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1.
J Chem Inf Model ; 64(3): 677-689, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38270063

RESUMO

Thermally activated delayed fluorescence (TADF) material has attracted great attention as a promising metal-free organic light-emitting diode material with a high theoretical efficiency. To accelerate the discovery of novel TADF materials, computer-aided material design strategies have been developed. However, they have clear limitations due to the accessibility of only a few computationally tractable properties. Here, we propose TADF-likeness, a quantitative score to evaluate the TADF potential of molecules based on a data-driven concept of chemical similarity to existing TADF molecules. We used a deep autoencoder to characterize the common features of existing TADF molecules with common chemical descriptors. The score was highly correlated with the four essential electronic properties of TADF molecules and had a high success rate in large-scale virtual screening of millions of molecules to identify promising candidates at almost no cost, validating its feasibility for accelerating TADF discovery. The concept of TADF-likeness can be extended to other fields of materials discovery.


Assuntos
Aprendizado Profundo , Desenho Assistido por Computador , Eletrônica , Fluorescência
2.
Pract Lab Med ; 38: e00347, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38188654

RESUMO

Background: Vitamin D (vit-D) deficiency is highly prevalent in the Korean population, highlighting the need for accurate measurements. In this study, the interferences by endogenous and cross-reactive substances were compared between routine vit-D immunoassays and mass spectrometry (MS) methods. Methods: Two MS methods and 4 immunoassays from different manufacturers (Abbott, Beckman Coulter, Roche, Siemens) were compared. Residual samples that were icteric, lipemic, hemolyzed, high in rheumatoid factor, from myeloma patients, or patients undergoing hemodialysis were collected. Also, 4 levels of National Institute of Standards and Technology (NIST) Standard Reference Material 972a, and 12 samples serially spiked with 3-epi-25-OH-D3 were prepared. Results: Significant interferences were observed in hemolytic (Roche), icteric (Beckman and Siemens) and lipemic samples (all 4 immunoassays). Level 4 NIST material and 3-epi-25-OH-D3-spiked samples induced significant cross-reactivity, yielding higher total vit-D measurements in non-epimer-separating MS methods, and both the Beckman and Roche immunoassays. Conclusion: Most observed interferences were consistent with manufacturers' claims, but overall improvement of immunoassay bias limits is required. Awareness of potential interference is important to increase the accuracy of vit-D measurements. Moreover, care is due when interpreting vit-D results of newborns, infants and less commonly, pregnant women, who are known to have physiologically high levels of the highly cross-reactive 3-epi-25-OH-D3.

3.
Stem Cells Dev ; 33(3-4): 89-103, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38164089

RESUMO

Mesenchymal stem cells (MSCs) directly differentiate into neurons and endothelial cells after transplantation, and their secretome has considerable potential for treating brain injuries. Previous studies have suggested that the effects of MSCs priming with exposure to hypoxia, cytokines, growth factors, or chemical agents could optimize the paracrine potency and therapeutic potential of MSCs. Studies have suggested that thrombin-primed Wharton's Jelly-derived mesenchymal stem cells (Th.WJ-MSCs) significantly enhance the neuroprotective beneficial effects of naive MSCs in brain injury such as hypoxic-ischemic brain injury (HIE) and intraventricular hemorrhage (IVH). This study aimed to characterize WJ-MSCs in terms of stem cell markers, differentiation, cell proliferation, and paracrine factors by comparing naive and Th.WJ-MSCs. We demonstrated that compared with naive MSCs, Th.MSCs significantly enhanced the neuroprotective effects in vitro. Moreover, we identified differentially expressed proteins in the conditioned media of naive and Th.WJ-MSCs by liquid chromatography-tandem mass spectrometry analysis. Secretome analysis of the conditioned medium of WJ-MSCs revealed that such neuroprotective effects were mediated by paracrine effects with secretomes of Th.WJ-MSCs, and hepatocyte growth factor was identified as a key paracrine mediator. These results can be applied further in the preclinical and clinical development of effective and safe cell therapeutics for brain injuries such as HIE and IVH.


