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1.
Adv Mater ; : e2407681, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39439150

RESUMO

Developing high-quality wide bandgap (WBG) perovskites with ≈1.7 eV bandgap (Eg) is critical to couple with silicon and create efficient silicon/perovskite tandem devices. The sufferings of large open-circuit voltage (VOC) loss and unstable power output under operation continuously highlight the criticality to fully develop high-quality WBG perovskite films. In this study, rubidium and thiocyanate as additive regulators in WBG perovskites are incorporated, significantly reducing non-radiative recombination, ion-migration, and phase segregation. The optimized 1.66 eV Eg perovskite solar cells achieved state-of-art 1.3 V VOC (0.36 V deficit), and delivered a stabilized power conversion efficiency of 24.3%, along with good device stability (20% degradation (T80) after over 994 h of operation under 1 sun at ≈65°C). When integrated with a flat front side silicon cell, silicon/perovskite two-terminal tandem device (30% efficient) is obtained with a 1.97 V VOC, and T90 operational lifetime of more than 600 h at room temperature.

2.
Langmuir ; 40(41): 21453-21459, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39353076

RESUMO

The two-dimensional ferroelectric van der Waals (vdW) heterojunction has been recognized as one of the most promising combinations for emerging ferroelectric memory materials due to its noncovalent bonding and flexible stacking of various materials. In this work, the first-principles calculations were performed to study the stable geometry and electronic structure of α-In2Se3/α-Te, incorporating the vdW correction via the DFT-D2 method. The reversal of the polarization direction in α-In2Se3 can induce a transition in the heterostructure from metallic to semiconductor, accompanied by a shift from type-III to type-I band alignment. These changes are attributed to variations in interfacial charge transfer. Analysis of the modulation effects of external electric fields reveals that the P↑ α-In2Se3/α-Te configuration maintains metallic, whereas the P↓ α-In2Se3/α-Te configuration exhibits a linear reduction in band gap. Furthermore, both heterostructural configurations will undergo transitions to type-II band alignment transitions at 0.2 V Å-1 and within a range from 0.2 to 0.3 V Å-1 under external electric fields. Our findings offer valuable insights for applications such as ferroelectric memory and static gate devices with multiband alignment.

3.
Nat Commun ; 15(1): 8620, 2024 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-39366950

RESUMO

Surface passivation has been developed as an effective strategy to reduce trap-state density and suppress non-radiation recombination process in perovskite solar cells. However, passivation agents usually own poor conductivity and hold negative impact on the charge carrier transport in device. Here, we report a binary and synergistical post-treatment method by blending 4-tert-butyl-benzylammonium iodide with phenylpropylammonium iodide and spin-coating on perovskite surface to form passivation layer. The binary and synergistical post-treated films show enhanced crystallinity and improved molecular packing as well as better energy band alignment, benefiting for the hole extraction and transfer. Moreover, the surface defects are further passivated compared with unary passivation. Based on the strategy, a record-certified quasi-steady power conversion efficiency of 26.0% perovskite solar cells is achieved. The devices could maintain 81% of initial efficiency after 450 h maximum power point tracking.

4.
Front Oncol ; 14: 1446321, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39372868

RESUMO

Background: Cancer-related fatigue (CRF) is a prevalent adverse effect experienced by cancer patients while receiving and after treatment, impacting as many as 90% of individuals. Although CRF is common, the genetic processes responsible for it and their influence on individual vulnerability are not well understood and are still being investigated. Objective: The primary objective of this scoping review is to identify and assess genes linked to the vulnerability and severity of CRF. This will help us better understand the genetic factors involved and assist in developing targeted nursing treatments in clinical settings. Methods: This review followed the PRISMA guidelines. A comprehensive search was performed in databases, such as PubMed, EMBASE, Web of Science, Cochrane Library, SinoMed, CNKI, and VIP, encompassing genetic association studies on CRF published up to February 25, 2024. The JBI Critical Appraisal Tools were used to assess the quality of observational studies. Results: This evaluation encompassed a comprehensive analysis of 14 studies that involved 3,254 patients. The results indicate strong connections between CRF and various inflammatory cytokines (IL-4, IL-6, IL-8, IL-10, IL-1ß), tumor necrosis factor-alpha (TNF-α), catechol-O-methyltransferase (COMT), and circadian rhythm genes (CLOCK, PER). Conclusion: This scoping review emphasizes the significant genetic factor in CRF, with multiple genes showing distinct effects on cancer fatigue symptoms. Identifying these genes enhances our comprehension of CRF and unveils novel avenues for cancer treatment approaches. Future research should prioritize conducting cohort studies to monitor alterations in gene expression pre- and post-treatment, hence improving individualized medicinal strategies in oncology.

