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1.
Chem Mater ; 36(12): 6017-6026, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38947979

RESUMO

Li6PS5Cl has attracted significant attention due to its high Li-ion conductivity and processability, facilitating large-scale solid-state battery applications. However, when paired with high-voltage cathodes, it experiences adverse side reactions. Li3InCl6 (LIC), known for its higher stability at high voltages and moderate Li-ion conductivity, is considered a catholyte to address the limitations of Li6PS5Cl. To extend the stability of Li6PS5Cl toward LiNi0.8Co0.15Al0.05O2 (NCA), we applied nanocrystalline LIC as a 180 nm-thick protective coating in a core-shell-like fashion (LIC@NCA) via mechanofusion. Solid-state batteries with LIC@NCA allow an initial discharge specific capacity of 148 mA h/g at 0.1C and 80% capacity retention for 200 cycles at 0.2C with a cutoff voltage of 4.2 V (vs Li/Li+), while cells without LIC coating suffers from low initial discharge capacity and poor retention. Using a wide spectrum of advanced characterization techniques, such as operando XRD, XPS, FIB-SEM, and TOF-SIMS, we reveal that the superior performance of solid-state batteries employing LIC@NCA is related to the suppression of detrimental interfacial reactions of NCA with Li6PS5Cl, delamination, and particle cracking compared to uncoated NCA.

3.
BMC Rheumatol ; 8(1): 24, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849947

RESUMO

BACKGROUND: In recent times, there has been acknowledgment of the prevalence of frailty and pre-frailty among individuals with rheumatoid arthritis (RA). Comprehensive Rheumatologic Assessment of Frailty (CRAF) stands out as a dependable tool grounded in synthesis and clinical judgment. Despite this, a validated Vietnamese rendition of the CRAF is currently unavailable. This study seeks to assess the reliability and validity of the CRAF in a patient with RA in Vietnam. METHODS: A cross-sectional investigation was carried out with 402 patients diagnosed with rheumatoid arthritis, encompassing both inpatients and outpatients at the Centre for Rheumatology at Bach Mai Hospital in Hanoi, Vietnam. CRAF was employed to gauge the extent of frailty. To establish convergent validity, the scores from the CRAF were correlated with those from the Fried phenotype. Discriminant validity was ascertained through the utilization of receiver operating characteristic (ROC) curve analysis. Additionally, a multivariate logistic regression model was applied to evaluate the individual determinants' relative impact on the CRAF. RESULTS: In testing for convergent validity, a significant correlation was found between CRAF and Fried phenotype (p < 0.001). The discriminatory power of CRAF was higher than those of the Fried phenotype (difference between areas under the ROC curves = 0.947 (95% CI: 0.927-0.967). Variables associated with frailty at the multivariate analysis were comorbitidy, medication intake, BMI, DAS28-CRP, and age (all at p < 0.01). CONCLUSION: CRAF exhibited strong validity and accurate discrimination. Incorporating frailty assessment into regular rheumatological practices could signify a significant advancement in the care of rheumatoid arthritis.

4.
bioRxiv ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38826450

RESUMO

Fibrosis drives end-organ damage in many diseases. However, clinical trials targeting individual upstream activators of fibroblasts, such as TGFß, have largely failed. Here, we target the leukemia inhibitory factor receptor (LIFR) as a "master amplifier" of multiple upstream activators of lung fibroblasts. In idiopathic pulmonary fibrosis (IPF), the most common fibrotic lung disease, we found that lung myofibroblasts had high LIF expression. Further, TGFß1, one of the key drivers of fibrosis, upregulated LIF expression in IPF fibroblasts. In vitro anti-LIFR antibody blocking on human IPF lung fibroblasts reduced induction of profibrotic genes downstream of TGFß1, IL-4 and IL-13. Further, siRNA silencing of LIFR in IPF precision cut lung slices reduced expression of fibrotic proteins. Together, we find that LIFR drives an autocrine positive feedback loop that amplifies and sustains pathogenic activation of IPF fibroblasts downstream of multiple external stimuli, implicating LIFR as a therapeutic target in fibrosis. Significance Statement: Fibroblasts have a central role in the pathogenesis of fibrotic diseases. However, due to in part to multiple profibrotic stimuli, targeting a single activator of fibroblasts, like TGFß, has not yielded successful clinical treatments. We hypothesized that a more effective therapeutic strategy is identifying a downstream "master amplifier" of a range of upstream profibrotic stimuli. This study identifies the leukemia inhibitory factor receptor (LIFR) on fibrotic lung fibroblasts amplifies multiple profibrotic stimuli, such as IL-13 and TGFß. Blocking LIFR reduced fibrosis in ex vivo lung tissue from patients with idiopathic pulmonary fibrosis (IPF). LIFR, acting as a master amplifier downstream of fibroblast activation, offers an alternative therapeutic strategy for fibrotic diseases.

