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1.
Proc Natl Acad Sci U S A ; 121(43): e2407355121, 2024 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-39405345

RESUMEN

Expanding the protein fold space beyond linear chains is of fundamental significance, yet remains largely unexplored. Herein, we report the creation of seven topological isoforms (i.e., linear, cyclic, knot, lasso, pseudorotaxane, and catenane) from a single protein fold precursor by rewiring the connectivity of secondary structure elements of the SpyTag-SpyCatcher complex and mutating the reactive residue on SpyTag to abolish the isopeptide bonding. These topological isoforms can be directly expressed in cells. Their topologies were confirmed by combined techniques of proteolytic digestion, fluorescence correlation spectroscopy (FCS), size-exclusion chromatography (SEC), and topological transformation. To study the effects of topology on their structures and properties, their biophysical properties were characterized by differential scanning calorimetry (DSC), heteronuclear single quantum coherence nuclear magnetic resonance spectroscopy (HSQC-NMR), and circular dichroism (CD) spectroscopy. Molecular dynamics (MD) simulations were further performed to reveal the atomic details of structural changes upon unfolding. Both experimental and simulation results suggest that they share a similar, well-folded hydrophobic core but exhibit distinct folding/unfolding dynamic behaviors. These results shed light onto the folding landscape of topological isoforms derived from the same protein fold. As a model system, this work improves our understanding of protein structure and dynamics beyond linear chains and suggests that protein folds are highly amenable to topological variation.


Asunto(s)
Simulación de Dinámica Molecular , Pliegue de Proteína , Isoformas de Proteínas , Isoformas de Proteínas/química , Dicroismo Circular , Rastreo Diferencial de Calorimetría , Estructura Secundaria de Proteína
2.
Chem Soc Rev ; 53(4): 1892-1914, 2024 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-38230701

RESUMEN

Molecular assembly is the process of organizing individual molecules into larger structures and complex systems. The self-assembly approach is predominantly utilized in creating artificial molecular assemblies, and was believed to be the primary mode of molecular assembly in living organisms as well. However, it has been shown that the assembly of many biological complexes is "catalysed" by other molecules, rather than relying solely on self-assembly. In this review, we summarize these catalysed-assembly (catassembly) phenomena in living organisms and systematically analyse their mechanisms. We then expand on these phenomena and discuss related concepts, including catalysed-disassembly and catalysed-reassembly. Catassembly proves to be an efficient and highly selective strategy for synergistically controlling and manipulating various noncovalent interactions, especially in hierarchical molecular assemblies. Overreliance on self-assembly may, to some extent, hinder the advancement of artificial molecular assembly with powerful features. Furthermore, inspired by the biological catassembly phenomena, we propose guidelines for designing artificial catassembly systems and developing characterization and theoretical methods, and review pioneering works along this new direction. Overall, this approach may broaden and deepen our understanding of molecular assembly, enabling the construction and control of intelligent assembly systems with advanced functionality.

3.
Cancer Sci ; 115(1): 83-93, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37985391

RESUMEN

Autoantibodies (AAbs) in the blood of colorectal cancer (CRC) patients have been evaluated for tumor detection. However, it remains uncertain whether these AAbs are specific to tumor-associated antigens. In this study, we explored the IgG and IgM autoantibody repertoires in both the in situ tissue microenvironment and peripheral blood as potential tumor-specific biomarkers. We applied high-density protein arrays to profile AAbs in the tumor-infiltrating lymphocyte supernatants and corresponding serum from four patients with CRC, as well as in the serum of three noncancer controls. Our findings revealed that there were more reactive IgM AAbs than IgG in both the cell supernatant and corresponding serum, with a difference of approximately 3-5 times. Immunoglobulin G was predominant in the serum, while IgM was more abundant in the cell supernatant. We identified a range of AAbs present in both the supernatant and the corresponding serum, numbering between 432 and 780, with an average of 53.3% shared. Only 4.7% (n = 23) and 0.2% (n = 2) of reactive antigens for IgG and IgM AAbs, respectively, were specific to CRC. Ultimately, we compiled a list of 19 IgG AAb targets as potential tumor-specific AAb candidates. Autoantibodies against one of the top candidates, p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A), were significantly elevated in 53 CRC patients compared to 119 controls (p < 0.0001). The project revealed that tissue-derived IgG AAbs, rather than IgM, are the primary source of tumor-specific AAbs in peripheral blood. It also identified potential tumor-specific AAbs that could be applied for noninvasive screening of CRC.


