Discovery of novel dual Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) inhibitors as a promising strategy for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronically systemic autoimmune disorder, which is related with various cellular signal pathways. Both BTK (Bruton's Tyrosine Kinase) and JAK3 (Janus Kinase 3) play important roles in the pathogenesis of rheumatoid arthritis. Herein, we reported the discovery of dual BTK/JAK3 inhibitors through bioisosterism and computer-aided drug design based on the structure of BTK inhibitor ibrutinib. We reported the discovery of dual BTK/JAK3 inhibitors which are based on the structure of BTK inhibitor ibrutinib via the method of bioisosterism and computer-aided drug design) Most of the target compounds exhibited moderate to strong inhibitory activities against BTK and JAK3. Among them, compound XL-12 stood out as the most promising candidate targeting BTK and JAK3 with potent inhibitory activities (IC50 = 2.0 nM and IC50 = 14.0 nM respectively). In the in vivo studies, compound XL-12 (40 mg/kg) exhibited more potent antiarthritic activity than ibrutinib (10 mg/kg) in adjuvant arthritis (AA) rat model. Furthermore, compound XL-12 (LD50 > 1600 mg/kg) exerted improved safety compared with ibrutinib (LD50 = 750 mg/kg). These results indicated that compound XL-12, the dual BTK/JAK3 inhibitor, might be a potent drug candidate for the treatment of RA.

Effects of salt and heat treatment on the physicochemical properties, microstructure, secondary structure, and simulated in vitro gastrointestinal digestion of duck egg white.

BACKGROUND: The texture and structure of the duck egg white (DEW) gel under salt and heat treatment are crucial to its digestibility. Specifically, the structural changes of food protein gels have been recognized for their potential to regulate in vitro digestion. In this study, the effects of gel characteristics and simulated in vitro gastrointestinal digestion of DEW under combined salt and heat treatment were investigated. RESULTS: With the increase in salting time and temperature, a porous opaque gel with large particles was formed, the moisture content of DEW showed a downward trend, and the same was true for hardness changes. The microstructure suggested that, with the penetration of NaCl, DEW proteins were denatured, and the protein molecules gradually unfolded and then aggregated after 7 days. The secondary structure revealed that, as the salting time and temperature increased, the proportion of intermolecular ß-sheets and α-helices decreased. In terms of in vitro digestion, the highest digestibility was obtained at 14 days of salting combined with 100 °C heat treatment, and the digestibility was the lowest when marinated for 7 days at 121 °C. Liquid chromatography and tandem mass spectrometry (LC-MS/MS) indicated that the number of different types of peptides and specific peptides was positively correlated with the salting time and temperature of the DEW at the end of gastric digestion. CONCLUSIONS: Heat treatment at 100 °C has a higher in vitro digestibility than at 121 °C. Gels with low hardness, large pores, and rough textures are easier to digest by pepsin and release more peptides. © 2021 Society of Chemical Industry.

Rutile Nanorod/Anatase Nanowire Junction Array as Both Sensor and Power Supplier for High-Performance, Self-Powered, Wireless UV Photodetector.

Self-powered UV photodetectors based on TiO2 nanotree arrays have captured much attention in recent years because of their many advantages. In this work, rutile/anatase TiO2 (R/A-TiO2 ) heterostructured nanotree arrays are fabricated by assembling anatase nanowires as branches on rutile nanorods. External quantum efficiencies as high as 90% are reached at 325 nm. These high quantum efficiencies are related to the higher amount of light harvesting due to the larger surface area, the better separation ability of the photogenerated carriers by the rutile/anatase heterostructure, and the faster electron transport, related to the 1D nanostructure and lattice connection at the interface of the two kinds of TiO2 . Furthermore, a self-powered wireless UV photodetector is shown with excellent wireless detection performance. Such devices will enable significant advances for next-generation photodetection and photosensing applications.

TiO2 Nanorod Array Constructed Nanotopography for Regulation of Mesenchymal Stem Cells Fate and the Realization of Location-Committed Stem Cell Differentiation.