Assuntos
Lesões Encefálicas , Células-Tronco Mesenquimais , Fármacos Neuroprotetores , Fator de Transcrição STAT3 , Geleia de Wharton , Humanos , Fator de Crescimento de Hepatócito/metabolismo , Fármacos Neuroprotetores/farmacologia , Trombina/farmacologia , Trombina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Endoteliais/metabolismo , Células Cultivadas , Transdução de Sinais , Diferenciação Celular , Fatores Imunológicos/metabolismo , Lesões Encefálicas/metabolismo , Proliferação de Células
4.
Adv Sci (Weinh) ; 11(6): e2307600, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38072639

RESUMO

Understanding the mechanism underlying the formation of quantum-sized semiconductor nanocrystals is crucial for controlling their synthesis for a wide array of applications. However, most studies of 2D CdSe nanocrystals have relied predominantly on ex situ analyses, obscuring key intermediate stages and raising fundamental questions regarding their lateral shapes. Herein, the formation pathways of two distinct quantum-sized 2D wurtzite-CdSe nanocrystals - nanoribbons and nanosheets - by employing a comprehensive approach, combining in situ small-angle X-ray scattering techniques with various ex situ characterization methods is studied. Although both nanostructures share the same thickness of ≈1.4 nm, they display contrasting lateral dimensions. The findings reveal the pivotal role of Se precursor reactivity in determining two distinct synthesis pathways. Specifically, highly reactive precursors promote the formation of the nanocluster-lamellar assemblies, leading to the synthesis of 2D nanoribbons with elongated shapes. In contrast, mild precursors produce nanosheets from a tiny seed of 2D nuclei, and the lateral growth is regulated by chloride ions, rather than relying on nanocluster-lamellar assemblies or Cd(halide)2 -alkylamine templates, resulting in 2D nanocrystals with relatively shorter lengths. These findings significantly advance the understanding of the growth mechanism governing quantum-sized 2D semiconductor nanocrystals and offer valuable guidelines for their rational synthesis.

5.
J Chem Inf Model ; 64(7): 2432-2444, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-37651152

RESUMO

Recently emerging generative AI models enable us to produce a vast number of compounds for potential applications. While they can provide novel molecular structures, the synthetic feasibility of the generated molecules is often questioned. To address this issue, a few recent studies have attempted to use deep learning models to estimate the synthetic accessibility of many molecules rapidly. However, retrosynthetic analysis tools used to train the models rely on reaction templates automatically extracted from a large reaction database that are not domain-specific and may exhibit low chemical correctness. To overcome this limitation, we introduce DFRscore (Drug-Focused Retrosynthetic score), a deep learning-based approach for a more practical assessment of synthetic accessibility in drug discovery. The DFRscore model is trained exclusively on drug-focused reactions, providing a predicted number of minimally required synthetic steps for each compound. This approach enables practitioners to filter out compounds that do not meet their desired level of synthetic accessibility at an early stage of high-throughput virtual screening for accelerated drug discovery. The proposed strategy can be easily adapted to other domains by adjusting the synthesis planning setup of the reaction templates and starting materials.


Assuntos
Aprendizado Profundo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Estrutura Molecular , Bases de Dados Factuais
7.
Gerontol Geriatr Med ; 9: 23337214231218796, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38146456

RESUMO

In response to the growing need for effective policy implementation strategies for older adults in South Korea, we propose the establishment of a user-centered institution tightly integrated with policies, termed, "comprehensive gateway institution for older adults." This research addresses the challenges 231 older adult users face when navigating various health policies. Our survey findings revealed that these users experienced difficulties in dealing with the current policy approach for older adults. The respondents expressed their expectations for improved service access through the proposed gateway institution. They emphasized the importance of universal access to services and the need for personalized offerings that consider their unique circumstances, physical abilities, and skills. By incorporating these research outcomes into practice, we can help lay the groundwork for more effective policies measures and create a system that better meets the needs of older adults in the future.

8.
Nat Commun ; 14(1): 7508, 2023 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-37980350

RESUMO

Designing robust blue organic light-emitting diodes is a long-standing challenge in the display industry. The highly energetic states of blue emitters cause various degradation paths, leading to collective luminance drops in a competitive manner. However, a key mechanism of the operational degradation of organic light-emitting diodes has yet to be elucidated. Here, we show that electron-induced degradation reactions play a critical role in the short lifetime of blue organic light-emitting diodes. Our control experiments demonstrate that the operational lifetime of a whole device can only be explained when excitons and electrons exist together. We examine the atomistic mechanisms of the electron-induced degradation reactions by analyzing their energetic profiles using computational methods. Mass spectrometric analysis of aged devices further confirm the key mechanisms. These results provide new insight into rational design of robust blue organic light-emitting diodes.

