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Objectives: Osteoporosis is a metabolic bone disease caused by various factors. As a prosthetic group of haemoglobin, heme can promote the formation of blood vessels and the regeneration of related cells by increasing the proliferation level of endothelial cells and reticulocytes. This study observed the anti-osteoporosis effect of heme on preosteoblast (POB) cells and rat models. Methods: Heme mimics were transfected into POB cells of patients in stable culture, and the effect of heme transfection on the activity of POB cells was detected via the cell scratch test and cell migration assay. 45 SD female rats were randomly divided into group A, the rats were only treated with surgery (n = 15); group B, the rats were given 30 mg/kg of heme chloride by tail vein injection on the 1st, 7th, and 14th days after surgery (n = 15); group C, rats were injected with the same amount of saline in the tail vein (n = 15). The mRNA and protein expressions of alkaline phosphatase (ALP), bone-specific alkaline phosphatase (B-ALP), and type I collagen C-terminal peptide (CTX) in rats serum were detected via western blot and real-time PCR (real-time polymerase chain reaction). The expressions of IL-6 and TNF-α in rats serum were detected via Elisa. The pathological changes in the morphology of distal femur were observed by Hematoxylin-eosin staining. Results: After transfected with heme mimics, the proliferation, migration and invasion ability of the patient’s cells increased significantly, and the apoptosis rate of the cells decreased significantly. The relative expression levels of ALP and CTX mRNA and protein in serum of osteoporosis patients and rat significantly decreased 24 hours after transfection of heme mimics (p < 0.05), while B-ALP significantly increased. The expression of IL-6 and TNF-α in the rat model of osteoporosis group significantly increased (p < 0.05), but after transfection with heme mimic, the expression of IL-6 and TNF-α in the rat reduced significantly. HE showed that, after transfection, the femoral trabeculae were substantially broader and thicker, and the number also increased significantly. The number of trabecular fractures and fat cells was decreased, the trabecular bones were smoother and close to the control group. Conclusion: Heme can significantly promote the proliferation, migration and invasion of POB cells in the body, and also can achieve the anti-osteoporosis effect by adjusting the expression of ALP, B-ALP, and CTX, IL-6 and TNF-α in osteoporosis model of rat.

Glucocorticoids are known to induce skeletal muscle atrophy by suppressing protein synthesis and promoting protein degradation. Tauroursodeoxycholic acid (TUDCA) has beneficial effects in several diseases, such as hepatobiliary disorders, hindlimb ischemia and glucocorticoid-induced osteoporosis. However, the effects of TUDCA on glucocorticoid -induced skeletal muscle atrophy remains unknown. Therefore, in the present research, we explored the effects of TUDCA on dexamethasone (DEX)-induced loss and the potential mechanisms involved. We found TUDCA alleviated DEX-induced muscle wasting in C2C12 myotubes, identified by improved myotube differentiation index and expression of myogenin and MHC. And it showed that TUDCA activated the Akt/mTOR/S6K signaling pathway and inhibited FoxO3a transcriptional activity to decreased expression of MuRF1 and Atrogin-1, while blocking Akt by MK2206 blocked these effects of TUDCA on myotubes. Besides, TUDCA also attenuated DEX-induced apoptosis of myotubes. Furthermore, TUDCA was administrated to the mouse model of DEX-induced skeletal muscle atrophy. The results showed that TUDCA improved DEX-induced skeletal muscle atrophy and weakness (identified by increased grip strength and prolonged running exhaustive time) in mice by suppression of apoptosis, reduction of protein degradation and promotion of protein synthesis. Taken together, our research proved for the first time that TUDCA protected against DEX-induced skeletal muscle atrophy not only by improving myogenic differentiation and protein synthesis, but also through decreasing protein degradation and apoptosis of skeletal muscle.

Chlamydia pneumoniae is a type of pathogenic gram-negative bacteria that causes various respiratory tract infections including asthma. Chlamydia species infect humans and cause respiratory infection by rupturing the lining of the respiratory which includes the throat, lungs and windpipe. Meanwhile, the function of interleukin-4 (IL-4) in Ch. pneumoniae respiratory infection and its association with the development of airway hyperresponsiveness (AHR) in adulthood and causing allergic airway disease (AAD) are not understood properly. We therefore investigated the role of IL-4 in respiratory infection and allergy caused by early life Chlamydia infection. In this study, Ch. pneumonia strain was propagated and cultured in HEp-2 cells according to standard protocol and infant C57BL/6 mice around 3-4 weeks old were infected to study the role of IL-4 in respiratory infection and allergy caused by early life Chlamydia infection. We observed that IL-4 is linked with Chlamydia respiratory infection and its absence lowers respiratory infection. IL-4R α2 is also responsible for controlling the IL-4 signaling pathway and averts the progression of infection and inflammation. Furthermore, the IL-4 signaling pathway also influences infection-induced AHR and aids in increasing AAD severity. STAT6 also promotes respiratory infection caused by Ch. pneumoniae and further enhanced its downstream process. Our study concluded that IL-4 is a potential target for preventing infection-induced AHR and severe asthma.