As a physical cue for controlling the fate of stem cells, surface nanotopography has attracted much attention to improve the integration between implants and local host tissues and cells. A biocompatible surface TiO2 nanorod array is proposed to regulate the fate of bone marrow derived mesenchymal stem cells (MSCs). TiO2 substrates with different surface nanotopographies: a TiO2 nanorod array and a polished TiO2 ceramic are built by hydrothermal and sintering processes, respectively. The assessment of morphology, viability, gene expression, and protein characterization of the MSCs cultured on the different TiO2 substrates proves that a TiO2 nanorod array promotes the osteogenic differentiation of MSCs, while a TiO2 ceramic with a smooth surface suppresses it. Periodically assembled TiO2 nanorod array stripes on the smooth TiO2 ceramic are constructed by a combination of microfabrication and a chemical synthesis process, which realizes the location-committed osteogenic differentiation of MSCs. A route to control the differentiation of MSCs by a nanostructured surface, which can also control the location and direction of MSCs on the surface of biomaterials with micro-nano scale surface engineering, is demonstrated.

A new species of Hemiphyllodactylus Bleeker, 1860 (Squamata: Gekkonidae) from western Yunnan, China.

A new species of the genus Hemiphyllodactylus is described from mountainous area of Changning County, Yunnan Province, China. Hemiphyllodactylus changningensis sp. nov. is distinguished from all other congeners by morphology and a significant genetic divergence of greater than 17% (ND2 gene). The new species from Changning is characterized by the following features: a maximum SVL of 40.1 mm in males and 43.8 mm in females; 11-15 dorsal scale rows; 6-8 ventral scale rows; a forefoot lamellar formula of 3-3/4-3/4-3; a hindfoot lamellar formula of 3-4-4-4 or 3-3-3-3; precloacal and femoral pore series continuous; cloacal spurs present in both sexes; dark dorsal transverse blotches; dark postorbital stripe; a brown postsacral mark bearing anteriorly projecting arms; and unpigmented caecum and gonads. The new species occurs also in Longyang District of Baoshan City, Yunnan Province, China.

Discovery of Highly Potent Small-Molecule PD-1/PD-L1 Inhibitors with a Novel Scaffold for Cancer Immunotherapy.

Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in cancer immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.

Correlation analysis of metabolic characteristics and the risk of metabolic-associated fatty liver disease - related hepatocellular carcinoma.

Metabolic-associated fatty liver disease (MAFLD) is currently the most common chronic liver disease worldwide and the main cause of hepatocellular carcinoma (HCC). To explore the risk factors of MAFLD-HCC, we evaluated the independent and combined effects of metabolic characteristics on the risk of MAFLD-HCC. We retrospectively analyzed 135 MAFLD-HCC patients who were treated at the Second Affiliated Hospital of Kunming Medical University from January 2015 to December 2020 and 135 MAFLD patients as the control group. Independent and joint effects of metabolic traits on the risk of HCC were evaluated. Each metabolic feature was significantly correlated with the increased risk of MAFLD-HCC (p < 0.05); obesity had the strongest correlation (adjusted odds ratio [OR] 3.63, 95% confidence interval [CI] 1.99-6.62). In patients with superimposed features, HCC risk was higher with more metabolic features (p < 0.05). The correlation between metabolic characteristics and risk of MAFLD-HCC in patients without cirrhosis or advanced fibrosis was basically consistent with the overall analysis. Metabolic characteristics increase the risk of MAFLD-HCC, and the risk is positively correlated with the number of metabolic characteristics. Obesity has the strongest correlation with HCC.

First-In-Human Study on Pharmacokinetics, Safety, and Tolerability of Single and Multiple Escalating Doses of Hepenofovir, a Novel Hepatic Targeting Prodrug of Tenofovir in Healthy Chinese Subjects.

