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1.
N Engl J Med ; 388(14): 1272-1283, 2023 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-36762852

RESUMEN

BACKGROUND: The role of endovascular therapy for acute stroke with a large infarction has not been extensively studied in differing populations. METHODS: We conducted a multicenter, prospective, open-label, randomized trial in China involving patients with acute large-vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower values indicating larger infarction) or an infarct-core volume of 70 to 100 ml. Patients were randomly assigned in a 1:1 ratio within 24 hours from the time they were last known to be well to undergo endovascular therapy and receive medical management or to receive medical management alone. The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability), and the primary objective was to determine whether a shift in the distribution of the scores on the modified Rankin scale at 90 days had occurred between the two groups. Secondary outcomes included scores of 0 to 2 and 0 to 3 on the modified Rankin scale. The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours after randomization. RESULTS: A total of 456 patients were enrolled; 231 were assigned to the endovascular-therapy group and 225 to the medical-management group. Approximately 28% of the patients in both groups received intravenous thrombolysis. The trial was stopped early owing to the efficacy of endovascular therapy after the second interim analysis. At 90 days, a shift in the distribution of scores on the modified Rankin scale toward better outcomes was observed in favor of endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval, 1.11 to 1.69; P = 0.004). Symptomatic intracranial hemorrhage occurred in 14 of 230 patients (6.1%) in the endovascular-therapy group and in 6 of 225 patients (2.7%) in the medical-management group; any intracranial hemorrhage occurred in 113 (49.1%) and 39 (17.3%), respectively. Results for the secondary outcomes generally supported those of the primary analysis. CONCLUSIONS: In a trial conducted in China, patients with large cerebral infarctions had better outcomes with endovascular therapy administered within 24 hours than with medical management alone but had more intracranial hemorrhages. (Funded by Covidien Healthcare International Trading [Shanghai] and others; ANGEL-ASPECT ClinicalTrials.gov number, NCT04551664.).


Asunto(s)
Isquemia Encefálica , Infarto Cerebral , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Trombectomía , Humanos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/cirugía , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/cirugía , China , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/métodos , Fibrinolíticos/efectos adversos , Fibrinolíticos/uso terapéutico , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/etiología , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/cirugía , Estudios Prospectivos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/cirugía , Trombectomía/efectos adversos , Trombectomía/métodos , Resultado del Tratamiento
2.
PLoS Pathog ; 20(2): e1011948, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38300972

RESUMEN

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins.


Asunto(s)
Virus de la Fiebre Hemorrágica de Crimea-Congo , Fiebre Hemorrágica de Crimea , Animales , Ratones , Humanos , Virus de la Fiebre Hemorrágica de Crimea-Congo/genética , Anticuerpos Monoclonales , Microscopía por Crioelectrón , Anticuerpos Neutralizantes , Epítopos
3.
Proc Natl Acad Sci U S A ; 120(21): e2212933120, 2023 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-37186852

RESUMEN

The glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transport is believed to be driven by the perivascular pumping effect created by the pulsation of the arterial wall caused by the cardiac cycle. Ultrasound sonication of circulating microbubbles (MBs) in the cerebral vasculature induces volumetric expansion and contraction of MBs that push and pull on the vessel wall to generate a MB pumping effect. The objective of this study was to evaluate whether glymphatic transport can be mechanically manipulated by focused ultrasound (FUS) sonication of MBs. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as fluid tracers, followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected MBs. Intracisternal magna injection, the conventional technique used in studying glymphatic transport, was employed to provide a comparative reference. Three-dimensional confocal microscopy imaging of optically cleared brain tissue revealed that FUS sonication enhanced the transport of fluorescently labeled albumin tracer in the perivascular space (PVS) along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the PVS into the interstitial space. This study revealed that ultrasound combined with circulating MBs could mechanically enhance glymphatic transport in the brain.


