Search

In this study, a label-free electrochemical immunosensor with high sensitivity for the detection of Aβ 1–42 was constructed based on Au-BSN-rGO. It has the advantages of low detection limits, high sensitivity and a wide linear range.

Addressing glycation-induced oxidative stress in Alzheimer's disease (AD) is an emerging pharmacotherapeutic strategy. Restoration of the brain glyoxalase enzyme system that neutralizes reactive dicarbonyls is one such approach. Toward this end, we designed, synthesized, and evaluated a γ-glutamyl transpeptidase-resistant glyoxalase substrate, ψ-GSH. Although mechanistically successful, the oral efficacy of ψ-GSH appeared as an area in need of improvement. Herein, we describe our rationale for the creation of prodrugs that mask the labile sulfhydryl group.

Data on the effect of food on the pharmacokinetics of senaparib (previously IMP4297), an oral poly (adenosine diphosphate-ribose) polymerase inhibitor, are limited. This study was conducted to evaluate the effect of food on the pharmacokinetics of senaparib in healthy Chinese subjects.This is a phase I, open-label, randomized, single-dose, two-way crossover study. Healthy Chinese male subjects were randomized 1:1 to receive a single dose of senaparib 100 mg in two prandial states: fasted or after a high-fat meal; subjects were given a second dose after switching prandial states and a washout period of at least 7 days. Pharmacokinetics were assessed at pre-dose and up to 72 h post-dose. Safety was assessed throughout the study.Sixteen subjects were randomized and included in the pharmacokinetic analysis; 15 completed the study. The presence of food slowed the rate of senaparib absorption (time to maximum concentration) by ~ 3 h and reduced the maximum concentration of senaparib by ~ 24%. Total exposure to senaparib was higher in the fed than fasted state; senaparib area under the plasma concentration-time curve from time zero to the last measurable concentration and area under the plasma concentration-time curve from time zero to infinity were increased by ~ 24 and ~28%, respectively. Safety profiles were similar in both prandial states. All treatment-emergent adverse events were grade 1 in severity; no serious adverse events or deaths were reported.Food slightly decreased the rate and increased the extent of senaparib absorption following oral administration. However, the effect of food on various exposure parameters was not considered clinically meaningful. Safety data were consistent with the known profile of senaparib and senaparib was well tolerated in the fed and fasted states in healthy subjects. These results indicated that senaparib could be administered orally with or without food.ClinicalTrials.gov NCT04057729.

In order to relieve the pain of incision after cesarean section, a method of foot and hand massage for abdominal pain of cesarean section incision under ultrasound guidance was proposed in this paper. In this paper, the experimental control method and retrospective analysis were used to relax the patients through massage, so that the pregnant women could focus on the reaction caused by hand and foot massage, distract their attention, and reduce the pain. The results showed that 60 cases of puerpera after cesarean section were divided into two groups with 30 cases in each group. The control group was only given routine care. The intervention group received 20 min hand and foot massage on the basis of routine care. The visual analog scale (VAS) of pain before, immediately after, 30 min after, and 60 min after massage in the intervention group was evaluated and recorded, and the VAS scores of the control group at the corresponding time points were recorded. The VAS score of the intervention group at each time point after massage was significantly lower than that before massage ( P < 0.05 ), and the VAS score of the intervention group at each time point was significantly lower than that of the control group ( P < 0.01 ). Hand and foot massage can effectively relieve incision pain after cesarean section.

Abstract: Therapeutic antisense oligonucleotides (ASOs) represent a diverse array of chemically modified singlestranded deoxyribonucleotides that work complementarily to affect their mRNA targets. They vastly differ from conventional small molecules. These newly developed therapeutic ASOs possess unique absorption, distribution, metabolism, and excretion (ADME) processes that ultimately determine their pharmacokinetic, efficacy and safety profiles. The ADME properties of ASOs and associated key factors have not been fully investigated. Therefore, thorough characterization and in-depth study of their ADME properties are critical to support drug discovery and development processes for safe and effective therapeutic ASOs. In this review, we discussed the main factors affecting the ADME characteristics of these novels and evolving therapies. The major changes to ASO backbone and sugar chemistry, conjugation approaches, sites and routes of administration, etc., are the principal determinants of ADME and PK profiles that consequentially impact their efficacy and safety profiles. In addition, species difference and DDI considerations are important in understanding ADME profile and PK translatability but are less studied for ASOs. We, therefore, have summarized these aspects based on current knowledge and provided discussions in this review. We also give an overview of the current tools, technologies, and approaches available to investigate key factors that influence the ADME of ASO drugs and provide future perspectives and knowledge gap analysis.

