With crucial roles on the differentiation of anterior pituitary and the regulation of the prolactin (PRL), growth hormone (GH) and thyroid-stimulating hormone-beta (TSH-beta) genes, the chicken PIT1 ...gene is regarded as a key candidate gene for production traits. In this study, five reported polymorphisms (MR1-MR5) of the PIT1 gene were genotyped in a full sib F2 resource population to evaluate their effects on growth, carcass and fatty traits in chickens.
Marker-trait association analyses showed that, MR1 was significantly associated with shank diameters (SD) at 84 days (P < 0.05), hatch weight (HW) and shank length (SL) at 84 days (P < 0.01), MR2 was significantly associated with BW at 28, 42 days and average daily gain (ADG) at 0-4 weeks (P < 0.05), and MR3 was significantly associated with ADG at 4-8 weeks (P < 0.05). MR4 was associated with SL at 63, 77, 84 days and BW at 84 days (P < 0.05), as well as SD at 77 days (P < 0.01). Significant association was also found of MR5 with BW at 21, 35 days and SD at 63 days (P < 0.05), BW at 28 days and ADG at 0-4 weeks (P < 0.01). Both T allele of MR4 and C allele of MR5 were advantageous for chicken growth. The PIT1 haplotypes were significantly associated with HW (P = 0.0252), BW at 28 days (P = 0.0390) and SD at 56 days (P = 0.0400). No significant association of single SNP and haplotypes with chicken carcass and fatty traits was found (P > 0.05).
Our study found that polymorphisms of PIT1 gene and their haplotypes were associated with chicken growth traits and not with carcass and fatty traits.
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Background: The tumor microenvironment (TME) contains regulatory T (Treg) cells, which play a critical role in immunosuppression and are thus an attractive target for cancer therapy. The ideal ...approach would be to inhibit Tregs within tumors while sparing those in peripheral and normal tissues. Tumor-associated Tregs express the chemokine receptor CCR8, which is involved in the induction, expansion, migration, and immunosuppression of Tregs, making targeted inhibition of CCR8 signaling a potential therapeutic strategy against cancer. Methods: We have developed IPG0521, a monoclonal antibody antagonist of CCR8, and characterized its properties, including signaling blocking, chemotaxis, species cross-reactivity, anti-tumor efficacy, and synergistic antitumor effect with PD1 antibody. Single-cell RNA sequencing with CD45
+
cells isolated from tumors treated with or without IPG0521 was also employed for profiling the mechanism of the antitumor effect of IPG0521 in the murine H22 cancer model. Results: IPG0521 inhibits receptor-mediated signaling and chemotaxis in Treg cells with a single-digit nanomolar IC50. It is cross-reactive in five species: mouse, rat, dog, monkey, and human. IPG0521 has shown excellent anti-tumor efficacy in several murine syngeneic cancer models, and its anti-tumor effect is enhanced when combined with a PD-1 antibody. Its sustained anti-tumor efficacy has been demonstrated in the murine H22 cancer model via even withdrawing the antibody during the study. The results of deep single-cell RNA sequencing on tumor-infiltrating lymphocytes (TILs) showed that the transcriptional profiles of these Treg cells could be distinguished into three distinct subsets based on molecular, functional, and immunosuppressive properties. These subsets were defined as the Treg_Foxp3 high subset, which exhibited low immunosuppression, the Treg_Foxp3 mild subset, which demonstrated mild immunosuppression, and the Treg_Foxp3 low subset, which had high proliferation. IPG0521 treatment resulted in a significant increase in the Treg_
Foxp3 high subset and a significant decrease in the Treg _
Foxp3 mild subset while no change in the Treg_
Foxp3 low subset, indicating a reduction in Treg immunosuppression. This change in Treg cells also altered the composition of other immune cells, including a significant increase in neutrophils and natural killer (NK) cells, which ultimately inhibited tumor growth. Conclusions: IPG0521 has potent anti-tumor effects in multiple tumor types, including lung, liver, and breast cancers, in both syngeneic and immune-humanized mouse models. It inhibits Tregs immunosuppression and activates CD8+ T cells to achieve its anti-tumor effects. These results support the development of IPG0521, which is currently under IND filing, as a novel therapeutic agent for the treatment of cancers.