Asunto(s)
Sistema Glinfático , Microburbujas , Ratones , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Sistema Glinfático/diagnóstico por imagen , Sistema Glinfático/metabolismo , Ultrasonografía , Albúminas/metabolismo
4.
Acc Chem Res ; 57(9): 1458-1466, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38654437

RESUMEN

ConspectusRecent years have witnessed the development of cluster materials as they are atomically precise molecules with uniform size and solution-processability, which are unattainable with traditional nanoparticles or framework materials. The motivation for studying Al(III) chemistry is not only to understand the aggregation process of aluminum in the environment but also to develop novel low-cost materials given its natural abundance. However, the Al-related clusters are underdeveloped compared to the coinage metals, lanthanides, and transition metals. The challenge in isolating crystalline compounds is the lack of an effective method to realize the controllable hydrolysis of Al(III) ions. Compared with the traditional hydrolysis of inorganic Al(III) salts in highly alkaline solutions and hydrolysis of aluminum trialkyl compounds conducted carefully in an inert operating environment, we herein developed an effective way to control the hydrolysis of aluminum isopropanol through an alcoxalation reaction. By solvothermal/low melting point solid melting synthesis and using "ligand aggregation, solvent regulation, and supracluster assembly" strategies, our laboratory has established an organic-inorganic hybrid system of aluminum oxo clusters (AlOCs). The employment of organic ligands promotes the aggregation and slows the hydrolysis of Al(III) ions, which in turn improves the crystallization process. The regulation of the structure types can be achieved through the selection of ligands and the supporting solvents. Compared with the traditional condensed polyoxoaluminates, we successfully isolated a broad range of porous AlOCs, including aluminum molecular rings and Archimedes aluminum oxo cages. By studying ring expansion, structural transformation, and intermolecular supramolecular assembly, we demonstrate unique and unprecedented structural controllability and assembly behavior in cluster science. The advancement of this universal synthetic method is to realize materials customization through modularly oriented supracluster assembly. In this Account, we will provide a clear-cut definition and terminology of "ligand aggregation, solvent regulation, and supracluster assembly". Then we will discuss the discovery in this area by using a strategy, such as aluminum molecular ring, ring size expansion, ring supracluster assembly, etc. Furthermore, given the internal and external pore structures, as well as the solubility and modifiability of the AlOCs, we will demonstrate their potential applications in both the solid and liquid phases, such as iodine capture, the optical limiting responses, and dopant in polymer dielectrics. The strategy herein can be applied to extensive cluster science and promote the research of main group element chemistry. The new synthetic method, fascinating clusters, and unprecedented assembly behaviors we have discovered will advance Al(III) chemistry and will also lay the foundation for functional applications.

5.
EMBO Rep ; 24(7): e56458, 2023 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-37249035

RESUMEN

DNA topoisomerase IIα (TOP2A) plays a vital role in replication and cell division by catalytically altering DNA topology. It is a prominent target for anticancer drugs, but clinical efficacy is often compromised due to chemoresistance. In this study, we investigate the role of TOP2A O-GlcNAcylation in breast cancer cells and patient tumor tissues. Our results demonstrate that elevated TOP2A, especially its O-GlcNAcylation, promotes breast cancer malignant progression and resistance to adriamycin (Adm). O-GlcNAcylation at Ser1469 enhances TOP2A chromatin DNA binding and catalytic activity, leading to resistance to Adm in breast cancer cells and xenograft models. Mechanistically, O-GlcNAcylation-modulated interactions between TOP2A and cell cycle regulators influence downstream gene expression and contribute to breast cancer drug resistance. These results reveal a previously unrecognized mechanistic role for TOP2A O-GlcNAcylation in breast cancer chemotherapy resistance and provide support for targeting TOP2A O-GlcNAcylation in cancer therapy.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Femenino , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos
6.
J Am Chem Soc ; 146(11): 7524-7532, 2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38451059

RESUMEN

Chiral aluminum oxo clusters (cAlOCs) are distinguished from other classes of materials on account of their abundance in the earth's crust and their potential for sustainable development. However, the practical synthesis of cAlOCs is rarely known. Herein, we adopt a synergistic coordination strategy by using chiral amino acid ligands as bridges and auxiliary pyridine-2,6-dicarboxylic acid as chelating ligands and successfully isolate an extensive family of cAlOCs. They integrate molecular chirality, absolute helicity, and intrinsic hydrogen-bonded chiral topology. Moreover, they have the structural characteristics of one-dimensional channels and replaceable counteranions, which make them well combined with fluorescent dyes for circularly polarized luminescence (CPL). The absolute luminescence dissymmetry factor (glum) of up to the 10-3 order is comparable to several noble metals, revealing the enormous potential of cAlOCs in low-cost chiral materials. We hope this work will inspire new discoveries in the field of chirality and provide new opportunities for constructing low-cost chiral materials.

