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1.
Int J Biol Macromol ; 278(Pt 4): 134946, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39187110

RESUMEN

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of cellular processes, with their dysregulation linked to various disease states. Among the structural motifs in lncRNAs, RNA G-quadruplexes (rG4s) have gained increasing attention due to their diverse roles in cellular function and disease pathogenesis. This review provides an updated and comprehensive overview of rG4s in lncRNAs, elucidating their formation, interaction with proteins, and distinctive roles in cellular processes. We discuss current methodologies for experimentally probing RNA G4s, including the use of specific small molecules, biomolecular ligands and fluorescent probes. The commonly found RNA G4-interacting protein domains are summarised along with potential strategies for disrupting lncRNA G4-protein interactions from a therapeutic perspective.


Asunto(s)
G-Cuádruplex , Unión Proteica , ARN Largo no Codificante , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/química , Humanos , Animales , Proteínas/química , Proteínas/metabolismo , Proteínas/genética
2.
Angew Chem Int Ed Engl ; 63(27): e202402497, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38679571

RESUMEN

The large size of K-ion makes the pursuit of stable high-capacity anodes for K-ion batteries (KIBs) a formidable challenge, particularly for high temperature KIBs as the electrode instability becomes more aggravated with temperature climbing. Herein, we demonstrate that a hollow ZnS@C nanocomposite (h-ZnS@C) with a precise shell modulation can resist electrode disintegration to enable stable high-capacity potassium storage at room and high temperature. Based on a model electrode, we identify an interesting structure-function correlation of the h-ZnS@C: with an increase in the shell thickness, the cyclability increases while the rate and capacity decrease, shedding light on the design of high-performance h-ZnS@C anodes via engineering the shell thickness. Typically, the h-ZnS@C anode with a shell thickness of 60 nm can deliver an impressive comprehensive performance at room temperature; the h-ZnS@C with shell thickness increasing to 75 nm can achieve an extraordinary stability (88.6 % capacity retention over 450 cycles) with a high capacity (450 mAh g-1) and a superb rate even at an extreme temperature of 60 °C, which is much superior than those reported anodes. This contribution envisions new perspectives on rational design of functional metal sulfides composite toward high-performance KIBs with insights into the significant structure-function correlation.

3.
Carbohydr Polym ; 333: 121978, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38494231

RESUMEN

Mushroom polysaccharides are recognized as "biological response modifiers". Besides several bioactivities, a growing interest in their prebiotic potential has been raised due to the gut microbiota modulation potential. This review comprehensively summarizes mushroom polysaccharides' biological properties, structure-function relationship, and underlying mechanisms. It provides a recent overview of the key findings in the field (2018-2024). Key findings and limitations on structure-function correlation are discussed. Although most studies focus on ß-glucans or extracts, α-glucans and chitin have gained interest. Prebiotic capacity has been associated with α-glucans and chitin, while antimicrobial and wound healing potential is attributed to chitin. However, further research is of utmost importance. Human fecal fermentation is the most reported approach to assess prebiotic potential, indicating impacts on intestinal biological, mechanical, chemical and immunological barriers. Gut microbiota dysbiosis has been directly connected with intestinal, cardiovascular, metabolic, and neurological diseases. Concerning gut microbiota modulation, animal experiments have suggested proinflammatory cytokines reduction and redox balance re-establishment. Most literature focused on the anticancer and immunomodulatory potential. However, anti-inflammatory, antimicrobial, antiviral, antidiabetic, hypocholesterolemic, antilipidemic, antioxidant, and neuroprotective properties are discussed. A significant overview of the gaps and research directions in synergistic effects, underlying mechanisms, structure-function correlation, clinical trials and scientific data is also given.