Pathogenic bacteria infection severely threatens human health and causes substantial medical and financial concern. Rapid, sensitive, specific, and reliable detection of pathogenic bacteria is crucial. In the current study, a CRISPR-Cas12a-powered dual-mode biosensor was developed for ultrasensitive and cross-validating detection of pathogenic bacteria. Simply, the amplicons of Salmonella (used as a model)-specific invA sequence triggered CRISPR-Cas12a-based indiscriminate degradation of single-stranded DNAs that were supposed to link two gold nanoparticle (AuNP) probe pairs, inducing an aggregation-to-dispersion change. This generated observable color changes that became even more apparent after centrifugation. The color changes can be discerned by naked eyes and recorded using a portable colorimeter. Meanwhile, the photothermal effect of CRISPR-Cas12-powered AuNPs was explored for the first time through 808 nm near-infrared irradiation such that quantitative measurement can be carried out by recording temperatures using a thermal camera. For both modes, a limit of detection of 1 CFU/mL and a dynamic range of detection from 100 to 108 CFU/mL were obtained, which were comparable with or better than previously reported methods. Our proposed biosensor demonstrated satisfactory selectivity for Salmonella against other interfering cells. Furthermore, this biosensor proved to be capable of Salmonella detection in food samples. Regarding the real applications, the result from each mode can be used for cross-validation. Only the case having doubly confirmed positive or negative results can be assured, which rendered a more dependable biosensing conclusion. This technology not only expands the reach of the CRISPR-Cas system in biosensing but also provides a general method for bacteria sensing with desirable sensitivity, specificity, and cross-validating capacity.

Extreme precipitation events exhibit an increasing trend for both the frequency and magnitude on global and regional scales and it has already proven the impact of man-made global warming on the extreme precipitation amplification. Based on the observed datasets and global climate model (GCM) output, this study has evaluated the impact from anthropogenic forcing on the trend and temporal non-uniformity (i.e. increase in unevenness or disparity) of the precipitation amounts (PRCPTOT), extremes (R95p and RX5day) and intensity (SDII) in Central Asia (CA) from 1961 to 2005. Results indicate that radiative forcing changes, mainly driven by human activities, have significantly augmented the extreme precipitation indices in CA. The median trend with the influence of anthropogenic activities for the PRCPTOT, SDII, R95p and RX5day amounted to 2.19 mm/decade, 0.019 mm/decade, 1.39 mm/decade and 0.21 mm/decade during the study period, respectively. A statistically insignificant decrease in non-uniformity was noticed for the PRCPTOT, SDII and RX5day in Central CA (CCA) and Western CA (WCA), while Eastern CA (ECA) was the only region with a statistically significant increase in non-uniformity of the PRCPTOT, SDII, R95p and RX5day by 4.22%, 3.98%, 3.73% and 3.97%, respectively from 1961 to 2005 due to anthropogenic forcing. These results reflect the difference in various regions regarding the impact of anthropogenic forcing on the non-uniformity of extreme precipitation events in CA, which might help to fully understand the role of anthropogenic forcing in the changes of the precipitation extremes in CA and contribute to the development of water resource management strategies.