9.
Nano Lett ; 23(15): 6799-6806, 2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37486984

RESUMO

Near the magic angle, strong correlations drive many intriguing phases in twisted bilayer graphene (tBG) including unconventional superconductivity and chern insulation. Whether correlations can tune symmetry breaking phases in tBG at intermediate (≳ 2°) twist angles remains an open fundamental question. Here, using ARPES, we study the effects of many-body interactions and displacement field on the band structure of tBG devices at an intermediate (3°) twist angle. We observe a layer- and doping-dependent renormalization of bands at the K points that is qualitatively consistent with moiré models of the Hartree-Fock interaction. We provide evidence of correlation-enhanced inversion symmetry-breaking, manifested by gaps at the Dirac points that are tunable with doping. These results suggest that electronic interactions play a significant role in the physics of tBG even at intermediate twist angles and present a new pathway toward engineering band structure and symmetry-breaking phases in moiré heterostructures.

10.
J Korean Med Sci ; 38(14): e101, 2023 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-37038640

RESUMO

The current guidelines for therapeutic drug monitoring (TDM) of vancomycin suggest a target 24-hour area under the curve (AUC0-24) of 400 to 600 mg*h/L for serious methicillin-resistant Staphylococcus aureus infections. In this study, the predictabilities of acute kidney injury (AKI) of various TDM target parameters, target levels, and sampling methods were evaluated in patients who underwent TDM from January 2020 to December 2020. The AUC0-24 and trough values were calculated by both one- and two-point sampling methods, and were evaluated for the predictability of AKI. Among the AUC0-24 cutoff comparisons, the threshold value of 500 mg*h/L in the two sampling methods was statistically significant (P = 0.042) when evaluated for the predictability of AKI. Analysis by an receiver operating characteristic curve estimated an AUC0-24 cutoff value of 563.45 mg*h/L as a predictor of AKI, and was proposed as the upper limit of TDM target.


Assuntos
Injúria Renal Aguda , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Vancomicina/uso terapêutico , Antibacterianos/uso terapêutico , Monitoramento de Medicamentos/métodos , Estudos Retrospectivos , Área Sob a Curva , Rim , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/prevenção & controle , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/prevenção & controle
11.
J Mass Spectrom Adv Clin Lab ; 28: 91-98, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36937812

RESUMO

Background: The VALID Act is a legislative effort that, if enacted, would alter the regulatory requirements of laboratory developed tests (LDTs) used for clinical testing in the United States. Benzodiazepines, which are primarily excreted into urine as glucuronidated metabolites such as lorazepam, cross-react poorly with FDA-cleared immunoassays, leading to false-negatives. This shortfall can be addressed with LDTs created by adding glucuronidase to the immunoassay reagents producing "high sensitivity" assays that detect glucuronidated metabolites. Methods: Precision and stability of two high-sensitivity (HS) benzodiazepine immunoassays from Roche and Thermo Scientific were evaluated using manufacturer-supplied quality control (QC) material and glucuronidated QC material. The immunoassays were directly compared to an LC-MS/MS LDT benzodiazepine assay to determine clinical sensitivity/specificity using urine specimens (n = 82 for Thermo Scientific; n = 265 for Roche). The clinical impact of the HS LDT immunoassay was determined by analyzing clinical testing results 60 days before and after its implementation. Results: The precision and clinical sensitivity/specificity of the HS-Thermo Scientific and HS-Roche benzodiazepine assays were acceptable. The reagent stability of the HS-Thermo Scientific immunoassay was poor, whereas the HS-Roche immunoassay was stable. After implementation of the HS-Roche benzodiazepine immunoassay as an LDT, there was a 30-fold increase (p-value: < 0.00001) in the percentage of lorazepam confirmations. Conclusions: We demonstrate the development and validation of an immunoassay LDT with improved sensitivity for glucuronidated benzodiazepines. This LDT can detect glucuronidated benzodiazepines in clinical urine specimens and is stable for 60 days. Importantly, we were able to validate the immunoassay as an LDT by utilizing an LC-MS/MS LDT.

