Effect of heat-reinforcing needling on hypoxia-inducible factor 1α and glycolysis activity in rabbits with cold syndrome of rheumatoid arthritis. / çƒ­è¡¥é’ˆæ³•å¯¹ç±»é£Žæ¹¿å ³èŠ‚ç‚Žå¯’è¯å®¶å ”è†å ³èŠ‚æ»‘è†œç»„ç»‡ç¼ºæ°§è¯±å¯¼å› å­1αå’Œç³–é µè§£æ´»æ€§çš„å½±å“.

OBJECTIVES: To observe the effect of heat-reinforcing needling (HRN) on synovial inflammation, hypoxia-inducible factor-1α (HIF-1α) and glycolytic activity in serum and synovial tissue in rabbits with cold syndrome of rheumatoid arthritis (RA), so as to explore its mechanisms underlying improvement of RA. METHODS: A total of 32 rabbits were randomly divided into normal, model, inhibitor and HRN groups, with 8 rabbits in each group. The RA with cold syndrome model was induced by injecting ovalbumin dry powder and Freund's complete adjuvant combined with cold freezing. Rabbits in the inhibitor group were intraperitoneally injected with 2-methoxyestradiol (2.5 mg/kg), rabbits in the HRN group were received HRN at bilateral "Zusanli" (ST36) for 30 min. The treatments were conducted once daily for 14 consecutive days. After the interventions, the knee circumference and pain threshold were measured. The contents of nicotinamide adenine dinucleotide phosphoric (NADPH), Hexokinase II (HK2) and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) in serum of rabbits were detected by ELISA. The pathological morphology of synovial tissue of the knee joints were observed by HE staining. The positive expressions of tumor necrosis factor (TNF-α), interleukin (IL)-1ß, IL-6 and IL-17 in synovial tissue of knee joint were detected by immunohistochemistry. The content of lactic acid in synovial tissue of rabbit knee joint was detected by spectrophotometry. The expression levels of HIF-1α, pyruvate kinase 2 (PKM2) and lactate dehydrogenase (LDHA) in synovial tissue of knee joint were detected by Western blot. RESULTS: After intervention, compared with the normal group, the knee circumference was significantly enlarged (P<0.05), the pain threshold was significantly decreased (P<0.05)；the synovial tissue of knee joints showed significant cell proliferation and inflammatory infiltration, the pathological score was significantly increased (P<0.05)；positive expressions of TNF-α, IL-1ß, IL-6 and IL-17, the content of lactic acid in synovial tissue, the contents of NADPH, HK2 and PFKFB3 in serum, and the protein expression levels of HIF-1α, PKM2 and LDHA in synovial tissue were increased (all P<0.05) in the model group. Compared with model group, the circumference of knee joint was significantly decreased (P<0.05), the pain threshold was significantly increased (P<0.05)；in synovial tissue, the pathological score was decreased (P<0.05)；the positive expressions of TNF-α, IL-1ß, IL-6 and IL-17 in synovial tissue were decreased (P<0.05), the lactic acid content in synovial tissue was decreased (P<0.05)；the contents of NADPH, HK2 and PFKFB3 in serum and the protein expression levels of HIF-1α, PKM2 and LDHA in synovial tissue were decreased (P<0.05) in inhibitor group and HRN group. Compared with the inhibitor group, the synovial pathological score was significantly increased (P<0.05), positive expressions of TNF-α, IL-1ß, IL-6 and IL-17, the content of lactic acid in synovial tissue, the contents of NADPH, HK2 and PFKFB3 in serum, and the protein expression levels of HIF-1α, PKM2 and LDHA in synovial tissue were increased (all P<0.05) in HRN group. CONCLUSIONS: HRN can increase the pain threshold, reduce the knee circumference and inhibit the inflammatory response in rabbits with cold syndrome of RA. The possible mechanism is related to the down-regulation of HIF-1α and glycolysis activity.

Electrochemical nickel-catalyzed cross-coupling of glycosyl thiols with preactivated phenols and ketones.

