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1.
Adv Mater ; : e2105228, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34599775

RESUMO

Encapsulation of lithium in the confined spaces within individual nanocapsules is intriguing and highly desirable for developing high-performance Li metal anodes. This work aims for a mechanistic understanding of Li encapsulation and its confined growth kinetics inside one-dimensional enclosed spaces. To achieve this, we employ amorphous carbon nanotubes as a model host using in situ transmission electron microscopy. The carbon shells have dual roles, providing geometric/mechanical constraints and electron/ion transport channels, which profoundly alter the Li growth patterns. Li growth/dissolution takes place via atom addition/removal at the free surfaces through Li+ diffusion along the shells in the electric field direction, resulting in the formation of unusual Li structures, such as poly-crystalline nanowires and free-standing two-dimensional ultrathin (1-2 nm) Li membranes. Such confined front-growth processes are dominated by Li {110} or {200} growing faces, distinct from the root growth of single-crystal Li dendrites outside the nanotubes. Controlled experiments show that high lithiophilicity and permeability, enabled by sufficient nitrogen/oxygen doping, is critical for the stable encapsulation of lithium inside carbonaceous nanocapsules. First-principles-based calculations reveal that N/O doping can reduce the diffusion barrier for Li+ penetration, and facilitate Li filling driven by energy minimization associated with the formation of low-energy Li/C interfaces. This article is protected by copyright. All rights reserved.

3.
Adv Mater ; : e2102560, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34632642

RESUMO

Phase transitions are universal in solid-state matters, as well as in periodic electromagnetic metasurfaces - the photonic analogues of crystals. Although such transitions dictate the properties of active metasurfaces, universal ways to describe the structure transition of periodic metasurfaces have not yet been established. Here, we report the strain-enable phase transition (or lattice deformation) of stretchable metasurfaces with the crystallographic description. We analytically and experimentally demonstrate the phase transition of plasmonic lattices between two arbitrary two-dimensional (2D) Bravais lattices under certain strain configurations. The strain-induced symmetry lowering of the structures gives rise to optical anisotropy upon polarization, namely, linearly and circularly polarized dichroism. We further demonstrate the potential of phase transition in information decoding with applied strain. Interpreting the phase transition of metesurfaces from a standpoint of symmetry would accelerate the discovery of emergent properties, and provide a generalizable approach to designing active metasurfaces. This article is protected by copyright. All rights reserved.

4.
Am Psychol ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34618515

RESUMO

African American adolescents are grossly overrepresented in rates of school suspensions for minor disciplinary infractions; however, the consequences associated with this disciplinary practice are unknown. African American adolescents who were suspended for minor infractions may perceive school rules and adults as unfair and illegitimate, and these poor perceptions toward school may compromise their social and interpersonal resources necessary for academic success. The present study investigates: (a) whether suspensions for minor infractions predict lower school grades longitudinally, and (b) whether poor school climate perceptions mediate the longitudinal link between suspensions for minor infractions and school grades. Based on 3 years of school records and social survey data from 2,381 adolescents (35% African American, 65% White), results illustrated that more African American adolescents were suspended for minor infractions than their White peers who committed similar infractions. In addition, African American adolescents suspended for minor infractions also had lower grades 1 and 2 years later. The longitudinal relation between suspensions for minor infractions and subsequent grades was partially mediated by African American adolescents' school climate perceptions. Implications are discussed in relation to racial biases and developmentally appropriate, equitable disciplinary practices. Public Significance Statement: The present study shows that more African American youth are suspended for minor infractions than White youth. In addition, these suspensions predicted poor school grades and school climate perceptions for African American youth. These findings raise concerns about school adults' discretion in using punitive school discipline policies and practices, as they may be contributing to academic disparities. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