Asunto(s)
Autoanticuerpos , Neoplasias Colorrectales , Humanos , Biomarcadores de Tumor , Inmunoglobulina G , Inmunoglobulina M , Microambiente Tumoral , Proteínas Represoras , Proteínas de Ciclo Celular
4.
FASEB J ; 37(6): e22955, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37159387

RESUMEN

The pathogenesis of allergic rhinitis (AR)-related olfactory dysfunction (OD) remains unknown. Inhibiting microglial response in olfactory bulb (OB) can ameliorate AR-related OD, but no precise targets have been available. In this study, we established a mouse model of ovalbumin (OVA)-induced AR and combined with the application of P2X7 receptor (P2X7R)-specific antagonists and cell culture in conditioned medium to investigate the role and mechanism of OB microglial P2X7R in AR-related OD. Serum IgE and IL-5 levels determined via ELISA and federated the number of nose-scratching to affirm the success of OVA-induced AR mouse model. Buried food pellet test was used to evaluate the olfactory function of mice. The changes of IBA1, GFAP, P2X7R, IL-1ß, IL-1Ra, and CASPASE 1 were detected by quantitative polymerase chain reaction and western blotting. The levels of adenosine triphosphate (ATP) were determined by the commercialized kit. The morphological changes of microglia were assessed using immunofluorescence staining and Sholl analysis. Findings showed that AR-related OD was associated with OB microglia-mediated imbalance between IL-1ß and IL-1Ra. Treatment with BBG improved the olfactory function in AR mice with restoring the balance between IL-1ß and IL-1Ra. In vitro, the conditioned medium obtained after HNEpC treatment with Der p1 could activate HMC3 to arise inflammatory reaction basing on "ATP-P2X7R-Caspase 1" axis, while inhibition of its P2X7R suppressed the reaction. In brief, microglial P2X7R in OB is a direct effector molecule in AR-related OD and inhibition of it may be a new strategy for the treatment of AR-related OD.


Asunto(s)
Trastornos del Olfato , Receptores Purinérgicos P2X7 , Rinitis Alérgica , Animales , Ratones , Adenosina Trifosfato , Caspasa 1 , Medios de Cultivo Condicionados , Modelos Animales de Enfermedad , Proteína Antagonista del Receptor de Interleucina 1 , Microglía , Bulbo Olfatorio , Ovalbúmina , Receptores Purinérgicos P2X7/genética , Rinitis Alérgica/complicaciones
5.
BMC Musculoskelet Disord ; 25(1): 718, 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39242516