12.
Am J Sports Med ; 51(3): 723-732, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36745013

RESUMO

BACKGROUND: There is a lack of studies about serum and tissue vitamin D levels of the rotator cuff muscle on muscle power, fatty degeneration, and healing failure after rotator cuff repair (RCR). Furthermore, no studies have evaluated vitamin D receptor proteins in the rotator cuff that show a close association with serum vitamin D levels. PURPOSE: To evaluate the correlations between serum vitamin D and tissue vitamin D as well as perioperative variables of arthroscopic RCR. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From March 2017 to October 2017, a total of 36 patients who underwent RCR were prospectively enrolled, and supraspinatus muscle tissue was obtained during surgery to analyze tissue vitamin D levels. Serum vitamin D levels were checked preoperatively and at 6 months and 1 year postoperatively. Tissue vitamin D levels were assessed using liquid chromatography, and the vitamin D receptor was measured by western blotting. Isokinetic muscle performance test (IMPT; peak torque and torque deficiency compared with the opposite shoulder) results and fatty degeneration of the rotator cuff using the Goutallier classification were assessed preoperatively and at 1 year after surgery. The American Shoulder and Elbow Surgeons score and Constant score were collected at 2 years after surgery. Healing failure of the repaired rotator cuff was analyzed by magnetic resonance imaging at 1 year after surgery. RESULTS: Overall, only three patients (8.3%) had serum vitamin D sufficiency (>20 ng/mL). Among 36 patients, 26 patients returned for their 1-year follow-up. Lower preoperative serum vitamin D levels resulted in lower serum vitamin D levels at 6 months and 1 year postoperatively (all P < .05). Lower preoperative and 1-year postoperative serum vitamin D levels resulted in more torque deficiency on the IMPT in abduction than higher preoperative and 1-year postoperative serum vitamin D levels (all P < .05). Tissue vitamin D levels had a strong correlation with preoperative serum vitamin D levels (P = .001). Lower tissue vitamin D levels were associated with lower peak torque on the IMPT in abduction (P = .043) and a tendency of lower peak torque on the IMPT in external rotation (P = .077) at 1 year postoperatively. There was no correlation between tissue and serum vitamin D levels and functional outcomes, fatty degeneration, and healing failure after surgery (all P > .05). The vitamin D receptor showed no correlation with any variables (all P > .05). CONCLUSION: Lower preoperative serum vitamin D levels had a strong correlation with lower tissue vitamin D levels and lower serum vitamin D levels at 1 year after surgery. Furthermore, the patients with lower serum vitamin D levels showed more weakness of muscle power perioperatively. The results of this study emphasized the association between vitamin D levels and rotator cuff muscle power.


Assuntos
Lesões do Manguito Rotador , Manguito Rotador , Humanos , Manguito Rotador/patologia , Vitamina D , Receptores de Calcitriol , Resultado do Tratamento , Artroscopia/métodos , Imageamento por Ressonância Magnética , Amplitude de Movimento Articular , Estudos Retrospectivos
13.
Protein Eng Des Sel ; 362023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36611015

RESUMO

Human transthyretin (TTR) is a homo-tetrameric plasma protein associated with a high percentage of ß-sheet forming amyloid fibrils. It accumulates in tissues or extracellular matrices to cause amyloid diseases. Free energy simulations with thermodynamic integration based on all-atom molecular dynamics simulations have been carried out to analyze the effects of the His88 â†’ Ala and Ser mutations on the stability of human TTR. The calculated free energy change differences (ΔΔG) caused by the His88 â†’ Ala and His88 â†’ Ser mutations are -1.84 ± 0.86 and 7.56 ± 0.55 kcal/mol, respectively, which are in excellent agreement with prior reported experimental values. The simulation results show that the H88A mutant is more stable than the wild type, whereas the H88S mutant is less stable than the wild type. The free energy component analysis shows that the contribution to the free energy change difference (ΔΔG) for the His88 â†’ Ala and His88 â†’ Ser mutations mainly arise from electrostatic and van der Waals interactions, respectively. The electrostatic term stabilizes the H88A mutant more than the wild type, but the van der Waals interaction destabilizes the H88S mutant relative to the wild type. Individual residue contributions to the free energy change show neighboring residues exert stabilizing and destabilizing influence on the mutants. The implications of the simulation results for understanding the stabilizing and destabilizing effect and its contribution to protein stability are discussed.