5.
Sleep Med ; 124: 540-550, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39447528

RESUMO

OBJECTIVE: This study aimed to investigate the association between insomnia and cognitive decline to provide insights for clinical interventions and future research. METHODS: The PubMed, Embase, Web of Science, Scopus, Cochrane Library, and ProQuest databases were systematically searched to identify studies on the association between insomnia and cognitive decline published within the last decade. The quality of the included studies was evaluated, followed by data extraction and summary analysis. RESULTS: A total of 36 studies were included in the review. Both subjective and objective measures were utilized across 12 indices to assess sleep status, while cognitive function was evaluated using 5 scales and 34 tests. The results revealed a significantly increased risk of cognitive decline or Alzheimer's disease among patients with insomnia, alongside notable impairments in attention, memory, visuospatial abilities, executive function, and verbal memory. Comprehensive assessments of cognitive domains were more sensitive in detecting group differences compared to assessments of specific cognitive sub-functions. Furthermore, MRI analyses showed reduced gray matter volumes in regions such as the prefrontal cortex, cingulate gyrus, temporal lobe, and hippocampus, together with reduced integrity of the white matter in patients with insomnia. CONCLUSIONS: The findings indicate a potentially bidirectional relationship between insomnia and cognitive decline, suggesting that each may influence and exacerbate the other. Insomnia may increase the risk of cognitive decline and appears to be associated with reduced gray matter volume and compromised white matter integrity in the brain, which could potentially lead to declines in attention, memory, visuospatial abilities, executive function, and verbal memory. Conversely, cognitive decline may contribute to the onset of insomnia, further deteriorating sleep quality. However, further research is necessary to fully comprehend this intricate relationship.

6.
Bioorg Med Chem ; 114: 117965, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39454561

RESUMO

Src Homology 2-containing Inositol 5'-Phosphatase-1 (SHIP-1), encoded by INPP5D, has been identified as an Alzheimer's disease (AD) risk-associated gene through recent genetic and epigenetic studies. SHIP-1 confers AD risk by inhibiting the TREM2 cascade and reducing beneficial microglial cellular processes, including phagocytosis. While several small molecules have been reported to modulate SHIP-1 activity, their limited selectivity and efficacy in advanced models restricted their potential as therapeutic agents or probes for biological studies. Herein, we validated and implemented a high-throughput screening platform to explore new chemotypes that can modulate the phosphatase activity of SHIP-1. We screened 49,260 central nervous system (CNS)-penetrate compounds sourced from commercial vendors using the malachite green-based assay for anti-SHIP-1 activity. Through analysis, prioritization, and validation of the screening hits, we identified three novel types of scaffolds that inhibit the SHIP-1 phosphatase activity with IC50s as low as 46.6 µM. To improve the inhibitory activity of these promising hits, we carried out structure-activity relationship (SAR) studies, resulting in a lead molecule SP3-12 that inhibits SHIP-1 with an IC50 value of 6.1 µM. Kinetic analyses of SP3-12 revealed that its inhibition mechanism is competitive, with a Ki value of 3.2 µM for SHIP-1 and a 7-fold selectivity over SHIP-2. Furthermore, results from testing in a microglial phagocytosis/cell health high content assay indicated that SP3-12 could effectively activate phagocytosis in human microglial clone 3 (HMC3) cells, with an EC50 of 2.0 µM, without cytotoxicity in the dose range. Given its potency, selectivity, and cellular activity, SP3-12 emerges as a promising small molecule inhibitor with potential for investigating the biological functions of SHIP-1.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/antagonistas & inibidores , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala
7.
bioRxiv ; 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39282328

RESUMO

Mass spectrometry imaging (MSI) is a powerful technique for label-free spatial mapping of multiple classes of biomolecules in tissue sections. However, differences in desorption and ionization efficiency of different classes of molecules make it challenging to simultaneously map biomolecules at each omics layer in the same tissue sample. Herein, we present a correlative imaging method using nanospray desorption electrospray ionization (nano-DESI) MSI, which enables the spatial mapping of lipids, metabolites, peptides, and proteins with cellular-level spatial resolution in a single tissue section. We demonstrate the molecular profiling of specific cell types and identify truncated peptides in mouse pancreatic tissue. Distinct chemical gradients of peptides and lipids extending from endocrine cells to exocrine cells indicate their different roles in endocrine-exocrine crosstalk and intracellular signaling. The results underscore the power of the developed imaging approach for spatial multi-omics analysis that provides deep insights into cellular diversity and the intricate molecular interactions that occur within heterogenous biological tissues.