Asunto(s)
Agaricales , Antiinfecciosos , Microbioma Gastrointestinal , Animales , Humanos , Prebióticos , Polisacáridos/farmacología , Polisacáridos/química , Quitina/farmacología , Glucanos/farmacología , Antiinfecciosos/farmacología
4.
Small ; 20(32): e2401054, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38488748

RESUMEN

2D conjugated extension on central units of small molecular acceptors (SMAs) has gained great successes in reaching the state-of-the-art organic photovoltaics. Whereas the limit size of 2D central planes and their dominant role in constructing 3D intermolecular packing networks are still elusive. Thus, by exploring a series of SMAs with gradually enlarged central planes, it is demonstrated that, at both single molecular and aggerated levels, there is an unexpected blue-shift for their film absorption but preferable reorganization energies, exciton lifetimes and binding energies with central planes enlarging, especially when comparing to their Y6 counterpart. More importantly, the significance of well-balanced molecular packing modes involving both central and end units is first disclosed through a systematic single crystal analysis, indicating that when the ratio of central planes area/end terminals area is no more than 3 likely provides a preferred 3D intermolecular packing network of SMAs. By exploring the limit size of 2D central planes, This work indicates that the structural profiles of ideal SMAs may require suitable central unit size together with proper heteroatom replacement instead of directly overextending 2D central planes to the maximum. These results will likely provide some guidelines for future better molecular design.

5.
Acta Ophthalmol ; 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-38041245

RESUMEN

PURPOSE: High Magnification Module (HMM™, Heidelberg Engineering, Heidelberg, Germany) imaging is a novel technique, designed to visualize the retina at a cellular level. To assess the potential of HMM™-based metrics as endpoints for future trials, we evaluated correlations between structural HMM™ cone metrics, spectral-domain OCT (SD-OCT, Heidelberg Engineering, Heidelberg, Germany) and retinal sensitivity on microperimetry (MP, MAIA, CenterVue, Padova, Italy) in healthy subjects and p.(Arg142Trp) PRPH2-associated Central Areolar Choroidal Dystrophy (CACD) patients. METHODS: We projected a default 10° MP grid on composite HMM™ images and performed automated cone density (CD), intercell distance (ICD) and nearest neighbour distance (NND) analysis at stimuli located at 3° and 5° retinal eccentricity. We manually measured intrasubject outer retinal thickness on SD-OCT in absolute and relative scotomas, located outside of focal atrophy. RESULTS: We included 15 CACD patients and five healthy subjects. We found moderate-to-strong correlations of HMM™ metrics and MP sensitivity at 3° eccentricity from the fovea. We found the outer retina at the locations of absolute scotomas to be statistically significant thinner (p = 0.000003, one-sample t-test), as the outer retinal thickness at locations of relative scotomas. Interestingly, HMM™ metrics of these areas did not differ significantly. CONCLUSIONS: We found significant correlations between structural photoreceptors metrics on HMM™ imaging and retinal sensitivity on MP in healthy subjects and CACD patients. A multimodal approach, combining SD-OCT, MP and HMM™ imaging, allows for detailed mapping of retinal photoreceptor integrity and restitution potential, important data that could serve as biomarkers in future clinical trials.

6.
Int J Biol Macromol ; 253(Pt 5): 127188, 2023 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-37783244

RESUMEN

The depolymerization of lignocellulosic biomass is facilitated by feruloyl esterases (FAEs), which hydrolyze ester bonds between lignin and polysaccharides. Fungal FAEs belonging to subfamily (SF) 6 release precursors such as ferulic acid derivatives, attractive for biochemical production. Among these, Aspergillus sydowii FAE (AsFaeE), an SF6 FAE, exhibits remarkable activity across various substrates. In this study, we conducted X-ray crystallography and kinetic analysis to unravel the molecular mechanisms governing substrate recognition and catalysis by AsFaeE. AsFaeE exhibits a typical α/ß-hydrolase fold, characterized by a catalytic triad of serine, aspartate, and histidine. Comparative analysis of substrate-free, ferulic acid-bound, and sinapic acid-bound forms of AsFaeE suggests a conformational change in the loop covering the substrate-binding pocket upon binding. Notably, Pro158 and Phe159 within this loop cover the phenolic part of the substrate, forming three layers of planar rings. Our structure-based functional mutagenesis clarifies the roles of the residues involved in substrate binding and catalytic activity. Furthermore, distinct substrate-binding mechanisms between AsFaeE and other studied FAEs are identified. This investigation offers the initial structural insights into substrate recognition by SF6 FAEs, equipping us with structural knowledge that might facilitate the design of FAE variants capable of efficiently processing a wider range of substrate sizes.


