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1.
Cell ; 187(9): 2305-2323.e33, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38614099

RESUMO

Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.


Assuntos
Complexo CD3 , Ativação Linfocitária , Linfócitos T , Evasão Tumoral , Microambiente Tumoral , Animais , Complexo CD3/metabolismo , Complexo CD3/imunologia , Humanos , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologia , Cães , Neoplasias/imunologia , Linhagem Celular Tumoral , Feminino , Ligação Proteica , Proteína-Tirosina Quinase ZAP-70/metabolismo , Anticorpos Neutralizantes/imunologia , Camundongos Endogâmicos C57BL
2.
J Med Genet ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38816193

RESUMO

BACKGROUND AND AIMS: Variants in ZFYVE19 underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism. METHODS: Zfyve19 knockout (Zfyve19-/- ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. ZFYVE19 knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death. RESULTS: The Zfyve19-/- mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, Zfyve19-/- mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from Zfyve19-/- mice and patients. Transforming growth factor-ß (TGF-ß) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12. CONCLUSIONS: Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-ß pathway in the disease.

3.
J Cell Mol Med ; 28(8): e18229, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38520217

RESUMO

Monoamine oxidase B (MAOB), a neurotransmitter-degrading enzyme, was reported to reveal conflicting roles in various cancers. However, the functional role of MAOB and impacts of its genetic variants on prostate cancer (PCa) is unknown. Herein, we genotyped four loci of MAOB single-nucleotide polymorphisms (SNPs), including rs1799836 (A/G), rs3027452 (G/A), rs6651806 (A/C) and rs6324 (G/A) in 702 PCa Taiwanese patients. We discovered that PCa patients carrying the MAOB rs6324 A-allele exhibited an increased risk of having a high initial prostate-specific antigen (iPSA) level (>10 ng/mL). Additionally, patients with the rs3027452 A-allele had a higher risk of developing distal metastasis, particularly in the subpopulation with high iPSA levels. In a subpopulation without postoperative biochemical recurrence, patients carrying the rs1799836 G-allele had a higher risk of developing lymph node metastasis and recurrence compared to those carrying the A-allele. Furthermore, genotype screening in PCa cell lines revealed that cells carrying the rs1799836 G-allele expressed lower MAOB levels than those carrying the A-allele. Functionally, overexpression and knockdown of MAOB in PCa cells respectively suppressed and enhanced cell motility and proliferation. In clinical observations, correlations of lower MAOB expression levels with higher Gleason scores, advanced clinical T stages, tumour metastasis, and poorer prognosis in PCa patients were noted. Our findings suggest that MAOB may act as a suppressor of PCa progression, and the rs3027452 and rs1799836 genetic variants of MAOB are linked to PCa metastasis within the Taiwanese population.


Assuntos
Monoaminoxidase , Neoplasias da Próstata , Humanos , Masculino , Alelos , Genótipo , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética
4.
Breast Cancer Res Treat ; 203(2): 291-306, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37851288

RESUMO

PURPOSE: Breast cancer is a molecularly heterogeneous disease, and multiple genetic variants contribute to its development and prognosis. Most of previous genome-wide association studies (GWASs) and polygenic risk scores (PRSs) analyses focused on studying breast cancers of Caucasian populations, which may not be applicable to other population. Therefore, we conducted the largest breast cancer cohort of Taiwanese population to fill in the knowledge gap. METHODS: A total of 152,534 Participants recruited by China Medical University Hospital between 2003 and 2019 were filtered by several patient selection criteria and GWAS quality control steps, resulting in the inclusion of 2496 cases and 9984 controls for this study. We then conducted GWAS for all breast cancers and PRS analyses for all breast cancers and the four breast cancer subtypes, including luminal A, luminal B, basal-like, and HER2-enriched. RESULTS: The GWAS analyses identified 113 SNPs, 50 of which were novel. The PRS models for all breast cancers and the luminal A subtype showed positively correlated trends between the PRS and the risk of developing breast cancer. The odds ratios (95% confidence intervals) for the groups with the highest PRS in all breast cancers and the luminal A subtype were 5.33 (3.79-7.66) and 3.55 (2.13-6.14), respectively. CONCLUSION: In summary, we explored the association of genetic variants with breast cancer in the largest Taiwanese cohort and developed two PRS models that can predict the risk of developing any breast cancer and the luminal A subtype in Taiwanese women.