Background Periodontal disease, an oral disease characterized by loss of alveolar bone and progressive teeth loss, is the sixth major complication of diabetes. It is spreading worldwide as it is difficult to be cured. The insulin-like growth factor 1 receptor (IGF-1R) plays an important role in regulating functional impairment associated with diabetes. However, it is unclear whether IGF-1R expression in periodontal tissue is related to alveolar bone destruction in diabetic patients. SUMO modification has been reported in various diseases and is associated with an increasing number of biological processes, but previous studies have not focused on diabetic periodontitis. This study aimed to explore the role of IGF-1R in osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in high glucose and control the multiple downstream damage signal factors. Methods PDLSCs were isolated and cultured after extraction of impacted teeth from healthy donors or subtractive orthodontic extraction in adolescents. PDLSCs were cultured in the osteogenic medium with different glucose concentrations prepared by medical 5% sterile glucose solution. The effects of different glucose concentrations on the osteogenic differentiation ability of PDLSCs were studied at the genetic and cellular levels by staining assay, Western Blot, RT-PCR, Co-IP and cytofluorescence. Results We found that SNAI2, RUNX2 expression decreased in PDLSCs cultured in high glucose osteogenic medium compared with that in normal glucose osteogenic medium, which were osteogenesis-related marker. In addition, the IGF-1R expression, sumoylation of IGF-1R and osteogenic differentiation in PDLSCs cultured in high glucose osteogenic medium were not consistent with those cultured in normal glucose osteogenic medium. However, osteogenic differentiation of PDLCSs enhanced after adding IGF-1R inhibitors to high glucose osteogenic medium. Conclusion Our data demonstrated that SUMO1 modification of IGF-1R inhibited osteogenic differentiation of PDLSCs by binding to SNAI2 in high glucose environment, a key factor leading to alveolar bone loss in diabetic patients. Thus we could maximize the control of multiple downstream damage signaling factors and bring new hope for alveolar bone regeneration in diabetic patients.

Background: The temporomandibular joint (TMJ) is a complex joint consisting of the mandibular condyle, temporal articular surface, and articular disc. The functions of mastication, swallowing and articulation are accomplished by the movements of the TMJ. To date, the TMJ has been studied more extensively, but the study of the TMJ is limited by the type of TMJ cells, their differentiation, and their interrelationship during growth and development is unclear. The aim of this study is to establish a molecular cellular developmental atlas of the human TMJ by single-cell RNA sequencing, which will contribute to understanding and solving. Results: We performed a comprehensive transcriptome analysis of TMJ tissue from 3- and 4-month-old human embryos using single-cell RNA sequencing. A total of 15,624 cells were captured and the gene expression profiles of 15 cell populations in human TMJ were determined, including 14 known cell types and a previously unknown cell type named "transition state cells (TSCs)". Immunofluorescence assays confirmed that TSCs are not the same cell cluster as mesenchymal stem cells (MSCs). Pseudotime trajectory and RNA velocity analysis showed that MSCs transformed into TSCs, and TSCs further differentiated into tenocytes, hypertrophic chondrocytes and osteoblasts. In addition, chondrocytes were detected only in 4-month-old human embryonic TMJ. Conclusions: Our study provides an atlas of the earlier cellular development of human embryonic TMJ tissue, which will contribute to a deeper understanding of the pathophysiology of TMJ tissue during repair and ultimately help to solve clinical problems.