5.
bioRxiv ; 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38853845

RESUMO

Drosophila germ granules enrich mRNAs critical for fly development. Within germ granules, mRNAs form multi-transcript clusters marked by increased mRNA concentration, creating an elevated potential for intermolecular base pairing. However, the type and abundance of intermolecular base pairing in mRNA clusters is poorly characterized. Using single-molecule super-resolution microscopy, chemical probing for base accessibility, phase separation assays, and simulations, we demonstrated that mRNAs remain well-folded upon localization to germ granules. While most base pairing is intramolecular, mRNAs still display the ability for intermolecular base pairing, facilitating clustering without high sequence complementarity or significant melting of secondary structure. This base pairing among mRNAs is driven by scattered and discontinuous stretches of bases appearing on the surface of folded RNAs, providing multivalency to clustering but exhibits low probability for sustained interactions. Notably, engineered germ granule mRNAs with exposed GC-rich complementary sequences (CSs) presented within stable stem loops induce sustained base pairing in vitro and enhanced intermolecular interactions in vivo. However, the presence of these stem loops alone disrupts fly development, and the addition of GC-rich CSs exacerbates this phenotype. Although germ granule mRNAs contain numerous GC-rich CSs capable of stable intermolecular base pairing, they are primarily embedded by RNA folding. This study emphasizes the role of RNA folding in controlling the type and abundance of intermolecular base pairing, thereby preserving the functional integrity of mRNAs within the germ granules.

6.
PLoS One ; 19(5): e0303846, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38820372

RESUMO

There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. This prospective trial in seven high tuberculosis burden countries evaluated the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatients and outpatients living with HIV. Diagnostic performance of FujiLAM was assessed against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard (eMRS), and a composite reference standard including clinical evaluation. Of 1637 participants considered for the analysis, 296 (18%) were tuberculosis positive by eMRS. Median age was 40 years, median CD4 cell count was 369 cells/ul, and 52% were female. Overall FujiLAM sensitivity was 54·4% (95% CI: 48·7-60·0), overall specificity was 85·2% (83·2-87·0) against eMRS. Sensitivity and specificity estimates varied between sites, ranging from 26·5% (95% CI: 17·4%-38·0%) to 73·2% (60·4%-83·0%), and 75·0 (65·0%-82·9%) to 96·5 (92·1%-98·5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Lot variability limited interpretation of FujiLAM test performance. Although results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. The trial is registered at clinicaltrials.gov (NCT04089423).


Assuntos
Infecções por HIV , Tuberculose , Humanos , Feminino , Masculino , Adulto , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Estudos Prospectivos , Tuberculose/diagnóstico , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Mycobacterium tuberculosis/isolamento & purificação , Lipopolissacarídeos/urina , Escarro/microbiologia
7.
Curr Protoc ; 4(5): e1036, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38713133