Assuntos
Neoplasias da Mama , Estudo de Associação Genômica Ampla , Feminino , Humanos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco , População do Leste Asiático/genética
5.
Opt Express ; 32(10): 18033-18043, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38858969

RESUMO

A photonic architecture for remote multi-parameter measurement and transmission of microwave signals is proposed and demonstrated, which utilizes a dual-parallel dual-drive Mach-Zehnder modulator (DP-DDMZM) in the antenna unit and a dual-drive Mach-Zehnder modulator (DDMZM) in the processing unit. Doppler frequency shift (DFS) and angle of arrival (AOA) can be determined by analyzing the down-converted intermediate frequency signals. Introducing a reference signal in the processing unit ensures DFS measurement without directional ambiguity. The proposed architecture can also be applied for instantaneous frequency measurement based on down-conversion. Due to the use of optical single sideband modulation, long-distance transmission of radio frequency (RF) signals without dispersion-induced power fading can be achieved. Experiments for accurate and stable DFS and AOA measurement as well as long-distance RF signal transmission with dispersion-induced power fading are presented. The approach avoids the use of optical filters and polarization-related devices, facilitating wideband and stable operation, which is highly desirable. The proposed architecture is a potential solution for microwave photonic antenna remoting, offering support for both remote transmission and multi-parameter measurement.

6.
Opt Lett ; 49(5): 1265-1268, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38426989

RESUMO

A harmonic active mode-locking optoelectronic oscillator (HAML-OEO) with pulse intensity feedback is proposed and experimentally demonstrated. It is capable of generating microwave pulses characterized by suppressed supermode noise, uniform intensity, and tunable repetition rates. Unlike traditional HAML-OEOs, active mode-locking and pulse intensity feedback are simultaneously achieved through the use of a dual-drive Mach-Zehnder modulator (DDMZM). By synchronously feeding back the generated microwave pulses to the DDMZM, each pulse undergoes a loss proportional to its intensity, facilitating pulse intensity equalization and supermode noise suppression. In the experiment, intensity-equalized microwave pulse trains with repetition rates of 499 kHz and 998 kHz are generated by the 5th- and 10th-order HAML-OEOs, respectively, with the measured supermode noise suppression ratios exceeding 40 dB.

7.
Opt Lett ; 49(7): 1832-1835, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38560876

RESUMO

We propose a novel, to the best of our knowledge, approach to realizing instantaneous frequency measurement with ultrahigh measurement bandwidth, which utilizes three-channel photonic compressive sensing (CS) with sub-Nyquist pseudo-random binary sequences (PRBSs). In each CS channel, an alias frequency is recovered due to the sub-Nyquist property of the applied PRBS. A frequency identification algorithm is employed to determine the frequency of the signal under measurement according to the three alias frequencies. The proposed approach significantly reduces the bit rate of the applied PRBSs and the sampling rate required by the digitizers in CS. A proof-of-concept experiment for measuring frequency in the Ku band is demonstrated using PRBSs at 1 Gb/s and digitizers with a sampling rate of 250 MS/s.

8.
Exp Eye Res ; 245: 109971, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38871165

RESUMO

PURPOSE: This study aims to reveal the immunopathogenesis of the high-risk corneal transplantation using a comparative proteomic approach. METHODS: The immunological properties of ocular tissues (including corneal grafts, aqueous humour, and iris-ciliary body) were analysed using a high-risk rabbit corneal transplantation model employing a comparative proteomic approach. RESULTS: The corneal grafts revealed a dramatic increase in the immune response both at the early (postoperative day 7) and rejection stages, along with the appearance of transplantation stress-induced cellular senescence in the early stage. The aqueous humour (AH) displayed persistent pathological alterations, indicated by the significant enrichment of complement and coagulation cascades pathway in the early stage and interleukin (IL)-17 signalling pathway in the rejection stage. More surprisingly, the pronounced elevation of immune response was also observed in the iris-ciliary body (I-CB) tissues at the early and rejection stages. The enriched immune-related pathways were associated with antigen processing and presentation, complement and coagulation cascades, and IL-17 signalling pathway. Furthermore, proteomic analysis revealed that the implantation of Cyclosporine A drug delivery system (CsA-DDS) into the anterior chamber obviously mitigated corneal transplantation rejection by inhibiting immunoreaction both in the corneal grafts and I-CB tissues. CONCLUSION: The results highlighted the involvement of intraocular immunity both in the grafts and I-CB tissues during corneal transplantation rejection, further suggesting the anterior chamber as an optimal drug-delivery site for its treatment.