An efficient electrochemical nickel-catalyzed cross-coupling reaction has been reported here for the synthesis of S-glycosides from preactivated phenols and ketones under mild conditions. Various glycosyl thiols, including unprotected sugar, and a diverse range of aryl/alkenyl triflates, including some complex biorelevant phenols and ketones, were well tolerated in this method.

QTL Mapping and Data Mining to Identify Genes Associated with Soybean Epicotyl Length Using Cultivated Soybean and Wild Soybean.

Soybean (Glycine max) plants first emerged in China, and they have since been established as an economically important oil crop and a major source of daily protein for individuals throughout the world. Seed emergence height is the first factor that ensures seedling adaptability to field management practices, and it is closely related to epicotyl length. In the present study, the Suinong 14 and ZYD00006 soybean lines were used as parents to construct chromosome segment substitution lines (CSSLs) for quantitative trait loci (QTL) identification. Seven QTLs were identified using two years of epicotyl length measurement data. The insertion region of the ZYD00006 fragment was identified through whole genome resequencing, with candidate gene screening and validation being performed through RNA-Seq and qPCR, and Glyma.08G142400 was ultimately selected as an epicotyl length-related gene. Through combined analyses of phenotypic data from the study population, Glyma.08G142400 expression was found to be elevated in those varieties exhibiting longer epicotyl length. Haplotype data analyses revealed that epicotyl data were consistent with haplotype typing. In summary, the QTLs found to be associated with the epicotyl length identified herein provide a valuable foundation for future molecular marker-assisted breeding efforts aimed at improving soybean emergence height in the field, with the Glyma.08G142400 gene serving as a regulator of epicotyl length, offering new insight into the mechanisms that govern epicotyl development.

pH-responsive resveratrol-loaded ZIF-8 nanoparticles modified with tannic acid for promoting colon cancer cell apoptosis.

Resveratrol (Res) is known for its potential in treating various types of cancers, with a particular advantage of causing minimal toxic side effects. However, its clinical application is constrained by challenges such as poor bioavailability, low water solubility, and chemical instability in neutral and alkaline environments. In light of these limitations, we have developed a pH-responsive drug delivery nanoplatform, Res@ZIF-8/TA NPs, which exhibits good biocompatibility and shows promise for in vitro cancer therapy. Benefiting from the mild reaction conditions provided by zeolitic imidazolate frameworks (ZIFs), a "one-pot method" was used for drug synthesis and loading, resulting in a satisfactory loading capacity. Notably, Res@ZIF-8/TA NPs respond to acidic environments, leading to an improved drug release profile with a controlled release effect. Our cell-based experiments indicated that tannic acid (TA) modification enhances the biocompatibility of ZIFs. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT assay), Hoechst 33342/PI staining, cell scratch assay, Transwell and Reverse Transcription quantitative PCR (RT-qPCR) assays further demonstrated that Res@ZIF-8/TA NPs inhibited colon cancer cell migration and invasion, and promoted apoptosis of colon cancer cells, suggesting a therapeutic potential and demonstrating anti-cancer properties. In conclusion, the Res@ZIF-8/TA NPs pH-responsive drug delivery systems we developed may offer a promising avenue for cancer therapy. By addressing some of the challenges associated with Res-based treatments, this system could contribute to advancements in cancer therapeutics.

NopC/T/L Signal Crosstalk Gene GmPHT1-4.

Symbiotic nodulation between leguminous plants and rhizobia is a critical biological interaction. The type III secretion system (T3SS) employed by rhizobia manipulates the host's nodulation signaling, analogous to mechanisms used by certain bacterial pathogens for effector protein delivery into host cells. This investigation explores the interactive signaling among type III effectors HH103ΩNopC, HH103ΩNopT, and HH103ΩNopL from SinoRhizobium fredii HH103. Experimental results revealed that these effectors positively regulate nodule formation. Transcriptomic analysis pinpointed GmPHT1-4 as the key gene facilitating this effector-mediated signaling. Overexpression of GmPHT1-4 enhances nodulation, indicating a dual function in nodulation and phosphorus homeostasis. This research elucidates the intricate regulatory network governing Rhizobium-soybean (Glycine max (L.) Merr) interactions and the complex interplay between type III effectors.