8.
J Clin Invest ; 134(15)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38842946

RESUMO

Aberrant activation of RAS/MAPK signaling is common in cancer, and efforts to inhibit pathway components have yielded drugs with promising clinical activities. Unfortunately, treatment-provoked adaptive resistance mechanisms inevitably develop, limiting their therapeutic potential. As a central node essential for receptor tyrosine kinase-mediated RAS activation, SHP2 has emerged as an attractive cancer target. Consequently, many SHP2 allosteric inhibitors are now in clinical testing. Here we discovered a previously unrecognized off-target effect associated with SHP2 allosteric inhibitors. We found that these inhibitors accumulate in the lysosome and block autophagic flux in an SHP2-independent manner. We showed that off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity. We also demonstrated that SHP2 allosteric inhibitors harboring this off-target activity not only suppress oncogenic RAS signaling but also overcome drug resistance such as MAPK rebound and protective autophagy in response to RAS/MAPK pathway blockage. Finally, we exemplified a therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS-driven and drug-resistant malignancies such as pancreatic and colorectal cancers.


Assuntos
Autofagia , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteínas ras , Animais , Humanos , Camundongos , Regulação Alostérica/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas ras/metabolismo , Proteínas ras/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Gastroenterol Hepatol ; 39(9): 1816-1826, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38725241

RESUMO

BACKGROUND AND AIM: In this study, a deep learning algorithm was used to predict the survival rate of colon cancer (CC) patients, and compared its performance with traditional Cox regression. METHODS: In this population-based cohort study, we used the characteristics of patients diagnosed with CC between 2010 and 2015 from the Surveillance, Epidemiology and End Results (SEER) database. The population was randomized into a training set (n = 10 596, 70%) and a test set (n = 4536, 30%). Brier scores, area under the (AUC) receiver operating characteristic curve and calibration curves were used to compare the performance of the three most popular deep learning models, namely, artificial neural networks (ANN), deep neural networks (DNN), and long-short term memory (LSTM) neural networks with Cox proportional hazard (CPH) model. RESULTS: In the independent test set, the Brier values of ANN, DNN, LSTM and CPH were 0.155, 0.149, 0.148, and 0.170, respectively. The AUC values were 0.906 (95% confidence interval [CI] 0.897-0.916), 0.908 (95% CI 0.899-0.918), 0.910 (95% CI 0.901-0.919), and 0.793 (95% CI 0.769-0.816), respectively. Deep learning showed superior promising results than CPH in predicting CC specific survival. CONCLUSIONS: Deep learning showed potential advantages over traditional CPH models in terms of prognostic assessment and treatment recommendations. LSTM exhibited optimal predictive accuracy and has the ability to provide reliable information on individual survival and treatment recommendations for CC patients.


Assuntos
Neoplasias do Colo , Aprendizado Profundo , Modelos de Riscos Proporcionais , Programa de SEER , Humanos , Neoplasias do Colo/mortalidade , Neoplasias do Colo/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Taxa de Sobrevida , Idoso , Estudos de Coortes , Redes Neurais de Computação , Curva ROC , Bases de Dados Factuais , Prognóstico
10.
J Med Chem ; 67(11): 8817-8835, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38768084

RESUMO

Together with protein tyrosine kinases, protein tyrosine phosphatases (PTPs) control protein tyrosine phosphorylation and regulate numerous cellular functions. Dysregulated PTP activity is associated with the onset of multiple human diseases. Nevertheless, understanding of the physiological function and disease biology of most PTPs remains limited, largely due to the lack of PTP-specific chemical probes. In this study, starting from a well-known nonhydrolyzable phosphotyrosine (pTyr) mimetic, phosphonodifluoromethyl phenylalanine (F2Pmp), we synthesized 7 novel phosphonodifluoromethyl-containing bicyclic/tricyclic aryl derivatives with improved cell permeability and potency toward various PTPs. Furthermore, with fragment- and structure-based design strategies, we advanced compound 9 to compound 15, a first-in-class, potent, selective, and bioavailable inhibitor of human CDC14A and B phosphatases. This study demonstrates the applicability of the fragment-based design strategy in creating potent, selective, and bioavailable PTP inhibitors and provides a valuable probe for interrogating the biological roles of hCDC14 phosphatases and assessing their potential for therapeutic interventions.