9.
Nat Chem Biol ; 18(8): 904-912, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35864333

RESUMO

Chemoproteomics has emerged as a key technology to expand the functional space in complex proteomes for probing fundamental biology and for discovering new small-molecule-based therapies. Here we report a modification-centric computational tool termed pChem to provide a streamlined pipeline for unbiased performance assessment of chemoproteomic probes. The pipeline starts with an experimental setting for isotopically coding probe-derived modifications that can be automatically recognized by pChem, with masses accurately calculated and sites precisely localized. pChem exports on-demand reports by scoring the profiling efficiency, modification homogeneity and proteome-wide residue selectivity of a tested probe. The performance and robustness of pChem were benchmarked by applying it to eighteen bioorthogonal probes. These analyses reveal that the formation of unexpected probe-derived modifications can be driven by endogenous reactive metabolites (for example, bioactive aldehydes and glutathione). pChem is a powerful and user-friendly tool that aims to facilitate the development of probes for the ever-growing field of chemoproteomics.


Assuntos
Aldeídos , Proteoma , Aldeídos/química , Proteoma/metabolismo
10.
BMC Neurol ; 24(1): 11, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38166825

RESUMO

INTRODUCTION: The prevalence of type 2 diabetes (T2D) has increased dramatically in recent decades, and there are increasing indications that dementia is related to T2D. Previous attempts to analyze such relationships principally relied on traditional multiple linear regression (MLR). However, recently developed machine learning methods (Mach-L) outperform MLR in capturing non-linear relationships. The present study applied four different Mach-L methods to analyze the relationships between risk factors and cognitive function in older T2D patients, seeking to compare the accuracy between MLR and Mach-L in predicting cognitive function and to rank the importance of risks factors for impaired cognitive function in T2D. METHODS: We recruited older T2D between 60-95 years old without other major comorbidities. Demographic factors and biochemistry data were used as independent variables and cognitive function assessment (CFA) was conducted using the Montreal Cognitive Assessment as an independent variable. In addition to traditional MLR, we applied random forest (RF), stochastic gradient boosting (SGB), Naïve Byer's classifier (NB) and eXtreme gradient boosting (XGBoost). RESULTS: Totally, the test cohort consisted of 197 T2D (98 men and 99 women). Results showed that all ML methods outperformed MLR, with symmetric mean absolute percentage errors for MLR, RF, SGB, NB and XGBoost respectively of 0.61, 0.599, 0.606, 0.599 and 0.2139. Education level, age, frailty score, fasting plasma glucose and body mass index were identified as key factors in descending order of importance. CONCLUSION: In conclusion, our study demonstrated that RF, SGB, NB and XGBoost are more accurate than MLR for predicting CFA score, and identify education level, age, frailty score, fasting plasma glucose, body fat and body mass index as important risk factors in an older Chinese T2D cohort.


Assuntos
Diabetes Mellitus Tipo 2 , Fragilidade , Masculino , Humanos , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Modelos Lineares , Glicemia , Cognição , Aprendizado de Máquina , China/epidemiologia
11.
Immun Ageing ; 21(1): 38, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877498

RESUMO

Alzheimer's disease (AD) is a serious brain disorder characterized by the presence of beta-amyloid plaques, tau pathology, inflammation, neurodegeneration, and cerebrovascular dysfunction. The presence of chronic neuroinflammation, breaches in the blood-brain barrier (BBB), and increased levels of inflammatory mediators are central to the pathogenesis of AD. These factors promote the penetration of immune cells into the brain, potentially exacerbating clinical symptoms and neuronal death in AD patients. While microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in AD, recent evidence suggests the infiltration of cerebral vessels and parenchyma by peripheral immune cells, including neutrophils, T lymphocytes, B lymphocytes, NK cells, and monocytes in AD. These cells participate in the regulation of immunity and inflammation, which is expected to play a huge role in future immunotherapy. Given the crucial role of peripheral immune cells in AD, this article seeks to offer a comprehensive overview of their contributions to neuroinflammation in the disease. Understanding the role of these cells in the neuroinflammatory response is vital for developing new diagnostic markers and therapeutic targets to enhance the diagnosis and treatment of AD patients.