Booster chlorination was usually employed in water distribution systems with a long hydraulic retention time. The free chlorine decay and disinfection by-products (DBPs) transformation under booster chlorination conditions were investigated within a pilot-scale water distribution system (WDS). Compared with the initial chlorination in water plants, the loss of chlorine was relatively slow and could be described with first-order kinetic model. The rate of chlorine decay and the generation of DBPs in WDS were much greater than those in beaker. High flow rate and the hydraulic transients both promoted chlorine decay and DBPs formation, especially for dichloroacetonitrile (DCAN). The formation of trihalomethanes (THMs) and haloacetic acids (HAAs) was higher in the ductile iron pipe than in the steel pipe. After booster chlorination, THMs, HAAs, and DCAN all climbed up and then declined continuously, but the peak times were different during the reaction process. The results showed the generation period of DBPs followed the order: THMs (27 h)HAAs (22 h)DCAN (5 h). DCAN was not stable in WDS and could be decomposed for a long hydraulic retention time (HRT). The decrease of dichloroacetic acid (DCAA) and increase of trichloroacetic acid (TCAA) indicated that DCAA may turn into TCAA. Linear relationships between the free chlorine demand (FCD) and the generation of THMs that considered both buck water and the pipe wall, as well as the different hydraulic conditions, were established to predict the formation of DBPs in WDS after booster chlorination.

The presence of metal ions in drinking water treatment and distribution systems may affect the disinfection process of organic matter, which had aroused people's concern. L-tyrosine can complex with metal ions through carboxyl, carbonyl, and amino groups and affect its chemical reactions. In this paper, the complexation of L-tyrosine with common metal ions was studied and the influence of complexation on chlorination with different experimental factors was investigated. It was inferred that L-tyrosine complexed with metal ions by single dentate ligand or double dentate chelation in a ratio of 2:1. The degradation of L-tyrosine-metal complex followed the pseudo-first-order reaction kinetic. TCM, DCAA, and TCAA were the main species DBPs in the chlorination of L-tyrosine. Compared with L-tyrosine, the reaction rate constants of complex increased by 5.6%, the formation of trihalomethane production decreased by 21.5% and the formation of haloacetic acids production increased by 26.9% at the state of metal complexation. The effect of metal complexation on chlorination was more obvious than that of metal coexistence. For different metal complexation, the order of inhibition on trihalomethane production was Ca

E7766 represents a novel class of macrocycle-bridged dinucleotides and is under clinical development for immuno-oncology. In this report, we identified mechanism of systemic clearance E7766 and investigated the hepatobiliary transporters involved in the disposition of E7766 and potential drug interactions of E7766 as a victim of organic anion-transporting polypeptide (OATP) inhibitors. In bile-duct cannulated rats and dogs, E7766 was mainly excreted unchanged in bile (>80%) and to a lesser extent in urine (

Tongue image segmentation is a base work of TCM tongue processing. Nowadays, deep learning methods are widely used on tongue segmentation, which has better performance than conventional methods. However, when the tongue color is close to the color of the adjoining area, the contour of tongue segmentation by deep learning may be coarse which could influence the subsequent analysis. Here a novel tongue image segmentation model based on a convolutional neural network fused with superpixel was proposed to solve the problem. Methods. On the basis of a convolutional neural network fused with superpixel, the novel tongue image segmentation model SpurNet was proposed in this study. The residual structure of ResNet18 was introduced as the feature extraction layer on the encoding path, to construct the first stage processing module UrNet of SpurNet. The superpixel segmentation was fused with UrNet to form the second stage process of SpurNet. To verify the effect of SpurNet. The models before and after fusion with superpixel, classical image segmentation models FCN and DeepLab were compared with SpurNet on the dataset of 367 manually labeled tongue images. Results. The SpurNet model performance test with 10-fold cross-validation showed PA of 0.9145 ± 0.0043, MPA of 0.9168 ± 0.0048, MIoU of 0.8417 ± 0.0072 and FWIoU of 0.8454 ± 0.0072. Relative to FCN, DeepLab and their superpixel fused models, the SpurNet model was superior in tongue image segmentation and could increase PA by 1.91%–3.17%, MPA by 1.38%–2.61%, MIoU by 3.09%–5.07%, and FWIoU by 3.11%–5.08%. Compared to UrNet, the first stage processing module, the SpurNet model also increased the PA, MPA, MIoU and FWIoU by 0.15%, 0.09%, 0.24% and 0.24%, respectively. Conclusion. The SpurNet model, after fusing with superpixel image segmentation, can better accomplish the task of tongue image segmentation, more accurately process the margins of tongue and resolve the over-segmentation and under-segmentation. The thought of this study is a new exploration in the field of tongue image segmentation, which could provide a reference for the modern research on TCM tongue images.