Assuntos
Inibidores Enzimáticos , Fosfotirosina , Humanos , Fosfotirosina/metabolismo , Fosfotirosina/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/metabolismo , Estrutura Molecular , Disponibilidade Biológica
11.
Tetrahedron ; 1562024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38618612

RESUMO

Natural products have been playing indispensable roles in the development of lifesaving drug molecules. They are also valuable sources for covalent protein modifiers. However, they often are scarce in nature and have complex chemical structures, which are limiting their further biomedical development. Thus, natural product-inspired small molecules which still contain the essence of the parent natural products but are readily available and amenable for structural modification, are important and desirable in searching for lead compounds for various disease treatment. Inspired by the complex and diverse ent-kaurene diterpenoids with significant biological activities, we have created a synthetically accessible and focused covalent library by incorporating the bicyclo[3.2.1]octane α-methylene ketone, which is considered as the pharmacophore of ent-kaurene diterpenoids, as half of the structure, and replacing the other half with much less complex but more druglike scaffolds. From this library, we have identified and characterized selective covalent inhibitors of protein tyrosine phosphatase SHP2, an important anti-cancer therapeutic target. The success of this study demonstrated the importance of creating and evaluating natural product-inspired library as well as their application in targeting challenging disease targets.

12.
BMC Sports Sci Med Rehabil ; 16(1): 100, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38689329

RESUMO

BACKGROUND: The prevalence of muscle atrophy in patients suffering from chronic kidney disease (CKD) presents a significant challenge to healthcare providers, necessitating innovative approaches to management and care. Against this backdrop, this study embarks on a comprehensive review of literature concerning the application of exercise interventions in the nursing care of these patients. Such interventions are critical in addressing the debilitating effects of the condition, which include progressive loss of muscle mass and strength, adversely affecting patient mobility, quality of life, and overall survival. This review aims to identify the specific exercise modalities, contents, outcome indicators, and application effects associated with this intervention, in the context of the complex interplay of metabolic, inflammatory, and hormonal factors contributing to muscle wasting in CKD patients. By examining the efficacy of various exercise interventions, this study seeks to elucidate optimal strategies for mitigating the impact of CKD-induced muscle atrophy, thereby informing clinical practices and improving patient outcomes. METHODS: According to the method of a scoping review, nine databases (Cochrane, PubMed, EMBASE, Web of Science, ProQuest, Ovid, CNKI, Wanfang Data, and VIP) were searched until September 28, 2023. The included literature was screened, summarized, and analyzed. RESULTS: A total of 20 pieces of literature were included. Some types include aerobic exercise, resistance exercise, and aerobic combined resistance exercise. The exercise intensity primarily falls within the mild to moderate range, with a recommended frequency of 2 - 3 times a week, lasting 30 - 60 min each time. The types of outcomes encompassed in this study include body composition, functional testing, strength measurements, laboratory examinations, cardiopulmonary function assessments, and patient-reported outcomes. To varying degrees, exercise intervention positively impacts the subjects' physical activity ability, body composition, and skeletal muscle status. Currently, resistance training is the primary type of intervention used for preventing and treating CKD patients induced by muscle atrophy. CONCLUSION: Exercise intervention can improve muscle strength, physical function, and quality of life in patients with CKD muscle atrophy. Therefore, patients should be fully informed of the effect of exercise intervention in the treatment of chronic kidney disease-induced muscle atrophy in future, so as to promote the standardized implementation of exercise intervention.

13.
J Food Sci ; 89(4): 2371-2383, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38488724

RESUMO

The "instant" quality of instant rice noodles is significantly affected by slow rehydration during cooking. This happens as a result of the native rice starch's low ability to gelatinize as well as the high shear and pressure utilized in industries during the widely used extrusion molding process. In order to address this issue, the rice flour was pretreated with mild steam (MS) technology. The results revealed that the rehydration qualities of the rice noodles that were extruded from the steam-treated flour significantly improved. There was a reduction of 25.5% in the rehydration time, from 443 to 330 s. The MS-treated rice starch's peak viscosity increased to 4503 from 4044 mPa/s. Decreases in gelatinization enthalpy (ΔH) and short-range ordering also suggest a reduction in difficulty in accomplishing starch gelatinization. Scanning electron microscopy studies showed particle aggregation increased as the treatment duration lasted longer. In conclusion, our findings indicate that we successfully addressed the issue of slow rehydration in instant rice noodles while presenting a novel approach for their manufacturing in the manufacturing sector.