12.
Appl Opt ; 63(1): 204-209, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38175022

RESUMO

The generation of an X-band dual-chirp waveform, which is capable of pulse compression, plays an important role in radar, electric warfare, and satellite communication systems. With the development of applications such as multi-static radar, transmission over long distances has attracted considerable attention. In this paper, a photonic system for X-band dual-chirp waveform generation and transmission based on frequency multiplication and power-fading compensation is put forward and experimentally carried out. Based on a compact dual-parallel Mach-Zehnder modulator (DPMZM), the dual-chirp waveforms of 8.6-9.6 GHz and 9.6-10.6 GHz are generated by an RF carrier of 4.8 GHz and transmitted through a 40 km single-mode fiber (SMF) spool. The dispersion-induced power fading of the chirp waveform is compensated for by about 13 dB. The full width at half maximum (FWHM) and the peak-to-sidelobe ratio (PSR) of the compressed pulses are 1 ns and 11.5 dB, respectively. Moreover, the compensation of power fading in the entire X-band is verified to demonstrate the applicability of our system. By flexibly adjusting the bias voltage of the built-in phase shifter, the system can be applied in more scenarios.

13.
Environ Toxicol ; 39(6): 3448-3472, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38450906

RESUMO

BACKGROUND: Globally, breast cancer, with diverse subtypes and prognoses, necessitates tailored therapies for enhanced survival rates. A key focus is glutamine metabolism, governed by select genes. This study explored genes associated with T cells and linked them to glutamine metabolism to construct a prognostic staging index for breast cancer patients for more precise medical treatment. METHODS: Two frameworks, T-cell related genes (TRG) and glutamine metabolism (GM), stratified breast cancer patients. TRG analysis identified key genes via hdWGCNA and machine learning. T-cell communication and spatial transcriptomics emphasized TRG's clinical value. GM was defined using Cox analyses and the Lasso algorithm. Scores categorized patients as TRG_high+GM_high (HH), TRG_high+GM_low (HL), TRG_low+GM_high (LH), or TRG_low+GM_low (LL). Similarities between HL and LH birthed a "Mixed" class and the TRG_GM classifier. This classifier illuminated gene variations, immune profiles, mutations, and drug responses. RESULTS: Utilizing a composite of two distinct criteria, we devised a typification index termed TRG_GM classifier, which exhibited robust prognostic potential for breast cancer patients. Our analysis elucidated distinct immunological attributes across the classifiers. Moreover, by scrutinizing the genetic variations across groups, we illuminated their unique genetic profiles. Insights into drug sensitivity further underscored avenues for tailored therapeutic interventions. CONCLUSION: Utilizing TRG and GM, a robust TRG_GM classifier was developed, integrating clinical indicators to create an accurate predictive diagnostic map. Analysis of enrichment disparities, immune responses, and mutation patterns across different subtypes yields crucial subtype-specific characteristics essential for prognostic assessment, clinical decision-making, and personalized therapies. Further exploration is warranted into multiple fusions between metrics to uncover prognostic presentations across various dimensions.


Assuntos
Neoplasias da Mama , Análise de Célula Única , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Prognóstico , Glutamina , Antineoplásicos/uso terapêutico , Medicina de Precisão , Genômica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
14.
J Cell Mol Med ; 27(17): 2507-2516, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37533175