Gut flora alterations among aquatic firefly Aquatica leii inhabiting various dissolved oxygen in fresh water.

Knowledge about the impact of different dissolved oxygen (DO) on the composition and function of gut bacteria of aquatic insects is largely unknown. Herein, we constructed freshwater environments with different DOs (hypoxia: 2.50 ± 0.50, normoxia: 7.00 ± 0.50, and hyperoxia: 13.00 ± 0.50 mg/L) where aquatic firefly Aquatica leii larvae lived for three months. Their gut flora was analyzed using the combination of 16S rRNA amplicon sequencing and metagenomics. The results showed no difference in alpha diversity of the gut flora between A. leii inhabiting various DOs. However, the relative abundance of several bacterial lineages presented significant changes, such as Pseudomonas. In addition, bacterial genes with an altered relative abundance in response to various DOs were primarily related to metabolism. The alteration of these functions correlated with the DO change. This is the first to uncover structure of gut flora under various DOs in aquatic insect larvae.

Enhancement of Alkali Resistance of Glass Fibers via In Situ Modification of Manganese-Based Nanomaterials.

Glass fibers are widely used in cement-based precast products, given the reinforcing requirements for toughness and strength. However, inferior alkali resistance hinders the effectiveness of glass fibers in reinforcing cement-based materials. In this paper, nanoparticle coatings were applied on the surface of alkali-resistant glass fiber (ARGF) as a protective layer via the in situ chemical reaction of oleic acid (OA) and potassium permanganate (PP). The morphology and constituents of the as-prepared ARGFs were examined using scanning electron microscopy (SEM) and obtaining X-ray photoelectron spectroscopy (XPS) measurements. Mass loss and strength retention were investigated to characterize alkali resistance of modified ARGFs. Results showed that ARGFs could be optimally coated by a layer of MnO2-based nanoparticles consisting of approximately 70% MnO2, 18% MnO, and 12% MnSiO3, when modified with an optimum OA to PP ratio of 10 for 24 h. The dissolution of ARGFs matrix in 4% and 10% NaOH solutions were distinctly delayed to 28 d, as a consequence of the introduction of the MnO2-based nanoparticle layer, compared with nontreated ARGF occurring at 3 d in 4% NaOH solution. For the optimally modified ARGFs, the mass loss was controlled to 1.76% and 2.91% after 90 d of corrosion in 4% and 10% NaOH solutions, and the retention of tensile strength was increased by approximately 25%. With respect to the increment in alkali-resistant performance, the modified ARGFs can be promising candidates for wide applications in alkaline cement-based products.

Extrathyroidal extension or tumor size of primary lesion influences thyroid cancer outcomes.

AIMS: Extrathyroidal extension (ETE) is a determined factor of T3 and T4 stage of differentiated thyroid cancer (DTC) in American Joint Committee on Cancer. We aimed to compare clinical outcomes between different extent of ETE according to tumor size. METHODS: Patients diagnosed with DTC were collected from the Surveillance, Epidemiology, and End Results database from 2004 to 2015. They were categorized into two groups by presence of lymph node metastases (LNM) or distant metastases (DM): group A: no presence of LNM and DM, and group B: presence of LNM or DM. Each group was further divided into four groups according to tumor size: <1 cm, 1-2 cm, 2-4 cm, >4 cm. ETE was divided into three groups by the extent: no ETE, microscopic ETE, and macroscopic ETE. Kaplan-Meier method and log-rank test were used to analyze cancer-specific survival (CSS). RESULTS: 91,975 patients were included. In groups A and B, for tumor size 1 cm, there was no significant difference in CSS between no ETE and microscopic ETE, while a significant difference was observed between no ETE and macroscopic ETE. For tumor size >1 cm, there were significant differences in CSS (both no ETE vs. micro ETE and no ETE vs. macro ETE). CONCLUSION: We suggests that when tumor size is more than 1 cm, micro ETE is significantly associated with poorer outcome. T3 and T4 stages may take account into tumor size rather than merely based on the presence and extent of ETE. It may be prudent to revisit the omission of micro ETE in TNM staging.