RESUMO

Identifying impacted pathways is important because it provides insights into the biology underlying conditions beyond the detection of differentially expressed genes. Because of the importance of such analysis, more than 100 pathway analysis methods have been developed thus far. Despite the availability of many methods, it is challenging for biomedical researchers to learn and properly perform pathway analysis. First, the sheer number of methods makes it challenging to learn and choose the correct method for a given experiment. Second, computational methods require users to be savvy with coding syntax, and comfortable with command-line environments, areas that are unfamiliar to most life scientists. Third, as learning tools and computational methods are typically implemented only for a few species (i.e., human and some model organisms), it is difficult to perform pathway analysis on other species that are not included in many of the current pathway analysis tools. Finally, existing pathway tools do not allow researchers to combine, compare, and contrast the results of different methods and experiments for both hypothesis testing and analysis purposes. To address these challenges, we developed an open-source R package for Consensus Pathway Analysis (RCPA) that allows researchers to conveniently: (1) download and process data from NCBI GEO; (2) perform differential analysis using established techniques developed for both microarray and sequencing data; (3) perform both gene set enrichment, as well as topology-based pathway analysis using different methods that seek to answer different research hypotheses; (4) combine methods and datasets to find consensus results; and (5) visualize analysis results and explore significantly impacted pathways across multiple analyses. This protocol provides many example code snippets with detailed explanations and supports the analysis of more than 1000 species, two pathway databases, three differential analysis techniques, eight pathway analysis tools, six meta-analysis methods, and two consensus analysis techniques. The package is freely available on the CRAN repository. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Processing Affymetrix microarrays Basic Protocol 2: Processing Agilent microarrays Support Protocol: Processing RNA sequencing (RNA-Seq) data Basic Protocol 3: Differential analysis of microarray data (Affymetrix and Agilent) Basic Protocol 4: Differential analysis of RNA-Seq data Basic Protocol 5: Gene set enrichment analysis Basic Protocol 6: Topology-based (TB) pathway analysis Basic Protocol 7: Data integration and visualization.


Assuntos
Biologia Computacional , Software , Humanos , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos
8.
Artigo em Inglês | MEDLINE | ID: mdl-38805332

RESUMO

Advancements in computational technology have led to a shift towards automated detection processes in lung cancer screening, particularly through nodule segmentation techniques. These techniques employ thresholding to distinguish between soft and firm tissues, including cancerous nodules. The challenge of accurately detecting nodules close to critical lung structures such as blood vessels, bronchi, and the pleura highlights the necessity for more sophisticated methods to enhance diagnostic accuracy. This paper proposed combined processing filters for data preparation before using one of the modified Convolutional Neural Networks (CNN) as the classifier. With refined filters, the nodule targets are solid, semi-solid, and ground glass, ranging from low-stage cancer (cancer screening data) to high-stage cancer. Furthermore, two additional works were added to address juxta-pleural nodules while the pre-processing end and classification are done in a 3-dimensional domain in opposition to the usual image classification. The accuracy output indicates that even using a simple Segmentation Network if modified correctly, can improve the classification result compared to the other eight models. The proposed sequence total accuracy reached 99.7%, with 99.71% cancer class accuracy and 99.82% non-cancer accuracy, much higher than any previous research, which can improve the detection efforts of the radiologist.

9.
Int J Biol Macromol ; 269(Pt 2): 132217, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38729491

RESUMO

Noni fruit (Morinda citrifolia L.) has many health-supporting compounds, but its biological extracts need protection against environmental impacts for stability and efficiency. To address this, microencapsulation is an advanced technology in food applications that require optimization of coating component and temperature regime. Gum arabic (GA) and maltodextrin (MD) were suitably combined at 2:1 ratio, which showed good and stable structure as well as successful microencapsulation efficiency of the enzymatic-ultrasonic assisted noni extract. A coating density of 20 % for the GA:MD formula was with highest performance. The heat setting of spray drying was optimized at 175 and 82 °C for inlet and outlet, respectively using response surface methodology with experimental validation of maximized TFC and TSC at 88.3 and 90.3 %, respectively. Noni microencapsulated powder was assessed via a series of reliably advanced techniques such as microscopy, spectrophotometry, diffraction, and calorimetry for structural properties. Noni powder was additionally tested for storage stability, heat exposure stability, and release efficiency in pH condition and in vitro digestive tract. Promising results were obtained with at least one year storage stability, better microcapsule stability at 60 and 100 °C, quite good release at pH 7.4, and suitable release efficiency in digestive tract simulation. These properties of microencapsulated noni powder open further scalability potential and various industrial applications.