RESUMO

CD26/dipeptidyl peptidase IV (DPP4) is a multifunctional cell-surface glycoprotein widely found in many cell types, and a soluble form is present in body fluids. There is longstanding evidence indicating a tumour-promoting or -suppressive role of DPP4 in different cancer types. However, studies focusing on the impacts of genetic variants of DPP4 on cancers are very rare. Herein, we conducted a case-control study to evaluate whether single-nucleotide polymorphisms (SNPs) of DPP4 were associated with the risk or clinicopathologic development of prostate cancer (PCa). We genotyped four loci of DPP4 SNPs, including rs7608798 (A/G), rs3788979 (C/T), rs2268889 (T/C) and rs6741949 (G/C), using a TaqMan allelic discrimination assay in 704 PCa patients and 704 healthy controls. Our results showed that PCa patients with the DPP4 rs7608798 AG+GG genotype or rs2268889 TC+CC genotype had a higher risk of developing an advanced clinical primary tumour (cT) stage (adjusted odds ratio (AOR): 1.680, 95% confidence interval (CI): 1.062-2.659, p = 0.025; AOR: 1.693, 95% CI: 1.092-2.624, p = 0.018). Additionally, in The Cancer Genome Atlas (TCGA) database, we observed that lower DPP4 expression levels were correlated with higher Gleason scores, advanced cT and pathological stages, tumour metastasis, and shorter progression-free survival rates in PCa patients. Furthermore, overexpression of DPP4 suppressed migration/invasion of metastatic PC3 PCa cells. Our findings suggest that DPP4 levels may affect the progression of PCa, and the DPP4 rs7608798 and rs2268889 SNPs are associated with the clinicopathologic development of PCa in a Taiwanese population.


Assuntos
Dipeptidil Peptidase 4 , Neoplasias da Próstata , Humanos , Masculino , Estudos de Casos e Controles , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Genótipo , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética
15.
J Cell Mol Med ; 27(24): 4202-4214, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37902124

RESUMO

Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in advanced stages of several cancer types, including prostate cancer (PCa). Impacts of genetic variants of CHI3L1 on PCa development have not yet been investigated. The most common well-studied genetic variations are single-nucleotide polymorphisms (SNPs). Therefore, the objective of this study was to explore associations of CHI3L1 SNPs with both the susceptibility to PCa and its clinicopathological development. Three promoter SNPs, rs6691378 (-1371, G>A), rs10399805 (-247, G>A) and rs4950928 (-131, C>G), and one non-synonymous SNP, rs880633 (+2950, T>C), were analysed using a TaqMan allelic discrimination assay for genotyping in a cohort of 701 PCa patients and 701 healthy controls. Results indicated that there were no significant associations of PCa susceptibility with these four CHI3L1 SNPs. However, among elderly PCa patients (aged >65 years), it was observed that polymorphic variants (GA + AA) of CHI3L1 rs6691378 and 10399805 were significantly linked to reduced risks of several clinicopathological characteristics, including a high Gleason grade, advanced pathologic T stage and tumour cell invasion. Moreover, analyses of The Cancer Genome Atlas database revealed that CHI3L1 expression levels were elevated in PCa tissues compared with normal tissues. Interestingly, higher CHI3L1 expression levels were found to be associated with longer progression-free survival rates in PCa patients. Our findings indicated that levels of CHI3L1 may influence the progression of PCa, and the rs6691378 and 10399805 SNP genetic variants of CHI3L1 are linked to the clinicopathological development of PCa within a Taiwanese population.


Assuntos
Proteína 1 Semelhante à Quitinase-3 , Neoplasias da Próstata , Idoso , Humanos , Masculino , Alelos , Quitinases/genética , Predisposição Genética para Doença , Glicoproteínas/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Proteína 1 Semelhante à Quitinase-3/genética , Proteína 1 Semelhante à Quitinase-3/metabolismo
16.
J Biol Chem ; 298(7): 102069, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35623388

RESUMO

Major depressive disorder is a critical public health problem with a lifetime prevalence of nearly 17% in the United States. One potential therapeutic target is the interaction between hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and an auxiliary subunit of the channel named tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). HCN channels regulate neuronal excitability in the mammalian hippocampus, and recent work has established that antagonizing HCN function rescues cognitive impairment caused by chronic stress. Here, we utilize a high-throughput virtual screen to find small molecules capable of disrupting the TRIP8b-HCN interaction. We found that the hit compound NUCC-0200590 disrupts the TRIP8b-HCN interaction in vitro and in vivo. These results provide a compelling strategy for developing new small molecules capable of disrupting the TRIP8b-HCN interaction.


