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Siamese networks have been extensively studied in recent years. Most of the previous research focuses on improving accuracy, while merely a few recognize the necessity of reducing parameter redundancy and computation load. Even less work has been done to optimize the runtime memory cost when designing networks, making the Siamese-network-based tracker difficult to deploy on edge devices. In this paper, we present SiamMixer, a lightweight and hardware-friendly visual object-tracking network. It uses patch-by-patch inference to reduce memory use in shallow layers, where each small image region is processed individually. It merges and globally encodes feature maps in deep layers to enhance accuracy. Benefiting from these techniques, SiamMixer demonstrates a comparable accuracy to other large trackers with only 286 kB parameters and 196 kB extra memory use for feature maps. Additionally, we verify the impact of various activation functions and replace all activation functions with ReLU in SiamMixer. This reduces the cost when deploying on mobile devices.

The multiple physiological properties of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor stability of GLP-1 has significantly limited its clinical utility; however, many studies are focused on extending its stability. Fatty acid conjugation is a traditional approach for extending the stability of therapeutic peptides because of the high binding affinity of human serum albumin for fatty acids. However, the conjugate requires a complex synthetic approach, usually involving Lys and occasionally involving a linker. In the current study, we conjugated the GLP-1 molecule with fatty acid derivatives to simplify the synthesis steps. Human serum albumin binding assays indicated that the retained carboxyl groups of the fatty acids helped maintain a tight affinity to HSA. The conjugation of fatty acid-like molecules improved the stability and increased the binding affinity of GLP-1 to HSA. The use of fatty acid-like molecules as conjugating components allowed variant conjugation positions and freed carboxyl groups for other potential uses. This may be a novel, long-acting strategy for the development of therapeutic peptides.

The inhibition of the PD-1/PD-L1 axis has exhibited significant advancements in cancer immunotherapy, improving patient outcomes in various cancers. However, the clinical efficacy of these monotherapies remains limited in many cases. Integrin αvβ3 has been identified as a positive regulator of PD-L1 expression and a critical contributor to cancer immune evasion. To address this, we developed a dual function antibody, B1451, that recognizes both PD-L1 and αvβ3 and evaluated its antitumor efficacy in pre-clinical models and . We first analyzed the correlation between PD-L1 and αvβ3 expression, as well as the role of αvβ3 in modulating sensitivity to immunotherapy, using the TISIDB database. Subsequently, we designed and constructed a dual function PD-L1×αvβ3 antibody (B1451) by conjugating an integrin αvβ3-binding peptide to the C-terminal of the heavy chain of the anti-PD-L1 monoclonal antibody, Atezolizumab, using a (G4S)×3 linker. The antitumor efficacy of B1451 was then evaluated in preclinical models and . Our findings demonstrated a significant positive correlation between the gene expression of PD-L1 and αvβ3 across various human solid tumors. Additionally, high αvβ3 expression appears to influence the sensitivity to immunotherapy. The dual function antibody B1451 was capable of recognizing human PD-L1 and αvβ3 antigens, effectively blocking both the PD-1/PD-L1 and vitronectin/αvβ3 pathways. B1451 inhibited tumor cell migration, adhesion, and angiogenesis , and exhibited superior anti-tumor activity than monotherapy. The dual function antibody targeting both αvβ3 and PD-L1 holds the potential to reverse immune evasion and exhibit synergistic anti-tumor effects, offering a promising therapeutic strategy for the treatment of solid tumor.

FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors’ lead discovery. After replacing the (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamide moiety in compound 3 with 5-(3-chlorophenyl)-1H-pyrazole-3-carboxamide, we traveled from FXIa inhibitor 3 to a scaffold that fused the privileged fragments into a pharmacophore for FXIa inhibitors. Subsequently, we synthesized and assessed the FXIa inhibitory potency of a series of 5-phenyl-1H-pyrazole-3-carboxamide derivatives with different P1, P1′ and P2′moiety. Finally, the SAR of them was systematically investigated to afford the lead compound 7za (FXIa Ki = 90.37 nM, 1.5× aPTT in rabbit plasma = 43.33 μM) which exhibited good in vitro inhibitory potency against FXIa and excellent in vitro coagulation activities. Furthermore, the binding mode of 7za with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of 7za makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making 7za binds to FXIa in a highly efficient manner.

The thienopyridines class of drugs used as P2Y12 receptor antagonists plays a vital role in antiplatelet therapy. To further optimized this compound class, we designed and synthesized a series of amino acid prodrugs of 2-hydroxytetrahydrothienopyridine. All compounds were then evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats and then ED50 and bleeding time of the most potent compounds were compared with commercial drugs. The results showed compound 5c could be a potent and safe candidate for further research.

FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1 -pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors' lead discovery. After replacing the ( )-3-(5-chloro-2-(1 -tetrazol-1-yl)phenyl)acrylamide moiety in compound with 5-(3-chlorophenyl)-1 -pyrazole-3-carboxamide, we traveled from FXIa inhibitor to a scaffold that fused the privileged fragments into a pharmacophore for FXIa inhibitors. Subsequently, we synthesized and assessed the FXIa inhibitory potency of a series of 5-phenyl-1 -pyrazole-3-carboxamide derivatives with different P1, P1' and P2'moiety. Finally, the SAR of them was systematically investigated to afford the lead compound (FXIa Ki = 90.37 nM, 1.5× aPTT in rabbit plasma = 43.33 μM) which exhibited good in vitro inhibitory potency against FXIa and excellent in vitro coagulation activities. Furthermore, the binding mode of with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making binds to FXIa in a highly efficient manner.