7.
J Am Chem Soc ; 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38838264

RESUMEN

Chiral atomically precise metal clusters, known for their remarkable chiroptical properties, hold great potential for applications in chirality recognition. However, advancements in this field have been constrained by the limited exploration of host-guest chemistry, involving metal clusters. This study reports the synthesis of a chiral Cu16(C2B10H10S2)8 (denoted as Cu16@CB8, where C2B10H12S2H2 = 9,12-(HS)2-1,2-closo-carborane) cluster by an achiral carboranylthiolate ligand. The chiral R-/S-Cu16@CB8 cluster features chiral cavities reminiscent of cyclodextrins, which are surrounded by carborane clusters, yet they crystallize in a racemate. These cyclodextrin-like cavities demonstrated the specific recognition of amino acids, as indicated by the responsive output of circular dichroism and circularly polarized luminescence signals of Cu16 moieties of the Cu16@CB8 cluster. Notably, a quantitative chiroptical analysis of amino acids in a short time and a concomitant deracemization of Cu16@CB8 were achieved. Density functional tight-binding molecular dynamics simulation and noncovalent interaction analysis further unraveled the great importance of the cavities and binding sites for chiral recognition. Dipeptide, tripeptide, and polypeptide containing the corresponding amino acids (Cys, Arg, or His residues) display the same chiral recognition, showing the generality of this approach. The functional synergy of dual clusters, comprising carborane and metal clusters, is for the first time demonstrated in the Cu16@CB8 cluster, resulting in the valuable quantification of the enantiomeric excess (ee) value of amino acids. This work opens a new avenue for chirality sensors based on chiral metal clusters with unique chiroptical properties and inspires the development of carborane clusters in host-guest chemistry.

8.
Neurobiol Dis ; 190: 106372, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38061397

RESUMEN

Gait disturbance is a manifestation of cerebral small vessel disease (CSVD). The posterolateral thalamus (PL), whose blood is mainly supplied by the P2 segment of posterior cerebral artery (P2-PCA), plays pivotal roles in gait regulation. We investigated the influence of the distance between P2-PCA and PL on gait with varying CSVD burden. 71 participants were divided into low and high CSVD burden groups. The distance from P2-PCA to PL was measured using 7 T TOF-MRA and categorized into an immediate or distant PCA-to-thalamus pattern. Functional connectivity (FC) and voxel-based morphometry were assessed to evaluate functional and structural alterations. In the low CSVD burden group, immediate PCA-to-thalamus supply strongly correlates with longer step length and higher wave phase time percent, and exhibited enhanced FCs in left supplementary motor area, right precentral cortex (PreCG.R). While in the high CSVD burden group, no association between PCA-to-thalamus pattern and gait was found, and we observed reduced FC in PreCG.R with immediate PCA-to-thalamus pattern. Higher CSVD burden was associated with decreased gray matter density in bilateral thalamus. However, no significant structural thalamic change was observed between the two types of PCA-to-thalamus patterns in all patients. Our study demonstrated patients with immediate PCA-to-thalamus supply exhibited better gait performance in low CSVD burden populations, which also correlated with enhanced FCs in motor-related cortex, indicating the beneficial effects of the immediate PCA-to-thalamus supply pattern. In the higher burden CSVD populations, the effects of PCA-to-thalamus pattern on gait are void, attributable to the CSVD-related thalamic destruction and impairment of thalamus-related FC.


Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales , Arteria Cerebral Posterior , Humanos , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Sustancia Gris , Imagen por Resonancia Magnética , Tálamo/diagnóstico por imagen
9.
Small ; 20(21): e2309856, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38100241

RESUMEN

Developing a facile strategy to activate the inert crystal face of an electrocatalyst is critical to full-facet utilization, yet still challenging. Herein, the electrocatalytic activity of the inert crystal face is activated by quenching Co3O4 cubes and hexagonal plates with different crystal faces in Fe(NO3)3 solution, and the regulation mechanism of facet-dependent quench-engineering is further revealed. Compared to the Co3O4 cube with exposed {100} facet, the Co3O4 hexagonal plate with exposed {111} facet is more responsive to quenching, accompanied by a rougher surface, richer defect, and more Fe doping. Theoretical calculations indicate that the {111} facet has a more open structure with lower defect formation energy and Fe doping energy, ensuring its electronic and coordination structure is easier to optimize. Therefore, quench-engineering largely increases the catalytic activity of {111) facet for oxygen evolution reaction by 13.2% (the overpotential at 10 mA cm-2 decreases from 380 to 330 mV), while {100} facet only increases by 7.6% (from 393 to 363 mV). The quenched Co3O4 hexagonal plate exhibits excellent electrocatalytic activity and stability in both zinc-air battery and water-splitting. The work reveals the influence mechanism of crystal face on quench-engineering and inspires the activation of the inert crystal face.

10.
PLoS Pathog ; 18(3): e1010366, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35235615

RESUMEN

Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is well known to play a critical function in cancer, autoimmune and neurodegenerative diseases. However, its role in host-pathogen interactions has not been characterized yet. Herein, we identified that kynurenine-3-monooxygenase (KMO), a key rate-limiting enzyme in the KP, and quinolinic acid (QUIN), a key enzymatic product of KMO enzyme, exerted a novel antiviral function against a broad range of viruses. Mechanistically, QUIN induced the production of type I interferon (IFN-I) via activating the N-methyl-d-aspartate receptor (NMDAR) and Ca2+ influx to activate Calcium/calmodulin-dependent protein kinase II (CaMKII)/interferon regulatory factor 3 (IRF3). Importantly, QUIN treatment effectively inhibited viral infections and alleviated disease progression in mice. Furthermore, kmo-/- mice were vulnerable to pathogenic viral challenge with severe clinical symptoms. Collectively, our results demonstrated that KMO and its enzymatic product QUIN were potential therapeutics against emerging pathogenic viruses.


Asunto(s)
Quinurenina 3-Monooxigenasa , Virosis , Animales , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Factor 3 Regulador del Interferón/metabolismo , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Ratones , Ácido Quinolínico/metabolismo , Ácido Quinolínico/farmacología , Virosis/tratamiento farmacológico
11.
FASEB J ; 37(3): e22820, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36801982

RESUMEN

Epidemiological studies suggest that fetal growth restriction (FGR) caused by gestational cholestasis is associated with elevated serum cholic acid (CA). Here, we explore the mechanism by which CA induces FGR. Pregnant mice except controls were orally administered with CA daily from gestational day 13 (GD13) to GD17. Results found that CA exposure decreased fetal weight and crown-rump length, and increased the incidence of FGR in a dose-dependent manner. Furthermore, CA caused placental glucocorticoid (GC) barrier dysfunction via down-regulating the protein but not the mRNA level of placental 11ß-Hydroxysteroid dehydrogenase-2 (11ß-HSD2). Additionally, CA activated placental GCN2/eIF2α pathway. GCN2iB, an inhibitor of GCN2, significantly inhibited CA-induced down-regulation of 11ß-HSD2 protein. We further found that CA caused excessive reactive oxygen species (ROS) production and oxidative stress in mouse placentas and human trophoblasts. NAC significantly rescued CA-induced placental barrier dysfunction by inhibiting activation of GCN2/eIF2α pathway and subsequent down-regulation of 11ß-HSD2 protein in placental trophoblasts. Importantly, NAC rescued CA-induced FGR in mice. Overall, our results suggest that CA exposure during late pregnancy induces placental GC barrier dysfunction and subsequent FGR may be via ROS-mediated placental GCN2/eIF2α activation. This study provides valuable insight for understanding the mechanism of cholestasis-induced placental dysfunction and subsequent FGR.