RESUMEN

OBJECTIVE: To systematically review the clinical efficacy (pain, function, quality of life) and safety of platelet-rich plasma (PRP) in the treatment of frozen shoulder through meta-analysis, and provide evidence-based medical evidence for the effectiveness of PRP in the treatment of frozen shoulder. METHODS: A search was conducted on international databases (Pubmed, Web of science, Embase) and Chinese databases (CNKI, Wanfang, VIP) to search the clinical studies on the efficacy of platelet-rich plasma in treating frozen shoulder (adhesive capsulitis/periarthritis/50 shoulder) and their corresponding references published from inception until January 2024. Thoroughly excluded literature not meeting the predetermined inclusion criteria, extracted relevant data from the literature, and input it into RevMan5.4 for meta-analysis. RESULTS: This study ultimately included 14 RCTs, with a total of 1024 patients. The results showed that PRP has significant advantages compared with control groups in VAS (mean difference (MD) =-0.38, 95% confidence interval(CI)(-0.73, -0.03), P = 0.03), UCLA (MD = 3.31, 95% CI (1.02,5.60),P = 0.005), DASH (MD = -4.94,95% CI (-9.34, -0.53),P = 0.03), SPADI (SPADI Total: MD =-16.87, 95% CI (-22.84, -10.91), P < 0.00001; SPADI Pain: MD =-5.38, 95% CI (-7.80, -2.97), P < 0.0001; SPADI Disability: MD =-11.00, 95% CI (-13.61,-8.39), P < 0.00001), and the active and passive Range of Motion (active flexion: MD = 12.70, 95% CI (7.44, 17.95), P < 0.00001; passive flexion: MD = 9.47, 95% CI(3.80, 15.14), P = 0.001; active extension: MD = 3.45, 95% CI(2.39, 4.50), P < 0.00001; active abduction: MD = 13.54, 95% CI(8.42, 18.67), P < 0.00001; passive abduction: MD = 14.26, 95% CI (5.97, 22.56), P = 0.0008; active internal rotation: MD = 5.16, 95% CI (1.84, 8.48), P = 0.002; passive internal rotation: MD = 3.65, 95% CI(1.15, 6.15), P = 0.004; active external rotation: MD = 10.50, 95% CI(5.47, 15.53), P < 0.0001; passive external rotation: MD = 6.00, 95% CI (1.82, 10.19), P = 0.005) except passive extension (MD = 2.25, 95% CI (-0.77, 5.28), P = 0.14). In terms of safety, most studies reported no adverse effects, and only one study reported common complications of joint puncture such as swelling and pain after treatment in both PRP and control groups. Previous studies have shown a risk of osteonecrosis caused by corticosteroids. Therefore, the safety of PRP treatment is more reliable. CONCLUSION: The results showed that PRP was more durable and safer than corticosteroids and other control groups in the treatment of frozen shoulder. STUDY DESIGN: Systematic review. TRIAL REGISTRATION: PROSPERO CRD42022359444, date of registration: 22-09-2022.


Asunto(s)
Bursitis , Plasma Rico en Plaquetas , Rango del Movimiento Articular , Humanos , Bursitis/complicaciones , Bursitis/fisiopatología , Bursitis/terapia , Dimensión del Dolor , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Rango del Movimiento Articular/fisiología , Articulación del Hombro/fisiopatología , Dolor de Hombro/diagnóstico , Dolor de Hombro/etiología , Dolor de Hombro/fisiopatología , Dolor de Hombro/terapia , Resultado del Tratamiento
6.
Int J Appl Earth Obs Geoinf ; 131: 103949, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38993519

RESUMEN

Timely and precise detection of emerging infections is imperative for effective outbreak management and disease control. Human mobility significantly influences the spatial transmission dynamics of infectious diseases. Spatial sampling, integrating the spatial structure of the target, holds promise as an approach for testing allocation in detecting infections, and leveraging information on individuals' movement and contact behavior can enhance targeting precision. This study introduces a spatial sampling framework informed by spatiotemporal analysis of human mobility data, aiming to optimize the allocation of testing resources for detecting emerging infections. Mobility patterns, derived from clustering point-of-interest and travel data, are integrated into four spatial sampling approaches at the community level. We evaluate the proposed mobility-based spatial sampling by analyzing both actual and simulated outbreaks, considering scenarios of transmissibility, intervention timing, and population density in cities. Results indicate that leveraging inter-community movement data and initial case locations, the proposed Case Flow Intensity (CFI) and Case Transmission Intensity (CTI)-informed spatial sampling enhances community-level testing efficiency by reducing the number of individuals screened while maintaining a high accuracy rate in infection identification. Furthermore, the prompt application of CFI and CTI within cities is crucial for effective detection, especially in highly contagious infections within densely populated areas. With the widespread use of human mobility data for infectious disease responses, the proposed theoretical framework extends spatiotemporal data analysis of mobility patterns into spatial sampling, providing a cost-effective solution to optimize testing resource deployment for containing emerging infectious diseases.