Nuclear receptor subfamily 4, group A, member 1 (NR4A1) can aggravate ischaemia‐reperfusion (I/R) injury in the heart, kidney and brain. Thus, the present study aimed to unravel the role of NR4A1 on hepatic I/R injury. For this purpose, the mouse hepatic I/R model and H/R‐exposed mouse hepatocytes model were established to stimulate the hepatic and hepatocellular damage. Then, the levels of ALT and AST as well as TNF‐α and IL‐1β expression were measured in the mouse serum and supernatant of hepatocyte s, respectively. Thereafter, we quantified the levels of NR4A1, CYR61, NF‐kB p65 and TGFβ1 under pathological conditions, and their interactions were analysed using ChIP and dual‐luciferase reporter gene assays. The in vivo and in vitro effects of NR4A1, CYR61, NF‐kB p65 and TGFβ1 on I/R‐induced hepatic and H/R‐induced hepatocellular damage were evaluated using gain‐ and loss‐of‐function approaches. NR4A1 was up‐regulated in the hepatic tissues of I/R‐operated mice and in H/R‐treated hepatocytes. Silencing NR4A1 relieved the I/R‐induced hepatic injury, as supported by suppression of ALT and AST as well as TNF‐α and IL‐1β. Meanwhile, NR4A1 knockdown attenuated the H/R‐induced hepatocellular damage by inhibiting the apoptosis of hepatocyte s. Moreover, we also found that NR4A1 up‐regulated the expression of CYR61 which resulted in the activation of the NF‐κB signalling pathway, thereby enhancing the transcription of TGFβ1, which was validated to be the mechanism underlying the contributory role of NR4A1 in hepatic I/R injury. Taken together, NR4A1 silencing reduced the expression of CYR61/NF‐κB/TGFβ1, thereby relieving the hepatic I/R injury.

Background To determine treatment effects on the incidence of post-stroke epilepsy (PSE) using different doses of statin, a prospective hospital-based cohort study was designed to explore whether a double-dose statin treatment can better prevent the occurrence of PSE. Methods A total of 1152 patients with newly diagnosed ischemic stroke admitted to our hospital from March to August 2017 were selected, 1033 of whom were followed-up. Patients were divided into two treatment groups:(1) standard-dose (20 mg atorvastatin or 10 mg rosuvastatin,daily oral; 788 patients); and (2) double-dose (40 mg atorvastatin or 20 mg rosuvastatin, daily oral; 245 patients).At 18 months follow-up was conducted to compare the incidence of PSE between groups. Results In general, in the standard-dose group we observed two cases of early seizure (ES) (0.25%), 22 cases oflate seizure (LS) (2.79%) and 20 cases of PSE (2.54%). In the double-dose group, onepatient had ES (0.41%), two patients had LS (0.82%), and onepatient had PSE (0.41%). The incidence of PSE was significantly lower in the double-dose group as compared to the standard-dose group. There was a higher proportion of PSE in patients younger than 65 years and in males. Three patients had ES; one presented with focal aware seizure (FAS), and two had focal to bilateral tonic-clonic seizure (FBTCS). Among the 21 patients with PSE, there were two cases of FAS, five cases of focal impaired awareness seizure (FIAS), five cases of FBTCS, and nine cases of GTCS, suggesting that partial seizure is the most common type of PSE. Cerebral cortex was involved in 85.75% of cases with PSE, and multiple lobes were involved in 61.9% of cases with PSE. Conclusion Increasing the dose of statin treatment during the acute phase of ischemic stroke reduces the incidence of PSE. Further research is needed to understand the mechanisms underlying the potential preventative effects of statins against PSE.

Objective To explore the effect of locating the ulnar nerve compression sites and guiding the small incision so as to decompress the ulnar nerve in situ on the elbow by high‐frequency ultrasound before operation. Methods A retrospective analysis was conducted on 56 patients who underwent ultrasound‐assisted in situ decompression for cubital tunnel syndrome from May 2018 to August 2019. The patients' average age was 51.13 ± 7.35 years, mean duration of symptoms was 6.51 ± 1.96 months, and mean postoperative follow‐up was 6.07 ± 0.82 months. Nine patients had Dellon's stage mild, 39 had stage moderate, and eight had stage severe. Ultrasound and electromyography were completed in all patients before operation. The presence of ulnar nerve compressive lesion, the specific location, and the reason and extent of compression were determined by ultrasound. A small incision in situ surgery was given to decompress the ulnar nerve according to the pre‐defined compressive sites. Results All patients underwent in situ decompression. The compression sites around the elbow were as follows: two in the arcade of Struthers, one in the medial intermuscular septum, four in the anconeus epitrochlearis muscle, five beside the cyst of the proximal flexor carpi ulnaris (FCU), and the remaining 44 cases were all from the compression between Osborne's ligament to the two heads of the FCU. The compression localizations diagnosed by ultrasound were confirmed by operations. Preoperative ultrasound confirmed no ulnar nerve subluxation in all cases. The postoperative outcomes were satisfactory. There was no recurrence or aggravation of symptoms in this group of patients according to the modified Bishop scoring system; results showed that 43 cases were excellent, 10 were good, and three were fair. Conclusions High‐frequency ultrasound can accurately and comprehensively evaluate the ulnar nerve compression and the surrounding tissues, thus providing significant guidance for the precise minimally invasive treatment of ulnar nerve compression., The ulnar nerve became thinner at the site of Osborne's ligament in the longitudinal section. The accurate site of ulnar nerve compression could be located by high‐frequency ultrasound, that is the important foundation for the precise in situ ulnar nerve decompression.

