright and inverted cuttings. The results show that methylation genes are commonly present in the poplar genome, but only a few of them are involved in the regulation of expression in the growth and development of inverted cuttings. From this, we screened the DET2 gene for significant differences in methylation levels in upright or inverted cuttings. The DET2 gene is a key gene in the Brassinolide (BRs) synthesis pathway, and BRs have an important influence on the growth and development process of plants. These results provide important clues for studying DNA methylation patterns in P. yunnanensis.


Asunto(s)
Metilación de ADN , Regulación de la Expresión Génica de las Plantas , Populus , Populus/genética , Populus/crecimiento & desarrollo , Populus/metabolismo , Epigénesis Genética , Genoma de Planta , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
8.
Biochem Biophys Res Commun ; 667: 186-193, 2023 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-37229827

RESUMEN

The deubiquitinating enzyme USP14 has been established as a crucial regulator in various diseases, including tumors, neurodegenerative diseases, and metabolic diseases, through its ability to stabilize its substrate proteins. Our group has utilized proteomic techniques to identify new potential substrate proteins for USP14, however, the underlying signaling pathways regulated by USP14 remain largely unknown. Here, we demonstrate the key role of USP14 in both heme metabolism and tumor invasion by stabilizing the protein BACH1. The cellular oxidative stress response factor NRF2 regulates antioxidant protein expression through binding to the antioxidant response element (ARE). BACH1 can compete with NRF2 for ARE binding, leading to the inhibition of the expression of antioxidant genes, including HMOX-1. Activated NRF2 also inhibits the degradation of BACH1, promoting cancer cell invasion and metastasis. Our findings showed a positive correlation between USP14 expression and NRF2 expression in various cancer tissues from the TCGA database and normal tissues from the GTEx database. Furthermore, activated NRF2 was found to increase USP14 expression in ovarian cancer (OV) cells. The overexpression of USP14 was observed to inhibit HMOX1 expression, while USP14 knockdown had the opposite effect, suggesting a role for USP14 in regulating heme metabolism. The depletion of BACH1 or inhibition of heme oxygenase 1 (coded by HMOX-1) was also found to significantly impair USP14-dependent OV cell invasion. In conclusion, our results highlight the importance of the NRF2-USP14-BACH1 axis in regulating OV cell invasion and heme metabolism, providing evidence for its potential as a therapeutic target in related diseases.


Asunto(s)
Factor 2 Relacionado con NF-E2 , Neoplasias Ováricas , Humanos , Femenino , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Antioxidantes , Proteómica , Neoplasias Ováricas/genética , Hemo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Ubiquitina Tiolesterasa/genética
9.
Phys Rev Lett ; 130(24): 243801, 2023 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-37390435

RESUMEN

Owing to the chirality of Weyl nodes characterized by the first Chern number, a Weyl system supports one-way chiral zero modes under a magnetic field, which underlies the celebrated chiral anomaly. As a generalization of Weyl nodes from three-dimensional to five-dimensional physical systems, Yang monopoles are topological singularities carrying nonzero second-order Chern numbers c_{2}=±1. Here, we couple a Yang monopole with an external gauge field using an inhomogeneous Yang monopole metamaterial and experimentally demonstrate the existence of a gapless chiral zero mode, where the judiciously designed metallic helical structures and the corresponding effective antisymmetric bianisotropic terms provide the means for controlling gauge fields in a synthetic five-dimensional space. This zeroth mode is found to originate from the coupling between the second Chern singularity and a generalized 4-form gauge field-the wedge product of the magnetic field with itself. This generalization reveals intrinsic connections between physical systems of different dimensions, while a higher-dimensional system exhibits much richer supersymmetric structures in Landau level degeneracy due to the internal degrees of freedom. Our study offers the possibility of controlling electromagnetic waves by leveraging the concept of higher-order and higher-dimensional topological phenomena.

10.
Chemistry ; 29(3): e202202106, 2023 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-36251739

RESUMEN

The mechanosensitive ion channel of large conductance (MscL) is a promising template for the development of new antibiotics due to its high conservation and uniqueness to microbes. Brilliant green (BG), a triarylmethane dye, has been identified as a new antibiotic targeted MscL. However, the detailed binding sites to MscL and the dynamic pathway of BG through the MscL channel remain unknown. Here, the dynamic interactions between BG and MscL were investigated using solid-state NMR spectroscopy and molecule dynamics (MD) simulations. Residue site-specific binding sites of BG to the MscL channel were identified by solid-state NMR. In addition, MD simulations revealed that BG conducts through the MscL channel via residues along the inner surface of the pore sequentially, in which the strong hydrophobic interactions between BG and hydrophobic residues F23 and I27 in the hydrophobic gate region of the MscL channel are major restrictions. Particularly, it was demonstrated that BG activates the MscL channel by reducing the hydrophobicity of the F23 in the gate region by water molecules that are bound to BG. Taken together, these simulations and experimental data provide novel insights into the dynamic interactions between BG and MscL, based on which new hydrophobic antibiotics and adjuvants targeting MscL can be developed.


