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1.
Nat Commun ; 15(1): 3221, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622129

RESUMO

The hippocampus creates a cognitive map of the external environment by encoding spatial and self-motion-related information. However, it is unclear whether hippocampal neurons could also incorporate internal cognitive states reflecting an animal's exploratory intention, which is not driven by rewards or unexpected sensory stimuli. In this study, a subgroup of CA1 neurons was found to encode both spatial information and animals' investigatory intentions in male mice. These neurons became active before the initiation of exploration behaviors at specific locations and were nearly silent when the same fields were traversed without exploration. Interestingly, this neuronal activity could not be explained by object features, rewards, or mismatches in environmental cues. Inhibition of the lateral entorhinal cortex decreased the activity of these cells during exploration. Our findings demonstrate that hippocampal neurons may bridge external and internal signals, indicating a potential connection between spatial representation and intentional states in the construction of internal navigation systems.


Assuntos
Intenção , Navegação Espacial , Masculino , Camundongos , Animais , Percepção Espacial/fisiologia , Hipocampo/fisiologia , Córtex Entorrinal , Sinais (Psicologia) , Navegação Espacial/fisiologia
2.
Mol Carcinog ; 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578157

RESUMO

Hepatocellular carcinoma (HCC) stands as one of the most malignant tumors characterized by poor prognosis and high mortality rates. Emerging evidence underscores the crucial role of the B7 protein family in various cancers, including HCC. However, the involvement of the human endogenous retrovirus H long-terminal repeat-associated protein 2 (HHLA2, or B7-H5) in HCC remains unclear. Immunohistochemistry was employed to assess the differential expression of HHLA2 between HCC and normal liver tissues. A battery of assays, including CCK8, EdU, tablet clone-forming, Transwell, and wound healing assays, were conducted to elucidate the function and potential mechanisms of HHLA2 in the malignant biological behaviors of HCC. Additionally, a xenograft mouse model was established to evaluate the tumorigenicity of hepatoma cell lines exhibiting different HHLA2 expression levels in vivo. Western blot analysis was used to analyze HHLA2, secretory phosphoprotein 1 (SPP1), and PI3K/AKT/mTOR levels. HHLA2 exhibited elevated expression in HCC tissues, correlating with poor tumor differentiation and shortened overall survival in HCC patients. In vitro experiments demonstrated that HHLA2 overexpression (OE) promoted the proliferation, migration, and invasion of hepatoma cells, while in vivo experiments revealed that HHLA2 OE enhanced HCC tumor growth. Conversely, inhibition of HHLA2 expression yielded the opposite effect. Downregulation of SPP1 inhibited the proliferation, migration, and invasion induced by HHLA2 OE, and this effect was linked to the PI3K/AKT/mTOR signaling pathway. Our findings indicate that HHLA2 promotes the proliferation, migration, and invasion of hepatoma cells via the SPP1/PI3K/AKT signaling pathway, establishing it as a potential therapeutic target for HCC.

3.
J Am Chem Soc ; 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38560787

RESUMO

Poly(vinylidene fluoride) (PVDF)-based solid electrolytes with a Li salt-polymer-little residual solvent configuration are promising candidates for solid-state batteries. Herein, we clarify the microstructure of PVDF-based composite electrolyte at the atomic level and demonstrate that the Li+-interaction environment determines both interfacial stability and ion-transport capability. The polymer works as a "solid diluent" and the filler realizes a uniform solvent distribution. We propose a universal strategy of constructing a weak-interaction environment by replacing the conventional N,N-dimethylformamide (DMF) solvent with the designed 2,2,2-trifluoroacetamide (TFA). The lower Li+ binding energy of TFA forms abundant aggregates to generate inorganic-rich interphases for interfacial compatibility. The weaker interactions of TFA with PVDF and filler achieve high ionic conductivity (7.0 × 10-4 S cm-1) of the electrolyte. The solid-state Li||LiNi0.8Co0.1Mn0.1O2 cells stably cycle 4900 and 3000 times with cutoff voltages of 4.3 and 4.5 V, respectively, as well as deliver superior stability at -20 to 45 °C and a high energy density of 300 Wh kg-1 in pouch cells.