The number of central and peripheral B cells and their responsiveness are decreased in aged mice. The diversity of mice central and peripheral B cell repertoires with increasing age has not been elucidated. In this study, we demonstrated that there were significant differences in the usage of some V, D, and J genes in the BCR H-CDR3 repertoire of bone marrow B cells, spleen B cells and spleen memory B cells in 3-, 12-, and 20-month-old mice. In the productive, pseudogene, and out-of-frame sequences, bone marrow B cells had significant differences in 5′J trimming with age; peripheral spleen B cells and memory B cells had significant differences in N1 insertion, N2 insertion, P5’D insertion, and 5’D trimming with age. The BCR H-CDR3 repertoire diversity of mice bone marrow B cells, spleen B cells and spleen memory B cells decreased with increasing age. The proportion of overlap in bone marrow and spleen B cells, but not spleen memory B cells, of mice at different ages was lower at 3 months than at 12 and 20 months. This study is the first to report the homogeneity and heterogeneity of the CDR3 repertoire of central and peripheral B cells change as mice age, to further investigation of the decline and response of B cell immunity in young/middle/old-aged mice.

PURPOSE: To identify a pathogenic gene mutation in a female infertility proband characterized by empty follicle syndrome (EFS) and explore the genetic cause of EFS. METHODS: Whole exome sequencing (WES) was performed to identify the candidate pathogenic mutation. Sanger sequencing was used to validate the mutation in family members. The pathogenicity of the identified variant and its possible effects on the protein were evaluated with in silico tools. Immunofluorescence staining was used to study the possible mechanism of the mutation on affected oocyte. RESULTS: We identified a family with a novel homozygous nonsense mutation in zona pellucida 1 (ZP1) (c.199G > T [p.Glu67Ter]). Based on bioinformatics analysis, the mutation was predicted to be pathogenic. This variant generates a premature stop codon in exon 2 at the 199th nucleotide, and was inferred to result in a truncated ZP1 protein of 67 amino acids at the ZP-N1 domain. An in vitro study showed that the oocyte of the EFS proband was degenerated and the zona pellucida was absent. Additionally, the mutant ZP1 proteins were localized in the cytoplasm of the degenerated oocyte but not at the surface. CONCLUSIONS: The novel mutation in ZP1 is a genetic cause of female infertility characterized by EFS. Our finding expands the genetic spectrum for EFS and will help justify the EFS diagnosis in patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02136-x.

Growing lncRNAs have been noted to involve in the initiation and development of several tumours including tongue squamous cell carcinomas (TSCCs). However, the biological role and mechanism of lncRNA RPSAP52 were not well‐explained. We indicated that RPSAP52 was higher in TSCC samples compared with that in control samples. The higher expression of RPSAP52 was positively correlated with higher T stage and TNM stage. Ectopic expression of RPSAP52 induced TSCC cell growth and cycle and induced cytokine secretion including IFN‐γ, IL‐1β and IL‐6, IL‐8, IL‐10 and TGF‐β. We found that the overexpression of RPSAP52 suppressed miR‐423‐5p expression in SCC‐4 cell. miR‐423‐5p was lower in TSCC samples compared with that in control samples, and miR‐423‐5p level was negatively correlated with higher T stage and TNM stage. Pearson's correlation indicated that miR‐423‐5p was negatively associated with that of RPSAP52 in TSCC tissues. Furthermore, MYBL2 was one direct gene of miR‐423‐5p and elevated expression of miR‐423‐5p suppressed MYBL2 expression and ectopic expression of RPSAP52 increased MYBL2 expression in SCC‐4 cell. Finally, we illustrated that RPSAP52 overexpression promoted TSCC cell growth and cycle and induced cytokine secretion including IFN‐γ, IL‐1β and IL‐6, IL‐8, IL‐10 and TGF‐β via modulating MYBL2. These data provided new insight into RPSAP52, which may be one potential treatment target for TSCC.