[Effect of heat-reinforcing needling on expression of serum inflammatory factors and autophagy of knee joint synovial tissue in rheumatoid arthritis rabbits with cold syndrome].

OBJECTIVE: To observe the effect of heat-reinforcing needling on the expression of serum inflammatory factors and autophagy of knee synovial tissue in rheumatoid arthritis (RA) rabbits with cold syndrome, so as to explore its mechanism of anti-inflammatory in the treatment of RA. METHODS: Fifty rabbits were randomly divided into normal, model, heat-reinforcing needling, inhibitor and agonist groups (n=10 rabbits in each group). The model of RA with cold syndrome was established by Freund's adjuvant and ovalbumin mixed solution injection combined with freezing and wind-cold dampness method. Heat-reinforcing needling was applied at "Zusanli" (ST36) for 30 min, once a day for 14 days. Rabbits of the inhibitor and agonist groups were given intraperitoneally injected with autophagy inhibitor 3-methyladenine (3-MA) or autophagy agonist rapamycin, once every 2 days for 7 days. The knee circumference and skin temperature of the rabbits in each group were measured. Color doppler ultrasonography was applied to examine the synovial membrane, joint effusion and blood flow signals in the knee joints of the rabbits in each group. Serum tumor necrosis factor (TNF) -α, interleukin (IL)-1ß, IL-6 and C-creactive protein (CRP) were detected by ELISA. Transmission electron microscopy was applied to observe the ultrastructure and autophagosomes of synovial cells. The protein expressions of autophagy-related protein Atg5, serine/threonine protein kinase-dysregulated 51-like kinase 1 (ULK1), microtubule-associated protein light chain 3B (LC3B), and Beclin-1 were detected by Western blot. Fluorescence quantitative PCR was used to detect the mRNA expressions of NOD-like receptor 3 (NLRP3) and nuclear factor-κB (NF-κB). RESULTS: Compared with the normal group, the circumference of the knee joint was increased (P<0.01), the skin temperature was decreased (P<0.01), the knee joint synovium was thickened and the blood flow signal was abundant, the contents of serum TNF-α, IL-1ß, IL-6, and CRP were increased (P<0.01), the protein expressions of Atg5, ULK1, Beclin-1 and LC3BⅡ/LC3BⅠof synovial tissue were significantly decreased (P<0.01), the mRNA expressions of NLRP3 and NF-κB were increased (P<0.01) in the model group. In comparison with the model and inhibitor groups, the circumference of the knee joint was decreased (P<0.01), whlie the skin temperature was increased (P<0.01), the synovial membrane became thinner and the blood flow signal was wea-kened, the contents of TNF-α, IL-1ß, IL-6 and CRP were decreased (P<0.01), the protein expressions of Atg5, ULK1, Beclin-1 and LC3B Ⅱ/LC3B Ⅰ were increased (P<0.01), and the mRNA expressions of NLRP3 and NF-κB were decreased (P<0.01) in the heat-reinforcing needling and agonist groups. CONCLUSION: Heat-reinforcing needling can alleviate the inflammatory response of the knee joint synovium in RA rabbits with cold syndrome, which may be related to its function in enhancing the autophagy activity of synovial cells and inhibiting the synthesis and release of inflammatory factors TNF-α, IL-1ß, IL-6 and CRP.

Robust High-Throughput Phenotyping with Deep Segmentation Enabled by a Web-Based Annotator.