5.
Artigo em Inglês | MEDLINE | ID: mdl-34622541

RESUMO

The delivery of protein into mammalian cells enables the dissection and manipulation of biological process, while this potency is challenged by lacking efficient protein delivery tool and the way to monitor its intracellular trafficking. Herein, we report that the hierarchical self-assembly of tetraphenylethylene (TPE)-featured metal-organic cages (MOCs) and ß-cyclodextrin-conjugated polyethylenimine can generate fluorescent supramolecular nanoparticles (FSNPs) to deliver protein into neural cells, a hard-to-transfect cell line using conventional strategy. Further, the aggregation-induced emission (AIE) feature of TPE enabled the fluorescent monitoring of cytosolic protein release. It is found that FSNPs can deliver and release protein into cytosol for subcellular targeting as fast as 18 h post-delivery. Moreover, the delivery of molecular chaperone DJ-1 using FSNPs activates MAPK/ERK signaling of neural cells to protect cells from oxidative stress. Together, our strategy provides a powerful tool for neural cell protein delivery and deciphering cell signaling for developing neurodegenerative disease treatment.

6.
JMIR Med Inform ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34623954

RESUMO

BACKGROUND: In 2020, the COVID-19 pandemic put the world in crisis on both physical and psychological health. Simultaneously, a myriad of unverified information flowed on social media and online outlets. The situation was so severe that the World Health Organization identified it as an infodemic in February 2020. OBJECTIVE: We want to study the propagation patterns and textual transformation of COVID-19 related rumors on a closed-platform. METHODS: We obtained a dataset of suspicious text messages collected on Taiwan's most popular instant messaging platform, LINE, between January and July 2020. We proposed a Classification-based Clustering algorithm that could efficiently cluster messages into groups, with each group representing a rumor. For ease of understanding, a group is referred to as a "rumor group". Messages in a rumor group could be identical or within limited textual differences with one another. Therefore, each message in a rumor group is a form of the rumor. RESULTS: A total of 936 rumor groups with at least 10 messages were discovered among 114,124 text messages collected from LINE. Among 936 rumors, 396 (42.3%) were related to COVID-19. Of 396 COVID-related rumors, 134 (33.8%) had been fact-checked by IFCN-certified agencies in Taiwan to be false or misleading. Studying the prevalence of Simplified Chinese characters or phrases that originated in China in the messages, we found that COVID-related messages, compared to non-COVID-related messages, were more likely to have been written by non-Taiwanese. The association was statistically significant with p < .01 by the chi-squared independence test. The qualitative investigations of the 3 most popular COVID-19 rumors revealed that key authoritative figures, mostly medical personnel, were often misquoted in the messages. In addition, these rumors resurfaced multiple times after being fact-checked, usually preceded by major societal events or textual transformations. CONCLUSIONS: To fight infodemic, it is crucial that we first understand why and how a rumor becomes popular. While social media gives rise to an unprecedented number of unverified rumors, it also provides a unique opportunity for us to study rumor propagations and the interactions with society. Therefore, we must put more effort in the areas.

7.
Proc Natl Acad Sci U S A ; 118(40)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34599099

RESUMO

Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone-releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates Gs while SV1 selectively couples to ß-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the apo state or GHRH-bound state in complex with the Gs protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, Gs versus ß-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward ß-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation.

8.
Phys Chem Chem Phys ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596195

RESUMO

The activation of carbon dioxide (CO2) mediated by NbBN2- cluster anions under the conditions of thermal collision has been investigated by time-of-flight mass spectrometry combined with density functional theory calculations. Two CO double bonds in the CO2 molecule are completely broken and two C-N bonds are further generated to form the novel molecule NCNBO-. To the best of our knowledge, this new molecule is synthesized and reported for the first time. In addition, one oxygen atom transfer channel produces another product, NbBN2O-. Both of the Nb and B atoms in NbBN2- donate electrons to reduce CO2, and the carbon atom originating from CO2 serves as an electron reservoir. The reaction of NbB- with N2 was also investigated theoretically, and the formation of NbBN2- from this reaction is thermodynamically and kinetically quite favorable, indicating that NCNBO- might be produced from the coupling of N2 and CO2 mediated by NbB- anions.