Ocular diseases are closely related to the physiological changes in the eye sphere and its contents. Using biomechanical methods to explore the relationship between the structure and function of ...ocular tissue is beneficial to reveal the pathological processes. Studying the pathogenesis of various ocular diseases will be helpful for the diagnosis and treatment of ocular diseases. We provide a critical review of recent biomechanical analysis of ocular diseases including glaucoma, high myopia, and diabetes. And try to summarize the research about the biomechanical changes in ocular tissues (e.g., optic nerve head, sclera, cornea, etc.) associated with those diseases. The methods of ocular biomechanics research in vitro in recent years are also reviewed, including the measurement of biomechanics by ophthalmic equipment, finite element modeling, and biomechanical analysis methods. And the preparation and application of microfluidic eye chips that emerged in recent years were summarized. It provides new inspiration and opportunity for the pathogenesis of eye diseases and personalized and precise treatment.
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in ...maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation.
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During normal operation, the doubly-fed induction generator (DFIG) generates certain range of reactive power. The DFIG based wind farm can participate in reactive power control of grid as a reactive ...power supply. In order to get a more stable input wind speed of the DFIG, wavelet multi-resolution analysis method is used. This paper proposes a kind of power dispatch model which considers a learning mechanism of minimum copper loss of all DFIGs in wind farm as an objective function. An active power and reactive power allocation optimization model is established. This power dispatch model makes the working condition of DFIGs and the PCC running in the optimum state. The active power and reactive power generated by wind farm satisfy the power gird requirements of both active power and reactive power. The advantage of the proposed method is verified by a case study which successfully demonstrates the learning mechanism.
Abstract
Within the tumor microenvironment (TME), regulatory T (Treg) cells are one attractive cell type for targeting as they play a critical role in immunosuppression. Therapeutic strategies that ...specifically inhibit tumor-infiltrating Tregs while sparing peripheral and normal tissue Tregs are highly desirable. The tumor-associated Tregs express the chemokine receptor CCR8, which plays a role in the induction, expansion, chemotactic migration, and immunosuppression of tumor-associated Tregs. Thus, targeted inhibition of CCR8 is a potential therapeutic strategy against cancer. We have developed a monoclonal antibody antagonist of CCR8, IPG0521, which potently inhibited the receptor-mediated signaling and chemotaxis in Treg cells with single digital nanomolar IC50. RNA sequencing (RNA-seq)analysis indicated that CCL1-induced up-regulation of immunosuppressive genes, including PD-1, CTLA4, IL-10, TIGIT etc., were reversed by IPG0521 in tumor-derived Treg cells. IPG0521 potently inhibited the growth of multiple tumor types in both syngeinic and immune-humanized mouse models, including lung cancer, liver cancer, breast cancer, via inhibiting Treg and activating CD8+ T cells. These data pave the way for the development of IPG0521, which is under IND filing, as a novel therapeutic agent against cancer.
Citation Format: Guohuang Fan, Jianfei Wang, Na Wang, Yuanyuan Zhang, Yong Zhang, Binle Tian, Xuebing Jia. Development of a CCR8 monoclonal antibody which blocks CCR8 signaling and abolishes the immunosuppressive function of Treg for the treatment of cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2340.
Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline due to the selective neuronal loss in the cortex and hippocampus of the brains. ...Generation of human induced pluoripotent stem (hiPS) cells holds great promise for disease modeling and drug discovery in AD. In this study, we used neurons with forebrain marker expression from two unrelated hiPS cell lines. As both populations of neurons were vulnerable to β-amyloid 1–42 (Aβ1–42) aggregates, a hallmark of AD pathology, we used them to investigate cellular mediators of Aβ1–42 toxicity. We observed in neurons differentiated from both hiPS cell lines that Aβ induced toxicity correlated with cell cycle re-entry and was inhibited by pharmacological inhibitors or shRNAs against Cyclin-dependent kinase 2 (Cdk2). As one of the hiPS cell lines has been developed commercially to supply large quantities of differentiated neurons (iCell® Neurons), we screened a chemical library containing several hundred compounds and discovered several small molecules as effective blockers against Aβ1–42 toxicity, including a Cdk2 inhibitor. To our knowledge, this is the first demonstration of an Aβ toxicity screen using hiPS cell-derived neurons. This study provided an excellent example of how hiPS cells can be used for disease modeling and high-throughput compound screening for neurodegenerative diseases.