To compare rib fracture detection and classification by radiologists using CT images with and without a deep learning model. A total of 8529 chest CT images were collected from multiple hospitals for training the deep learning model. The test dataset included 300 chest CT images acquired using a single CT scanner. The rib fractures were marked in the bone window on each CT slice by experienced radiologists, and the ground truth included 861 rib fractures. We proposed a heterogeneous neural network for rib fracture detection and classification consisting of a cascaded feature pyramid network and a classification network. The deep learning-based model was evaluated based on the external testing data. The precision rate, recall rate, F1-score, and diagnostic time of two junior radiologists with and without the deep learning model were computed, and the Chi-square, one-way analysis of variance, and least significant difference tests were used to analyze the results. The use of the deep learning model increased detection recall and classification accuracy (0.922 and 0.863) compared with the radiologists alone (0.812 vs. 0.850). The radiologists achieved a higher precision rate, recall rate, and F1-score for fracture detection when using the deep learning model, at 0.943, 0.978, and 0.960, respectively. When using the deep learning model, the radiologist’s reading time was decreased from 158.3 ± 35.7 s to 42.3 ± 6.8 s. Radiologists achieved the highest performance in diagnosing and classifying rib fractures on CT images when assisted by the deep learning model.

Due to multi-source data information fusion, the precision of eco-hydrology models is improving rapidly. In particular, the fractional vegetation coverage (FVC) is of great significance in the remo...

This paper studies a non-linear energy harvesting (EH) enabled full-duplex (FD) cooperative non-orthogonal multiple access (C-NOMA) system, where the near user acts as an FD relay to assist the transmission from BS to far user with power-splitting (PS) protocol. We derive the close-form expressions of outage probability in this considered system, and also give the asymptotic outage probability under high signal-to-noise ratio (SNR) regime. Additionally, we obtain the optimal power allocation parameter to minimize the outage probability, and discuss the impact of self-interference (SI) on outage performance. Moreover, it is observed from simulation results that the presence of SI improve the outage performance, which is caused by the so-called self-energy recycling.

To study the homogeneity and heterogeneity of CD4+CD25+ T cells receptor β-chain complementarity determining region 3 (TCR β CDR3) repertoires in breast tumor tissues, lung metastatic tissues, and spleens from 4T1 tumor-bearing BALB/c mice. We used high-throughput sequencing to analyze the characteristics and changes of CD4+CD25+ TCR β CDR3 repertoires among tumor tissues, lung metastatic tissues, and spleens. The diversity of the CD4+CD25+ TCR β CDR3 repertoires in breast tumor tissue was similar to that of lung metastatic tissues and less pronounced than that of spleen tissues. Breast tumor tissues and lung metastatic tissues had a greater number of high-frequency CDR3 sequences and intermediate-frequency CDR3 sequences than those of spleens. The proportion of unique productive CDR3 sequences in breast tumor tissues and lung metastatic tissues was significantly greater than that in the spleens. The diversity and frequency of the CDR3 repertoires remained homogeneous in breast tumors and lung metastatic tissues and showed great heterogeneity in the spleens, which suggested that the breast tissues and lung metastatic tissues have characteristics of CD4+CD25+ T cells that relate to the tumor microenvironment. However, the number and characteristics of overlapping CDR3 sequences suggested that there were some different CD4+CD25+ T cells in tumors and in the circulatory immune system. The study may be used to further explore the characteristics of the CDR3 repertoires and determine the source of the CD4+CD25+ T cells in the breast cancer microenvironment.

Background Long non-coding RNAs (lncRNAs) function as a class of significant mediators in prostate cancer (PCa), and this study mainly discussed the molecular mechanism of lncRNA growth arrest-specific 5 (GAS5) in PCa progression and radiosensitivity. Materials and methods GAS5 and microRNA-320a (miR-320a) levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability and migration were severally examined through 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) and transwell assays. PCa cells were treated with X-ray irradiation. Cell survival and apoptosis rate were assayed using colony formation assay and flow cytometry, respectively. The apoptosis-related protein and Rab GTPase 21 (RAB21) protein levels were measured by Western blot. The relation between miR-320a and GAS5 or RAB21 was assessed via the dual-luciferase reporter assay. The effect of GAS5 on radiosensitivity of PCa in vivo was evaluated by xenotransplantation assay. Results GAS5 was down-regulated in PCa tissues and cells. GAS5 overexpression suppressed cell viability and migration while facilitated radiosensitivity of PCa cells. GAS5 was a molecular sponge of miR-320a. The effects of GAS5 up-regulation on PCa cells were accomplished by sponging miR-320a. MiR-320a targeted RAB21 and GAS5 up-regulated RAB21 expression via targeting miR-320a. RAB21 knockdown reversed the effects of miR-320a inhibition on PCa cells. GAS5 promoted the radiosensitivity of PCa by the miR-320a/RAB21 axis in vivo. Conclusion Collectively, GAS5 restrained tumor development and expedited the radiosensitivity in PCa by the miR-320a/RAB21 axis, which provided a molecular regulatory mechanism of GAS5/miR-320a/RAB21 in PCa development and radioresistance.