10.
J Res Adolesc ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34605113

RESUMO

This brief report examines whether the effects of direct and vicarious police stops on adolescents' academic adjustment via their psychological and physical well-being differ across ethnic-racial and gender groups. Using national and longitudinal survey data from Black, Latinx, and White adolescents (N = 3004; 49% girls), we found that the police stopped more Black boys and Black girls than their ethnic-racial peers. Vicarious stops were prevalent among all groups. The effects of police stops on adolescents' adjustment outcomes were more detrimental for adolescents of color and particularly Black boys relative to their White peers. Implications are discussed regarding how law enforcement shapes disparities that disadvantage particular adolescents at the intersections of their ethnicity-race and gender.

11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1570-1576, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34627442

RESUMO

OBJECTIVE: To investigate the expressions of microRNAs in peripheral blood of patients with primary immune thrombocytopenia(ITP) and its correlation with the imbalance of Th1/Th2 cells. METHODS: Thirty patients with ITP (ITP group) and 15 healthy people (control group) were enrolled.Real-time polymerase chain reaction (RT-PCR) was used to detect the expressions of six miRNAs (miR-107,miR-205-5p,miR-138-5p,miR-326,miR-1827,miR-185-5p) and Th1-specific transcription factor T-bet mRNA and Th2-specific transcription factor GATA-3 mRNA in the peripheral blood of the two groups. Th1 and Th2 cells were detected by flow cytometry. The expressions of Th1-cytokines TNF-α and IFN-γ and Th2-cytokines IL-4 and IL-10 were detected by AimPlex multiple immunoassays for Flow. The expression difference of miRNAs, mRNA, Th1, Th2 cells and cytokines of the two groups were compared, and the correlations of miRNAs to mRNA, Th1, Th2 cells and cytokines were analyzed in ITP group. RESULTS: The expressions of miRNAs(miR-107, miR-205-5p, miR-138-5p, miR-326, miR-1827, miR-185-5p)and Th2-specific transcription factor GATA-3 mRNA of the patients in ITP group were significantly decreased (P<0.05) as compared with those in control, while the expressions of Th1 cells and Th1-specific transcription factor T-bet mRNA and Th1-cytokines TNF-α were significantly increased (P<0.05), also for the ratios of T-bet mRNA/GATA-3 mRNA and Th1/Th2 cells were significantly increased (P<0.05). The relative expressions of miR-107, miR-205-5p, miR-138-5p in ITP patients were negatively correlated with Th2 cells (r=-0.411, r=-0.593, r=-0.403,P<0.05) and the relative expression of miR-1827 was negatively correlated with TNF-α (r=-0.390). CONCLUSION: The relative expressions of the six miRNAs in peripheral blood of patients with ITP are significantly decreased, which result in the increasing ratio of T-bet mRNA/GATA-3 mRNA, then lead to the imbalance of Th1/Th2.


Assuntos
MicroRNAs , Púrpura Trombocitopênica Idiopática , Humanos , RNA Mensageiro , Células Th1 , Células Th2
12.
World J Gastroenterol ; 27(34): 5753-5763, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34629799

RESUMO

BACKGROUND: Non-invasive fibrosis scores are not yet validated in the newly defined metabolic associated fatty liver disease (MAFLD). AIM: To evaluate the diagnostic performance of four non-invasive scores including aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4 index (FIB-4), body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes score (BARD), and nonalcoholic fatty liver disease fibrosis score (NFS) in patients with MAFLD. METHODS: Consecutive patients with histologically confirmed MAFLD were included. The discrimination ability of different non-invasive scores was compared. RESULTS: A total of 417 patients were included; 156 (37.4%) of them had advanced fibrosis (Metavir ≥ F3). The area under receiver operating characteristic curve of FIB-4, NFS, APRI, and BARD for predicting advanced fibrosis was 0.736, 0.724, 0.671, and 0.609, respectively. The area under receiver operating characteristic curve of FIB-4 and NFS was similar (P = 0.523), while the difference between FIB-4 and APRI (P = 0.001) and FIB-4 and BARD (P < 0.001) was statistically significant. The best thresholds of FIB-4, NFS, APRI, and BARD for diagnosis of advanced fibrosis in MAFLD were 1.05, -2.1, 0.42, and 2. A subgroup analysis showed that FIB-4, APRI, and NFS performed worse in the pure MAFLD group than in the hepatitis B virus-MAFLD group. CONCLUSION: APRI and BARD scores do not perform well in MAFLD. The FIB-4 and NFS could be more useful, but a new threshold is needed. Novel non-invasive scoring systems for fibrosis are required for MAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Biópsia , Humanos , Cirrose Hepática/diagnóstico , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Contagem de Plaquetas , Valor Preditivo dos Testes
13.
J Hematol Oncol ; 14(1): 165, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641921