4.
Opt Express ; 32(6): 8638-8656, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38571118

RESUMO

The laser-induced damage of ultraviolet fused silica optics is a critical factor that limits the performance enhancement of high-power laser facility. Currently, wet etching technology based on hydrofluoric acid (HF) can effectively eliminate absorbing impurities and subsurface defects, thereby significantly enhancing the damage resistance of fused silica optics. However, with an increase in the operating fluence, the redeposition defects generated during wet etching gradually become the primary bottleneck that restricts its performance improvement. The composition and morphology of redeposition defects were initially identified in this study, followed by an elucidation of their formation mechanism. A mitigation strategy was then proposed, which combines a reduction in the generation of precipitation with an acceleration of the precipitation dissolution process. Additionally, we systematically investigated the influence of various process parameters such as extrinsic impurity, etching depth, and megasonic excitation on the mitigation of deposition defects. Furthermore, a novel multiple-step dynamic etching method was developed. Through comprehensive characterization techniques, it has been confirmed that this new etching process not only effectively mitigate redeposition defects under low fluence conditions but also exhibits significant inhibition effects on high fluence precursors. Consequently, it significantly enhances the laser damage resistance performance of fused silica optics.

5.
Neoplasia ; 52: 100996, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38593698

RESUMO

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, and its incidence has increased rapidly in recent years. The BRAF inhibitor vemurafenib is effective against BRAFV600E-positive PTC; however, acquired resistance to single agent therapy frequently leads to tumor recurrence and metastasis, underscoring the need to develop tailored treatment strategies. We previously showed that the oncogenic kinase PIM1 was associated with the malignant phenotype and prognosis of PTC. In this study, we showed that sustained expression of the PIM1 protein in PTC was affected by the BRAFV600E mutation. Based on this regulatory mechanism, we tested the synergistic effects of inhibitors of BRAF (BRAFi) and PIM1 in BRAFV600E-positive PTC cell lines and xenograft tumors. LC-MS metabolomics analyses suggested that BRAFi/PIMi therapy acted by restricting the amounts of critical amino acids and nucleotides required by cancer cells as well as modulating DNA methylation. This study elucidates the role of BRAFV600E in the regulation of PIM1 in PTC and demonstrates the synergistic effect of a novel combination, BRAFi/PIMi, for the treatment of PTC. This discovery, along with the pathways that may be involved in the powerful efficacy of BRAFi/PIMi strategy from the perspective of cell metabolism, provides insight into the molecular basis of PTC progression and offers new perspectives for BRAF-resistant PTC treatment.

6.
BMC Urol ; 24(1): 91, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38643096

RESUMO

BACKGROUND: Sleep quality may be related to benign prostatic hyperplasia (BPH), however causal associations have not been established. This study aimed to evaluate causal relationships between six sleep traits ([i] day time napping, [ii] daytime sleepiness, [iii] insomnia, [iv] long sleep duration, [v] short sleep duration, and [vi] sleep duration per hour) and BPH through a bidirectional Mendelian randomization (MR) study. METHODS: Genome-wide association summary statistics of sleep traits and BPH were downloaded from public databases. Inverse variance weighting (IVW) was used as the main approach for causal inference. For causal estimates identified by IVW, various sensitivity analyses were performed to assess the reliability of the results: (i) four additional MR methods to complement IVW; (ii) Cochran's Q test to assess heterogeneity; (iii) MR-Egger intercept test and MR-PRESSO global test to assess horizontal pleiotropy; and (iv) leave-one-out method to assess stability. RESULTS: Forward MR analyses indicated that genetically predicted insomnia symptom significantly increased BPH risk (OR = 1.267, 95% CI: 1.003-1.601, P = 0.048), while reverse MR analyses identified that genetically predicted liability to BPH significantly increased the incidence of insomnia (OR = 1.026, 95% CI: 1.000-1.052, P = 0.048). In a replicate MR analysis based on summary statistics including exclusively male participants, the finding of increased risk of BPH due to genetically predicted insomnia symptom was further validated (OR = 1.488, 95% CI: 1.096-2.022, P = 0.011). No further causal links were identified. In addition, sensitivity tests demonstrated the reliability of the MR results. CONCLUSION: This study identified that a higher prevalence of genetically predicted insomnia symptoms may significantly increase the risk of BPH, while genetically predicted liability to BPH may in turn increase the incidence of insomnia symptom. Therefore, improving sleep quality and reducing the risk of insomnia could be a crucial approach for the prevention of BPH.