Asunto(s)
Hidrolasas de Éster Carboxílico , Hidrólisis , Cinética , Hidrolasas de Éster Carboxílico/química , Especificidad por Sustrato
7.
Curr Eye Res ; 48(11): 1050-1056, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37539829

RESUMEN

PURPOSE: Photoreceptor (PR) outer segments, retinal pigment epithelium apical processes, and inter-PR matrix contribute to the interdigitation zone (IZ) of optical coherence tomography (OCT). We hypothesize that this interface degrades over adulthood, in concert with a delay of rod mediated dark adaptation (RMDA). To explore this idea, we determined IZ discernibility and RMDA in younger and older adults. METHODS: For this cross-sectional study, eyes of 20 young (20-30 years) and 40 older (≥60 years) participants with normal maculas according to the AREDS 9-step grading system underwent OCT imaging and RMDA testing at 5° superior to the fovea. Custom FIJI plugins enabled analysis for IZ discernibility at 9 eccentricities in 0.5 mm steps on one single horizontal B-scan through the fovea. Locations with discernible IZ met two criteria: visibility on B-scans and a distinct peak on a longitudinal reflectivity profile. The frequency of sites meeting both criteria was compared between both age groups and correlated with rod intercept time (RIT). RESULTS: The median number of locations with discernible IZ was significantly higher (foveal, 4 vs. 0, p = 0.0099; extra-foveal 6 vs. 0, p < 0.001) in eyes of young (26 ± 3 years) compared to older (73 ± 5 years) participants. For the combined young and older sample, the higher frequency of discernible IZ was correlated with shorter RIT (faster dark adaptation) (rs = -0.56, p < 0.0001). This association was significant within young eyes (rs = -0.54; p = 0.0134) and not within older eyes (rs = -0.29, p = 0.706). CONCLUSIONS: Results suggest that the interface between outer segments and apical processes degrades in normal aging, potentially contributing to delayed rod-mediated dark adaptation. More research is needed to verify an age-related association between IZ discernibility and rod-mediated dark adaptation. If confirmed in a large sample, IZ discernibility might prove to be a valuable biomarker and predictor for visual function in aging.

8.
Biomolecules ; 13(1)2023 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-36671521

RESUMEN

Structure-function relationships in proteins have been one of the crucial scientific topics in recent research. Heme proteins have diverse and pivotal biological functions. Therefore, clarifying their structure-function correlation is significant to understand their functional mechanism and is informative for various fields of science. In this study, we constructed convolutional neural network models for predicting protein functions from the tertiary structures of heme-binding sites (active sites) of heme proteins to examine the structure-function correlation. As a result, we succeeded in the classification of oxygen-binding protein (OB), oxidoreductase (OR), proteins with both functions (OB-OR), and electron transport protein (ET) with high accuracy. Although the misclassification rate for OR and ET was high, the rates between OB and ET and between OB and OR were almost zero, indicating that the prediction model works well between protein groups with quite different functions. However, predicting the function of proteins modified with amino acid mutation(s) remains a challenge. Our findings indicate a structure-function correlation in the active site of heme proteins. This study is expected to be applied to the prediction of more detailed protein functions such as catalytic reactions.