Assuntos
Composição de Medicamentos , Frutas , Goma Arábica , Morinda , Extratos Vegetais , Polissacarídeos , Goma Arábica/química , Polissacarídeos/química , Extratos Vegetais/química , Composição de Medicamentos/métodos , Frutas/química , Morinda/química , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Cápsulas
10.
J Phys Chem Lett ; 15(14): 3820-3827, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38557079

RESUMO

Repeat RNA sequences self-associate to form condensates. Simulations of a coarse-grained single-interaction site model for (CAG)n (n = 30 and 31) show that the salt-dependent free energy gap, ΔGS, between the ground (perfect hairpin) and the excited state (slipped hairpin (SH) with one CAG overhang) of the monomer for (n even) is the primary factor that determines the rates and yield of self-assembly. For odd n, the free energy (GS) of the ground state, which is an SH, is used to predict the self-association kinetics. As the monovalent salt concentration, CS, increases, ΔGS and GS increase, which decreases the rates of dimer formation. In contrast, ΔGS for shuffled sequences, with the same length and sequence composition as (CAG)31, is larger, which suppresses their propensities to aggregate. Although demonstrated explicitly for (CAG) polymers, the finding of inverse correlation between the free energy gap and RNA aggregation is general.


Assuntos
RNA , Repetições de Trinucleotídeos , Conformação de Ácido Nucleico , Cloreto de Sódio
11.
Nucleic Acids Res ; 52(9): 4761-4783, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38619038

RESUMO

Single-cell RNA sequencing (scRNA-Seq) is a recent technology that allows for the measurement of the expression of all genes in each individual cell contained in a sample. Information at the single-cell level has been shown to be extremely useful in many areas. However, performing single-cell experiments is expensive. Although cellular deconvolution cannot provide the same comprehensive information as single-cell experiments, it can extract cell-type information from bulk RNA data, and therefore it allows researchers to conduct studies at cell-type resolution from existing bulk datasets. For these reasons, a great effort has been made to develop such methods for cellular deconvolution. The large number of methods available, the requirement of coding skills, inadequate documentation, and lack of performance assessment all make it extremely difficult for life scientists to choose a suitable method for their experiment. This paper aims to fill this gap by providing a comprehensive review of 53 deconvolution methods regarding their methodology, applications, performance, and outstanding challenges. More importantly, the article presents a benchmarking of all these 53 methods using 283 cell types from 30 tissues of 63 individuals. We also provide an R package named DeconBenchmark that allows readers to execute and benchmark the reviewed methods (https://github.com/tinnlab/DeconBenchmark).


Assuntos
Análise de Célula Única , Software , Análise de Célula Única/métodos , Humanos , Análise de Sequência de RNA/métodos , Animais , RNA-Seq/métodos , Benchmarking , Algoritmos , Perfilação da Expressão Gênica/métodos
12.
Int J Biol Macromol ; 268(Pt 2): 131760, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38663693

RESUMO

In the adsorption process for wastewater treatment, the adsorbent plays an important role. A composite adsorptive material composed of graphitic carbon nitride and agar-derived porous carbon (CNPC) was fabricated from simple precursors (melamine, thiourea, and agar) and through a facile procedure with different melamine and thiourea ratios. Characterization of CNPC proved a successful formation of a porous structure consisting of mesopores and macropores, wherein CNPC holds distinctive electrochemical (lowered resistance and higher specific capacity) and photochemical properties (lowered bandgap to 2.33 eV) thanks to the combination of graphitic carbon nitride (CN) and agar-derived porous carbon (PC). Inheriting the immanent nature, CNPC was subjected to the adsorption of methylene blue (MB) dye in an aqueous solution. The highest adsorption capacity was 133 mg/g for CNPC-4 which was prepared using a melamine to thiourea ratio of 4:4 - equivalent to the removal rate of 53.2 % and following the pseudo-I-order reaction rate. The effect of pH points out that pH 7 and 9 were susceptible to maximum removal and pretreatment is not required while the optimal ratio of 7.5 mg of MB and 30 mg of material was also determined to yield the highest performance. Furthermore, the reusability of the material for three consecutive cycles was evaluated based on two methods pyrolysis at 200 °C and photocatalytic degradation by irradiation under visible light. In general, the photocatalytic regeneration pathway is more ample and efficient than pyrolysis in terms of energy efficiency (saving energy over 10 times) and adsorption capacity stability. As a whole, the construction of accessible regenerative and stable adsorbent could be a venturing step into the sustainable development spearhead for industries.