Assuntos
Alanina , Pré-Albumina , Humanos , Pré-Albumina/genética , Pré-Albumina/química , Pré-Albumina/metabolismo , Alanina/genética , Serina/genética , Simulação de Dinâmica Molecular , Estabilidade Proteica , Termodinâmica
14.
J Biomol Struct Dyn ; 41(13): 6040-6050, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35899456

RESUMO

Human serum retinol-binding protein (RBP) is a plasma transport protein for vitamin A. RBP is a prime subclass of lipocalins, which bind nonpolar ligands within a ß-barrel. To understand the role of Trp 24, one of the highly conserved residues in RBP, free energy simulations have been carried out to understand the effects of the mutations from Trp at position 24 to Leu, Phe, and Tyr in the apo-RBP on its thermal stability. We examine various unfolded systems to study the dependence of the free energy differences on the denatured structure. Our calculated free energy difference values for the three mutations are in excellent agreement with the experimental values when the initial coordinates of the seven-residue peptide segments truncated from the crystal structure are used for the denatured systems. Our free energy change differences for the Trp→Leu, Trp→Phe, and Trp→Tyr mutations are 2.50 ± 0.69, 2.58 ± 0.50, and 2.49 ± 0.48 kcal/mol, respectively, when the native-like seven-residue peptides are used as models for the denatured systems. The main contributions to the free energy change differences for the Trp24→Leu and Trp24→Phe mutations are mainly from van der Waals and covalent interactions, respectively. Electrostatic, van der Waals and covalent terms equally contribute to the free energy change difference for the Trp24→Tyr mutation. The free energy simulation helps understand the detailed microscopic mechanism of the stability of the RBP mutants relative to the wild type and the role of the highly conserved residue, Trp24, of the human RBP.Communicated by Ramaswamy H. Sarma.


Assuntos
Proteínas de Transporte , Vitamina A , Humanos , Proteínas de Transporte/química , Mutação , Peptídeos/metabolismo , Proteínas de Ligação ao Retinol/química , Proteínas de Ligação ao Retinol/genética , Proteínas de Ligação ao Retinol/metabolismo
15.
Ann Neurol ; 93(4): 768-782, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36541592

RESUMO

OBJECTIVE: Heritability of stroke is assumed not to be low, especially in the young stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population. METHODS: We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGVs) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next generation sequencing panel. RESULTS: Among 1,033 patients, 131 (12.7%) had 28 CRGVs, most frequently in RNF213 (n = 59), followed by ABCC6 (n = 53) and NOTCH3 (n = 15). The frequency of CRGVs differed by ischemic stroke subtypes (p < 0.01): the highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51 to 55 years (17.1% vs 9.3%, p = 0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUSs) were found in 15.4% patients. INTERPRETATION: CRGVs in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGVs did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGVs or VUSs should be explored. ANN NEUROL 2023;93:768-782.


Assuntos
Ataque Isquêmico Transitório , Acidente Vascular Cerebral , Humanos , Estudos Prospectivos , Prevalência , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Mutação/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Receptores de Activinas Tipo II/genética , Adenosina Trifosfatases/genética , Ubiquitina-Proteína Ligases/genética
16.
J Biomol Struct Dyn ; 41(7): 2619-2629, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-35176965

RESUMO

Prion diseases are neurodegenerative disorders caused by spongiform degeneration of the brain. Understanding the fundamental mechanism of prion protein aggregation caused by mutations is very crucial to resolve the pathology of prion diseases. To help understand the roles of individual residues on the stability of the human prion protein, the computational method of free energy simulations based on atomistic molecular dynamics trajectories is applied to Phe175 → Ala, Val180 → Ala, and Val209 → Ala mutations of the human prion protein. The simulations show that all three alanine mutations destabilize the human prion protein. The calculated free energy change differences, ΔΔG, for the Phe175 → Ala, Val180 → Ala, and Val209 → Ala mutations are in good agreement with the experimental values. The significant destabilizing effects on the mutants relative to the wild-type protein arise from van der Waals terms. Furthermore, our free energy decomposition analysis shows that the major contribution to destabilizing the V180A and V209A mutants relative to the wild-type protein is originated from van der Waals interactions from residues near the mutation sites. In contrast, the contribution to destabilizing the F175A mutant is mainly caused by van der Waals interactions from residues near and far away from the mutation site. Our results show that the free energy simulation with a thermodynamic integration approach for selected alanine scanning mutations is beneficial for understanding the detailed mechanism of human prion protein destabilization, specific residues' role, and the hydrophobic effect on protein stability.Communicated by Ramaswamy H. Sarma.