Asunto(s)
Hemoproteínas , Hemoproteínas/genética , Dominio Catalítico , Redes Neurales de la Computación , Sitios de Unión , Aminoácidos
9.
Curr Pharm Des ; 29(37): 2954-2976, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38173051

RESUMEN

BACKGROUND: In the plant kingdom, flavonoids are widely distributed with multifunctional immunomodulatory actions. Hesperetin (HST) remains one of the well-studied compounds in this domain, initially perceived in citrus plants as an aglycone derivative of hesperidin (HDN). OBSERVATIONS: Natural origin, low in vivo toxicity, and pleiotropic functional essence are the foremost fascinations for HST use as an anticancer drug. However, low aqueous solubility accompanied with a prompt degradation by intestinal and hepatocellular enzymes impairs HST physiological absorption. MOTIVATION: Remedies attempted herein comprise the synthesis of derivatives and nanocarrier (NC)-mediated delivery. As the derivative synthesis aggravates the structural complexity, NC-driven HST delivery has emerged as a sustainable approach for its sustained release. Recent interest in HST has been due to its significant anticancer potential, characterized via inhibited cell division (proliferation), new blood vessel formation (angiogenesis), forceful occupation of neighboring cell's space (invasion), migration to erstwhile physiological locations (metastasis) and apoptotic induction. The sensitization of chemotherapeutic drugs (CDs) by HST is driven via stoichiometrically regulated synergistic actions. Purpose and Conclusion: This article sheds light on HST structure-function correlation and pleiotropic anticancer mechanisms, in unaided and NC-administered delivery in singular and with CDs synergy. The discussion could streamline the HST usefulness and long-term anticancer efficacy.


Asunto(s)
Hesperidina , Humanos , Hesperidina/farmacología , Hesperidina/química , Flavonoides , Antioxidantes/farmacología
10.
J Clin Med ; 11(16)2022 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-36013117

RESUMEN

(1) Background: to investigate the correlation between structural (retinal ganglion cells and retinal nerve fibers) and functional alterations analyzed point-by-point in the central 10 degrees of the visual field of patients with advanced glaucoma using Humphrey 10-2 visual field tests. (2) Methods: Single-center prospective cohort study carried on from October 2018 to February 2019 at the Croix-Rousse hospital, Lyon, France. The primary outcome measure was the point-by-point correlation between retinal sensitivity (Humphrey 10-2) and retinal ganglion cell complex (GCC) thickness. (3) Results: 29 eyes of 27 patients were examined. Of these, 15 eyes had a mean deviation (MD) less than −20 dB. There were statistically significant linear relationships between GCC thickness and 10-2 visual field sensitivity for several points in the lower part of the visual field, with lower retinal sensitivity being associated with thicker GCC layers. There were no strong linear relationships or statistically significant correlations in the other regions of the visual field. For the patients with MD < −20 dB, there were statistically significant linear relationships between GCC thickness and 10-2 visual field sensitivity for several points in the superior nasal region. Retinal sensitivity was not correlated with retinal nerve fibre layer thickness. (4) Conclusions: In this study of patients with advanced glaucoma, GCC thickness was linearly associated with 10-2 visual field sensitivity in certain regions, negatively for patients with less-severe glaucoma. The initial thickening raises questions about the apoptosis mechanism, while the thinning observed in the most severe cases is consistent with the ganglion cell death identified on visual field tests.

11.
Int J Mol Sci ; 23(13)2022 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-35806176

RESUMEN

The plethora of flavonoid antioxidants in plant organisms, widespread in nature, and the appropriate metal ions known for their influence on biological processes constitute the crux of investigations toward the development of preventive metallodrugs and therapeutics in several human pathophysiologies. To that end, driven by the need to enhance the structural and (bio)chemical attributes of the flavonoid chrysin, as a metal ion complexation agent, thereby rendering it bioavailable toward oxidative stress, synthetic efforts in our lab targeted ternary Cr(III)-chrysin species in the presence of auxiliary aromatic N,N'-chelators. The crystalline metal-organic Cr(III)-chrysin-L (L = bipyridine (1) and phenanthroline (2)) compounds that arose were physicochemically characterized by elemental analysis, FT-IR, UV-Visible, ESI-MS, luminescence, and X-ray crystallography. The properties of these compounds in a solid state and in solution formulate a well-defined profile for the two species, thereby justifying their further use in biological experiments, intimately related to cellular processes on oxidative stress. Experiments in C2C12 myoblasts at the cellular level (a) focus on the antioxidant capacity of the Cr(III)-complexed flavonoids, emphasizing their distinct antiradical activity under oxidative stress conditions, and (b) exemplify the importance of structural speciation in Cr(III)-flavonoid interactions, thereby formulating correlations with the antioxidant activity of a bioavailable flavonoid toward cellular pathophysiologies, collectively supporting flavonoid introduction in new metallo-therapeutics.