Assuntos
Hiperplasia Prostática , Distúrbios do Início e da Manutenção do Sono , Humanos , Masculino , Distúrbios do Início e da Manutenção do Sono/genética , Hiperplasia Prostática/complicações , Hiperplasia Prostática/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Reprodutibilidade dos Testes
7.
J Chem Neuroanat ; 138: 102420, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38626816

RESUMO

Protein aggregation is a pathological feature in various neurodegenerative diseases and is thought to play a crucial role in the onset and progression of neurological disorders. This pathological phenomenon has attracted increasing attention from researchers, but the underlying mechanism has not been fully elucidated yet. Researchers are increasingly interested in identifying chemicals or methods that can effectively detect protein aggregation or maintain protein stability to prevent aggregation formation. To date, several methods are available for detecting protein aggregates, including fluorescence correlation spectroscopy, electron microscopy, and molecular detection methods. Unfortunately, there is still a lack of methods to observe protein aggregation in situ under a microscope. This article reviews the two main aspects of protein aggregation: the mechanisms and detection methods of protein aggregation. The aim is to provide clues for the development of new methods to study this pathological phenomenon.

8.
J Genet Genomics ; 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38599515

RESUMO

The early development of the endosperm is crucial for balancing the allocation of maternal nutrients to offspring. This process is believed to be evolutionarily associated with genomic imprinting, resulting in parentally biased allelic gene expression. Beyond FIS (Fertilization Independent Seed) genes, the number of imprinted genes involved in early endosperm development and seed size determination remains limited. This study introduces two early endosperm-expressed ICF1 and ICF2, as maternally expressed imprinted genes (MEGs). Although these genes are also demethylated by DEMETER (DME) in the central cell, their activation differs from the direct DME-mediated activation seen in classical MEGs such as the FIS genes. Instead, ICF maternal alleles carry pre-established hypomethylation in their promoters, priming them for activation by the WRKY10 transcription factor in the endosperm. On the contrary, paternal alleles are predominantly suppressed by CG methylation. Furthermore, we demonstrated that ICF genes partially contribute to the small seed size observed in iku mutants. Our discovery reveals a two-step regulatory mechanism that highlights the important role of conventional transcription factors in the activation of imprinted genes, which was previously not fully recognized. Therefore, the mechanism provides a new dimension to understanding the transcriptional regulation of imprinting in plant reproduction and development.

9.
Reprod Toxicol ; : 108597, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38643889

RESUMO

Previous studies indicated conflicting findings regarding the association between vitamin D and abnormal spermatozoa. Herein, we assessed the causal association between circulating 25-Hydroxyvitamin D (25OHD) levels and the risk of abnormal spermatozoa by utilizing bidirectional Mendelian randomization (MR) analysis. Genome-wide association study summary statistics for 25OHD and abnormal spermatozoa were obtained from publicly accessible databases. Single nucleotide polymorphisms (SNPs) associated with 25OHD and SNPs associated with abnormal spermatozoa were used as instrumental variables (IVs) for forward MR analysis and reverse MR analysis, respectively. Inverse variance weighted (IVW) was the main MR approach, while weighted median, MR-Egger and maximum likelihood methods were employed to supplement IVW. In addition, several sensitivity tests assessed the reliability of MR analysis. Forward MR analysis showed that elevated 25OHD levels significantly reduced abnormal spermatozoa risk (odds ratio [OR] = 0.75, 95% confidence interval [CI]: 0.56-1.00, P = 4.98E-02), and the effect remained statistically significant after excluding SNPs associated with confounders (OR = 0.73, 95% CI: 0.54-0.98, P = 3.83E-02) or only utilizing SNPs located near 25OHD-associated genes only as IVs (OR = 0.58, 95% CI: 0.41-0.81, P = 1.67E-03). Reverse MR analysis indicated abnormal spermatozoa not affecting 25OHD level (P > 0.05). Sensitivity tests showed that MR analyses were not affected by heterogeneity and horizontal polytropy. Overall, the present MR study supports that elevated 25OHD levels reduce the risk of abnormal spermatozoa. Therefore, ensuring adequate vitamin D intake and maintaining stable levels of 25OHD may be effective strategies to optimize reproductive outcomes.