Assuntos
Ágar , Grafite , Azul de Metileno , Poluentes Químicos da Água , Adsorção , Grafite/química , Porosidade , Poluentes Químicos da Água/química , Poluentes Químicos da Água/isolamento & purificação , Azul de Metileno/química , Ágar/química , Purificação da Água/métodos , Triazinas/química , Recuperação e Remediação Ambiental/métodos , Carbono/química , Águas Residuárias/química , Concentração de Íons de Hidrogênio , Compostos de Nitrogênio/química , Cinética , Tioureia/química
13.
Geriatrics (Basel) ; 9(2)2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38667519

RESUMO

(1) Background: Up until now, there is still no medicine that can cure dementia, but there are some that can only help slow down the progression of the disease and reduce some symptoms. Pharmacological interventions for dementia have many side effects and are expensive, so non-pharmacological treatments for dementia become more urgent. This study aimed to evaluate the effectiveness of multifactorial non-pharmacological interventions in dementia patients; (2) Methods: This is a randomized controlled trial conducted in Hai Duong from July 2021 to December 2022. Selected subjects included 88 patients diagnosed with very mild, mild, and moderate dementia, of whom 44 patients were assigned to the intervention group and 44 patients to the control group; (3) Results: For the effectiveness of the non-pharmacological multifactorial intervention on depression severity: in the intervention group, the GDS 15 depression score decreased from 4.8 to 2.9, while, in the control group, the GDS 15 depression score increased by 1.3 points after six months of no intervention. For the effect of the non-pharmacological multifactorial intervention on the level of sleep disturbance, in the intervention group, the PSQI sleep disturbance score decreased by nearly half (from 10.2 to 5.6), while, in the control group, this trend was not clear. For the effect of the non-pharmacological multifactorial intervention on daily functioning: in the intervention group, the ADL and IADL scores improved (1.02 ± 1.32 and 1.23 ± 1.75), while, in the control group, the ADL and IADL scores decreased (0.93 ± 1.2 and 0.98 ± 2.19). For the effect of the non-pharmacological multifactorial intervention on quality of life: in the intervention group, the EQ-5D-5L scores improved (0.17 ± 0.19), while, in the control group, the EQ-5D-5L scores decreased (0.20 ± 0.30); (4) Conclusions: Non-pharmacological multifactorial interventions, including physical activity, cognitive training, listening to educational lectures, and organizing miniature social models, have been shown to improve mental health, self-control, and quality of life.

14.
Molecules ; 29(8)2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38675609

RESUMO

This first study investigated the presence of dioxins and furans in river sediments around a craft village in Vietnam, focusing on Secondary Steel Recycling. Sediment samples were collected from various locations along the riverbed near the Da Hoi Secondary Steel Recycling village in Bac Ninh province. The analysis was conducted using a HRGC/HRMS-DFS device, detecting a total of 17 dioxin/furan isomers in all samples, with an average total concentration of 288.86 ng/kg d.w. The concentrations of dioxin/furan congeners showed minimal variation among sediment samples, ranging from 253.9 to 344.2 ng/kg d.w. The predominant compounds in the dioxin group were OCDD, while in the furan group, they were 1,2,3,4,6,7,8-HpCDF and OCDF. The chlorine content in the molecule appeared to be closely related to the concentration of dioxins and their percentage distribution. However, the levels of furan isomers did not vary significantly. The distribution of these compounds was not dependent on the flow direction, as they were mainly found in solid waste and are not water-soluble. Although the hepta and octa congeners had high concentrations, when converted to TEQ values, the tetra and penta groups (for dioxins) and the penta and hexa groups (for furans) contributed more to toxicity. Furthermore, the source of dioxins in sediments at Da Hoi does not only originate from steel recycling production activities but also from other combustion sites. The average total toxicity was 10.92 ng TEQ/kg d.w, ranging from 4.99 to 17.88 ng TEQ/kg d.w, which did not exceed the threshold specified in QCVN 43:2017/BTNMT, the National Technical Regulation on Sediment Quality. Nonetheless, these levels are still concerning. The presence of these toxic substances not only impacts aquatic organisms in the sampled water environment but also poses potential health risks to residents living nearby.