Asunto(s)
Antioxidantes , Cromo , Antioxidantes/farmacología , Quelantes/química , Cromo/química , Flavonoides/química , Humanos , Espectroscopía Infrarroja por Transformada de Fourier
12.
Int Ophthalmol ; 42(12): 3645-3659, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35579770

RESUMEN

PURPOSE: To evaluate the relationship between structure and function in moderate and advanced primary open-angle glaucoma (POAG) and to determine the accuracy of structure and vasculature for discriminating moderate from advanced POAG. METHODS: In this cross-sectional study, 25 eyes with moderate and 40 eyes with advanced POAG were enrolled. All eyes underwent measurement of the thickness of circumpapillary retinal nerve fiber layer (cpRNFL) and macular ganglion cell complex (GCC), and optical coherence tomography angiography (OCTA) of the optic nerve head (ONH) and macula. Visual field (VF) was evaluated by Swedish interactive threshold algorithm and 24-2 and 10-2 patterns. The correlation between structure and vasculature and the mean deviation (MD) of the VFs was evaluated by a partial correlation coefficient. The area under the receiver operating characteristic curve (AUC) was applied for assessing the power of variables for discrimination moderate from advanced POAG. RESULTS: Including all eyes, whole image vessel density (wiVD) of the ONH area, and vessel density (VD) in the inferior quadrant of perifovea were the parameters with significant correlation with the mean deviation (MD) of the VF 24-2 in OCTA of the ONH and macula (r = .649 and .397; p < .05). The greatest AUCs for discriminating moderate and advanced POAG belonged to VD of the inferior hemifield of ONH area (.886; 95% CI (.805, .967)), and VD in the inferior quadrant of perifovea (.833; 95% CI (.736, .930)) without statistically significant difference (.886 Versus .833; p = .601). CONCLUSION: Among vascular parameters of the ONH area, wiVD had the strongest correlation with the MD of the VF 24-2 while VD of the inferior hemifield of the ONH area had the greatest AUC for discriminating moderate and advanced POAG. Vessel density in the inferior quadrant of perifovea had a significant correlation with the MD of VF 24-2 and also the greatest AUC for discriminating moderate and advanced POAG.


Asunto(s)
Glaucoma de Ángulo Abierto , Disco Óptico , Humanos , Glaucoma de Ángulo Abierto/diagnóstico , Tomografía de Coherencia Óptica/métodos , Estudios Transversales , Vasos Retinianos/diagnóstico por imagen , Disco Óptico/irrigación sanguínea , Angiografía/métodos , Presión Intraocular
13.
Int J Biol Macromol ; 209(Pt A): 991-1000, 2022 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-35429515

RESUMEN

Ubiquitination is an important posttranslational modification of proteins in eukaryotic cells, wherein ubiquitin molecules are conjugated to target proteins. Ubiquitination is catalyzed by the cascade of ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3). The number of E2s encoded in eukaryotes partly explains their contribution to the inherent specificity of the ubiquitin system. The ubiquitin conjugating enzyme UBC1 of Saccharomyces cerevisiae participates the degradation of short-lived and abnormal proteins. UBC1 consists of two well-defined domains separated by a long flexible linker. E2-25K, the human homolog of UBC1 is crucial to neurons and its failure leads to neurodegenerative disorders. The linker of UBC1 is of 22 amino acids, while that of E2-25K has 6 amino acids. To understand the importance of the linker, the chimeric protein, cUBC1 was constructed by substituting the linker of E2-25K in UBC1. cUBC1 shows minor changes in its secondary structure. cUBC1 expression in ubc1 deletion mutants showed no effect over growth, thermotolerance and resistance to antibiotic stress. However, survival under heat stress was enhanced with cUBC1. Western blot analysis of the enzymatic activity showed cUBC1 performed equally well as UBC1. Hence, cUBC1 demonstrates that the shorter linker increased the stability of UBC1.


Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Aminoácidos/metabolismo , Humanos , Proteínas Recombinantes de Fusión/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Ubiquitina/química , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo
14.
ChemSusChem ; 15(7): e202200068, 2022 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-35166058

RESUMEN

The increasing global demand for sustainable energy sources and emerging environmental issues have pushed the development of energy conversion and storage technologies to the forefront of chemical research. Electrochemical carbon dioxide (CO2 ) conversion provides an attractive approach to synthesizing fuels and chemical feedstocks using renewable energy. On the path to deploying this technology, basic and applied scientific hurdles remain. Copper, as the only metal catalyst that is capable to produce C2+ fuels from CO2 reduction (CO2 R), still faces challenges in the improvement of electrosynthesis pathways for highly selective fuel production. In this regard, mechanistically understanding CO2 R on Cu-based electrocatalysts, particularly identifying the structure-function correlation, is crucial. Here, a broad view of the variable structural parameters and their complex interplay in CO2 R catalysis on Cu was given, with the purpose of providing deep insights and guiding the future rational design of CO2 R electrocatalysts. First, this Review described the progress and recent advances in the development of well-defined nanostructured catalysts and the mechanistic understanding on the influences from a particular structure of a catalyst, such as facet, defects, morphology, oxidation state, composition, and interface. Next, the in-situ dynamic restructuring of Cu was presented. The importance of operando characterization methods to understand the catalyst structure-sensitivity was also discussed. Finally, some perspectives on the future outlook for electrochemical CO2 R were offered.

15.
Ann N Y Acad Sci ; 1511(1): 133-141, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35029314

RESUMEN

We compare the focal structure-function correlation of structural measurements of peripapillary retinal nerve fiber layer thickness (RNFL-T) using optical coherence tomography (OCT), capillary density (CD) measurements using OCT-angiography (OCT-A), or a combination of both, with visual field deviation (VFD) in early to advanced glaucoma. Primary open angle glaucoma patients (n = 46, mean ± SD age: 67 ± 10 years; VF mean deviation: -10.41 ± 6.76 dB) were included in this cross-sectional study. We performed 30-2 standard automated perimetry OCT (3.5-mm diameter ring scan) and 15°×15° OCT-A (superficial vascular complex slab). Based on a nerve fiber trajectory model, each VF test spot was assigned to an OCT-A wedge and an OCT ring-sector. Two univariate linear models (Mv and Mt ) using either CD-based vascular (Mv ) or RNFL-T-based thickness information (Mt ) and one multivariate model using both (Mv:t ) were compared in their associations with measured focal VFD, which were higher for the multivariate model Mv:t (mean ± SD correlation coefficient: 0.710 ± 0.086) than for either nested model (0.627 ± 0.078 for Mv and 0.578 ± 0.095 for Mt ). Using a focal visual field approach, the combination of RNFL-T and CD showed better structure-function correlations than thickness or vascular information only.