Asunto(s)
Proteínas de Escherichia coli , Simulación de Dinámica Molecular , Proteínas de Escherichia coli/química , Escherichia coli/metabolismo , Canales Iónicos/química , Espectroscopía de Resonancia Magnética , Antibacterianos/química
11.
Proc Natl Acad Sci U S A ; 117(29): 16739-16742, 2020 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-32636263

RESUMEN

Metal and dielectric have long been thought as two different states of matter possessing highly contrasting electric and optical properties. A metal is a material highly reflective to electromagnetic waves for frequencies up to the optical region. In contrast, a dielectric is transparent to electromagnetic waves. These two different classical electrodynamic properties are distinguished by different signs of the real part of permittivity: The metal has a negative sign while the dielectric has a positive one. Here, we propose a different topological understanding of metal and dielectric. By considering metal and dielectric as just two limiting cases of a periodic metal-dielectric layered metamaterial, from which a metal can continuously transform into a dielectric by varying the metal filling ratio from 1 to 0, we further demonstrate the abrupt change of a topological invariant at a certain point during this transition, classifying the metamaterials into metallic state and dielectric state. The topological phase transition from the metallic state to the dielectric state occurs when the filling ratio is one-half. These two states generalize our previous understanding of metal and dielectric: The metamaterial with metal filling ratio larger/smaller than one-half is named as the "generalized metal/dielectric." Interestingly, the surface plasmon polariton (SPP) at a metal/dielectric interface can be understood as the limiting case of a topological edge state.

12.
Pestic Biochem Physiol ; 194: 105507, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37532360

RESUMEN

As a common fungicide, difenoconazole (DFZ) is widespread in the natural environment and poses many potential threats. Carp makes up a significant proportion of China's freshwater aquaculture population and are vulnerable to the DFZ. Therefore, this study investigated the effects of DFZ (0.488 mg/L and 1.953 mg/L) exposure for 4 d on the intestinal tissues of carp and explored the mechanisms. Specifically, DFZ exposure caused pathological damage to the intestinal tissues of carp, reducing the expression levels of intestinal tight junction proteins, and leading to damage to the intestinal barrier. In addition, DFZ exposure activated the NF-κB signaling pathway, increasing the levels of pro-inflammatory factors (TNF-α, IL-1ß, IL-6) and decreasing the levels of anti-inflammatory factors (IL-10, TGF-ß1). As disruption of the intestinal barrier is closely linked to oxidative stress and apoptosis, we have conducted research in both areas for this reason. The results showed that DFZ exposure elevated reactive oxygen species in carp intestines, decreased antioxidant enzyme activity, and suppressed the expression of oxidative stress-related genes. TUNEL results showed that DFZ induced the onset of apoptosis. In addition, the expression levels of apoptosis-related genes and proteins were examined. Western blotting results showed that DFZ could upregulate the protein expression levels of Bax, Cytochrome C and downregulate the protein levels of Bcl-2. qPCR results showed that DFZ could upregulate the transcript levels of Bax, Caspase-3, Caspase-8 and Caspase-9 and downregulate the transcript levels of Bcl-2 transcript levels. This suggests that DFZ can induce apoptosis of mitochondrial pathway in carp intestine. In conclusion, DFZ can induce oxidative stress and apoptosis in carp intestine, leading to the destruction of intestinal physical barrier and the occurrence of inflammation. Our data support the idea that oxidative stress and apoptosis are important triggers of pesticide-induced inflammatory bowel illness.


Asunto(s)
Carpas , Animales , Carpas/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Proteínas de Peces/farmacología , Intestinos , Estrés Oxidativo , Antioxidantes/farmacología , Apoptosis , FN-kappa B/metabolismo
13.
Int J Mol Sci ; 24(19)2023 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-37834105