Asunto(s)
Enfermedades Placentarias , Placenta , Embarazo , Femenino , Ratones , Humanos , Animales , Placenta/metabolismo , Especies Reactivas de Oxígeno/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/genética , Retardo del Crecimiento Fetal/inducido químicamente , Factor 2 Eucariótico de Iniciación/metabolismo , Enfermedades Placentarias/metabolismo
12.
Neuroradiology ; 66(3): 399-407, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38183425

RESUMEN

PURPOSE: The optimal primary recanalization strategy for intracranial atherosclerosis-related emergent large vessel occlusion (ICAS-ELVO) remains controversial. We aimed to explore the safety and efficacy of balloon angioplasty as the first-choice recanalization strategy for ICAS-ELVO with small clot burden. METHODS: Consecutive ICAS-ELVO patients presenting with microcatheter "first-pass effect" during endovascular treatment (EVT) were retrospectively analyzed. Patients were divided into preferred balloon angioplasty (PBA) and preferred mechanical thrombectomy (PMT) groups based on the first-choice recanalization strategy. The reperfusion and clinical outcomes between the two groups were compared. RESULTS: Seventy-six patients with ICAS-ELVO involving the microcatheter "first-pass effect" during EVT were enrolled. Compared with patients in the PMT group, those in the PBA group were associated with (i) a higher rate of first-pass recanalization (54.0% vs. 28.9%, p = .010) and complete reperfusion (expanded thrombolysis in cerebral ischemia ≥ 2c; 76.0% vs. 53.8%, p = .049), (ii) shorter puncture-to-recanalization time (49.5 min vs. 89.0 min, p < .001), (iii) lower operation costs (¥48,499.5 vs. ¥ 99,086.0, p < .001), and (iv) better 90-day functional outcomes (modified Rankin scale:0-1; 44.0% vs. 19.2%, p = .032). Logistic regression analysis revealed that balloon angioplasty as the first-choice recanalization strategy was an independent predictor of 90-day excellent functional outcomes for ICAS-ELVO patients with microcatheter "first-pass effect" (adjusted odds ratio = 6.01, 95% confidence interval: 1.15-31.51, p = .034). CONCLUSION: Direct balloon angioplasty potentially improves 90-day functional outcomes for ICAS-ELVO patients with small clot burden, and may be a more appropriate first-choice recanalization strategy than mechanical thrombectomy for these patients.


Asunto(s)
Angioplastia de Balón , Arteriosclerosis Intracraneal , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/cirugía , Estudios Retrospectivos , Trombectomía , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/terapia , Arteriosclerosis Intracraneal/complicaciones , Resultado del Tratamiento
13.
J Comput Assist Tomogr ; 48(1): 169-174, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37531630

RESUMEN

OBJECTIVE: Intracranial aneurysm (IAN) is a class of cerebrovascular diseases with a serious threat to patients, and an accurate diagnosis of IAN is very important for both selection of the appropriate therapy and prediction of the prognosis. This study aimed to evaluate the diagnostic values of zero-echo-time magnetic resonance angiography (ZTE-MRA) and time-of-flight magnetic resonance angiography (TOF-MRA) in patients with IAN. METHODS: Digital subtraction angiography, ZTE-MRA, and TOF-MRA were performed in 18 patients diagnosed with IAN. The images of ZTE-MRA and TOF-MRA were compared for image quality, qualitative diagnosis, detailed diagnosis, number of thrombi, and residual aneurysm lumen, with digital subtraction angiography as the reference. RESULTS: Zero-echo-time MRA and TOF-MRA did not show a significant difference in image quality or detailed information (including aneurysm size, growth direction, and angle with the aneurysm-carrying vessel) ( P > 0.05). However, ZTE-MRA showed advantages over TOF-MRA in terms of qualitative diagnosis (sensitivity and specificity), intra-aneurismal thrombus detection, and residual aneurysm lumen detection after embolization ( P < 0.05). CONCLUSIONS: Compared with TOF-MRA, ZTE-MRA showed greater diagnostic value for IAN patients in terms of qualitative diagnosis, as well as the detection of intra-aneurysm thrombi and residual aneurysm lumen after embolization.


