SIRT1-mediated downregulation of p27(Kip1) is essential for overcoming contact inhibition of Kaposi's sarcoma-associated herpesvirus transformed cells

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with Kaposi's sarcoma (KS), a malignancy commonly found in AIDS patients. Despite intensive studies in the last two decades, the mechanism of KSHV-induced cellular transformation and tumorigenesis remains unclear. In this study, we found that the expression of SIRT1, a metabolic sensor, was upregulated in a variety of KSHV-infected cells. In a model of KSHV-induced cellular transformation, SIRT1 knockdown with shRNAs or knockout by CRISPR/Cas9 gene editing dramatically suppressed cell proliferation and colony formation in soft agar of KSHV-transformed cells by inducing cell cycle arrest and contact inhibition. SIRT1 knockdown or knockout induced the expression of cyclin-dependent kinase inhibitor 1B (p27(Kip1)). Consequently, p27 knockdown rescued the inhibitory effect of SIRT1 knockdown or knockout on cell proliferation and colony formation. Furthermore, treatment of KSHV-transformed cells with a SIRT1 inhibitor, nicotinamide (NAM), had the same effect as SIRT1 knockdown and knockout. NAM significantly inhibited cell proliferation in culture and colony formation in soft agar, and induced cell cycle arrest. Significantly, NAM inhibited the progression of tumors and extended the survival of mice in a KSHV-induced tumor model. Collectively, these results demonstrate that SIRT1 suppression of p27 is required for KSHV-induced tumorigenesis and identify a potential therapeutic target for KS.

Effects of selenoprotein extracts from Cardamine hupingshanensis on growth, selenium metabolism, antioxidant capacity, immunity and intestinal health in largemouth bass Micropterus salmoides

This study aimed to assess the impact of dietary selenoprotein extracts from Cardamine hupingshanensis (SePCH) on the growth, hematological parameters, selenium metabolism, immune responses, antioxidant capacities, inflammatory reactions and intestinal barrier functions in juvenile largemouth bass (Micropterus salmoides). The base diet was supplemented with four different concentrations of SePCH: 0.00, 0.30, 0.60 and 1.20 g/Kg (actual selenium contents: 0.37, 0.59, 0.84 and 1.30 mg/kg). These concentrations were used to formulate four isonitrogenous and isoenergetic diets for juvenile largemouth bass during a 60-day culture period. Adequate dietary SePCH (0.60 and 1.20 g/Kg) significantly increased weight gain and daily growth rate compared to the control groups (0.00 g/Kg). Furthermore, 0.60 and 1.20 g/Kg SePCH significantly enhanced amounts of white blood cells, red blood cells, platelets, lymphocytes and monocytes, and levels of hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin in the hemocytes. In addition, 0.60 and 1.20 g/Kg SePCH increased the mRNA expression levels of selenocysteine lyase, selenophosphate synthase 1, 15 kDa selenoprotein, selenoprotein T2, selenoprotein H, selenoprotein P and selenoprotein K in the fish liver and intestine compared to the controls. Adequate SePCH not only significantly elevated the activities of antioxidant enzymes (Total superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase), the levels of total antioxidant capacity and glutathione, while increased mRNA transcription levels of NF-E2-related factor 2, Cu/Zn-superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase. However, adequate SePCH significantly decreased levels of malondialdehyde and H2O2 and the mRNA expression levels of kelch-like ECH-associated protein 1a and kelch-like ECH-associated protein 1b in the fish liver and intestine compared to the controls. Meanwhile, adequate SePCH markedly enhanced the levels of immune factors (alkaline phosphatase, acid phosphatase, lysozyme, complement component 3, complement component 4 and immunoglobulin M) and innate immune-related genes (lysozyme, hepcidin, liver-expressed antimicrobial peptide 2, complement component 3 and complement component 4) in the fish liver and intestine compared to the controls. Adequate SePCH reduced the levels of pro-inflammatory cytokines (tumour necrosis factor-α, interleukin 8, interleukin 1β and interferon γ), while increasing transforming growth factor β1 levels at both transcriptional and protein levels in the liver and intestine. The mRNA expression levels of mitogen-activated protein kinase 13 (MAPK 13), MAPK14 and nuclear factor kappa B p65 were significantly reduced in the liver and intestine of fish fed with 0.60 and 1.20 g/Kg SePCH compared to the controls. Histological sections also demonstrated that 0.60 and 1.20 g/Kg SePCH significantly increased intestinal villus height and villus width compared to the controls. Furthermore, the mRNA expression levels of tight junction proteins (zonula occludens-1, zonula occludens-3, Claudin-1, Claudin-3, Claudin-5, Claudin-11, Claudin-23 and Claudin-34) and Mucin-17 were significantly upregulated in the intestinal epithelial cells of 0.60 and 1.20 g/Kg SePCH groups compared to the controls. In conclusion, these results found that 0.60 and 1.20 g/Kg dietary SePCH can not only improve growth, hematological parameters, selenium metabolism, antioxidant capacities, enhance immune responses and intestinal functions, but also alleviate inflammatory responses. This information can serve as a useful reference for formulating feeds for largemouth bass

A new species of forest hedgehog (Mesechinus, Erinaceidae, Eulipotyphla, Mammalia) from eastern China