Assuntos
Dioxinas , Monitoramento Ambiental , Furanos , Sedimentos Geológicos , Rios , Aço , Poluentes Químicos da Água , Rios/química , Vietnã , Sedimentos Geológicos/química , Sedimentos Geológicos/análise , Dioxinas/análise , Aço/química , Poluentes Químicos da Água/análise , Furanos/análise , Furanos/química , Monitoramento Ambiental/métodos , Reciclagem
15.
Plant Physiol Biochem ; 210: 108614, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38626655

RESUMO

Heat-priming improves plants' tolerance to a recurring heat stress event. The underlying molecular mechanisms of heat-priming are largely unknown in seagrasses. Here, ad hoc mesocosm experiments were conducted with two Mediterranean seagrass species, Posidonia oceanica and Cymodocea nodosa. Plants were first exposed to heat-priming, followed by a heat-triggering event. A comprehensive assessment of plant stress response across different levels of biological organization was performed at the end of the triggering event. Morphological and physiological results showed an improved response of heat-primed P. oceanica plants while in C. nodosa both heat- and non-primed plants enhanced their growth rates at the end of the triggering event. As resulting from whole transcriptome sequencing, molecular functions related to several cellular compartments and processes were involved in the response to warming of non-primed plants, while the response of heat-primed plants involved a limited group of processes. Our results suggest that seagrasses acquire a primed state during the priming event, that eventually gives plants the ability to induce a more energy-effective response when the thermal stress event recurs. Different species may differ in their ability to perform an improved heat stress response after priming. This study provides pioneer molecular insights into the emerging topic of seagrass stress priming and may benefit future studies in the field.


Assuntos
Alismatales , Transcriptoma , Alismatales/genética , Alismatales/metabolismo , Transcriptoma/genética , Especificidade da Espécie , Resposta ao Choque Térmico/genética , Resposta ao Choque Térmico/fisiologia , Regulação da Expressão Gênica de Plantas , Mar Mediterrâneo , Temperatura Alta
16.
J Neurosci ; 44(21)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38569926

RESUMO

Proteoglycans containing link domains modify the extracellular matrix (ECM) to regulate cellular homeostasis and can also sensitize tissues/organs to injury and stress. Hypoxic-ischemic (H-I) injury disrupts cellular homeostasis by activating inflammation and attenuating regeneration and repair pathways. In the brain, the main component of the ECM is the glycosaminoglycan hyaluronic acid (HA), but whether HA modifications of the ECM regulate cellular homeostasis and response to H-I injury is not known. In this report, employing both male and female mice, we demonstrate that link-domain-containing proteoglycan, TNFα-stimulated gene-6 (TSG-6), is active in the brain from birth onward and differentially modifies ECM HA during discrete neurodevelopmental windows. ECM HA modification by TSG-6 enables it to serve as a developmental switch to regulate the activity of the Hippo pathway effector protein, yes-associated protein 1 (YAP1), in the maturing brain and in response to H-I injury. Mice that lack TSG-6 expression display dysregulated expression of YAP1 targets, excitatory amino acid transporter 1 (EAAT1; glutamate-aspartate transporter) and 2 (EAAT2; glutamate transporter-1). Dysregulation of YAP1 activation in TSG-6-/- mice coincides with age- and sex-dependent sensitization of the brain to H-I injury such that 1-week-old neonates display an anti-inflammatory response in contrast to an enhanced proinflammatory injury reaction in 3-month-old adult males but not females. Our findings thus support that a key regulator of age- and sex-dependent H-I injury response in the mouse brain is modulation of the Hippo-YAP1 pathway by TSG-6-dependent ECM modifications.