10.
J Multidiscip Healthc ; 17: 1641-1651, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38646015

RESUMO

Background: Interpretation of ultrasound findings of thyroid nodules is subjective and labor-intensive for radiologists. Artificial intelligence (AI) is a relatively objective and efficient technology. We aimed to establish a fully automatic detection and diagnosis system for thyroid nodules based on AI technology by analyzing ultrasound video sequences. Patients and Methods: We prospectively acquired dynamic ultrasound videos of 1067 thyroid nodules (804 for training and 263 for validation) from December 2018 to January 2021. All the patients underwent hemithyroidectomy or total thyroidectomy. Dynamic ultrasound videos were used to develop an AI system consisting of two deep learning models that could automatically detect and diagnose thyroid nodules. Average precision (AP) was used to estimate the performance of the detection model. The area under the receiver operating characteristic curve (AUC) was used to measure the performance of the diagnostic model. Results: Location and shape were accurately detected with a high AP of 0.914 in the validation cohort. The AUC of the diagnostic model was 0.953 in the validation cohort. The sensitivity and specificity of junior and senior radiologists were 76.9% vs 78.3% and 68.4% vs 81.1%, respectively. The diagnostic performance of the AI diagnostic model was superior to that of junior radiologists (P = 0.016) and was not significantly different from that of senior radiologists (P = 0.281). Conclusion: We established a fully automatic detection and diagnosis system for thyroid nodules based on ultrasound video using an AI approach that can be conveniently applied to optimize the management of patients with thyroid nodules.

11.
World J Gastroenterol ; 30(8): 969-983, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38516239

RESUMO

BACKGROUND: Three-dimensional organoid culture systems have been established as a robust tool for elucidating mechanisms and performing drug efficacy testing. The use of gastric organoid models holds significant promise for advancing personalized medicine research. However, a comprehensive bibliometric review of this bur-geoning field has not yet been published. AIM: To analyze and understand the development, impact, and direction of gastric organoid research using bibliometric methods using data from the Web of Science Core Collection (WoSCC) database. METHODS: This analysis encompassed literature pertaining to gastric organoids published between 2010 and 2023, as indexed in the WoSCC. CiteSpace and VOSviewer were used to depict network maps illustrating collaborations among authors, institutions and keywords related to gastric organoid. Citation, co-citation, and burst analysis methodologies were applied to assess the impact and progress of research. RESULTS: A total of 656 relevant studies were evaluated. The majority of research was published in gastroenterology-focused journals. Globally, Yana Zavros, Hans Clevers, James M Wells, Sina Bartfeld, and Chen Zheng were the 5 most productive authors, while Hans Clevers, Huch Meritxell, Johan H van Es, Marc Van de Wetering, and Sato Toshiro were the foremost influential scientists in this area. Institutions from the University Medical Center Utrecht, Netherlands Institute for Developmental Biology (Utrecht), and University of Cincinnati (Cincinnati, OH, United States) made the most significant contributions. Currently, gastric organoids are used mainly in studies investigating gastric cancer (GC), Helicobacter pylori-infective gastritis, with a focus on the mechanisms of GC, and drug screening tests. CONCLUSION: Key focus areas of research using gastric organoids include unraveling disease mechanisms and enhancing drug screening techniques. Major contributions from renowned academic institutions highlight this field's dynamic growth.


Assuntos
Gastrite , Infecções Intra-Abdominais , Neoplasias Gástricas , Humanos , Centros Médicos Acadêmicos , Bibliometria
12.
Viruses ; 16(3)2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38543783

RESUMO

Despite the rapid development of vaccines against COVID-19, they have important limitations, such as safety issues, the scope of their efficacy, and the induction of mucosal immunity. The present study proposes a potential component for a new generation of vaccines. The recombinant nucleocapsid (N) protein from the SARS-CoV-2 Delta variant was combined with the ODN-39M, a synthetic 39 mer unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN), used as an adjuvant. The evaluation of its immunogenicity in Balb/C mice revealed that only administration by intranasal route induced a systemic cross-reactive, cell-mediated immunity (CMI). In turn, this combination was able to induce anti-N IgA in the lungs, which, along with the specific IgG in sera and CMI in the spleen, was cross-reactive against the nucleocapsid protein of SARS-CoV-1. Furthermore, the nasal administration of the N + ODN-39M preparation, combined with RBD Delta protein, enhanced the local and systemic immune response against RBD, with a neutralizing capacity. Results make the N + ODN-39M preparation a suitable component for a future intranasal vaccine with broader functionality against Sarbecoviruses.