Self-assembling peptides are capable of forming a complex containing a cavity where cytotoxic agents can be wrapped in a self-assembling manner. These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel. In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics. The MMP-2 specific substrate fragment, PVGLIG, makes this supramolecule disassociate in the presence of MMP-2, and this system is considered to be a powerful tool for the treatment of tumors with high expression of MMP-2 or tumor metastasis. Our findings show that this modified self-assembling peptide with the PVGLIG fragment was able to significantly enhance specificity against HT1080 cells, a tumor cell line with high expression of MMP-2. In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule. Our results suggest that the modified MMP-2 specific substrate, SAMTA7, could act as a controlled and sustained drug carrier for treatment of tumors with high expression of MMP-2 and for tumor metastasis.

We construct a \"universe\" of over 18,000 fundamental signals from financial statements and use a bootstrap approach to evaluate the impact of data mining on fundamental-based anomalies. We find that many fundamental signals are significant predictors of cross-sectional stock returns even after accounting for data mining. This predictive ability is more pronounced following high-sentiment periods and among stocks with greater limits to arbitrage. Our evidence suggests that fundamental-based anomalies, including those newly discovered in this study, cannot be attributed to random chance, and they are better explained by mispricing. Our approach is general and we also apply it to past return–based anomalies.

Ferroptosis is a phospholipid peroxidation-mediated and iron-dependent cell death form, involved in sepsis-induced organ injury and other lung diseases. Yes-associated protein 1 (YAP1), a key regulator of the Hippo signaling pathway, could target multiple ferroptosis regulators. Herein, this study aimed to explore the involvement of ferroptosis in the etiopathogenesis of sepsis-induced acute lung injury (ALI) and demonstrate that YAP1 could disrupt ferritinophagy and moderate sepsis-induced ALI. Cecal ligation and puncture (CLP) models were constructed in wild-type (WT) and pulmonary epithelium-conditional knockout (YAP1 f/f ) mice to induce ALI, while MLE-12 cells with or without YAP1 overexpression were stimulated by lipopolysaccharide (LPS) in vitro . In-vivo modes showed that YAP1 knockout aggravated CLP-induced ALI and also accelerated pulmonary ferroptosis, as presented by the downregulated expression of GPX4, FTH1, and SLC7A11, along with the upregulated expression of SFXN1 and NCOA4. Transcriptome research identified these key genes and ferroptosis pathways involved in sepsis-induced ALI. In-vitro modes consistently verified that YAP1 deficiency boosted the ferrous iron accumulation and mitochondrial dysfunction in response to LPS. Furthermore, the co-IP assay revealed that YAP1 overexpression could prevent the degradation of ferritin to a mass of Fe 2+ (ferritinophagy) via disrupting the NCOA4–FTH1 interaction, which blocked the transport of cytoplasmic Fe 2+ into the mitochondria via the mitochondrial membrane protein (SFXN1), further reducing the generation of mitochondrial ROS. Therefore, these findings revealed that YAP1 could inhibit ferroptosis in a ferritinophagy-mediated manner, thus alleviating sepsis-induced ALI, which may provide a new approach to the therapeutic orientation for sepsis-induced ALI.

The fifth generation (5G) wireless communication networks are being deployed worldwide from 2020 and more capabilities are in the process of being standardized, such as mass connectivity, ultra-reliability, and guaranteed low latency. However, 5G will not meet all requirements of the future in 2030 and beyond, and sixth generation (6G) wireless communication networks are expected to provide global coverage, enhanced spectral/energy/cost efficiency, better intelligence level and security, etc. To meet these requirements, 6G networks will rely on new enabling technologies, i.e., air interface and transmission technologies and novel network architecture, such as waveform design, multiple access, channel coding schemes, multi-antenna technologies, network slicing, cell-free architecture, and cloud/fog/edge computing. Our vision on 6G is that it will have four new paradigm shifts. First, to satisfy the requirement of global coverage, 6G will not be limited to terrestrial communication networks, which will need to be complemented with non-terrestrial networks such as satellite and unmanned aerial vehicle (UAV) communication networks, thus achieving a space-air-ground-sea integrated communication network. Second, all spectra will be fully explored to further increase data rates and connection density, including the sub-6 GHz, millimeter wave (mmWave), terahertz (THz), and optical frequency bands. Third, facing the big datasets generated by the use of extremely heterogeneous networks, diverse communication scenarios, large numbers of antennas, wide bandwidths, and new service requirements, 6G networks will enable a new range of smart applications with the aid of artificial intelligence (AI) and big data technologies. Fourth, network security will have to be strengthened when developing 6G networks. This article provides a comprehensive survey of recent advances and future trends in these four aspects. Clearly, 6G with additional technical requirements beyond those of 5G will enable faster and further communications to the extent that the boundary between physical and cyber worlds disappears.