Myocardial infarction (MI) leads to cardiac remodelling and heart failure. Cardiomyocyte apoptosis is considered a critical pathological phenomenon accompanying MI, but the pathogenesis mechanism remains to be explored. MicroRNAs (miRs), with the identity of negative regulator of gene expression, exist as an important contributor to apoptosis. During the experiment of this study, MI mice models were successfully established and sequencing data showed that the expression of miR-23a-5p was significantly enhanced during MI progression. Further steps were taken and it showed that apoptosis of cardiac cells weakened as miR-23a-5p was downregulated and on the contrary that apoptosis strengthened with the overexpression of miR-23a-5p. To explore its working mechanisms, bioinformatics analysis was conducted by referring to multi-databases to predict the targets of miR-23a-5p. Further analysis suggested that those downstream genes enriched in several pathways, especially in the PI3K/Akt singling pathway. Furthermore, it demonstrated that miR-23a-5p was negatively related to the phosphorylation of PI3K/Akt, which plays a critical role in triggering cell apoptosis during MI. Recilisib-activated PI3K/Akt singling pathway could restrain apoptosis from inducing miR-23a-5p overexpression, and Miltefosine-blocked PI3K/Akt singling pathway could restrict apoptosis from inhibiting miR-23a-5p reduction. In conclusion, these findings revealed the pivotal role of miR-23a-5p-PI3K/Akt axis in regulating apoptosis during MI, introducing this novel axis as a potential indicator to detect ischemic heart disease and it could be used for therapeutic intervention.

Although thoracoscopic lung segmentectomy has made significant achievements, there is little known about how to perform subsegmentectomy, which can also acquire a safe margin for curability but with more pulmonary volume reserved. This report presents the surgical procedure for subsegmental anatomic resection of left lower lobe subsegment 6b guided by the simulation of bronchovascular branching through the use of 3-dimensional computed tomographic bronchography and angiography.

Dental pulp stem cells (DPSCs) are well known for their capable of both self-renewal and multilineage differentiation. Dental tissue diseases, include caries, are often accompanied by inflammatory microenvironment, and muramyl dipeptide (MDP) is involved in the inflammatory stimuli to influence the differentiation of DPSCs. Nucleotide-binding oligomerization domain 2 (NOD2), a member of the cytosolic Nod-like receptor (NLR) family, plays a key role in inflammatory homeostasis regulation, but the role of NOD2 in DPSCs differentiation under inflammatory is still unclear. In this study, we identified that MDP suppressed odontogenic differentiation of DPSCs via NOD2/ NF-κB/p65 signaling pathway. Alizarin red staining and ALP activity showed the odontogenic differentiation was suppressed by MDP in a concentration-dependent manner, and the expression of dentin differentiation marker protein dentin matrix protein 1 (DMP-1) and dentin Sialophosphoprotein (DSPP) also indicated the same results. The expression of NOD2 increased gradually with the concentration of MDP as well as the phosphorylation and nuclear translocation of p65, which meant NF-κB signaling pathway was activated. Further, the interference of NOD2 inhibited the phosphorylation and nuclear translocation of p65 and reversed the MDP-mediated decrease of odontoblast differentiation of DPSCs. Our study showed that MDP can inhibit the odontoblast differentiation of DPSCs in a concentration-dependent manner. The NF-κB signaling pathway was activated by increasing expression of NOD2. Interference of NOD2 reversed the negative ability odontoblast differentiation of DPSCs in the inflammatory environment. Our study might provide a theoretical basis for the clinical treatment for dentinogenesis of DPSCs.

Pulpitis is an inflammatory condition that can lead to the loss of tooth vitality. The odontogenic differentiation potential of the dental pulp stem cells (DPSCs) is significantly decreased in the pulpitis microenvironment. The aim of this study was to determine the mechanism of the impaired odontogenic differentiation of the DPSCs in an inflammatory microenvironment. Overexpression and inhibition of the JunB were performed to evaluate its effect on the odontogenic differentiation potential of the DPSCs. The results showed that the JunB was positively correlated with the odontogenic differentiation ability of the DPSCs. The co-immunoprecipitation assay coupled with the mass spectrometry showed that peptidyl-prolyl cis-trans Isomerase NIMA-Interacting 1 (PIN1) was a downstream target of the JunB. Moreover, the expression of PIN1 was negatively correlated with the odontogenic differentiation potential of the DPSCs. Taken together, the decreased expression level of the JunB in an inflammatory state can impair the odontogenic differentiation ability of the DPSCs by upregulating the expression of the PIN1, a negative regulator of the odontogenic differentiation of the DPSCs.