Assuntos
COVID-19 , Vacinas , Animais , Camundongos , Humanos , Administração Intranasal , Proteínas do Nucleocapsídeo , Vacinas Combinadas , SARS-CoV-2/genética , Vacinas contra COVID-19 , COVID-19/prevenção & controle , Imunidade nas Mucosas , Adjuvantes Imunológicos , Anticorpos Antivirais , Anticorpos Neutralizantes
13.
Sci Total Environ ; 926: 171855, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38522538

RESUMO

Coal-based solid waste (CSW) is the solid waste generated in the process of coal mining, washing and pyrolysis, which is an important industrial solid waste. The comprehensive utilization of CSW is a key link in the process of clean and efficient utilization of coal, and the use of CSW for coal mine filling mining is an important means of "harmless, resourceful and large-scale" utilization. In order to study the research status of comprehensive utilization of CSW and key technologies of filling mining in China, this paper combs and analyzes the current situation of comprehensive utilization of CSW from three parts, namely, physical and chemical properties of CSW, Industry-related policies, and ways and means of comprehensive utilization. It is found that coal mine filling mining is a green disposal method with relatively reliable technical means, low supervision cost and large-scale disposal of CSW in the comprehensive utilization of CSW in China. Furthermore, an analysis was conducted on the current research status of key technologies in the CSW filling and mining process, including the integration of "mining, selection and filling", adsorption and complexation passivation of heavy metals in CSW, the preparation of CSW collaborative filling materials, and monitoring and control of the whole filling process, etc. Based on the above analysis and research, it was pointed out that there were some problems, namely: (1) large output of CSW and low level of comprehensive utilization; (2) high investment and high cost of CSW filling and mining; and (3) imperfect CSW waste filling mining theory and technology. In response to these issues, prospects have been made from the aspects of policy incentive mechanisms, collaborative utilization of CSW with multi-industry links, and the theory and technology of CSW filling mining. This study provided reference and inspiration for the comprehensive utilization of CSW in the world, and provides guidance for the large-scale promotion and application of CSW filling mining methods.

14.
Animals (Basel) ; 14(6)2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38540076

RESUMO

A prior investigation revealed that a lack of Zinc (Zn) could hinder intestinal cell proliferation in broiler chickens; however, the mechanisms responsible for this effect remain unclear. We aimed to investigate the possible mechanisms of dietary Zn deficiency in inhibiting the jejunal cell proliferation of broilers. For this study, a total of 112 chickens (21 days old) were randomly divided into two treatments (seven replicate cages per treatment, eight chickens per replicate cage): the control group (CON) and the Zn deficiency group. The duration of feeding was 21 d. Chickens in the control group were provided with a basal diet containing an extra addition of 40 mg Zn/kg in the form of Zn sulfate, whereas chickens in the Zn deficiency group were given the basal diet with no Zn supplementation. The results indicated that, in comparison to the CON, Zn deficiency increased (p < 0.05) the duodenal and jejunal crypt depth (CD) of broilers on d 28 and jejunal and ileal CD on d 35, and decreased (p < 0.05) the duodenal, jejunal, and ileal villus height/crypt depth (VH/CD) on d 28 and the jejunal VH, jejunal and ileal villus surface area, and VH/CD on d 35. Furthermore, Zn deficiency decreased (p < 0.0001) the number of proliferating cell nuclear antigen-positive cells and downregulated (p < 0.01) the mRNA or protein expression levels of phosphatidylinositol 3-kinase (PI3K), phosphorylated PI3K, phosphorylated serine-threonine kinase (AKT), phosphorylated mechanistic target of rapamycin (mTOR), G protein-coupled receptor 39 (GPR39), and extracellular-regulated protein kinase, but upregulated (p < 0.05) the mRNA or protein expression levels of P38 mitogen-activated protein kinase, c-jun N-terminal kinase (JNK) 1 and JNK2, and phosphorylated protein kinase C in the jejunum of the broilers on d 42. It was concluded that dietary Zn deficiency inhibited cell proliferation possibly via the GPR39-mediated suppression of the PI3K/AKT/mTOR signaling pathway in the jejunum of broilers.