In patients with hepatocellular carcinoma (HCC), disease progression and associated bone metastasis (BM) can markedly reduce quality of life. While the long non-coding RNA (lncRNA) zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) has been shown to function as a key regulator of oncogenic processes in HCC and other tumor types, whether it plays a role in controlling HCC BM remains to be established. In the current study, we detected the significant upregulation of lncZEB1-AS1 in HCC tissues, and we found this expression to be associated with BM progression. When we knocked down this lncRNA in HCC cells, we found that this significantly reduced their migratory, invasive, and metastatic activity both in vitro and in vivo. At a mechanistic level, we found that lncZEB1-AS1 was able to target miR-302b and to thereby increase PI3K-AKT pathway activation and EGFR expression, resulting in the enhanced expression of downstream matrix metalloproteinase genes in HCC cells. In summary, our results provide novel evidence that lncZEB1-AS1 can promote HCC BM through a mechanism dependent upon the activation of PI3K-AKT signaling, thus highlighting a potentially novel therapeutic avenue for the treatment of such metastatic progression in HCC patients.

To enhance the angiogenic capacity of tissue-engineered peripheral nerves, we have constructed revascularized tissue-engineered nerves based on a vascular endothelial growth factor (VEGF)-heparin sustained release system. However, the effects of the repair of large peripheral nerve defects are not known. In this study, we used the above revascularized tissue-engineered nerve to repair large nerve defects in rats. The repair effects were observed through general observation, functional evaluation of nerve regeneration, ultrasound examination, neural electrophysiology, wet weight ratio of bilateral gastrocnemius muscle, histological evaluation, and quantitative real-time polymerase chain reaction (PCR) analysis. The results showed that the tissue-engineered peripheral nerve based on a VEGF-heparin sustained release system can achieve early vascularization and restore blood supply in the nerve graft area. The realization of early vascularization in the area of the nerve defect greatly promotes the speed of nerve regeneration and reconstruction in the area of the nerve defect, which greatly advances the process of nerve repair and reconstruction and accelerates the restoration of the normal morphological structure and function of peripheral nerves.

A supramolecular dimer of doxorubicin (DOX) was constructed via ternary host-guest interactions between cucurbit[8]uril (CB[8]) and tryptophan modified DOX (DOX-Trp, connected with an acid-labile bond) and we demonstrate for the first time that a supramolecular dimer of DOX can be formed upon homo-dimerization by CB[8], which may act as a stimuli pH-responsive, supramolecular DOX dimer prodrug system. This supramolecular DOX dimer transported DOX efficiently and selectively to cancer cells, thereby exhibiting significantly minimized cytotoxicity against noncancerous cells while maintaining effective cytotoxicity against cancer cells. Under this strategy, many other anticancer drugs could be chemically modified and loaded as a dimeric “ammunition” into CB[8] as supramolecular dimer prodrug systems (or a “jet fighter”) for improved cancer therapy.

The first documented avian influenza virus subtype H16N3 was isolated in 1975 and is currently detectable in many countries worldwide. However, the prevalence, biological characteristics and threat to humans of the avian influenza virus H16N3 subtype in China remain poorly understood. We performed avian influenza surveillance in major wild bird gatherings across the country from 2017 to 2019, resulting in the isolation of two H16N3 subtype influenza viruses. Phylogenetic analysis showed these viruses belong to the Eurasian lineage, and both viruses presented the characteristics of inter‐species reassortment. In addition, the two viruses exhibited limited growth capacity in MDCK and A549 cells. Receptor‐binding assays indicated that the two H16N3 viruses presented dual receptor‐binding profiles, being able to bind to both human and avian‐type receptors, where GBHG/NX/2/2018(H16N3) preferentially bound the avian‐type receptor, while GBHG/NX/1/2018(H16N3) showed greater binding to the human‐type receptor, even the mice virulence data showed the negative results. Segments from other species have been introduced into the H16N3 avian influenza virus, which may alter its pathogenicity and host tropism, potentially posing a threat to animal and human health in the future. Consequently, it is necessary to increase monitoring of the emergence and spread of avian influenza subtype H16N3 in wild birds.