Assuntos
Oryza , Vapor , Oryza/química , Culinária , Amido/química , Viscosidade , Farinha/análise
14.
Phys Chem Chem Phys ; 26(5): 4555-4563, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38247301

RESUMO

Nowadays, two-dimensional (2D) materials with Janus structures evoke much attention due to their unique mechanical and electronic properties. In this work, Janus Pma2-Si2XY (X/Y = S/Se/Te, X ≠ Y) ferroelectric monolayers are firstly proposed and systematically investigated by first-principles calculations. These monolayers exhibit remarkable mechanical properties, including small Young's modulus values, negative Poisson's ratios (NPRs) and large critical strains, reflecting their exceptional flexibility and stretchability. More strikingly, the novel structures of Si2STe and Si2SeTe also endow them with in-plane spontaneous polarization (Ps) and low energy barrier for phase transition, with Ps and energy barrier values being 1.632 × 10-10 C m-1 and 159 meV for Si2STe and 1.149 × 10-10 C m-1 and 196.6 meV for Si2SeTe. The ab initio molecular dynamics (AIMD) simulations reveal high Curie temperatures (Tc) for Si2STe and Si2SeTe, ranging between 1300 K and 1400 K. Additionally, Si2XY monolayers exhibit high anisotropic carrier mobility (∼103 cm2 V-1 s-1) and an extraordinary light absorption coefficient (∼105 cm-1). Our research not only broadens the family of 2D Janus ferroelectric materials, but also demonstrates their potential applications in nanomechanical, nanoelectronic and optoelectronic devices.

15.
Phys Chem Chem Phys ; 26(5): 4564-4571, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38247318

RESUMO

Two-dimensional (2D) Janus materials have attracted considerable attention in photocatalysis owing to their robust redox capability and efficient segregation. In this study, we propose a novel Janus monolayer structure, denoted as PXC (X = As/Sb), exhibiting favorable stability in terms of dynamics, thermal properties, and mechanical characteristics. The PXC monolayers demonstrate a relatively smaller Young's modulus (132.5/119.5 N m-1 for PAsC/PSbC) and large negative Poisson's ratios (-0.15/-0.101 for PAsC/PSbC). Moreover, the HSE06 + SOC functional results show that PAsC/PSbC are indirect semiconductors with a 2.33/1.43 eV band gap, exhibiting a suitable band alignment for photocatalytic water splitting. The calculated high carrier mobility (104 cm2 V-1 s-1), along with a significant discrepancy, determined by the deformation potential theory and the built-up field induced by the large intrinsic dipole, effectively suppresses the recombination of photogenerated carriers. Furthermore, PXC monolayers possess a strong absorption capacity in the visible and ultraviolet light region (105 cm-1). Therefore, our results indicate that PXC monolayers hold great potential for application in the field of photocatalytic water splitting.

16.
J Affect Disord ; 346: 234-241, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-37944709

RESUMO

PURPOSE: The first year of the COVID-19 pandemic constituted a major life stress event for many adolescents, associated with disrupted school, behaviors, social networks, and health concerns. However, pandemic-related stress was not equivalent for everyone and could have been influenced by pre-pandemic factors including brain structure and sleep, which both undergo substantial development during adolescence. Here, we analyzed clusters of perceived stress levels across the pandemic and determined developmentally relevant pre-pandemic risk factors in brain structure and sleep of persistently high stress during the first year of the COVID-19 pandemic. METHODS: We investigated longitudinal changes in perceived stress at six timepoints across the first year of the pandemic (May 2020-March 2021) in 5559 adolescents (50 % female; age range: 11-14 years) in the United States (U.S.) participating in the Adolescent Brain Cognitive Development (ABCD) study. In 3141 of these adolescents, we fitted machine learning models to identify the most important pre-pandemic predictors from structural MRI brain measures and self-reported sleep data that were associated with persistently high stress across the first year of the pandemic. RESULTS: Patterns of perceived stress levels varied across the pandemic, with 5 % reporting persistently high stress. Our classifiers accurately detected persistently high stress (AUC > 0.7). Pre-pandemic brain structure, specifically cortical volume in temporal regions, and cortical thickness in multiple parietal and occipital regions, predicted persistent stress. Pre-pandemic sleep difficulties and short sleep duration were also strong predictors of persistent stress, along with more advanced pubertal stage. CONCLUSIONS: Adolescents showed variable stress responses during the first year of the COVID-19 pandemic, and some reported persistently high stress across the whole first year. Vulnerability to persistent stress was evident in several brain structural and self-reported sleep measures, collected before the pandemic, suggesting the relevance of other pre-existing individual factors beyond pandemic-related factors, for persistently high stress responses.