Asunto(s)
Trastornos Cerebrovasculares , Embolización Terapéutica , Aneurisma Intracraneal , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Angiografía por Resonancia Magnética/métodos , Estudios de Seguimiento , Pronóstico , Embolización Terapéutica/métodos , Angiografía de Substracción Digital/métodos
14.
J Med Genet ; 60(7): 655-661, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36446583

RESUMEN

BACKGROUND: Diagnosis of a genetic disease and determination of the causative molecular lesion rely on the availability of the disease-associated pedigrees. Microphthalmia is a congenital eye defect due to an insufficiently developed visual system; its prevalence is 1-3 in 10 000 live births. OBJECTIVE: We analysed a pedigree exhibiting autosomal dominant inheritance of microphthalmia to determine the genetic lesion; used AlphaFold2 to predict the changes in the protein's 3-Dimensional structure; and compared wild-type and variant proteins in cultured cells or Drosophila model was used to explore the cellular or developmental function of the encoded product. RESULTS: We identified a novel missense variation, F52L, in MAB21L1 that is absent in population databases and present exclusively in the individuals diagnosed with microphthalmia in this pedigree. Common structural changes were predicted for the disease-associated variants clustered at amino acids 49-52, and these variant products were also predominantly trapped in the cytoplasm of cultured human lens epithelia. To recapitulate its dominant effect in development, we expressed the Drosophila homologue corresponding to MAB21L1F52L and caused malformation of sensory organs. CONCLUSION: Mutations at the residues 49-52 of MAB21L1 compromise eye development. We recommend including MAB21L1 in the genetic testing panel for congenital eye disorders.


Asunto(s)
Anomalías del Ojo , Microftalmía , Humanos , Microftalmía/genética , Aminoácidos/genética , Pruebas Genéticas , Anomalías del Ojo/genética , Mutación , Linaje , Proteínas de Homeodominio/genética
15.
Angew Chem Int Ed Engl ; : e202411576, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38984566

RESUMEN

Mechanically interlocked molecules, such as rotaxanes, have drawn significant attention within supramolecular chemistry. Although a variety of macrocycles have been thoroughly explored in rotaxane synthesis, metal-organic macrocycles remain relatively under-investigated. Aluminum molecular rings, with their inner cavities and numerous binding sites, present a promising option for constructing rotaxanes. Here, we introduce an innovative "ring-donor···axle-acceptor" motif utilizing Al8 molecular rings, enabling the stepwise assembly of molecules, complexes, and polymers through tailored coordination chemistry. This novel approach can not only be applied to macrocycle-based systems like catenanes but also enhance specific functionalities progressively.

16.
J Neurosci ; 42(27): 5427-5437, 2022 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-35641188

RESUMEN

Autism spectrum disorder (ASD) is a developmental disorder that is characterized by difficulties with social interaction and interpersonal communication. It has been argued that abnormal attentional function to exogenous stimuli precedes and contributes to the core ASD symptoms. Notably, the locus ceruleus (LC) and its noradrenergic projections throughout the brain modulate attentional function, but the extent to which this locus ceruleus-norepinephrine (LC-NE) system influences attention in individuals with ASD, who frequently exhibit dysregulated alerting and attention orienting, is unknown. We examined dynamic attention control in girls and boys with ASD at rest using the pupil dilation response (PDR) as a noninvasive measure of LC-NE activity. When gender- and age-matched neurotypical participants were passively exposed to an auditory stream, their PDR decreased for recurrent stimuli but remained sensitive to surprising deviant stimuli. In contrast, children with ASD showed less habituation to recurrent stimuli as well as a diminished phasic response to deviants, particularly those containing social information. Their tonic habituation impairment predicts their phasic orienting impairment, and both impairments correlated with the severity of ASD symptom. Because of the fact that these pupil-linked responses are observed when individuals passively listen without any task engagement, our findings imply that the intricate and dynamic attention allocation mechanism, mediated by the subcortical LC-NE system, is impaired in ASD.SIGNIFICANCE STATEMENT Autistic individuals show attentional abnormalities to even simple sensory inputs, which emerge even before formal diagnosis. One possible mechanism behind these abnormalities is a malfunctioning pacemaker of their attention system, the locus ceruleus-norepinephrine pathway. Here we found, according to the pupillary response (a noradrenergic activity proxy), autistic children are hypersensitive to repeated sounds but hyposensitive to surprising deviant sounds when compared with age-matched controls. Importantly, hypersensitivity to repetitions predicts hyposensitivity to deviant sounds, and both abnormalities positively correlate to the severity of autistic symptoms. This provides strong evidence that autistic children have faulty noradrenergic regulation, which might underly the attentional atypicalities previously evidenced in various cortical responses in autistic individuals.