RESUMO

BACKGROUND AND AIMS: Although adjuvant transcatheter arterial chemoembolization (TACE) for resected hepatocellular carcinoma (HCC) may improve survival for some patients, identifying which patients can benefit remains challenging. The present study aimed to construct a survival prediction calculator for individualized estimating the net survival benefit of adjuvant TACE for patients with resected HCC. METHODS: From a multicenter database, consecutive patients undergoing curative resection for HCC were enrolled and divided into the developing and validation cohorts. Using the independent survival predictors in the developing cohort, two nomogram models were constructed for patients with and without adjuvant TACE, respectively, which predictive performance was validated internally and externally by measuring concordance index (C-index) and calibration. The difference between two estimates of the prediction models was the expected survival benefit of adjuvant TACE. RESULTS: A total of 2514 patients met the inclusion criteria for the study. The nomogram prediction models for patients with and without adjuvant TACE were, respectively, built by incorporating the same eight independent survival predictors, including portal hypertension, Child-Pugh score, alpha-fetoprotein level, tumor size and number, macrovascular and microvascular invasion, and resection margin. These two prediction models demonstrated good calibration and discrimination, with all the C-indexes of greater than 0.75 in the developing and validation cohorts. A browser-based calculator was generated for individualized estimating the net survival benefit of adjuvant TACE. CONCLUSIONS: Based on large-scale real-world data, an easy-to-use online calculator can be adopted as a decision aid to predict which patients with resected HCC can benefit from adjuvant TACE.

14.
Asia Pac J Clin Nutr ; 30(3): 383-391, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34587698

RESUMO

BACKGROUND AND OBJECTIVES: Poor nutritional status is associated with benign paroxysmal positional vertigo (BPPV). Transthyretin (TTR) is a more sensitive marker than is albumin for nutritional status assessment. This study was conducted to confirm an association between serum transthyretin levels and BPPV. METHODS AND STUDY DESIGN: In total, 320 patients with BPPV and 320 age- and gender-matched controls were recruited between July 1, 2018, and July 1, 2020. All patients underwent audiovestibular tests, including the Dix-Hallpike test for the posterior semicircular canal and the supine roll test for the horizontal semicircular canal. Furthermore, serum transthyretin levels and other biochemical indicators were tested. Risk factors, including a history of heart and cerebral vascular diseases, were examined, and compared between groups. Hematolgical and biochemical tests were performed and subjected to between-group analysis. Multiple logistic regression models were employed to evaluate the TTR-BPPV. Interaction and stratified analyses were conducted. RESULTS: Patients with BPPV had significantly lower TTR levels than controls (213±49.3 vs 284±56.4 p<0.001). Alcohol consumption and anemia played an interactive role in the association between BPPV and low TTR levels. After adjustments for triglycerides, BMI, uric acid, HbA1C, 25-OH vitamin D3, alcohol consumption, and anemia, the multiple logistic regression revealed that participants with low TTR levels had a significantly increased risk of BPPV (OR: 5.5; 95% CI, 2.55-11.9; p<0.001). CONCLUSIONS: Chinese older adults with low serum transthyretin levels have an increased risk of BPPV.