7.
Mol Plant Microbe Interact ; 36(2): 119-130, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36515967

RESUMEN

Most bacteria use type II fatty acid synthesis (FAS) systems for synthesizing fatty acids, of which the conserved FabA-FabB pathway is considered to be crucial for unsaturated fatty acid (UFA) synthesis in gram-negative bacteria. Xanthomonas campestris pv. campestris, the phytopathogen of black rot disease in crucifers, produces higher quantities of UFAs under low-temperature conditions for increasing membrane fluidity. The fabA and fabB genes were identified in the X. campestris pv. campestris genome by BLAST analysis; however, the growth of the X. campestris pv. campestris fabA and fabB deletion mutants was comparable to that of the wild-type strain in nutrient and minimal media. The X. campestris pv. campestris ΔfabA and ΔfabB strains produced large quantities of UFAs and, altogether, these results indicated that the FabA-FabB pathway is not essential for growth or UFA synthesis in X. campestris pv. campestris. We also observed that the expression of X. campestris pv. campestris fabA and fabB restored the growth of the temperature-sensitive Escherichia coli fabA and fabB mutants CL104 and CY242, respectively, under non-permissive conditions. The in-vitro assays demonstrated that the FabA and FabB proteins of X. campestris pv. campestris catalyzed FAS. Our study also demonstrated that the production of diffusible signal factor family signals that mediate quorum sensing was higher in the X. campestris pv. campestris ΔfabA and ΔfabB strains and greatly reduced in the complementary strains, which exhibited reduced swimming motility and attenuated host-plant pathogenicity. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.


Asunto(s)
Xanthomonas campestris , Xanthomonas campestris/metabolismo , Ácidos Grasos/metabolismo , Escherichia coli/genética , Percepción de Quorum , Ácidos Grasos Insaturados/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo
8.
Anal Chem ; 95(45): 16435-16446, 2023 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-37921449

RESUMEN

Biomolecular characterization is essential in fields such as drug discovery, glycomics, and cell biology. This feature article focuses on the experimental use of quartz crystal microbalance with dissipation (QCM-D) as a powerful analytical technique to probe biological events ranging from biomacromolecular interactions and conformational changes of biomacromolecules to surface immobilization of biomacromolecules and cell morphological changes.

9.
J Neurosci Res ; 101(4): 480-491, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36564932

RESUMEN

In addition to typical nasal symptoms, patients with allergic rhinitis (AR) will further lead to symptoms related to brain function such as hyposmia, anxiety, depression, cognitive impairment, memory loss, etc., which seriously affect the quality of life of patients and bring a heavy burden to the patient's family and society. Some scholars have speculated that there may be potential "nose-brain communication" mechanism in AR that rely on neuro-immunity. This mechanism plays an important role in AR-associated brain response process. However, no study has directly demonstrated which neural circuits will change in the connection between the nose and brain during the onset of AR, and the mechanism which underlines this question is also lack. Focusing on the topic of "nose-brain communication", this paper systematically summarizes the latest research progress between AR and related brain responses and discusses the mechanism of AR-related neurological phenotypes. Hope new diagnostic and therapeutic targets to ameliorate the brain function-related symptoms and improve the quality of life of AR patients will be developed.


Asunto(s)
Calidad de Vida , Rinitis Alérgica , Humanos , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/terapia , Encéfalo
10.
Macromol Rapid Commun ; 44(1): e2200319, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35652408