Asunto(s)
Trastorno del Espectro Autista , Nivel de Alerta , Atención/fisiología , Niño , Femenino , Humanos , Masculino , Norepinefrina/metabolismo , Pupila
17.
Chemistry ; 29(2): e202202638, 2023 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-36180419

RESUMEN

The treatment of radioactive iodine in nuclear waste has always been a critical issue of social concern. The rational design of targeted and efficient capture materials is of great significance to the sustainable development of the ecological environment. In recent decades, crystalline materials have served as a molecular platform to study the binding process and capture mechanism of iodine molecules, enabling people to understand the interaction between radioactive iodine guests and pores intuitively. Cluster-based crystalline materials, including molecular clusters and cluster-based metal-organic frameworks, are emerging candidates for iodine capture due to their aggregative binding sites, precise structural information, tunable pores/packing patterns, and abundant modifications. Herein, recent progress of different types of cluster materials and cluster-dominated metal-organic porous materials for iodine capture is reviewed. Research prospects, design strategies to improve the affinity for iodine and possible capture mechanisms are discussed.


Asunto(s)
Yodo , Estructuras Metalorgánicas , Neoplasias de la Tiroides , Humanos , Radioisótopos de Yodo , Sitios de Unión
18.
J Magn Reson Imaging ; 58(2): 630-639, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-36444747

RESUMEN

BACKGROUND: Reactive stroma is recognized as one of the independent prognostic factors in prostate cancer (PCa). Intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) may be useful for assessing the reactive stromal grade (RSG). PURPOSE: To investigate whether IVIM and DKI models can evaluate RSG in PCa patients. STUDY TYPE: Retrospective. SUBJECTS: A total of 56 PCa patients aged 73 years on average confirmed by MRI and transrectal ultrasound (MRI/TRUS) fusion biopsy divided into two subgroups (18 high RSG and 38 low RSG). FIELD STRENGTH/SEQUENCE: A 3 T/T1 WI-fs, T1 WI, T2 WI-fs, T2 WI, DWI, IVIM, and DKI. ASSESSMENT: Apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), mean diffusion (MD), mean kurtosis (MK) were obtained. Patients were divided into high RSG PCa (>50% reactive stroma) and low RSG PCa (≤50% reactive stroma) groups on hematoxylin and eosin (H&E) stained sections. STATISTICAL TESTS: Spearman correlation and independent sample t-test or Wilcoxon's rank sum test was used to investigate the relationship between each imaging parameter and RSG. The combined parameters were calculated using a binary logistic regression model. Receiver operating characteristic (ROC) analysis was used to explore the value of individual and combined parameters to differentiate between high and low RSG group. Area under the ROC curves (AUC) > 0.7 were used as reference standards. RESULTS: ADC, D, f, and MD values showed positive correlation with RSG (r = 0.489, 0.619, 0.318, and 0.544, respectively); MK showed negative correlation with RSG (r = -0.444). ADC, D, f, and MD values were significantly lower in the low RSG group than in the high RSG group. The combined model showed the best diagnostic ability to differentiate low and high RSG groups (AUC = 0.887). DATA CONCLUSION: Parameters of IVIM and DKI may be promising methods for assessment of RSG in PCa patients. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 3.