MiR-361-5p, a tumor-related microRNA, has been reported to be implicated in the tumorigenesis and progression of diverse types of human malignancies; however, its role in gastric carcinoma remains unclear. This study aimed to explore the biological role of miR-361-5p in gastric carcinoma and clarify the potential mechanisms involved. In the present study, miR-361-5p was found to be significantly downregulated in both gastric carcinoma tissues and cell lines. Functional studies demonstrated that enhanced expression of miR-361-5p suppressed gastric carcinoma cell proliferation in vitro, inhibited tumor growth in vivo, and induced gastric carcinoma cell apoptosis. Moreover, the tumor-suppressing effects of miR-361-5p in gastric carcinoma were abrogated by the miR-361-5p inhibitor treatment. Notably, syndecan-binding protein was downregulated by miR-361-5p via direct binding to its 3' untranslated region in gastric carcinoma cells. Furthermore, syndecan-binding protein expression was discovered to be markedly upregulated and inversely correlated with miR-361-5p expression in gastric carcinoma tissues. Mechanistic studies revealed that restoring the expression of syndecan-binding protein alleviated miR-361-5p-induced inhibitory effects on proliferation of gastric carcinoma cells. Taken together, these findings suggest that miR-361-5p functions as a tumor suppressor in gastric carcinoma by directly targeting syndecan-binding protein and that miR-361-5p might be a novel therapeutic target for gastric carcinoma.

Fe3O4 magnetic nanoparticles (MNPs), as one of the most intensively researched NPs, have a range of applications in cancer treatments. In current research, we have focused on the influences of MNPs on cancer cells. We chose polyethyleneimine (PEI) coated MNPs (PEI-MNPs) as a model and they are colloidally stable in biological media. It can be proved that PEI-MNPs result in autophagy induction via mTOR-Akt-p70S6 K and ATG7 signaling pathways. For the first time, we have reported that PEI-MNPs activate both NF-κB and TGF-β signaling, two key pro-inflammatory pathways, in cancer cells. More significantly, we have found that autophagy induction and NF-κB and TGF-β activation can be efficiently suppressed through the inhibition of PEI-MNP dependent reactive oxygen species (ROS) over-production. ROS are deemed as a ‘double edge sword’ for cancer cells, owing to the cancer-suppressing and cancer-promoting actions. Our findings would be useful for designing MNPs induced ROS anti-cancer strategies or diminishing long-term toxic effects.

Curcumin, the main active ingredient of turmeric, is widely used as a kind of food additive and also displays a range of pharmacological activities, such as anti-inflammation, anti-tumor, liver and kidney protection, and so forth. Sorafenib was the first targeted agent against hepatocellular carcinoma (HCC), whose intolerance is related to the promotion of lipid synthesis and epithelial-to-mesenchymal transition (EMT) formation. In this study, biochemical analysis, immune cells composition, the tumor microenvironment, metabolomics, and relative metabolic enzymes and transporters were detected in H22-bearing mice treated with curcumin combined with sorafenib vs. control groups. It was found that curcumin protected against liver cancer progression through reducing the level of alpha fetoprotein in liver tissues, increasing the number of immune cells, like NK cells, inhibiting EMT via the regulation of IL-6/JAK/STAT3 and IL-1β/NF-κB pathways, suppressing anaerobic glycolysis through the inhibition of LDH and HIF-1α, and decreasing the lipid synthesis via the downregulation of FASN, and upregulated the serum HDL-C and mRNA levels of apoA1 in the sorafenib-treated mice. Furthermore, curcumin regulation of the disorder of glycolipid metabolism and EMT was also based on the PI3K/AKT pathway. A docking study was performed and proved the strong affinity between curcumin and the proteins of STAT3, FASN, and AKT. All in all, this experiment provided evidence for the addition of curcumin in the diet to enhance the antitumor efficacy of sorafenib through activating immune function, downregulating EMT, and reversing disorders of the metabolism.

Introduction Owing to the development of the laparoendoscopic single-site (LESS) procedure, transumbilical LESS nephroureterectomy (LESS-NU) has become a new approach for treating upper tract urothelial carcinoma. Aim The aim of this study is to introduce a modified LESS-NU procedure with bladder cuff excision for treating upper tract urothelial carcinoma (UTUC). We compared its clinical efficacy and postoperative outcomes in terms of follow-up time with traditional retroperitoneal laparoscopic nephroureterectomy (RL-NU). Material and methods From May 2014 to May 2019, we performed nephroureterectomy on 42 patients using the retroperitoneal approach and a modified LESS approach. A retrospective analysis was conducted for the evaluation of the clinical and postoperative outcomes between the two groups. Results The study included 25 LESS-NU and 17 RL-NU patients. All the procedures were completed successfully. The LESS-NU group had a significantly shorter mean operative time than the RL-NU group (204.4 min, 236.18 min, p = 0.005). The differences in skin incision length (2.88 cm, 8.94 cm, p < 0.001) and oral analgesic dose (n = 1.12, n = 2.75, p < 0.001) between LESS-NU and RL-NU were statistically significant. Conclusions Modified LESS-NU is a feasible and safe procedure. Compared with the retroperitoneal laparoscopic approach, the single-site approach did not alter the patients’ position. LESS-NU is a better procedure for treating UTUC than RL-NU in terms of cosmetic result and postoperative pain.