RESUMEN

Due to the fast phase separation kinetics and small feature size, the self-assembly of giant molecules has attracted lots of attention. However, there is not much study on multicomponent giant surfactants. In this work, through a modular synthetic strategy, different polyhedral oligomeric silsesquioxane (POSS)-based molecular nanoparticles are installed with diverse functionalities (hydrophobic octavinyl POSS (VPOSS), hydrophilic dihydroxyl-functionalized POSS (DPOSS), and omniphobic perfluoroalkyl-chain-functionalized POSS (FPOSS)) on the ends of one polystyrene (PS) chain to build up a series of triblock bola-form giant surfactants denoted as XPOSS-PSn -FPOSS (X represents V or D). The target molecules are prepared by a combination of atom transfer radical polymerization (ATRP), esterification, as well as Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and thiol-ene "click" reactions. These macromolecules are thoroughly characterized by combined technologies including nuclear magnetic resonance (NMR), size exclusion chromatography (SEC), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analyses. It is revealed by small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) that VPOSS-PSn -FPOSS adopts a two-phase separation scenario where VPOSS and POSS are segregated in one phase. DPOSS-PSn -FPOSS with a third hydrophilic DPOSS shows a three-phase separation scenario, where highly ordered phase structures are difficult to develop owing to the competition of mutual phase separation processes and may be trapped in kinetically metastable states.


Asunto(s)
Nanopartículas , Tensoactivos , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Nanopartículas/química
11.
Mediators Inflamm ; 2023: 1265449, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37091903

RESUMEN

Allergic rhinitis (AR) is a chronic upper airway immune-inflammation response mediated by immunoglobulin E (IgE) to allergens and can seriously affect the quality of life and work efficiency. Previous studies have shown that interleukin-1ß (IL-1ß) acts as a key cytokine to participate in and promote the occurrence and development of allergic diseases. It has been proposed that IL-1ß may be a potential biomarker of AR. However, its definitive role and potential mechanism in AR have not been fully elucidated, and the clinical sample collection and detection methods were inconsistent among different studies, which have limited the use of IL-1ß as a clinical diagnosis and treatment marker for AR. This article systematically summarizes the research advances in the roles of IL-1ß in allergic diseases, focusing on the changes of IL-1ß in AR and the possible interventions. In addition, based on the findings by our team, we provided new insights into the use of IL-1ß in AR diagnosis and treatment, in an attempt to further promote the clinical application of IL-1ß in AR and other allergic diseases.


Asunto(s)
Calidad de Vida , Rinitis Alérgica , Humanos , Animales , Interleucina-1beta , Rinitis Alérgica/terapia , Alérgenos , Citocinas , Modelos Animales de Enfermedad
12.
Angew Chem Int Ed Engl ; 62(51): e202314980, 2023 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-37937859

RESUMEN

A technique combining ion mobility spectrometry-mass spectrometry (IMS-MS) and supercharging electrospray ionization (ESI) has been demonstrated to differentiate protein chemical topology effectively. Incorporating as many charges as possible into proteins via supercharging ESI allows the protein chains to be largely unfolded and stretched, revealing their hidden chemical topology. Different chemical topologies result in differing geometrical sizes of the unfolded proteins due to constraints in torsional rotations in cyclic domains. By introducing new topological indices, such as the chain-length-normalized collision cross-section (CCS) and the maximum charge state (zM ) in the extensively unfolded state, we were able to successfully differentiate various protein chemical topologies, including linear chains, ring-containing topologies (lasso, tadpole, multicyclics, etc.), and mechanically interlocked rings, like catenanes.


Asunto(s)
Espectrometría de Movilidad Iónica , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Movilidad Iónica/métodos , Proteínas/química
13.
Trends Biochem Sci ; 43(10): 806-817, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30041839

RESUMEN

Chemical topology has emerged as one intriguing feature in protein engineering. Nature demonstrates the elegance and power of protein topology engineering in the unique biofunctions and exceptional stabilities of cyclotides and lasso peptides. With entangling protein motifs and genetically encoded peptide-protein chemistry, artificial proteins with complex topologies, including cyclic proteins, star proteins, and protein catenanes, have become accessible. Among them, proteins with mechanical bonds ('mechanoproteins') are of special interest, owing to their potential functional benefits such as structure stabilization, quaternary structure control, synergistic multivalency effect, and dynamic mechanical sliding/switching properties. In this review article, we summarize recent progress in the field of protein topology engineering as well as the challenges and opportunities that it holds.