Asunto(s)
Imagen de Difusión Tensora , Neoplasias de la Próstata , Masculino , Humanos , Estudios Retrospectivos , Imagen de Difusión Tensora/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Curva ROC , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Movimiento (Física)
19.
J Magn Reson Imaging ; 57(5): 1406-1413, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-35864603

RESUMEN

BACKGROUND: Diffusion-weighted imaging (DWI) has demonstrated great potential in predicting the expression of tumor cell proliferation and apoptosis indexes. PURPOSE: To evaluate the impact of four region of interest (ROI) methods on interobserver variability and apparent diffusion coefficient (ADC) values and to examine the correlation of ADC values with Ki-67, Bcl-2, and P53 labeling indexes (LIs) in a murine model of fibrosarcoma. STUDY TYPE: Prospective, animal model. ANIMAL MODEL: A total of 22 female BALB/c mice bearing intramuscular fibrosarcoma xenografts. FIELD STRENGTH/SEQUENCE: A 3.0 T/T1-weighted fast spin-echo (FSE), T2-weighted fast relaxation fast spin-echo, and DWI PROPELLER FSE sequences. ASSESSMENT: Four radiologists measured ADC values using four ROI methods (oval, freehand, small-sample, and whole-volume). Immunohistochemical assessment of Ki-67, Bcl-2, and P53 LIs was performed. STATISTICAL TESTS: Interclass correlation coefficient (ICC), one-way analysis of variance followed by LSD-t post hoc analysis, and Pearson correlation test were performed. The statistical threshold was defined as a P-value of <0.05. RESULTS: All ROI methods for ADC measurements showed excellent interobserver agreement (ICC range, 0.832-0.986). The ADC values demonstrated significant differences among the four ROI methods. The ADC values for oval, freehand, small-sample, and whole-volume ROI methods showed a moderately negative correlation with Ki-67 (r = -0.623; r = -0.629; r = -0.642, and r = -0.431) and Bcl-2 (r = -0.590; r = -0.597; r = -0.659, and r = -0.425) LIs, but no correlation with P53 LI (r = 0.364, P = 0.104; r = 0.350, P = 0.120; r = 0.379, P = 0.091; r = 0.390, P = 0.080). DATA CONCLUSION: The ADC value can be used to evaluate cell proliferation and apoptosis indexes in a murine model of fibrosarcoma, employing the small-sample ROI as a reliable method. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.


Asunto(s)
Fibrosarcoma , Proteína p53 Supresora de Tumor , Humanos , Femenino , Animales , Ratones , Antígeno Ki-67 , Estudios Prospectivos , Modelos Animales de Enfermedad , Reproducibilidad de los Resultados , Imagen por Resonancia Magnética/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Proliferación Celular
20.
Appl Opt ; 62(25): 6771-6778, 2023 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-37706810

RESUMEN

This paper elaborates on the design and simulation of a multifunctional optical sensor that features simultaneous detection of pressure and temperature, which is based on the metal-insulator-metal waveguide structure with two T-shaped resonant cavities. Depending on the simulation findings, pressure and temperature can be measured separately by two T-shaped cavities at different Fano resonance wavelengths. As the pressure applied to the upper T-shaped cavity increases, the resonance wavelength first shifts linearly due to the slight deformation of the cavity, and the maximum pressure sensitivity reaches 12.48 nm/MPa. After the pressure exceeds a threshold, the relationship between pressure and resonance wavelength transforms into a quadratic polynomial. In the lower T-shaped cavity, solid polydimethylsiloxane is sealed as a thermal-sensitive material, effectively preventing material overflow brought on by structural micro-vibration under pressure, and its high thermo-optical coefficient prompts a temperature sensitivity of 0.36 nm/°C. Furthermore, by optimizing the choice of Fano resonances, pressure and temperature can be sensed independently without mutual interference. The designed sensor provides extensive application possibilities for scenarios where multiparameter monitoring is required.

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