Objective: Hepenofovir, a novel hepatic targeting prodrug of tenofovir, has been developed for the treatment of chronic hepatitis B (CHB). This is a first-in-human study to evaluate the pharmacokinetics (PK) and tolerability of single and multiple escalating doses of hepenofovir in healthy Chinese subjects. Methods: This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (25-200 mg) study under fasted conditions comprising a food-effect investigation (200 mg) and a multiple-ascending-dose (MAD) (25 mg) study under fasted conditions. Results: Hepenofovir was well tolerated in healthy Chinese subjects. There was no significant difference in adverse reaction rates between hepenofovir and placebo groups. Hepenofovir was rapidly absorbed and metabolized into tenofovir after dosing. In healthy participants, the median Tmax of hepenofovir and tenofovir was 0.33-0.50 h and 0.62-0.75 h, respectively, and their mean half-life was 2.5-12.3 h and 49.7-53.8 h, respectively. Systemic exposure to tenofovir increased in proportion to the dose. The mean accumulation indexes of hepenofovir and tenofovir were 1.1 vs. 1.8. Moreover, food could reduce the Cmax of both hepenofovir and tenofovir, but did not affect their area under the curve (AUC). Conclusions: Hepenofovir has shown a favorable safety and PK profile, which support the further evaluation of its safety and efficacy in CHB patients. Clinical trial registration number: The trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20191953).

Comparison of plasma exchange, double plasma molecular adsorption system, and their combination in treating acute-on-chronic liver failure.

OBJECTIVE: Our objective was to compare the effectiveness of nonbiological artificial liver (NBAL) support, particularly short-term (28-day) survival rates, in patients who underwent treatment using double plasma molecular adsorption system (DPMAS), plasma exchange (PE), or combined PE+DPMAS, in addition to comprehensive physical treatment for different stages of acute-on-chronic liver failure (ACLF). METHODS: We retrospectively reviewed clinical data of 135 patients with ACLF who received NBAL treatment between November 2015 and February 2019. The patients were categorized into PE, DPMAS, and PE+DPMAS groups. Short-term effectiveness of treatment was assessed and compared based on selected clinical findings, laboratory parameters, and liver function markers. RESULTS: Coagulation function improved significantly in all groups after treatment. In the PE and PE+DPMAS groups, prothrombin time decreased to different degrees, whereas plasma thromboplastin antecedent increased significantly after treatment. White blood cell counts increased and platelet counts decreased in all groups after treatment. The model for end-stage liver disease score, Child-Pugh grade, systematic inflammatory syndrome score, and sepsis-related organ failure score decreased in all three groups after treatment. CONCLUSIONS: PE, DPMAS, and PE+DPMAS improved disease indicators in all patients with ACLF. The combined treatment improved the short-term effectiveness of treatment, especially in patients with mild ACLF.

Changes in physicochemical properties, gel structure and in vitro digestion of marinated egg white gel during braising.

In this paper, changes in physicochemical properties, gel structure and in vitro digestion of marinated egg with spice or tea during braising were investigated. Results indicated that the moisture content and surface hydrophobicity of marinated egg white showed an overall decreased trend. The springiness of marinated egg white showed an increased trend, and the hardness in the late stage showed an increased trend. Microstructure showed that compact gel structures formed many holes during the braising. Intermolecular forces showed that ionic bonds and disulfide bonds played a dominant role in the marinated egg white. Secondary structure showed that the ß-turn showed a decreased trend, contrary to that of random coils and α-helices. Appropriate braising increased the digestibility of marinated egg white, but excessively long-time braising could reduce it. Both spice and tea braising could improve the gel strength of protein, and the tea braising was also slightly better than spice braising.

Molecular phylogeny of Entomobrya (Collembola: Entomobryidae) from China: Color pattern groups and multiple origins.

Highly diversified colorations among springtails (Collembola) have been widely used for species diagnosis, but their phylogenetic significance is poorly known. We addressed this issue in the largest Entomobryinae genus Entomobrya, which possesses variable color patterns among species. The relationships within the genus and to other genera have also rarely been studied. Based on material mainly from China, we have conducted a multilocus phylogeny and topology tests with likelihood and Bayesian algorithms, and accordingly demonstrated the non-monophyly of Chinese Entomobrya. The division of five clades, including Entomobrya and several related genera, coincided well with five types of colorations, respectively. Further analyses of divergence time and historical biogeography revealed that Chinese Entomobrya originated mainly from Palearctic (northern and western) China in the Paleocene and Eocene. This study highlights the great phylogenetic values as well as taxonomic uses of coloration in Chinese Entomobrya. Multiple phylogenetic and biogeographic origins of Entomobrya imply its complicated relationships with both scaled and unscaled genera of Entomobryinae.

Relationship between protein structure changes and in vitro digestion of preserved egg white during pickling.