RESUMEN

Having a spiral grain is considered to be one of the most important wood properties influencing wood quality. Here, transcriptome profiles and metabolome data were analyzed in the straight grain and twist grain of Pinus yunnanensis. A total of 6644 differential expression genes were found between the straight type and the twist type. A total of 126 differentially accumulated metabolites were detected. There were 24 common differential pathways identified from the transcriptome and metabolome, and these pathways were mainly annotated in ABC transporters, arginine and proline metabolism, flavonoid biosynthesis, isoquinoline alkaloid biosynthesis, linoleic acid metabolism, phenylpropanoid, tryptophan metabolism, etc. A weighted gene coexpression network analysis showed that the lightblue4 module was significantly correlated with 2'-deoxyuridine and that transcription factors (basic leucine zipper (bZIP), homeodomain leucine zipper (HD-ZIP), basic helix-loop-helix (bHLH), p-coumarate 3-hydroxylase (C3H), and N-acetylcysteine (NAC)) play important roles in regulating 2'-deoxyuridine, which may be involved in the formation of spiral grains. Meanwhile, the signal transduction of hormones may be related to spiral grain, as previously reported. ARF7 and MKK4_5, as indoleacetic acid (IAA)- and ethylene (ET)-related receptors, may explain the contribution of plant hormones in spiral grain. This study provided useful information on spiral grain in P. yunnanensis by transcriptome and metabolome analyses and could lay the foundation for future molecular breeding.


Asunto(s)
Pinus , Transcriptoma , Pinus/genética , Perfilación de la Expresión Génica , Metabolómica , Metaboloma , Grano Comestible/genética , Desoxiuridina , Regulación de la Expresión Génica de las Plantas
14.
J Am Chem Soc ; 144(48): 22229-22241, 2022 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-36413513

RESUMEN

Aquaporins are transmembrane channels that allow for the passive permeation of water and other small molecules across biological membranes. Their channel activities are sensitive to mercury ions. Intriguingly, while most aquaporins are inhibited by mercury ions, several aquaporins are activated by mercury ions. The molecular basis of the opposing aquaporin regulation by mercury remains poorly understood. Herein, we investigated AqpZ inhibition and AQP6 activation upon binding of mercury ions using solid-state NMR (ssNMR) and molecular dynamics (MD) simulations. Based on the structure of the Hg-AqpZ complex constructed by MD simulations and ssNMR, we identified that the pore closure was caused by mercury-induced conformational changes of the key residue R189 in the selectivity filter region, while pore opening was caused by conformational changes of residues H181 and R196 in the selectivity filter region in AQP6. Both conformational changes were caused by the disruption of the H-bond network of R189/R196 by mercury. The molecular details provided a structural basis for mercury-mediated functional changes in aquaporins.


Asunto(s)
Mercurio
15.
Biochem Biophys Res Commun ; 618: 1-7, 2022 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-35714565

RESUMEN

Aquaporins (AQPs) transport water molecules across cell membranes. Although most aquaporins are inhibited by mercury ions, AQP6 was reported to be activated by binding mercury ions to residues C155 and C190. Different from C190 and the other pore-line cysteine residues, C155 is located outside the pore, thus not directly affecting the internal pathway by mercury binding to it. The molecular mechanism of unusual water channel activation by mercury ion binding to the C155 site remains unknown. Here, we investigate the activation of AQP6 by mercury ions binding to C155 by molecular dynamics (MD) simulations. The MD simulation results show that the mercury-induced water permeation activation is derived from the conformational change of a pore-line residue M160, from a point-to-pore conformation before mercury binding to an away-pore conformation after mercury binding. The conformation change of M160 is derived from the reduction of the hydrogen bonding between C155 and S159 in the α-helix with the coordination of C155 to mercury ion altering their conformation significantly. This study reveals the complex mechanism of water channel activation by mercury ion binding to pore-external residues in water channels.


Asunto(s)
Acuaporinas , Mercurio , Acuaporinas/metabolismo , Iones/metabolismo , Mercurio/metabolismo , Simulación de Dinámica Molecular , Agua/química
16.
Phys Rev Lett ; 129(12): 123901, 2022 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-36179206

RESUMEN

Quantum tunneling, one of the most celebrated effects arising from the wave nature of matter, describes the partial penetration of an incident propagating wave through a potential barrier in the form of an evanescent field that exponentially decays from the incident interface. A similar tunneling effect has also been observed in classical systems, such as the frustrated total internal reflection. Here we reveal an unexplored form of tunneling for electromagnetic waves which features opposite behaviors for the electric and magnetic fields, with one turning into a growing field, and the other a decaying field, in a medium that exhibits both ϵ-µ-zero and bianisotropy. Our Letter provides a new mechanism for manipulating electromagnetic waves for novel device applications.