Asunto(s)
Proteínas/química , Modelos Moleculares , Conformación Proteica , Ingeniería de Proteínas , Estabilidad Proteica
14.
Mol Plant Microbe Interact ; 35(4): 323-335, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35286156

RESUMEN

In Xanthomonas spp., the biosynthesis of the yellow pigment xanthomonadin and fatty acids originates in the type II polyketide synthase (PKS II) and fatty acid synthase (FAS) pathways, respectively. The acyl carrier protein (ACP) is the central component of PKS II and FAS and requires posttranslational phosphopantetheinylation to initiate these pathways. In this study, for the first time, we demonstrate that the posttranslational modification of ACPs in X. campestris pv. campestris is performed by an essential 4'-phosphopantetheinyl transferase (PPTase), XcHetI (encoded by Xc_4132). X. campestris pv. campestris strain XchetI could not be deleted from the X. campestris pv. campestris genome unless another PPTase-encoding gene such as Escherichia coli acpS or Pseudomonas aeruginosa pcpS was present. Compared with wild-type strain X. campestris pv. campestris 8004 and mutant XchetI::PapcpS, strain XchetI::EcacpS failed to generate xanthomonadin pigments and displayed reduced pathogenicity for the host plant, Brassica oleracea. Further experiments showed that the expression of XchetI restored the growth of E. coli acpS mutant HT253 and, when a plasmid bearing XchetI was introduced into P. aeruginosa, pcpS, which encodes the sole PPTase in P. aeruginosa, could be deleted. In in vitro enzymatic assays, XcHetI catalyzed the transformation of 4'-phosphopantetheine from coenzyme A to two X. campestris pv. campestris apo-acyl carrier proteins, XcAcpP and XcAcpC. All of these findings indicate that XcHetI is a surfactin PPTase-like PPTase with a broad substrate preference. Moreover, the HetI-like PPTase is ubiquitously conserved in Xanthomonas spp., making it a potential new drug target for the prevention of plant diseases caused by Xanthomonas.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.


Asunto(s)
Xanthomonas campestris , Xanthomonas , Proteína Transportadora de Acilo/genética , Proteína Transportadora de Acilo/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Escherichia coli/genética , Pseudomonas aeruginosa/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismo , Xanthomonas/genética , Xanthomonas/metabolismo , Xanthomonas campestris/metabolismo
15.
J Am Chem Soc ; 144(40): 18387-18396, 2022 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-36178288

RESUMEN

Bioconjugation is a powerful protein modification strategy to improve protein properties. Herein, we report mechano-bioconjugation as a novel approach to empower fusion protein therapeutics and demonstrate its utility by a protein heterocatenane (cat-IFN-ABD) containing interferon-α2b (IFN) mechanically interlocked with a consensus albumin-binding domain (ABD). The conjugate was selectively synthesized in cellulo following a cascade of post-translational events using a pair of heterodimerizing p53dim variants and two orthogonal split-intein reactions. The catenane topology was proven by combined techniques of LC-MS, SDS-PAGE, SEC, and controlled proteolytic digestion. Not only did cat-IFN-ABD retain activities comparable to those of the wild-type IFN and ABD, the conjugate also exhibited enhanced aggregation resistance and prolonged circulation time over the simple linear and cyclic fusions. Consequently, cat-IFN-ABD potently inhibited tumor growth in the mouse xenograft model. Therefore, mechano-bioconjugation by catenation accomplishes function integration with additional benefits, providing an alternative pathway for developing advanced protein therapeutics.