In this paper, the relationship between protein structure changes and in vitro digestion of preserved egg white (PEW) during pickling was studied. Results showed that as the pickling time increased, moisture content of PEW exhibited a decreasing trend, pH value and hardness of PEW exhibited an increasing trend. Environmental Scanning Electron Microscopy (ESEM) revealed that alkali-treated duck egg white could form a more compact gel network structure during pickling. Transmission Electron Microscopy (TEM) showed that PEW consisted of two sorts of structures, namely fibrillar (from 7th to 21st day) and particulate (from 28th to 42nd day). Fourier Transform Infrared (FTIR) spectroscopy showed that there was an increase in the content of ß-sheets and a decrease in the content of α-helices during pickling. Protein digestibility of PEW was highest at day 14 and the lowest at day 42. Moreover, the content of ß-sheets was negatively correlated with protein digestibility. Peptides identification using LC-MS/MS highlighted that the number of different peptides were positively correlated with the pickling. The number of unique peptides was negatively correlated with protein digestibility at the end of gastric and intestinal digestion. This study would provide guidance for studying nutritional value and controlling quality of preserved eggs.

Graphene microfiber as a scaffold for regulation of neural stem cells differentiation.

We report the cytocompatibility and regulating effects of the nanostructured reduced graphene oxide (rGO) microfibers, which are synthesized through a capillary hydrothermal method, on neural differentiation of neural stem cells (NSCs). Our findings indicate that the flexible, mechanically strong, surface nanoporous, biodegradable, and cytocompatible nanostructured rGO microfibers not only offer a more powerful substrate for NSCs adhesion and proliferation compared with 2D graphene film and tissue cluture plate but also regulate the NSCs differentiation into neurons and form a dense neural network surrounding the microfiber. These results illustrate the great potential of nanostructured rGO microfibers as an artificial neural tissue engineering (NTE) scaffold for nerve regeneration.

Mitochondrial genome of Pachytriton feii (Urodela: Salamandridae).

In this paper, the complete mitochondrial genome of Pachytriton feii is sequenced and reported for the first time. In our result, the complete mitochondrial genome of P. feii is 16 293 bp in length. Similar to the typical mtDNA of vertebrates, it contained 37 genes (13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes) and 1 non-coding region (D-loop). All the genes in P. feii were distributed on the H-strand, except for the ND6 subunit gene and eight tRNA genes which were encoded on the L-strand. The phylogenetic tree was reconstructed using the Bayesian analysis method and contained two major clades. Among Pachytriton (P. feii, Pachytriton labiatus, and Pachytriton brevipes), Paramesotriton laoensis make up the first lineage.

A new species of Rana from the Dabie Mountains in eastern China (Anura, Ranidae).

A new species Rana dabieshanensissp. n. is described from the Dabie Mountains in Anhui Province, China, based on morphological character differences and molecular analyses. The new species can be distinguished from its congeners by a combination of diagnostic characters. The results of phylogenetic analyses (based on 12s rRNA, 16s rRNA, ND2, Cyt b, RAG1, BDNF and Tyr) and genetic distances (based on Cyt b) indicate that the new species belongs to the Rana longicrus group, and is placed as the sister taxon to R. hanluica.

A Nanostructured Molybdenum Disulfide Film for Promoting Neural Stem Cell Neuronal Differentiation: toward a Nerve Tissue-Engineered 3D Scaffold.

Physical cues from nanostructured biomaterials have been shown to possess regulating effects on stem cell fate. In this study, nanostructured molybdenum disulfide (MoS2 ) thin films (MTFs) are prepared by assembling MoS2 nanosheets on a flat substrate. These films are used as a new biocompatible platform for promoting neural stem cell (NSC) differentiation. The results show that the nanostructured MTFs exhibit significantly positive effects on NSC attachment and proliferation without measurable toxicity. More importantly, immunostaining and real-time polymerase chain reaction assessments show that the nanostructured MTFs induce NSC differentiation into neural cells at higher efficiency. It is found that the MTFs have a good electrical conductivity and offer larger surface areas for NSC attachment and spreading compared with conventional tissue culture plates. Furthermore, multilayered cylindrical 3D living scaffolds are constructed by rolling up NSC-cultured MoS2 -polyvinylidene fluoride (PVDF) nanofiber films that are prepared by chemically assembling MoS2 nanostructures on electrospun PVDF flexible films. These living nerve scaffolds have a great potential for applications in nerve regeneration as cylindrical 3D living scaffolds.