Assuntos
Moléculas de Adesão Celular , Matriz Extracelular , Hipóxia-Isquemia Encefálica , Proteínas de Sinalização YAP , Animais , Feminino , Masculino , Moléculas de Adesão Celular/metabolismo , Camundongos , Matriz Extracelular/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Proteínas de Sinalização YAP/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Ácido Hialurônico/metabolismo , Camundongos Knockout , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética
17.
ACS Macro Lett ; 13(5): 571-576, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38647178

RESUMO

Controlling the access of proteases to cleavable peptides placed at specific locations within macromolecular architectures represents a powerful strategy for biologically responsive materials design. Here, we report the synthesis of peptide-containing bivalent bottlebrush (co)polymers (BBPs) featuring polyethylene glycol (PEG) and 7-amino-4-methylcoumarin (AMC) pendants on each backbone repeat unit. The AMCs are linked via caspase-3-cleavable peptides which, upon enzymatic cleavage, provide a "turn-on" fluorescence signal due to the release of free AMC. Time-dependent fluorscence measurements demonstrate that the caspase-3-induced peptide cleavage and AMC release from BBPs is strongly dependent on the BBP backbone length and the AMC-peptide linker location within the BBP architecture, revealing fundamental insights into the interactions of enzymes with BBPs.


Assuntos
Caspase 3 , Corantes Fluorescentes , Polietilenoglicóis , Corantes Fluorescentes/química , Caspase 3/metabolismo , Polietilenoglicóis/química , Cumarínicos/química , Peptídeos/química , Peptídeos/metabolismo , Polímeros/química , Humanos
18.
Endoscopy ; 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38641337

RESUMO

BACKGROUND: The optimal treatment for malignant gastric outlet obstruction (GOO) remains uncertain. This systematic review aimed to comprehensively investigate the efficacy and safety of four palliative treatments for malignant GOO: gastrojejunostomy, endoscopic ultrasound-guided gastroenterostomy (EUS-GE), stomach-partitioning gastrojejunostomy (PGJ), and endoscopic stenting. METHODS: We searched PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform for randomized controlled trials (RCTs) and cohort studies comparing the four treatments for malignant GOO. We included studies that reported at least one of the following clinical outcomes: clinical success, 30-day mortality, reintervention rate, or length of hospital stay. Evidence from RCTs and non-RCTs was naïve combined to perform network meta-analysis through the frequentist approach using an inverse variance model. Treatments were ranked by P score. RESULTS: This network meta-analysis included 3617 patients from 4 RCTs, 4 prospective cohort studies, and 32 retrospective cohort studies. PGJ was the optimal approach in terms of clinical success and reintervention (P scores: 0.95 and 0.90, respectively). EUS-GE had the highest probability of being the optimal treatment in terms of 30-day mortality and complications (P scores: 0.82 and 0.99, respectively). Cluster ranking to combine the P scores for 30-day mortality and reintervention indicated the benefits of PGJ and EUS-GE (cophenetic correlation coefficient: 0.94; PGJ and EUS-GE were in the same cluster). CONCLUSION: PGJ and EUS-GE are recommended for malignant GOO. PGJ could be the alternative choice in centers with limited resources or in patients who are unsuitable for EUS-GE.