15.
ACS Appl Bio Mater ; 7(3): 1748-1762, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38428026

RESUMO

In this work, an investigation on the Zn-Cu alloy coated with heparin was conducted in order to explore the potentiality of its application as a feasible alternative for biodegradable implants, with the specific goal of addressing the issue of encrustation in the urinary system. The stability of the nanoparticles were characterized by dynamic light scattering. Typical surface characterization such as X-ray photoelectron spectroscopy, scanning electron microscopy, and atomic force microscopy were used to demonstrate a successful immobilization of the NPs. The in vitro corrosion behavior was studied by potentiodynamic polarization and immersion tests in artificial urine (AU) at 37 °C. The 8 weeks in vivo degradation, encrustation resistance, hemocompatibility, and histocompatibility were investigated by means of implantation into the bladders of rats. Both in vitro and in vivo degradation tests exhibited a higher degradation rate for Zn-Cu and NPs groups when compared to pure Zn. Histological evaluations and hemocompatibility revealed that there was no tissue damage or pathological alterations caused by the degradation process. Furthermore, antiencrustation performance and urinalysis results confirmed that the modified alloy demonstrated significant encrustation inhibitory properties and bactericidal activity compared to the pure Zn control. Our findings highlight the potential of this modified alloy as an antiencrustation biodegradable ureteral stent.


Assuntos
Heparina , Nanopartículas , Animais , Ratos , Heparina/farmacologia , Próteses e Implantes , Ligas , Zinco
16.
J Cell Biol ; 223(5)2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38470362

RESUMO

The eukaryotic p24 family, consisting of α-, ß-, γ- and δ-p24 subfamilies, has long been known to be involved in regulating secretion. Despite increasing interest in these proteins, fundamental questions remain about their role. Here, we systematically investigated Drosophila p24 proteins. We discovered that members of all four p24 subfamilies are required for general secretion and that their localizations between ER exit site (ERES) and Golgi are interdependent in an α→ßδ→γ sequence. We also found that localization of p24 proteins and ERES determinant Tango1 requires interaction through their respective GOLD and SH3 lumenal domains, with Tango1 loss sending p24 proteins to the plasma membrane and vice versa. Finally, we show that p24 loss expands the COPII zone at ERES and increases the number of ER-Golgi vesicles, supporting a restrictive role of p24 proteins on vesicle budding for efficient transport. Our results reveal Tango1-p24 interplay as central to the generation of a stable ER-Golgi interface.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto , Proteínas de Drosophila , Retículo Endoplasmático , Complexo de Golgi , Proteínas de Membrana Transportadoras , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Membrana Celular , Drosophila melanogaster , Proteínas de Drosophila/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Domínios de Homologia de src , Proteínas de Membrana Transportadoras/metabolismo
17.
Protein Sci ; 33(4): e4944, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38501479

RESUMO

Antibody (Ab)-based drugs have been widely used in targeted therapies and immunotherapies, leading to significant improvements in tumor therapy. However, the failure of Ab therapy due to the loss of target antigens or Ab modifications that affect its function limits its application. In this study, we expanded the application of antibodies (Abs) by constructing a fusion protein as a versatile tool for Ab-based target cell detection, delivery, and therapy. We first constructed a SpaC Catcher (SpaCC for short) fusion protein that included the C domains of Staphylococcal protein A (SpaC) and the SpyCatcher. SpaCC conjugated with SpyTag-X (S-X) to form the SpaCC-S-X complex, which binds non-covalently to an Ab to form the Ab-SpaCC-S-X protein complex. The "X" can be a variety of small molecules such as fluoresceins, cell-penetrating peptide TAT, Monomethyl auristatin E (MMAE), and DNA. We found that Ab-SpaCC-S-FITC(-TAT) could be used for target cell detection and delivery. Besides, we synthesized the Ab-SpaCC-SN3-MMAE complex by linking Ab with MMAE by SpaCC, which improved the cytotoxicity of small molecule toxins. Moreover, we constructed an Ab-DNA complex by conjugating SpaCC with the aptamer (Ap) and found that Ab-SpaCC-SN3-Ap boosted the tumor-killing function of T-cells by retargeting tumor cells. Thus, we developed a multifunctional tool that could be used for targeted therapies and immunotherapies, providing a cheap and convenient novel drug development strategy.