The hedgehog genus Mesechinus (Erinaceidae, Eulipotyphla) is currently comprised of four species, M. dauuricus, M. hughi, M. miodon, and M. wangi. Except for M. wangi, which is found in southwestern China, the other three species are mainly distributed in northern China and adjacent Mongolia and Russia. From 2018 to 2023, we collected seven Mesechinus specimens from Anhui and Zhejiang provinces, eastern China. Here, we evaluate the taxonomic and phylogenetic status of these specimens by integrating molecular, morphometric, and karyotypic approaches. Our results indicate that the Anhui and Zhejiang specimens are distinct from the four previously recognized species and are a new species. We formally described it here as Mesechinus orientalis sp. nov. It is the only Mesechinus species occurring in eastern China and is geographically distant from all known congeners. Morphologically, the new species is most similar to M. hughi, but it is distinguishable from that species by the combination of its smaller size, shorter spines, and several cranial characteristics. Mesechinus orientalis sp. nov. is a sister to the lineage composed of M. hughi and M. wangi from which it diverged approximately 1.10 Ma

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

AbstractThe identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.</jats:p

A Study of Eye-Tracking Gaze Point Classification and Application Based on Conditional Random Field

The head-mounted eye-tracking technology is often used to manipulate the motion of servo platform in remote tasks, so as to achieve visual aiming of servo platform, which is a highly integrated human-computer interaction effect. However, it is difficult to achieve accurate manipulation for the uncertain meanings of gaze points in eye-tracking. To solve this problem, a method of classifying gaze points based on a conditional random field is proposed. It first describes the features of gaze points and gaze images, according to the eye visual characteristic. An LSTM model is then introduced to merge these two features. Afterwards, the merge features are learned by CRF model to obtain the classified gaze points. Finally, the meaning of gaze point is classified for target, in order to accurately manipulate the servo platform. The experimental results show that the proposed method can classify more accurate target gaze points for 100 images, the average evaluation values Precision = 86.81%, Recall = 86.79%, We = 86.79%, these are better than relevant methods. In addition, the isolated gaze points can be eliminated, and the meanings of gaze points can be classified to achieve the accuracy of servo platform visual aiming

Interaction in Li@Fullerenes and Li⁺@Fullerenes: First Principle Insights to Li-Based Endohedral Fullerenes

This work reveals first principle results of the endohedral fullerenes made from neutral or charged single atomic lithium (Li or Li+) encapsulated in fullerenes with various cage sizes. According to the calculated binding energies, it is found that the encapsulation of a single lithium atom is energetically more favorable than that of lithium cation. Lithium, in both atomic and cationic forms, exhibits a clear tendency to depart from the center in large cages. Interaction effects dominate the whole encapsulation process of lithium to carbon cages. Further, the nature of the interaction between Li (or Li+) and carbon cages is discussed based on reduced density gradient, energy decomposition analysis, and charge transfer

The Effect of Inferior Rectus Muscle Thickening on Intraocular Pressure in Thyroid-Associated Ophthalmopathy

Objective. We aimed to evaluate the effect of inferior rectus muscle thickening on intraocular pressure (IOP) in patients with thyroid-associated ophthalmopathy (TAO). Materials and Methods. We analyzed 33 patients with TAO (50 eyes) who presented with hypotropia in the primary position. There was significant eyeball movement restriction and inferior rectus muscle thickening was confirmed on computed tomography or magnetic resonance imaging. We measured IOP changes in patients with TAO and normal participants in the primary position and upgaze using Icare tonometer. Moreover, we measured the preoperative and postoperative IOP in 13 patients with hypotropia who underwent inferior rectus recession. Results. The average inferior rectus thickness in the TAO and control groups was 0.71 ± 0.13 mm and 0.36 ± 0.12 mm, respectively. In the TAO group, the mean IOP was 16.8 ± 2.1 mm Hg in primary position (hypotropia), which increased by 8.9 ± 2.7 mm Hg to 25.7 ± 3.1 mm Hg in upgaze (horizontal vision). In the control group, the mean IOP in the primary position (horizontal vision) was 15.1 ± 1.9 mm Hg, which increased by 2.5 ± 1.4 mm Hg to 17.6 ± 2.1 mm Hg in upgaze. Compared with normal participants, patients with TAO who presented inferior rectus muscle thickening had a significantly greater increase in the IOP P<0.0001. In the patients with TAO who underwent inferior rectus muscle recession, there was a postoperative reduction in the IOP in the horizontal vision by 9.4 ± 5.2 mm Hg. Conclusion. Inferior rectus muscle thickening in patients with TAO causes a significant increase in the IOP upon upgaze compared to that in normal individuals. Given the ease of misdiagnosis as glaucoma, IOP measurement in patients with TAO should be performed in the primary position

Surface Treatment of Composites with Bismaleimide Resin-Based Wet Peel Ply for Enhanced Adhesive Bonding Performance

Surface treatment is typically required to improve the bonding performance of carbon-fiber-reinforced composites. Herein, a wet peel ply was prepared using bismaleimide (BMI) resins as a matrix resin. The temperature–heating rate extrapolation method and rheological method were employed to study the reaction characteristics and viscosity-temperature characteristics of the matrix in the BMI wet peel ply. The curing temperatures of the BMI wet peel ply and the BMI prepreg were the same (200 °C), making this wet peel ply suitable for co-curing with the BMI prepreg. After treatment with the wet peel ply, the bonding strength of the BMI composite joint showed a mean shear strength of 35.5 MPa, which was 1.72% higher than that of the sanded composite and 17.5% higher than that of the composite treated with the dry peel ply. In addition, the BMI composite treated with the BMI wet peel ply exhibited good bonding stability with a coefficient of variation of 3.9. After damp-heat aging for 1440 h, the retention rate of shear strength at room-temperature was 82.3%. The relatively loosely woven carrier in the BMI wet peel ply increased the surface roughness of the composite, thus improving the bonding strength