17.
J Nanobiotechnology ; 20(1): 414, 2022 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-36109762

RESUMEN

The chemotherapy effect of docetaxel (DTX) against triple-negative breast cancer (TNBC) remains mediocre and limited when encapsulated in conventional cholesterol liposomes, mainly ascribed to poor penetration and immunosuppressive tumor microenvironment (TME) caused by tumor stroma cells, especially cancer-associated fibroblasts (CAFs). Many studies have attempted to address these problems but trapped into the common dilemma of excessively complicated formulation strategies at the expense of druggability as well as clinical translational feasibility. To better address the discrepancy, ginsenoside Rg3 was utilized to substitute cholesterol to develop a multifunctional DTX-loaded Rg3 liposome (Rg3-Lp/DTX). The obtained Rg3-Lp/DTX was proved to be preferentially uptake by 4T1 cells and accumulate more at tumor site via the interaction between the glycosyl moiety of Rg3 exposed on liposome surface and glucose transporter1 (Glut1) overexpressed on tumor cells. After reaching tumor site, Rg3 was shown to reverse the activated CAFs to the resting stage and attenuate the dense stroma barrier by suppressing secretion of TGF-ß from tumor cells and regulating TGF-ß/Smad signaling. Therefore, reduced levels of CAFs and collagens were found in TME after incorporation of Rg3, inducing enhanced penetration of Rg3-Lp/DTX in the tumor and reversed immune system which can detect and neutralize tumor cells. Compared with wooden cholesterol liposomes, the smart and versatile Rg3-Lp/DTX could significantly improve the anti-tumor effect of DTX, providing a promising approach for TNBC therapy with excellent therapeutic efficacy and simple preparation process.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Docetaxel , Ginsenósidos , Glucosa , Transportador de Glucosa de Tipo 1 , Humanos , Liposomas , Factor de Crecimiento Transformador beta , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Microambiente Tumoral
18.
BMC Biol ; 19(1): 117, 2021 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-34088313

RESUMEN

BACKGROUND: The vacuole/lysosome is the final destination of autophagic pathways, but can also itself be degraded in whole or in part by selective macroautophagic or microautophagic processes. Diverse molecular mechanisms are involved in these processes, the characterization of which has lagged behind those of ATG-dependent macroautophagy and ESCRT-dependent endosomal multivesicular body pathways. RESULTS: Here we show that as yeast cells gradually exhaust available nutrients and approach stationary phase, multiple vacuolar integral membrane proteins with unrelated functions are degraded in the vacuolar lumen. This degradation depends on the ESCRT machinery, but does not strictly require ubiquitination of cargos or trafficking of cargos out of the vacuole. It is also temporally and mechanistically distinct from NPC-dependent microlipophagy. The turnover is facilitated by Atg8, an exception among autophagy proteins, and an Atg8-interacting vacuolar membrane protein, Hfl1. Lack of Atg8 or Hfl1 led to the accumulation of enlarged lumenal membrane structures in the vacuole. We further show that a key function of Hfl1 is the membrane recruitment of Atg8. In the presence of Hfl1, lipidation of Atg8 is not required for efficient cargo turnover. The need for Hfl1 can be partially bypassed by blocking Atg8 delipidation. CONCLUSIONS: Our data reveal a vacuolar membrane protein degradation process with a unique dependence on vacuole-associated Atg8 downstream of ESCRTs, and we identify a specific role of Hfl1, a protein conserved from yeast to plants and animals, in membrane targeting of Atg8.


Asunto(s)
Saccharomyces cerevisiae , Vacuolas , Animales , Autofagia , Familia de las Proteínas 8 Relacionadas con la Autofagia/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Proteínas de la Membrana/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
19.
Opt Lett ; 46(11): 2758-2761, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-34061106

RESUMEN

In general, a spin-polarized light beam cannot couple its spin angular momentum (SAM) with intrinsic orbital angular momentum (IOAM) without spin reversal. Here we find that nonlinear media can give the spin-polarized photon an IOAM, as they travel in the media due to the nonlinear susceptibility along the transmission direction, which does not require spin reversal. To characterize this SAM-to-IOAM conversion process, we establish an evolution ray equation for photons carrying IOAM by reference to the Schrödinger equation. We further reveal the inherent physics of such a phenomenon from a full-wave perspective and find that the vortex generation originates from the nonlinear-induced geometric phase.

20.
Cereb Cortex ; 30(7): 4121-4139, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32198502

RESUMEN

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.


Asunto(s)
Aptitud/fisiología , Selección de Profesión , Corteza Cerebral/crecimiento & desarrollo , Percepción de Forma/genética , Corteza Visual/crecimiento & desarrollo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Grosor de la Corteza Cerebral , Femenino , Regulación del Desarrollo de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Proteínas de Microfilamentos/genética , Persona de Mediana Edad , Análisis de Componente Principal , Proteínas de Unión al ARN/genética , Transcriptoma , Adulto Joven , Proteínas de Unión al GTP rho/genética , Proteínas tau/genética
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