The abilities of plant biologists and breeders to characterize the genetic basis of physiological traits are limited by their abilities to obtain quantitative data representing precise details of trait variation, and particularly to collect this data at a high-throughput scale with low cost. Although deep learning methods have demonstrated unprecedented potential to automate plant phenotyping, these methods commonly rely on large training sets that can be time-consuming to generate. Intelligent algorithms have therefore been proposed to enhance the productivity of these annotations and reduce human efforts. We propose a high-throughput phenotyping system which features a Graphical User Interface (GUI) and a novel interactive segmentation algorithm: Semantic-Guided Interactive Object Segmentation (SGIOS). By providing a user-friendly interface and intelligent assistance with annotation, this system offers potential to streamline and accelerate the generation of training sets, reducing the effort required by the user. Our evaluation shows that our proposed SGIOS model requires fewer user inputs compared to the state-of-art models for interactive segmentation. As a case study of the use of the GUI applied for genetic discovery in plants, we present an example of results from a preliminary genome-wide association study (GWAS) of in planta regeneration in Populus trichocarpa (poplar). We further demonstrate that the inclusion of a semantic prior map with SGIOS can accelerate the training process for future GWAS, using a sample of a dataset extracted from a poplar GWAS of in vitro regeneration. The capabilities of our phenotyping system surpass those of unassisted humans to rapidly and precisely phenotype our traits of interest. The scalability of this system enables large-scale phenomic screens that would otherwise be time-prohibitive, thereby providing increased power for GWAS, mutant screens, and other studies relying on large sample sizes to characterize the genetic basis of trait variation. Our user-friendly system can be used by researchers lacking a computational background, thus helping to democratize the use of deep segmentation as a tool for plant phenotyping.

'Mito-Bomb': a novel mitochondria-targeting nanosystem for ferroptosis-boosted sonodynamic antitumor therapy.

Mitochondria play an important role in regulating tumor cell death and metabolism so that they can be potential therapeutic targets. Sonodynamic therapy (SDT) represents an attractive antitumor method that induces apoptosis by producing highly toxic reactive oxygen species (ROS). Mitochondria-targeting SDT can cause oxidative damage and improve the efficiency of tumor therapy. However, due to the nonselective distribution of nanosystems and the anti-apoptotic mechanism of cancer cells, the therapeutic effect of SDT is not ideal. Therefore, we proposed a novel mitochondria-targeting nanosystem ('Mito-Bomb') for ferroptosis-boosted SDT. Sonosensitizer IR780 and ferroptosis activator RSL-3 were both encapsulated in biocompatible poly(lactic-co-glycolic acid) (PLGA) nanoparticles to form 'Mito-Bomb' (named IRP NPs). IR780 in this nanosystem was used to mediate mitochondria-targeting SDT. RSL-3 inhibited the activity of GPX4 in the antioxidant system to induce ferroptosis of tumor cells, which could rewire tumor metabolism and make tumor cells extremely sensitive to SDT-induced apoptosis. Notably, we also found that RSL-3 can inhibit hypoxia inducible factor-1α (HIF-1α) and induce ROS production to improve the efficacy of SDT to synergistically antitumor. RSL-3 was applied as a 'One-Stone-Three-Birds' agent for cooperatively enhanced SDT against triple-negative breast cancer. This study presented the first example of RSL-3 boosting mitochondria-targeting SDT as a ferroptosis activator. The 'Mito-Bomb' biocompatible nanosystem was expected to become an innovative tumor treatment method and clinical transformation.

Single-Cell RNA Sequencing Revealed a 3-Gene Panel Predicted the Diagnosis and Prognosis of Thyroid Papillary Carcinoma and Associated With Tumor Immune Microenvironment.