15.
Dalton Trans ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34590650

RESUMO

Structural stability and rapid charge-discharge capability of electrode materials are required for high performance lithium-ion batteries (LIBs). The materials derived from polyoxometalates (POMs) show special advantages in inhibiting capacity attenuation, and good dispersion or combination of POMs with metal-organic frameworks (MOFs) is an important method to obtain high activity anode composites for LIBs. In this study, a uniform MoO2/MoS2 heterostructure with surface supported carbon (C-MoO2/MoS2) was successfully fabricated from a [Cu2(BTC)4/3(H2O)2]6[H3PMo12O40] precursor, which showed not only the designed octahedral morphology but also fast charge transfer, long working life, and high rate performance. Superior reversible lithium storage capacity of 1047 mA h g-1 after 300 cycles was obtained at 1 A g-1. Even after 700 cycles at 5 A g-1, the discharge specific capacity of 646 mA h g-1 was maintained, and rate capability of 610 mA h g-1 could be achieved at 10 A g-1. The high capacitive contribution could be explained by the relatively large specific surface area of porous C-MoO2/MoS2, which was mainly caused by the supported carbon network and MoS2 nanosheets, resulting in fast lithiation/delithiation processes.

16.
Microbiol Spectr ; : e0022321, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523948

RESUMO

To date, much progress has been made in dietary therapy for obese patients. A low-carbohydrate diet (LCD) has reached a revival in its clinical use during the past decade with undefined mechanisms and debatable efficacy. The gut microbiota has been suggested to promote energy harvesting. Here, we propose that the gut microbiota contributes to the inconsistent outcome under an LCD. To test this hypothesis, patients with obesity or patients who were overweight were randomly assigned to a normal diet (ND) or an LCD group with ad libitum energy intake for 12 weeks. Using matched sampling, the microbiome profile at baseline and end stage was examined. The relative abundance of butyrate-producing bacteria, including Porphyromonadaceae Parabacteroides and Ruminococcaceae Oscillospira, was markedly increased after LCD intervention for 12 weeks. Moreover, within the LCD group, participants with a higher relative abundance of Bacteroidaceae Bacteroides at baseline exhibited a better response to LCD intervention and achieved greater weight loss outcomes. Nevertheless, the adoption of an artificial neural network (ANN)-based prediction model greatly surpasses a general linear model in predicting weight loss outcomes after LCD intervention. Therefore, the gut microbiota served as a positive outcome predictor and has the potential to predict weight loss outcomes after short-term LCD intervention. Gut microbiota may help to guide the clinical application of short-term LCD intervention to develop effective weight loss strategies. (This study has been registered at the China Clinical Trial Registry under approval no. ChiCTR1800015156). IMPORTANCE Obesity and its related complications pose a serious threat to human health. Short-term low-carbohydrate diet (LCD) intervention without calorie restriction has a significant weight loss effect for overweight/obese people. Furthermore, the relative abundance of Bacteroidaceae Bacteroides is a positive outcome predictor of individual weight loss after short-term LCD intervention. Moreover, leveraging on these distinct gut microbial structures at baseline, we have established a prediction model based on the artificial neural network (ANN) algorithm that could be used to estimate weight loss potential before each clinical trial (with Chinese patent number 2021104655623). This will help to guide the clinical application of short-term LCD intervention to improve weight loss strategies.

17.
Biochem Biophys Res Commun ; 576: 1-6, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34474244

RESUMO

Wnt signaling is one of the major signaling pathways that regulate cell differentiation, tissue patterning and stem cell homeostasis and its dysfunction causes many human diseases, such as cancer. It is of tremendous interests to understand how Wnt signaling is regulated in a precise manner both temporally and spatially. Naked cuticle (Nkd) acts as a negative-feedback inhibitor for Wingless (Wg, a fly Wnt) signaling in Drosophila embryonic development. However, the role of Nkd remains controversial in later fly development, particularly on the canonical Wg pathway. In the present study, we show that nkd is essential for wing pattern formation, such that both gain and loss of nkd result in the disruption of Wg target expression in larvae stage and abnormal adult wing morphologies. Furthermore, we demonstrate that a thirty amino acid fragment in Nkd, identified previously in Wharton lab, is critical for the canonical Wg signaling, but is dispensable for Wg/planar cell polarity pathway. Putting aside the pleiotropic nature of nkd function, i.e. its role in the Decapentaplegic signaling, we conclude that Nkd universally inhibits the canonical Wg pathway across a life span of Drosophila development.