Static pressure-induced neural differentiation of mesenchymal stem cells.

Growing experimental evidence suggests that physical cues play an important role in regulating the fate of stem cells and stimulating their differentiation behavior. We report here that static pressure enables the differentiation of rat bone marrow-derived mesenchymal stem cells (MSCs) into neural-like cells within several hours in the absence of disruptive bio-factors or chemicals. The realization of such differentiation is supported by the observation of characteristic morphology of neural-like cells with neurites, and an up-regulated expression level of neural-specific markers. Our finding also demonstrates the utility of the static pressure-based approach for in situ and specifically localized creation of neural cell systems, thereby providing profound implications for developing therapeutic application of stem cells.

A new species of Hemiphyllodactylus Bleeker, 1860 (Squamata: Gekkonidae) from Guizhou, China.

A new species of the genus Hemiphyllodactylus is described from Huishui County, Guizhou Province, Southwest China. Hemiphyllodactylus huishuiensis sp. nov. is distinguished from all other congeners by having the unique combination of the following characters: a maximum SVL of 51.2 mm; 8 or 10 chin scales; enlarged postmental scales; 3 circumnasal scales; 2 or 3 scales between the supranasals; 9-11 supralabials; 9-11 infralabials; 13-15 dorsal scales; 7-9 ventral scales; a lamellar hand formula of 3-4-4-4 or 4-4/5-5-4; a lamellar foot formula of 4-4/5-5-4/5; 3 subdigital lamellae on the first finger and first toe; a continuous precloacal and femoral pore series of less than 20; one cloacal spur in both males and females; no enlarged subcaudal scales; dark dorsal transverse blotches; dark postorbital stripe; a brown postsacral mark bearing anteriorly projecting arms; and unpigmented caecum and gonads. The new species also occurs in Ziyun County, Guizhou Province, China.

Construction of titanium dioxide nanorod/graphite microfiber hybrid electrodes for a high performance electrochemical glucose biosensor.

The demand for a highly sensitive and selective glucose biosensor which can be used for implantable or on-time monitoring is constantly increasing. In this work, TiO2 nanorods were synthesized in situ on the surface of graphite microfibers to yield TiO2 nanorod/graphite microfiber hybrid electrodes. The TiO2 nanorods not only retain the high activity of the immobilized glucose molecule, but also promote the direct electron transfer process on the electrode surface. As a working electrode in an electrochemical glucose biosensor in a flowing system, the microfiber hybrid electrodes exhibit high sensitivity, selectivity and stability. Due to its simplicity, low cost, high stability, and unique morphology, the TiO2 nanorod/graphite microfiber hybrid electrode is expected to be an excellent candidate for an implantable biosensor or for in situ flow monitoring.

Cellular internalization of LiNbO3 nanocrystals for second harmonic imaging and the effects on stem cell differentiation.

Second harmonic generation (SHG) nanocrystals have recently been reported to label cancer cells and other functional cell lines due to their unique double-frequency property. In this paper, we report for the first time the use of lithium niobate (LiNbO3, LN) nanocrystals as SHG labels for imaging stem cells. Rat mesenchymal stem cells (rMSCs) were labeled with LN nanocrystals in order to study the cellular internalization of the nanocrystals and the influence on stem cell differentiation. The results showed that LN nanocrystals were endocytosed by the rMSCs and the distribution of the internalized nanoparticles demonstrated a high consistency with the orientation of the actin filaments. Besides, LN-labeled rMSCs showed a concentration-dependent viability. Most importantly, rMSCs labeled with 50 µg per mL of LN nanocrystals retained their ability to differentiate into both osteogenic and adipogenic lineages. The results prove that LN nanocrystals can be used as a cytocompatible, near-infrared (NIR) light driven cell label for long-term imaging, without hindering stem cell differentiation. This work will promote the use of LN nanocrystals to broader applications like deep-tissue tracking, remote drug delivery and stem cell therapy.