Asunto(s)
Glaucoma de Ángulo Abierto , Pruebas del Campo Visual , Anciano , Estudios Transversales , Humanos , Persona de Mediana Edad , Fibras Nerviosas , Células Ganglionares de la Retina , Tomografía de Coherencia Óptica/métodos , Trastornos de la Visión , Pruebas del Campo Visual/métodos , Campos Visuales
16.
Ophthalmol Retina ; 6(4): 291-297, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34922038

RESUMEN

PURPOSE: To investigate the functional associations of intraretinal fluid (IRF) and subretinal fluid (SRF) volumes at baseline and after the loading dose as well as fluid change after the first injection with best-corrected visual acuity (BCVA) in patients with neovascular age-related macular degeneration (nAMD) who received an anti-VEGF treatment over 24 months. DESIGN: Post hoc analysis of a phase III, randomized, multicenter trial in which ranibizumab was administered monthly or in a pro re nata regimen (HARBOR). PARTICIPANTS: Study eyes of 1094 treatment-naïve patients with nAMD. METHODS: IRF and SRF volumes were segmented automatically on monthly spectral domain OCT images. Fluid volumes and changes thereof were included as covariates into longitudinal mixed-effects models, which modeled BCVA trajectories. MAIN OUTCOME MEASURES: BCVA estimates corresponding to baseline, follow-up, and persistent IRF/SRF volumes after the loading dose; BCVA estimates of change in fluid volumes after the first injection; and marginal and conditional R2. RESULTS: Analysis of 22 494 volumetric scans revealed that foveal IRF consistently shows a negative correlation with BCVA at baseline and subsequent visits (-3.23 and -4.32 letters/100 nL, respectively). After the first injection, BCVA increased by +2.13 letters/100 nL decrease in foveal IRF. Persistent IRF was associated with lower baseline BCVA and less improvement. Foveal SRF correlated with better BCVA at baseline and subsequent visits (+6.52 and +1.42 letters/100 nL, respectively). After the first injection, SRF decrease was associated with significant vision gain (+5.88 letters/100 nL). Foveal fluid correlated more with BCVA than parafoveal IRF/SRF. CONCLUSIONS: Although IRF consistently correlates with decreased function and recovery throughout therapy, SRF is associated with a more pronounced functional improvement. Moreover, SRF resolution provides increased benefit. Fluid-function correlation represents an essential base for the development of personalized treatment regimens, optimizing functional outcomes, and reducing treatment burden.


Asunto(s)
Líquido Subretiniano , Factor A de Crecimiento Endotelial Vascular , Preescolar , Humanos , Inyecciones Intravítreas , Líquido Subretiniano/diagnóstico por imagen , Tomografía de Coherencia Óptica , Agudeza Visual
17.
Front Mol Biosci ; 7: 569990, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33195416

RESUMEN

The Green Fluorescent Protein (GFP) is a widely studied chemical system both for its large amount of applications and the complexity of the excited state proton transfer responsible of the change in the protonation state of the chromophore. A detailed investigation on the structure of the chromophore environment and the influence of chromophore form (either neutral or anionic) on it is of crucial importance to understand how these factors could potentially influence the protein function. In this study, we perform a detailed computational investigation based on the analysis of ab-initio molecular dynamics simulations, to disentangle the main structural quantities determining the fine balance in the chromophore environment. We found that specific hydrogen bonds interactions directly involving the chromophore (or not), are correlated to quantities, such as the volume of the cavity in which the chromophore is embedded and that it is importantly affected by the chromophore protonation state. The cross-correlation analysis performed on some of these hydrogen bonds and the cavity volume, demonstrates a direct correlation among them and we also identified the ones specifically involved in this correlation. We also found that specific interactions among residues far in the space are correlated, demonstrating the complexity of the chromophore environment and that many structural quantities have to be taken into account to properly describe and understand the main factors tuning the active site of the protein. From an overall evaluation of the results obtained in this work, it is shown that the residues which a priori are perceived to be spectators play instead an important role in both influencing the chromophore environment (cavity volume) and its dynamics (cross-correlations among spatially distant residues).