Objective: The objective of this research was to screen prognostic related genes of thyroid papillary carcinoma (PTC) by single-cell RNA sequencing (scRNA-seq), to construct the diagnostic and prognostic models based on The Cancer Genome Atlas Thyroid Cancer (TCGA-THCA) data, and to evaluate the association between tumor immune microenvironment and the prognostic model. Method: The differentially expressed genes (DEGs) and tumor evolution were analyzed by scRNA-seq based on public databases. The potential regulatory networks of DEGs related to prognosis were analyzed by multi-omics data in the THCA. Logistic regression and Cox proportional hazards regression were utilized to construct the diagnosis and prognostic model of PTC. The performance of the diagnostic model was verified by bulk RNA sequencing (RNA-seq) of our cohort. The tumor immune microenvironment associated with the prognostic model was evaluated using multi-omics data. In addition, qRT-PCR was performed on tumor tissues and adjacent normal tissues of 20 patients to verify the expression levels of DEGs. Results: The DEGs screened by scRNA-seq can distinguish between tumor and healthy samples. DEGs play different roles in the evolution from normal epithelial cells to malignant cells. Three DEGs ((FN1, CLU, and ANXA1)) related to prognosis were filtered, which may be regulated by DNA methylation, RNA methylation (m6A) and upstream transcription factors. The area under curve (AUC) of the diagnostic model based on 3-gene in the validation of our RNA-seq was 1. In the prognostic model based on 3-gene, the overall survival (OS) of high-risk patients was shorter. Combined with the clinical information of patients, a nomogram was constructed by using tumor size (pT) and risk score to quantify the prognostic risk. The age and tumor size of high-risk patients in the prognostic model were greater. In addition, the increase of tumor mutation burden (TMB) and diversity of T cell receptor (TCR), and the decrease of CD8+ T cells in high-risk group suggest the existence of immunosuppressive microenvironment. Conclusion: We applied the scRNA-seq pipeline to focus on epithelial cells in PTC, simulated the process of tumor evolution, and revealed a prognostic prediction model based on 3 genes, which is related to tumor immune microenvironment.

Oxidative stress and expression of inflammatory factors in lung tissue of acute mountain sickness rats.

The aim of the present study was to investigate the changes in lung histomorphology and oxidative stress, as well as the expression of interleukin (IL)­17C and other inflammatory factors during acute mountain sickness (AMS) in male Sprague­Dawley rats and to explore the underlying mechanism. Rats were randomly divided into a control group (0 h) and three hypoxia stress groups, exposed to low­pressure oxygen storage at a simulated altitude of 6,000 m for 24, 48 and 72 h, respectively. Morphological changes in lung tissue were observed by hematoxylin and eosin staining under light microscopy and transmission electron microscopy. The expression of inflammatory factors IL­17C, nuclear factor­κB (NF­κB), IL­1ß, IL­6 and tumor necrosis factor­α (TNF­α) in lung tissue was assessed by RNA sequencing and verified by reverse transcription­quantitative PCR (RT­qPCR) and western blotting (WB). Superoxide dismutase (SOD) and glutathione peroxidase (GSH­Px) enzyme activity and malondialdehyde (MDA) expression were also measured. Experimental groups were compared to the control group following 24, 48 and 72 h of hypoxic stress. Lung tissue suffered from different degrees of injury, and the damage was the most severe after 48 h of hypoxic stress. RNA sequencing data from the lung tissue of rats from each group suggested that the expression of IL­17C, NF­κB, IL­1ß, IL­6, and TNF­α increased significantly after hypoxic stress. RT­qPCR and WB demonstrated that the expression of IL­17C and NF­κB increased significantly after hypoxia lasting 48 and 72 h. IL­1ß expression increased significantly after hypoxia stress lasting 24 and 48 h, and the expressions of TNF­α and IL­6 increased significantly after hypoxia stress lasting 24, 48 and 72 h (P<0.01). The enzyme activity of SOD and GSH­Px decreased significantly after lasting 24, 48 and 72 h of hypoxia (P<0.01), and MDA increased significantly after hypoxic stress lasting 48 and 72 h (P<0.01). In conclusion, under hypoxic stress, rats quickly initiate oxidative stress and immune responses. However, with prolonged hypoxic stress time, excessive oxidative stress can further stimulate the immune system in vivo, and release a large quantity of inflammatory factors accumulating in the body. This, in turn, may lead to the occurrence of inflammatory storms and further damage the lung tissue resulting in AMS.

Polyvinyl-Alcohol-Modified Calcium Sulphoaluminate Cement Repair Mortar: Hydration and Properties.