Assuntos
Proteínas Priônicas , Humanos , Alanina/química , Simulação de Dinâmica Molecular , Mutação , Proteínas Priônicas/química , Proteínas Priônicas/genética , Príons/genética , Dobramento de Proteína
18.
Aging (Albany NY) ; 14(22): 8944-8969, 2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36446389

RESUMO

Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 105 ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in in vitro stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke.


Assuntos
AVC Isquêmico , Células-Tronco Neurais , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Animais , Humanos , Ratos , Indutores da Angiogênese , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/tratamento farmacológico , AVC Isquêmico/terapia , Janus Quinase 2/metabolismo , Modelos Animais , Células-Tronco Neurais/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico
19.
Front Endocrinol (Lausanne) ; 13: 997631, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339444

RESUMO

Background: Considering the roles of 25-hydroxyvitamin D (25OHD) in glucose homeostasis and immune modulation, vitamin D deficiency may be related to the development of type 1 diabetes (T1DM) and diabetic ketoacidosis (DKA). We evaluated the total, free, bioavailable 25OHD levels and vitamin D binding protein (VDBP) levels and genotypes between T1DM patients and controls. Methods: This retrospective, cross-sectional study included 84 children with T1DM (38 boys and 46 girls, 8.0 ± 3.6 years) and 1:1 age- and sex-matched healthy controls. A multiplex liquid chromatography-tandem mass spectrometry-based assay was used to simultaneously measure vitamin D metabolites. Results: Patients with T1DM had lower levels of total 25OHD (16.3 ± 5.1 vs. 19.9 ± 6.5 ng/mL, P< 0.001) and VDBP (146.0 ± 27.8 vs. 224.9 ± 36.1 µg/mL, P = 0.001), but higher free 25OHD (8.0 ± 2.5 vs. 6.5 ± 2.3 pg/mL, P< 0.001) than controls. Patients who presented with DKA had lower levels of 25OHD in the total (15.0 ± 4.6 vs. 17.6 ± 5.2 ng/mL, P = 0.020), free (7.5 ± 2.6 vs. 8.4 ± 2.4 pg/mL, P = 0.059), and bioavailable (2.3 ± 0.9 vs. 2.8 ± 0.8 ng/mL, P = 0.014) forms than those without DKA at the T1DM diagnosis. The lower the total, free, and bioavailable 25OHD levels at diagnosis, the lower the pH and HCO3-. The proportions of the VDBP genotypes did not differ between the patients and controls. Conclusion: Patients with T1DM had higher levels of free 25OHD than healthy children, despite lower levels of total 25OHD. However, patients with DKA exhibited lower levels of bioavailable 25OHD than those without DKA at the T1DM diagnosis. The lower the concentrations of free and bioavailable 25OHD, the more severe the acidosis at the initial T1DM presentation.


Assuntos
Diabetes Mellitus Tipo 1 , Cetoacidose Diabética , Criança , Masculino , Feminino , Humanos , Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/etiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Estudos Transversais , Estudos Retrospectivos , Vitamina D
20.
Sci Adv ; 8(43): eadd0697, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36288304

RESUMO

High-definition red/green/blue (RGB) pixels and deformable form factors are essential for the next-generation advanced displays. Here, we present ultrahigh-resolution full-color perovskite nanocrystal (PeNC) patterning for ultrathin wearable displays. Double-layer transfer printing of the PeNC and organic charge transport layers is developed, which prevents internal cracking of the PeNC film during the transfer printing process. This results in RGB pixelated PeNC patterns of 2550 pixels per inch (PPI) and monochromic patterns of 33,000 line pairs per inch with 100% transfer yield. The perovskite light-emitting diodes (PeLEDs) with transfer-printed active layers exhibit outstanding electroluminescence characteristics with remarkable external quantum efficiencies (15.3, 14.8, and 2.5% for red, green, and blue, respectively), which are high compared to the printed PeLEDs reported to date. Furthermore, double-layer transfer printing enables the fabrication of ultrathin multicolor PeLEDs that can operate on curvilinear surfaces, including human skin, under various mechanical deformations. These results highlight that PeLEDs are promising for high-definition full-color wearable displays.

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