Assuntos
COVID-19 , Humanos , Adolescente , Feminino , Criança , Masculino , Pandemias , Sono , Duração do Sono , Lobo Occipital
17.
Methods Mol Biol ; 2743: 301-316, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38147223

RESUMO

Covalent inhibition has gained increasing interest in targeting the undruggable protein tyrosine phosphatases (PTPs). However, a systematic method for discovering and characterizing covalent PTP inhibitors has yet to be established. Here, we describe a workflow involving high-throughput screening of covalent fragment libraries and a novel biochemical assay that enables the acquisition of kinetics parameters of PTP inhibition by covalent inhibitors with higher throughput.


Assuntos
Bioensaio , Ensaios de Triagem em Larga Escala , Cinética , Física , Proteínas Tirosina Fosfatases
18.
Br J Pharmacol ; 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-38116815

RESUMO

Contemporary strategies in cancer immunotherapy, despite remarkable success, remain constrained by inherent limitations such as suboptimal patient responses, the emergence of drug resistance, and the manifestation of pronounced adverse effects. Consequently, the need for alternative strategies for immunotherapy becomes clear. Protein tyrosine phosphatases (PTPs) wield a pivotal regulatory influence over an array of essential cellular processes. Substantial research has underscored the potential in targeting PTPs to modulate the immune responses and/or regulate antigen presentation, thereby presenting a novel paradigm for cancer immunotherapy. In this review, we focus on recent advances in genetic and biological validation of several PTPs as emerging targets for immunotherapy. We also highlight recent development of small molecule inhibitors and degraders targeting these PTPs as novel cancer immunotherapeutic agents.

19.
Chem Sci ; 14(44): 12606-12614, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38020389

RESUMO

T-cell protein tyrosine phosphatase (TC-PTP), encoded by PTPN2, has emerged as a promising target for cancer immunotherapy. TC-PTP deletion in B16 melanoma cells promotes tumor cell antigen presentation, while loss of TC-PTP in T-cells enhances T-cell receptor (TCR) signaling and stimulates cell proliferation and activation. Therefore, there is keen interest in developing TC-PTP inhibitors as novel immunotherapeutic agents. Through rational design and systematic screening, we discovered the first highly potent and selective TC-PTP PROTAC degrader, TP1L, which induces degradation of TC-PTP in multiple cell lines with low nanomolar DC50s and >110-fold selectivity over the closely related PTP1B. TP1L elevates the phosphorylation level of TC-PTP substrates including pSTAT1 and pJAK1, while pJAK2, the substrate of PTP1B, is unaffected by the TC-PTP degrader. TP1L also intensifies interferon gamma (IFN-γ) signaling and increases MHC-I expression. In Jurkat cells, TP1L activates TCR signaling through increased phosphorylation of LCK. Furthermore, in a CAR-T cell and KB tumor cell co-culture model, TP1L enhances CAR-T cell mediated tumor killing efficacy through activation of the CAR-T cells. Thus, we surmise that TP1L not only provides a unique opportunity for in-depth interrogation of TC-PTP biology but also serves as an excellent starting point for the development of novel immunotherapeutic agents targeting TC-PTP.

20.
Science ; 382(6677): 1399-1404, 2023 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-37995210

RESUMO

The power conversion efficiency (PCE) of inverted perovskite solar cells (PSCs) is still lagging behind that of conventional PSCs, in part because of inefficient carrier transport and poor morphology of hole transport layers (HTLs). We optimized self-assembly of [4-(3,6-dimethyl-9H-carbazol-9-yl)butyl]phosphonic acid (Me-4PACz) onto nickel oxide (NiOx) nanoparticles as an HTL through treatment with hydrogen peroxide, which created a more uniform dispersion of nanoparticles with high conductivity attributed to the formation of Ni3+ as well as surface hydroxyl groups for bonding. A 25.2% certified PCE for a mask size of 0.074 square centimeters was obtained. This device maintained 85.4% of the initial PCE after 1000 hours of stabilized power output operation under 1 sun light irradiation at about 50°C and 85.1% of the initial PCE after 500 hours of accelerated aging at 85°C. We obtained a PCE of 21.0% for a minimodule with an aperture area of 14.65 square centimeters.

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