18.
Amino Acids ; 52(6-7): 893-904, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32468185

RESUMEN

Hemoglobinopathies are examples of autosomal recessive disorders of human hemoglobin. Hemoglobin E (HbE) and Hemoglobin D Punjab (HbD Punjab) are two of the most common hemoglobin variants geographically spread across Asian continent. These two variants differ from normal human hemoglobin (HbA) at a single amino acid residue caused by the point mutation of ß globin gene. The presence of the mutated amino acid residue causes perturbation in the function of both variants. However, the structure-function correlation of these variants has not been established yet. In the present study, we analyzed the conformational changes associated with oxygenation of hemoglobin variants using hydrogen/deuterium exchange-based mass spectrometry of backbone amide hydrogens of α and ß globin chains in the tetrameric hemoglobin molecule. We also performed the functional assay of these variants using oxygen dissociation equilibrium curve. Compared to HbA, both variants showed reduced oxygen affinity, as reported earlier. The functional perturbations exhibited by these variants were correlated well with their structural alterations with respect to the reported changes in the residue level interactions upon oxygenation of normal hemoglobin, monitored through the hydrogen/deuterium exchange kinetics of several peptic peptides originated from the isotopically exchanged oxy and deoxy forms of HbE and HbD Punjab.


Asunto(s)
Hemoglobina E/química , Hemoglobina E/genética , Hemoglobinas Anormales/química , Hemoglobinas Anormales/genética , Mutación Puntual/genética , Humanos , Espectrometría de Masas de Intercambio de Hidrógeno-Deuterio/métodos , Oxígeno/análisis , Oxihemoglobinas/análisis
19.
Ophthalmic Res ; 63(2): 88-96, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31935739

RESUMEN

Glaucoma is the leading cause of irreversible blindness worldwide, with an increasing prevalence. The complexity of the disease has been a major challenge in moving the field forward with regard to both pathophysiological insight and treatment. In this context, discussing possible outcome measures in glaucoma trials is of utmost importance and clinical relevance. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "New Technologies for Outcome Measures in Retina and Glaucoma," addressing both functional and structural outcomes, as well as translational hot topics in glaucoma and retina research. In conjunction with the published literature, this review summarizes the meeting focusing on glaucoma.


Asunto(s)
Academias e Institutos , Grupos Focales , Glaucoma/fisiopatología , Nervio Óptico/fisiopatología , Evaluación de Resultado en la Atención de Salud , Visión Ocular/fisiología , Europa (Continente) , Humanos , Nervio Óptico/patología , Células Ganglionares de la Retina/patología
20.
Transl Vis Sci Technol ; 8(6): 46, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31879568

RESUMEN

PURPOSE: To evaluate the functional relevance and structural correlates of autofluorescence (AF) alterations under short-wavelength (SW) and near-infrared (NIR) excitation light in ABCA4-related retinopathy. METHODS: In this prospective, cross-sectional case series, 88 eyes of 44 patients with ABCA4-related retinopathy (mean age, 37.6 years; range, 9-77 years) underwent SW-AF and NIR-AF imaging. The AF images were graded for disease characteristic patterns by two independent readers and correlated with alterations in optical coherence tomography (OCT) and impairment of retinal sensitivity along a foveo-papillary line assessed by fundus-controlled microperimetry. RESULTS: A centrifugal sequence of AF patterns from atrophic lesions to homogeneous background was found for both AF modalities. The eccentricity of each AF pattern in NIR-AF was larger compared to those in SW-AF (P < 0.001). Increasing eccentricity of each pattern correlated with increasing retinal sensitivity. The distant border of the zone of hyperfluorescent flecks in SW-AF and hypoautofluorescent flecks in NIR-AF correlated with the margins of the ellipsoid zone loss in OCT (r = 0.979 and r = 0.971, P < 0.001). The expansion of hypofluorescent flecks in SW-AF was associated with the boundaries of external limiting membrane loss (r = 0.933, P < 0.001). CONCLUSIONS: SW-AF and NIR-AF revealed a characteristic sequence of AF patterns that correlated with functional and structural alterations, suggesting different stages in disease progression. TRANSLATIONAL RELEVANCE: Alterations in NIR-AF exceeded those in SW-AF images, substantiating the hypothesis of different AF origins and suggesting NIR-AF as surrogate marker for early disease-related changes.

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