Asunto(s)
Catenanos , Albúmina Sérica , Animales , Humanos , Interferón-alfa/química , Ratones , Poder Psicológico , Unión Proteica , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Albúmina Sérica/química
16.
Catheter Cardiovasc Interv ; 99 Suppl 1: 1440-1447, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35077596

RESUMEN

OBJECTIVES: To investigate the potential predictors and clinical significance of periprocedural myocardial infarction (PMI), as defined by the latest Fourth Universal Definition of Myocardial Infarction (2018), following rotational atherectomy (RA). BACKGROUND: PMI is not uncommon in patients undergoing RA, although the predictors and prognostic impact are unknown. METHODS: Data from 229 consecutive patients who had undergone RA before drug-eluting stent (DES) implantation in a single center were analyzed. Patients' demographic information, clinical, angiographic, and procedural characteristics, and 1-year follow-up outcomes were collected retrospectively. RESULTS: The overall incidence of PMI in patients undergoing RA was 48.5%. Age (adjusted odds ratio [OR]: 1.024, 95% confidence interval [CI]: 1.001-1.047, p = 0.043) and ejection fraction (adjusted OR: 0.977, 95% CI: 0.962-0.993, p = 0.004) were independent predictors of PMI in RA, although PMI was not associated with an increased risk of major adverse cardiovascular and cerebrovascular events (MACCEs) at the 1-year follow-up in patients undergoing RA. CONCLUSION: Age and ejection fraction were independently associated with an elevated risk of PMI in patients undergoing RA. However, post-RA microinfarcts were not associated with an increased risk of MACCEs over the short-term follow-up period.


Asunto(s)
Aterectomía Coronaria , Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Infarto del Miocardio , Intervención Coronaria Percutánea , Aterectomía Coronaria/efectos adversos , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Stents Liberadores de Fármacos/efectos adversos , Humanos , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Intervención Coronaria Percutánea/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento
17.
Int J Appl Earth Obs Geoinf ; 106: 102649, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35110979

RESUMEN

Governments worldwide have rapidly deployed non-pharmaceutical interventions (NPIs) to mitigate the COVID-19 pandemic. However, the effect of these individual NPI measures across space and time has yet to be sufficiently assessed, especially with the increase of policy fatigue and the urge for NPI relaxation in the vaccination era. Using the decay ratio in the suppression of COVID-19 infections and multi-source big data, we investigated the changing performance of different NPIs across waves from global and regional levels (in 133 countries) to national and subnational (in the United States of America [USA]) scales before the implementation of mass vaccination. The synergistic effectiveness of all NPIs for reducing COVID-19 infections declined along waves, from 95.4% in the first wave to 56.0% in the third wave recently at the global level and similarly from 83.3% to 58.7% at the USA national level, while it had fluctuating performance across waves on regional and subnational scales. Regardless of geographical scale, gathering restrictions and facial coverings played significant roles in epidemic mitigation before the vaccine rollout. Our findings have important implications for continued tailoring and implementation of NPI strategies, together with vaccination, to mitigate future COVID-19 waves, caused by new variants, and other emerging respiratory infectious diseases.

18.
J Am Chem Soc ; 143(43): 18029-18040, 2021 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-34664942

RESUMEN

The chemical topology is a unique dimension for protein engineering, yet the topological diversity and architectural complexity of proteins remain largely untapped. Herein, we report the biosynthesis of complex topological proteins using a rationally engineered, cross-entwining peptide heterodimer motif derived from p53dim (an entangled homodimeric mutant of the tetramerization domain of the tumor suppressor protein p53). The incorporation of an electrostatic interaction at specific sites converts the p53dim homodimer motif into a pair of heterodimer motifs with high specificity for directing chain entanglement upon folding. Its combination with split-intein-mediated ligation and/or SpyTag/SpyCatcher chemistry facilitates the programmed synthesis of protein heterocatenane or [n]catenanes in cells, leading to a general and modular approach to complex protein catenanes containing various proteins of interest. Concatenation enhances not only the target protein's affinity but also the in vivo stability as shown by its prolonged circulation time in blood. As a proof of concept, artificial antibodies have been developed by embedding a human epidermal growth factor receptor 2-specific affibody onto the [n]catenane scaffolds and shown to exhibit a higher affinity and a better pharmacokinetic profile than the wild-type affibody. These results suggest that topology engineering holds great promise in the development of therapeutic proteins.