19.
J Neurosurg Spine ; 41(1): 135-145, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38626470

RESUMO

OBJECTIVE: Physical stress associated with the static posture of neurosurgeons over prolonged periods can result in fatigue and musculoskeletal disorders. Objective assessment of surgical ergonomics may contribute to postural awareness and prevent further complications. This pilot study examined the feasibility of using wearable technology as a biofeedback tool to address this gap. METHODS: Ten neurosurgeons, including 5 attendings (all faculty) and 5 trainees (1 fellow, 4 residents), were recruited and equipped with two wearable sensors attached to the back of their head and their upper back. The sensors collected the average time spent in extended (≤ -10°), neutral (> -10° and < 10°), and flexed (≥ 10°) static postures (undetected activity for more than 10 seconds) during spine and cranial procedures. Feasibility outcomes aimed for more than 70% of accurate data collection. Exploratory outcomes included the comparison of postural variability within and between participants adjusted to their demographics excluding nonrelated surgical activities, and postoperative self-assessment surveys. RESULTS: Sixteen (80%) of 20 possible recordings were successfully collected and analyzed from 11 procedures (8 spine, 3 cranial). Surgeons maintained a static posture during 52.7% of the active surgical time (mean 1.58 hrs). During spine procedures, all surgeons used an exoscope while standing, leading to a significantly longer time spent in a neutral static posture (p < 0.001, partial η2 = 0.14): attendings remained longer in a neutral static posture (36.4% ± 15.3%) than in the extended (9% ± 6.3%) and flexed (5.7% ± 3.4%) static postures; trainees also remained longer in a neutral static posture (30.2% ± 13.8%) than in the extended (11.1% ± 6.3%) and flexed (11.9% ± 6.6%) static postures. During cranial procedures, surgeons intermittently transitioned between standing/exoscope use and sitting/microscope use, with trainees spending a shorter time in a neutral static posture (16.3% vs 48.5%, p < 0.001) and a longer time in a flexed static posture (18.5% vs 2.7%, p < 0.001) compared with attendings. Additionally, longer cranial procedures correlated with surgeons spending a longer time (r = 0.94) in any static posture (extended, flexed, and neutral), with taller surgeons exhibiting longer periods in flexed and extended static postures (r = 0.86). Postoperative self-assessment revealed that attendings perceived spine procedures as more difficult than trainees (p = 0.029), while trainees found cranial procedures to be of greater difficulty than spine procedures (p = 0.012). Attendings felt more stressed (p = 0.048), less calmed (p = 0.024), less relaxed (p = 0.048), and experienced greater stiffness in their upper body (p = 0.048) and more shoulder pain (p = 0.024) during cranial versus spine procedures. CONCLUSIONS: Wearable technology is feasible to assess postural ergonomics and provide objective biofeedback to neurosurgeons during spine and cranial procedures. This study showed reproducibility for future comparative protocols focused on correcting posture and surgical ergonomic education.


Assuntos
Ergonomia , Procedimentos Neurocirúrgicos , Salas Cirúrgicas , Postura , Dispositivos Eletrônicos Vestíveis , Humanos , Postura/fisiologia , Masculino , Feminino , Projetos Piloto , Adulto , Procedimentos Neurocirúrgicos/instrumentação , Cirurgiões , Estudos de Viabilidade , Pessoa de Meia-Idade , Neurocirurgia
20.
Pulm Circ ; 14(2): e12360, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38618291

RESUMO

Cardiac catheterization remains the gold standard for the diagnosis and management of pediatric pulmonary hypertension (PH). There is lack of consensus regarding optimal anesthetic and airway regimen. This retrospective study describes the anesthetic/airway experience of our single center cohort of pediatric PH patients undergoing catheterization, in which obtaining hemodynamic data during spontaneous breathing is preferential. A total of 448 catheterizations were performed in 232 patients. Of the 379 cases that began with a natural airway, 274 (72%) completed the procedure without an invasive airway, 90 (24%) received a planned invasive airway, and 15 (4%) required an unplanned invasive airway. Median age was 3.4 years (interquartile range [IQR] 0.7-9.7); the majority were either Nice Classification Group 1 (48%) or Group 3 (42%). Vasoactive medications and cardiopulmonary resuscitation were required in 14 (3.7%) and eight (2.1%) cases, respectively; there was one death. Characteristics associated with use of an invasive airway included age <1 year, Group 3, congenital heart disease, trisomy 21, prematurity, bronchopulmonary dysplasia, WHO functional class III/IV, no PH therapy at time of case, preoperative respiratory support, and having had an intervention (p < 0.05). A composite predictor of age <1 year, Group 3, prematurity, and any preoperative respiratory support was significantly associated with unplanned airway escalation (26.7% vs. 6.9%, odds ratio: 4.9, confidence interval: 1.4-17.0). This approach appears safe, with serious adverse event rates similar to previous reports despite the predominant use of natural airways. However, research is needed to further investigate the optimal anesthetic regimen and respiratory support for pediatric PH patients undergoing cardiac catheterization.

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