Assuntos
Peptídeos Penetradores de Células , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Imunoterapia , Anticorpos , DNA , Linhagem Celular Tumoral
18.
bioRxiv ; 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38464206

RESUMO

Aberrant formation and deposition of human transthyretin (TTR) aggregates causes transthyretin amyloidosis. To initialize aggregation, transthyretin tetramers must first dissociate into monomers that partially unfold to promote entry into the aggregation pathway. The native TTR tetramer (T) is stabilized by docking of the F87 sidechain into an interfacial cavity enclosed by several hydrophobic residues including A120. We have previously shown that an alternative tetramer (T*) with mispacked F87 sidechains is more prone to dissociation and aggregation than the native T state. However, the molecular basis for the reduced stability in T* remains unclear. Here we report characterization of the A120L mutant, where steric hindrance is introduced into the F87 binding site. The X-ray structure of A120L shows that the F87 sidechain is displaced from its docking site across the subunit interface. In A120S, a naturally occurring pathogenic mutant that is less aggregation-prone than A120L, the F87 sidechain is correctly docked, as in the native TTR tetramer. Nevertheless, 19F-NMR aggregation assays show an elevated population of a monomeric aggregation intermediate in A120S relative to a control containing the native A120, due to accelerated tetramer dissociation and slowed monomer tetramerization. The mispacking of the F87 sidechain is associated with enhanced exchange dynamics for interfacial residues. At 298 K, the T* populations of various naturally occurring mutants fall between 4-7% (ΔG ~ 1.5-1.9 kcal/mol), consistent with the free energy change expected for undocking and solvent exposure of one of the four F87 sidechains in the tetramer (ΔG ~ 1.6 kcal/mol). Our data provide a molecular-level picture of the likely universal F87 sidechain mispacking in tetrameric TTR that promotes interfacial conformational dynamics and increases aggregation propensity.

19.
Small ; : e2400961, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38534173

RESUMO

Functionalized nanochannels can convert environmental thermal energy into electrical energy by driving water evaporation. This process involves the interaction between the solid-liquid interface and the natural water evaporation. The evaporation-driven water potential effect is a novel green environmental energy capture technology that has a wide range of applications and does not depend on geographical location or environmental conditions, it can generate power as long as there is water, light, and heat. However, suitable materials and structures are needed to harness this natural process for power generation. MOF materials are an emerging field for water evaporation power generation, but there are still many challenges to overcome. This work uses MOF-801, which has high porosity, charged surface, and hydrophilicity, to enhance the output performance of evaporation-driven power generation. It can produce an open circuit voltage of ≈2.2 V and a short circuit current of ≈1.9 µA. This work has a simple structure, easy preparation, low-cost and readily available materials, and good stability. It can operate stably in natural environments with high practical value.

20.
Proc Natl Acad Sci U S A ; 121(12): e2320232121, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38478684

RESUMO

The chemisorption energy of reactants on a catalyst surface, [Formula: see text], is among the most informative characteristics of understanding and pinpointing the optimal catalyst. The intrinsic complexity of catalyst surfaces and chemisorption reactions presents significant difficulties in identifying the pivotal physical quantities determining [Formula: see text]. In response to this, the study proposes a methodology, the feature deletion experiment, based on Automatic Machine Learning (AutoML) for knowledge extraction from a high-throughput density functional theory (DFT) database. The study reveals that, for binary alloy surfaces, the local adsorption site geometric information is the primary physical quantity determining [Formula: see text], compared to the electronic and physiochemical properties of the catalyst alloys. By integrating the feature deletion experiment with instance-wise variable selection (INVASE), a neural network-based explainable AI (XAI) tool, we established the best-performing feature set containing 21 intrinsic, non-DFT computed properties, achieving an MAE of 0.23 eV across a periodic table-wide chemical space involving more than 1,600 types of alloys surfaces and 8,400 chemisorption reactions. This study demonstrates the stability, consistency, and potential of AutoML-based feature deletion experiment in developing concise, predictive, and theoretically meaningful models for complex chemical problems with minimal human intervention.

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