Asunto(s)
Anticuerpos/química , Materiales Biomiméticos/metabolismo , Catenanos/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Secuencia de Aminoácidos , Animales , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacocinética , Catenanos/química , Catenanos/farmacocinética , Línea Celular Tumoral , Femenino , Humanos , Ratones Endogámicos BALB C , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacocinética , Prueba de Estudio Conceptual , Dominios Proteicos , Ingeniería de Proteínas , Estructura Cuaternaria de Proteína , Receptor ErbB-2/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/farmacocinética , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/farmacocinética
19.
Langmuir ; 37(37): 11084-11092, 2021 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-34493039

RESUMEN

Giant surfactants with different numbers of aryl-trifluorovinyl ether-functionalized polyhedral oligomeric silsesquioxane (FVPOSS) heads and one poly(ethylene oxide) (PEO) tail, (FVPOSS)n-PEO227, are precisely synthesized. The phase behaviors of (FVPOSS)n-PEO227 at the air-water interface were investigated through surface pressure measurements (isotherm and hysteresis experiments) and the Brewster angle microscopy. Upon increasing the number of FVPOSS heads, the interfacial behaviors of these giant surfactants greatly change. More phase transitions occur during the compression as the number of FVPOSS heads increased from one to two and three. The evolution of morphologies of Langmuir films and compression-expansion hysteresis curves further illustrate phase transitions at the air-water interface. Furthermore, molecular mechanisms to describe phase transitions of (FVPOSS)n-PEO227 at the interface are put forward. This study deepens the understanding of interfacial phase behaviors of special giant surfactants and provides knowledge of nanostructure design and construction at the interface.

20.
Gastric Cancer ; 24(1): 245-257, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32712769

RESUMEN

BACKGROUND: For patients with locally advanced proximal gastric cancer (LAPGC), the individualized selection of patients with highly suspected splenic hilar (No. 10) lymph node (LN) metastasis to undergo splenic hilar lymphadenectomy, is a clinical dilemma. This study aimed to re-evaluate the feasibility and safety of laparoscopic spleen-preserving splenic hilar lymphadenectomy (LSPSHL) and to identify the population who would benefit from it. METHODS: A total of 1068 patients (D2 group = 409; D2 + No. 10 group = 659) who underwent laparoscopic total gastrectomy from four prospective trials between January 2015 and July 2019 were analyzed. RESULTS: No significant difference in the incidence (16.9% vs. 16.4%; P = 0.837) of postoperative complications were found between the two groups. The metastasis rate of No. 10 LN among patients in the D2 + No. 10 group was 10.3% (68/659). Based on the decision tree, patients with LAPGC with tumor invading the greater curvature (Gre), patients with non-Gre-invading LAPGC with a tumor size > 5 cm and clinical positive locoregional LNs were defined as the high-priority No. 10 dissection group. The metastasis rate of No. 10 LNs in the high-priority group was 19.4% (41/211). In high-priority group, the 3-year overall survival of the D2 + No. 10 group was better than that of the D2 group (74.4% vs. 42.1%; P = 0.005), and the therapeutic index of No. 10 was higher than the indices of most suprapancreatic stations. CONCLUSIONS: LSPSHL for LAPGC is safe and feasible when performed by experienced surgeons. LSPSHL could be recommended for the high-priority group patients even without invasion of the Gre.


Asunto(s)
Gastrectomía/métodos , Laparoscopía/métodos , Escisión del Ganglio Linfático/métodos , Bazo/cirugía , Neoplasias Gástricas/cirugía , Ensayos Clínicos como Asunto , Estudios de Factibilidad , Femenino , Gastrectomía/efectos adversos , Humanos , Incidencia , Análisis de Intención de Tratar , Laparoscopía/efectos adversos , Escisión del Ganglio Linfático/efectos adversos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Tratamientos Conservadores del Órgano/efectos adversos , Tratamientos Conservadores del Órgano/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Puntaje de Propensión , Estudios Prospectivos , Neoplasias Gástricas/patología
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