18.
Thromb Haemost ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34555861

RESUMO

The objective of this study was to assess the relationship between factor XI (FXI) deficiency and the risks of bleeding and cardiovascular (CV) events. We conducted a retrospective cohort study using data from Maccabi Healthcare Services (MHS). We identified adults with FXI deficiency (severe: <15%, partial: 15 to <50%, any deficiency: <50%) that had been tested for FXI between 2007 and 2018 and matched to patients from the general MHS population. We estimated 10-year risks of outcomes using the Kaplan-Meier approach. Using Cox proportional hazards regression, we compared outcomes among patients with versus without FXI deficiency. Less than 10% of patients tested for FXI activity had activity levels <50% (mean age: 39 years; 72.2% females). Compared with the general population, patients with any FXI deficiency were at higher risk of severe bleeding (adjusted hazard ratio [aHR]: 2.56, 95% confidence interval [CI]: 1.13-5.81; 10-year risk: 1.90%, 95% CI: 0.50-3.20% vs. 0.90%, 95% CI: 0.50-1.30%) and clinically relevant nonsevere bleeding (CRNSB) (aHR: 1.45, 95% CI: 1.08-1.97; 10-year risk: 11.60%, 95% CI: 8.30-14.80% vs. 9.20%, 95% CI: 8.00-10.40%). Severe FXI deficiency was associated with a greater risk of CRNSB. While few CV events (N = 2) and venous thromboembolisms (VTE) (N = 1) were observed in the FXI overall deficient group, there was a nonsignificant negative association between any FXI deficiency and CV events (aHR: 0.55; 95% CI: 0.13-2.36) and VTEs (aHR: 0.45; 95% CI: 0.06-3.47). Overall FXI deficiency was associated with an increased risk of severe bleeding and CRNSB. Further research is warranted to explore the lower risk of CV and VTE among patients with FXI deficiency compared with the general population.

19.
Nat Chem Biol ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556863

RESUMO

Cholecystokinin receptors, CCKAR and CCKBR, are important neurointestinal peptide hormone receptors and play a vital role in food intake and appetite regulation. Here, we report three crystal structures of the human CCKAR in complex with different ligands, including one peptide agonist and two small-molecule antagonists, as well as two cryo-electron microscopy structures of CCKBR-gastrin in complex with Gi2 and Gq, respectively. These structures reveal the recognition pattern of different ligand types and the molecular basis of peptide selectivity in the cholecystokinin receptor family. By comparing receptor structures in different conformational states, a stepwise activation process of cholecystokinin receptors is proposed. Combined with pharmacological data, our results provide atomic details for differential ligand recognition and receptor activation mechanisms. These insights will facilitate the discovery of potential therapeutics targeting cholecystokinin receptors.

20.
Sci Rep ; 11(1): 18630, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545109

RESUMO

While achieving rapid developments in recent years, bispecific antibodies are still difficult to design and manufacture, due to mispair of both heavy and light chains. Here we report a novel technology to make bispecific molecules. The knob-into-hole method was used to pair two distinct heavy chains as a heterodimer. IgG4 S228P CH1-CL interface was then partially replaced by T-cell receptor α/ß constant domain to increase the efficiency of cognate heavy and light chain pairing. Following expression and purification, the bispecific antibody interface exchange was confirmed by Western blotting and LC-MS/MS. To ensure its validity, we combined a monovalent bispecific antibody against PD-1 (sequence from Pembrolizumab) and LAG3 (sequence from Relatlimab). The results showed that the molecule could be assembled correctly at a ratio of 95% in cells. In vitro functional assay demonstrated that the purified bispecific antibody exhibits an enhanced agonist activity compared to that of the parental antibodies. Low immunogenicity was predicted by an open-access software and ADA test.

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