Assuntos
Transtorno Depressivo Maior , Animais , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Transtorno Depressivo Maior/metabolismo , Hipocampo/metabolismo , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Mamíferos/metabolismo , Neurônios/metabolismo
17.
Small ; : e2306367, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38054805

RESUMO

Developing highly efficient bi-functional noble-metal-free oxygen electrocatalysts with low-cost and scalable synthesis approach is challenging for zinc-air batteries (ZABs). Due to the flexible valence state of manganese, MnF2 is expected to provide efficient OER. However, its insulating properties may inhibit its OER process to a certain degree. Herein, during the process of converting the manganese source in the precursor of porous carbon nanofibers (PCNFs) to manganese fluoride, the manganese source is changed to manganese acetate, which allows PCNFs to grow a large number of hollow carbon nanorods (HCNRs). Meanwhile, manganese fluoride will transform from the aggregation state into uniformly dispersed MnF2 nanodots, thereby achieving highly efficient OER catalytic activity. Furthermore, the intrinsic ORR catalytic activity of the HCNRs/MnF2 @PCNFs can be enhanced due to the charge modulation effect of MnF2 nanodots inside HCNR. In addition, the HCNRs stretched toward the liquid electrolyte can increase the capture capacity of dissolved oxygen and protect the inner MnF2 , thereby enhancing the stability of HCNRs/MnF2 @PCNFs for the oxygen electrocatalytic process. MnF2 surface-modulated HCNRs can strongly enhance ORR activity, and the uniformly dispersed MnF2 can also provide higher OER activity. Thus, the prepared HCNRs/MnF2 @PCNFs obtain efficient bifunctional oxygen catalytic ability and high-performance rechargeable ZABs.

18.
J Med Virol ; 95(7): e28950, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37465863

RESUMO

With the rapid increase in the incidence of cervical cancer, anal cancer and other cancers, human papillomavirus (HPV) infection has become a growing concern. Persistent infection with high-risk HPV is a major cause of malignant tumors. In addition, microbiota and viruses such as human immunodeficiency virus, herpes simplex virus, and Epstein-Barr virus are closely associated with HPV infection. The limited effectiveness of existing treatments for HPV-associated tumors and the high rates of recurrence and metastasis in patients create an urgent need for novel and effective approaches. In recent years, HPV vaccine coverage has increased and can reduce the incidence of serious adverse events. Overall, this article provides a comprehensive overview of HPV biology, microbiome, and other viral interactions in cancer development, highlighting the need for a more comprehensive approach to cancer prevention and treatment. Current and emerging HPV-related cancer control and treatment strategies are also further explored.


Assuntos
Infecções por Vírus Epstein-Barr , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/prevenção & controle , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/epidemiologia , HIV , Vacinas contra Papillomavirus/uso terapêutico , Papillomaviridae
19.
Opt Express ; 31(2): 2135-2146, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36785234

RESUMO

Analog photonic down-conversion links have been widely used in radar, electronic warfare, and satellite communication systems. Aiming at the optimization demands of the link performance, we demonstrate and experimentally verify a Ku-band photonic down-conversion link based on coherent in-phase/quadrature (I/Q) image rejection and digital nonlinear compensation. The image-rejection ratio at 17.5 GHz is measured to be 47 dB. After digital processing, the image intermodulation distortions (MMD) and the intermodulation distortions (IMD3) are suppressed by 18.1 dB and 10.9 dB, respectively. The corresponding spurious-free dynamic range (SFDR) reaches 108.83 dB·Hz2/3.

20.
Opt Express ; 31(11): 18159-18166, 2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37381532

RESUMO

Photonic compressive sampling (PCS) is an effective method to recover wideband sparse radio frequency (RF) signals. However, the noisy and high-loss photonic link leads to signal-to-noise ratio (SNR) degradation of the RF signal to be tested, which limits the recovery performance of the PCS system. In this paper, a random demodulator-based PCS system with 1-bit quantization is proposed. The system consists of a photonic mixer, a low-pass filter, a 1-bit analog-to-digital converter (ADC), and a digital signal processor (DSP). The 1-bit quantized result is used to recover the spectra of the wideband sparse RF signal with the binary iterative hard thresholding (BIHT) algorithm, which can alleviate the negative impact of the SNR degradation caused by the photonic link. A full theoretical framework of the PCS system with 1-bit quantization is given. Simulation results show that the PCS system with 1-bit quantization can provide better recovery performance than the traditional PCS system under low SNR and stringent bit budget.

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