Polyvinyl alcohol (PVA) and calcium sulphoaluminate (CSA) cement were used to prepare repair mortar for the restoration of the walls of a building built with bricks. The preparation, hydration, and properties of the PVA-modified CSA cement repair mortar were studied. Besides this, the mechanism by which PVA improves the bonding strength is also discussed. The results demonstrate that PVA prolongs the setting time of CSA cement, which is ascribed to PVA inhibiting the dissolution of C4A3$ (4CaO·3Al2O3·SO3) and the precipitation of AFt (3CaO·Al2O3·3CaSO4·26H2O) within the hydration age of 0~60 min. PVA lowers the mechanical strength of CSA cement repair mortar at the hydration age of 6 h. After 6 h, the mechanical strength is improved. PVA could also improve the bonding strength between CSA repair mortar and bricks. This is mainly ascribed to the Al ions in both the hydration products of CSA cement and the clay bricks reacting with the hydroxyl group of PVA and forming the chemical bond C-O-Al. Therefore, a tighter combination between CSA cement repair mortar and the clay bricks forms, thereby improving the bonding strength.

Morphodynamics facilitate cancer cells to navigate 3D extracellular matrix.

Cell shape is linked to cell function. The significance of cell morphodynamics, namely the temporal fluctuation of cell shape, is much less understood. Here we study the morphodynamics of MDA-MB-231 cells in type I collagen extracellular matrix (ECM). We systematically vary ECM physical properties by tuning collagen concentrations, alignment, and gelation temperatures. We find that morphodynamics of 3D migrating cells are externally controlled by ECM mechanics and internally modulated by Rho/ROCK-signaling. We employ machine learning to classify cell shape into four different morphological phenotypes, each corresponding to a distinct migration mode. As a result, we map cell morphodynamics at mesoscale into the temporal evolution of morphological phenotypes. We characterize the mesoscale dynamics including occurrence probability, dwell time and transition matrix at varying ECM conditions, which demonstrate the complex phenotype landscape and optimal pathways for phenotype transitions. In light of the mesoscale dynamics, we show that 3D cancer cell motility is a hidden Markov process whereby the step size distributions of cell migration are coupled with simultaneous cell morphodynamics. Morphological phenotype transitions also facilitate cancer cells to navigate non-uniform ECM such as traversing the interface between matrices of two distinct microstructures. In conclusion, we demonstrate that 3D migrating cancer cells exhibit rich morphodynamics that is controlled by ECM mechanics, Rho/ROCK-signaling, and regulate cell motility. Our results pave the way to the functional understanding and mechanical programming of cell morphodynamics as a route to predict and control 3D cell motility.

Identification of related impurities in an oral pharmaceutical formulation of tebipenem pivoxil using ultra-high-performance liquid chromatography/electrospray ionization quadrupole time-of-flight tandem mass spectrometry.

RATIONALE: Tebipenem pivoxil (TBPM-PI) has been developed as the first oral carbapenem drug in the world to treat otolaryngological and respiratory infections in pediatric patients. Due to its structural properties and external factors, some related impurities, which may cause side effects in patients, might be formed during the synthesis and storage of TBPM-PI. It was vital to rapidly separate and identify the related impurities to guarantee the safe use of TBPM-PI. METHODS: A method using ultra-high-performance liquid chromatography (UHPLC) coupled with quadrupole time-of-flight tandem mass spectrometry (QTOF-MS/MS) was developed to separate and detect TBPM-PI and related impurities in an oral pharmaceutical formulation. LC/MS and MS/MS spectra of these compounds in the formulation were acquired to confirm their elemental compositions and propose their structures based on LC/MS data and fragmentation pathways of available reference substances. RESULTS: LC/MS parameters and MS/MS fragmentation pathways of reference substances of TBPM-PI and related impurities were summarized in detail. Based on this, a total of 23 related impurities were found and characterized in the oral pharmaceutical formulation. Eight of these were verified by comparison with reference substances and the structures of the other 15 were proposed for the first time. In addition, four of these compounds were produced by the reaction of excipients and pre-existing related impurities. CONCLUSIONS: A UHPLC/QTOF-MS method was established and used for the separation and identification of 23 related impurities in a TBPM-PI oral pharmaceutical formulation. Moreover, it was proved that new related impurities could be produced by the reaction of excipients in the pharmaceutical formulation and related impurities in the corresponding active pharmaceutical ingredient (API).

The complete chloroplast genome sequence of Potentilla glabra Lodd.