► Generation of enriched functional forebrain neurons from human iPS cells ► Modeling Alzheimer's disease by demonstration of Aβ toxicity to human iPS neurons ► Performing a high-throughput screen for compounds blocking Aβ toxicity ► Validation of Cdk2 as a target for blocking Aβ toxic effects
In this paper, a novel direction of arrival (DOA) estimation algorithm called the Toeplitz fourth order cumulants multiple signal classification method (TFOC-MUSIC) algorithm is proposed through ...combining a fast MUSIC-like algorithm termed the modified fourth order cumulants MUSIC (MFOC-MUSIC) algorithm and Toeplitz approximation. In the proposed algorithm, the redundant information in the cumulants is removed. Besides, the computational complexity is reduced due to the decreased dimension of the fourth-order cumulants matrix, which is equal to the number of the virtual array elements. That is, the effective array aperture of a physical array remains unchanged. However, due to finite sampling snapshots, there exists an estimation error of the reduced-rank FOC matrix and thus the capacity of DOA estimation degrades. In order to improve the estimation performance, Toeplitz approximation is introduced to recover the Toeplitz structure of the reduced-dimension FOC matrix just like the ideal one which has the Toeplitz structure possessing optimal estimated results. The theoretical formulas of the proposed algorithm are derived, and the simulations results are presented. From the simulations, in comparison with the MFOC-MUSIC algorithm, it is concluded that the TFOC-MUSIC algorithm yields an excellent performance in both spatially-white noise and in spatially-color noise environments.
Cutaneous melanoma is a highly malignant and metastatic skin cancer with high mortality. However, its underlying mechanisms remain largely unclear. Here, we found that retrotransposon-like 1 (RTL1) ...is highly enriched in melanoma tissue, especially in early and horizontal growth tissues. Knockdown of RTL1 in melanoma cells resulted in cell proliferation suppression; cell cycle arrest at G1 phase; and down-regulation of E2F1, CYCLIN D1, cyclin-dependent kinase 6 (CDK6) and c-MYC. Moreover, overexpression of RTL1 in melanoma cells accelerated cell proliferation, promoted passage of the cell cycle beyond G1 phase, and increased the expression of cell cycle related genes. Mechanistically, we found that knockdown of RTL1 inhibited the Wnt/β-Catenin pathway by regulating the expression of genes specifically involved in β-CATENIN stabilization. Furthermore, the overexpression and knockdown of β-CATENIN rescued the effects of RTL1 on melanoma cell proliferation and the cell cycle. These findings were also confirmed via tumour xenografts in nude mice. Together, our results demonstrated that RTL1 promotes melanoma cell proliferation by regulating the Wnt/β-Catenin signalling pathway.
The transient receptor potential TRPM8 ion channel is required for cellular proliferation in pancreatic epithelia and adenocarcinoma. To elucidate the mechanism that mediates the function of TRPM8, ...we examined its role in the proliferation and invasion of pancreatic cancer (PC) cells. TRPM8 expression increased in both the PC tissues and cell lines; a high TRPM8 expression was correlated with poorer prognosis in patients with PC. In PC cell lines, PACN-1 and BxPC-3, Ca2+ influxes could be evoked by TRPM8; the sensitivity of PC cells to gemcitabine was increased, while the proliferation and invasion of PC cells were suppressed after RNA interference-mediated silencing of TRPM8. The mechanism of TRPM8 in gemcitabine-based chemotherapy was then investigated. The expression and activity of multidrug resistance-associated proteins, P-gp, MRP-2, LRP, was significantly reduced in response to TRPM8 silence. Moreover, TRPM8 knockdown significantly increased hENT1 protein levels and the ratio of Bax/Bcl-2 while decreased the protein levels of RRM1. Thus, TRPM8 is required for PC cell proliferation and invasion and was closely related to the gemcitabine sensitivity of PC. The modulation of TRPM8 expression may help improve treatment response of PC by combining with traditional chemotherapy.
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