A sensitive unlabeled ratiometric biosensor was developed to the detection of cardiac troponin I (cTnI). This biosensor was established by using the glassy carbon electrode coated with graphene oxide to form a platform bonded with N, Zn co-doped graphene quantum dots (N, Zn-GQDs). The N, Zn-GQDs was successfully prepared as the raw materials of graphite powder and characterized. Antibodies of cTnI were bonded to the surface of N, Zn-GQDs as the nanoprobe by amide bonds. The signals of electrochemiluminescence (ECL) and differential pulse voltammetry (DPV) were exposed to decrease in the presence of cTnI, which caused the signal substance to move farther away from the electrode. It was found that the immune complex layer attenuated the intensity of ECL and DPV which could be used as the good overall signal for determining concentration of cTnI. The ratiometric biosensor had a good response to cTnI with the detection limit is 4.59 pg L

We present a design and development of a high-performance light-emitting diode (LED)-side-pumped Nd:YAG rod laser with strong pulse energy, high efficiency, and consistency, very good beam quality, and high uniform pumping intensity in the active area which reduces the effects of thermal gradient significantly. A five-dimensional 810 nm LED array with a full width of 30 nm at half maximum was intended to achieve high coupling efficiency by putting the LED array as close as possible to the side of the Nd:YAG laser rod for overcoming the large pumped divergence. Under 2.25 J pump energy, maximum single pulse energy of 35.86 mJ with duration of 1.24 μs at 1063.68 nm was obtained, equivalent to optical efficiency of 1.59% and a slope efficiency of 2.53%. The laser was set to repeat at a rate of 10 Hz with a beam quality factor of M x 2 = 2.94 and M y 2 = 3.35 , as well as with the output power stability of < 4.1% (root mean square) and < 7.3% (peak to peak). To the best of our ability, this is the highest performance for an LED-side-pumped Nd:YAG rod laser oscillator with a 10-mJ-level output ever reported.

This paper introduces the application of multi-dimensional state parameter monitoring and fault diagnosis system in transformer state maintenance. It mainly solves the problem of how to improve the level of condition monitoring, evaluation and maintenance. The system integrates the multi-dimensional state monitoring methods of capacitive equipment such as leakage current, partial discharge, oil chromatography and vibration signal. Through a successful case of 500 kV main transformer operation condition monitoring, evaluation, diagnosis and maintenance, this paper describes how to realize the functions of insulation condition monitoring, evaluation, diagnosis and auxiliary maintenance of power network equipment in order to eliminate equipment faults and avoid major power failure. Therefore, the application of the system in smart city can effectively improve the monitoring and maintenance level of power grid equipment and the reliability of Power Grid, and provide support for big data analysis of Smart City Power Grid.

Background: Clinical treatment of gastrointestinal neoplasms in patients with severe coronary stenosis is difficult, and it remains controversial to perform staged or simultaneous surgeries. The purpose of this study was to retrospectively analyze the feasibility and indications for simultaneous gastrointestinal tumor resection and off-pump coronary artery bypass (OPCAB) graft surgery.Methods: Data collected from a total of five patients, including three patients with gastric cancer and two patients with colorectal cancer, who underwent simultaneous radical cancer resection and OPCAB between September 2010 and October 2019, were retrospectively analyzed. Among these patients, one had an incomplete colonic obstruction. All patients had severe coronary stenosis, and one experienced acute heart failure before surgery. OPCAB was performed first, followed by the radical cancer resection. Results: All five patients were discharged from hospital without perioperative death, major cardiovascular events or anastomotic leakage. The mean postoperative hospital stay was 9.4 days. One patient experienced slight gastrointestinal bleeding after surgery, which improved with conservative treatment. After a mean follow-up of 39 months, two patients with gastric cancer died from tumor metastasis at 28 months and 37 months, while the remaining three patients did not have tumor recurrence or metastasis. None of the patients experienced myocardial ischemia.Conclusion: It is safe and feasible to perform simultaneous OPCAB and gastrointestinal surgeries on the premise of strictly controlling the indications for patients with gastrointestinal tumors complicated with severe coronary artery stenosis.