Potentilla glabra Lodd is an important traditional Chinese medicine, which is widely distributed in many areas of China. It has a variety of pharmacological activities and has been drunk as a tea for a long time. Therefore, it has great economic, research, and social value. However, no plastid genome has been reported to date. Here, we report species of this genus complete chloroplast genome of Potentilla glabra Lodd. The chloroplast genome of Potentilla glabra Lodd is found to be 152,900 bp in length with 37.24% GC contents. The cp genome sequences contained 130 genes, including 84 mRNA genes, 37 tRNA, eight rRNA genes, and one pseudogenes, respectively. A phylogenetic tree reconstructed by 42 chloroplast genomes reveals that Potentilla glabra Lodd is most related with Potentilla parvifolia. The complete chloroplast genome of these plants will be benefit for studies on the general characteristics and evolution of the Potentilla family genome.

Identification of a Six Gene Prognosis Signature for Papillary Thyroid Cancer Using Multi-Omics Methods and Bioinformatics Analysis.

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. PTC is typically curable with an excellent survival rate; however, some patients experience disease recurrence or death. This study aimed to discover potential key genes and signaling pathways of PTC, which could provide new insights for thyroid lesions. Four GEO microarray datasets were integrated to screen for candidate genes involved in PTC progression. A total of 164 upregulated and 168 downregulated differentially expressed genes (DEGs) were screened. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes were used in pathway enrichment analyses for DEGs. A protein-protein interaction network was then built and analyzed utilizing STRING and Cytoscape, followed by the identification of 13 hub genes by cytoHubba. CDH3, CTGF, CYR61, OGN, FGF13, and CHRDL1 were selected through survival analyses. Furthermore, immune infiltration, mutations and methylation analysis indicated that these six hub genes played vital roles in immune surveillance and tumor progression. ROC and K-M plots showed that these genes had good prognostic values for PTC which was validated by TCGA dataset. Finally, GSEA for a single hub gene revealed that each candidate hub gene had close associations with PTC development. These findings provided new insights into PTC pathogenesis and identified six candidate gene prognosis signature for PTC.

Early detection of ocular abnormalities in a Chinese multicentre neonatal eye screening programme-1-year result.

PURPOSE: Early detection of ocular abnormalities in newborns is essential for timely diagnosis and treatment. This study aimed to assess the 1-year result of a multicentre prospective neonatal eye examination programme with wide-field digital imaging system in China. METHODS: A multicentre collaborative prospective study group for neonatal eye screening was established in nine hospitals, including eight Maternal and Children's Hospitals, and one general hospital across China from July 2016 to June 2017. Ocular examinations were performed on newborns within 28 days after birth using a wide-field digital imaging system. Data were reviewed and analysed. The primary outcome was the prevalence of ocular abnormalities in neonates. RESULTS: We detected 13 514 (20.91%) abnormal cases in 64 632 newborns. The most frequent abnormality was retinal haemorrhage (RH; 11.83%). Most of mild RH resolved spontaneously. Among those who were beyond retinopathy of prematurity (ROP) screening criteria of China (gestational age ≥32 w and birthweight ≥2000 g), the total number of neonates with ocular abnormality was 12 218/62 799(19.45%). 59.44% of neonatal ocular abnormalities detected (accounting for 11.56% of all the screened population) needed further interference or observation. Among them, 258 patients (0.41% of all the screened population) needed immediate or timely intervention, including congenital cataract, retinal detachment, retinoblastoma and other ocular abnormalities. One thousand and ninety-eight patients (1.75% of all the screened neonates) should be followed up closely and needed further diagnosis or intervention if necessary, such as ROP or ROP-like retinopathy, familial exudative vitreoretinopathy and persistent hyperplasia of primary vitreous. Five thousand nine hundred and six patients (9.4%) with minor clinical significance needed short-term follow-up. CONCLUSIONS: This prospective multicentre study of newborn ocular examination showed a relatively high prevalence of ocular abnormalities. There are a relatively high percentage of congenital eye pathology that required further referral and treatment in those neonates who were not screened routinely. According to the benefits and risks associated with neonatal eye examinations, neonatal ocular screening programme can detect ocular abnormalities at the very early stage and may play a positive role in promoting paediatric eye health.