NALCN (Na+ leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

Pseudomonas aeruginosa is a major public health concern, as drug-resistant strains increase mortality in hospital-acquired infections. We report the isolation and complete genome sequences of four lytic bacteriophages that target clinical multidrug-resistant P. aeruginosa strains.

Background: Wound healing is a dynamic, sequential,and complex physiological process, including a variety of cellular events, such as proliferation, adhesion, chemotaxis, and apoptosis. Skin fibroblasts and keratinocytes are the two most important cells involved in wound repair, and Relying on the proliferation and differentiation of keratinocytes to form epithelium to completely cover the wound is the most ideal result for wound repair, so expanding the source of keratinocytes is a huge challenge. In this study, we examined the phenomenon that fetal skin fibroblasts spontaneously transdifferentiated into keratinocyte-like cells in conventional culture, and evaluated the characteristics of KLCs and the potential mechanisms of the transdifferentiation process.Methods: HFF-1 were routinely cultured in ordinary DMEM medium for more than 40 days,and observed the cell morphology. The cytological properties of KLCs at the cellular and molecular levels were detected by RT-PCR, Western-blot, immunofluorescence, Transwell, and cell scratch experiments.The functionality and safety of KLCs were determined through wound healing and tumorigenicity experiments. And high-throughput transcriptome sequencing (RNA-seq) was performed to explore the mechanism underlying HFF-1 transdifferentiation.Results: The transdifferentiation process started on the 25th day and was completed by the 40th day. KLCs and KCs had similar expressions at the molecular and protein levels, both functioned similarly in wound healing and were non-tumorigenic.RNA-seq revealed that the transdifferentiation process was regulated by the activation of the classical Wnt/β-catenin signaling pathway, which could shorten the process to 10 days.Conclusion: This study demonstrates that HFF-1 can spontaneously transdifferentiate into KLCs with conventional culture conditions, and the Wnt/β-catenin signaling pathway regulates the transdifferentiation process.

Osteoarthritis (OA) is a chronic, progressive and degenerative disease, and its incidence is increasing on a yearly basis. However, the pathological mechanism of OA at each stage is still unclear. The present study aimed to explore the underlying mechanism of dihydroartemisinin (DHA) in terms of its ability to inhibit osteoclast activation, and to determine its effects on OA in rats. Bone marrow-derived macrophages were isolated as osteoclast precursors. In the presence or absence of DHA, osteoclast formation was assessed by tartrate-resistant acid phosphatase (TRAP) staining, cell viability was assessed by Cell Counting Kit-8 assay, the presence of F-actin rings was assessed by immunofluorescence, bone resorption was determined by bone slices, luciferase activities of NF-κB and nuclear factor of activated T cell cytoplasmic 1 (NFATc1) were determined using luciferase assay kits, the protein levels of biomolecules associated with the NF-κB, MAPK and NFATc1 signaling pathways were determined using western blotting, and the expression of genes involved in osteoclastogenesis were measured using reverse transcription-quantitative PCR. A knee OA rat model was designed by destabilizing the medial meniscus (DMM). A total of 36 rats were assigned to three groups, namely the sham-operated, DMM + vehicle and DMM + DHA groups, and the rats were administered DHA or DMSO. At 4 and 8 weeks postoperatively, the micro-architecture of the subchondral bone was analyzed using micro-CT, the thickness of the cartilage layers was calculated using H&E staining, the extent of cartilage degeneration was scored using Safranin O-Fast Green staining, TRAP-stained osteoclasts were counted, and the levels of receptor activator of NF-κB ligand (RANKL), C-X-C-motif chemokine ligand 12 (CXCL12) and NFATc1 were measured using immunohistochemistry. DHA was found to inhibit osteoclast formation without cytotoxicity, and furthermore, it did not affect bone formation. In addition, DHA suppressed the expression levels of NF-κB, MAPK, NFATc1 and genes involved in osteoclastogenesis. Progressive cartilage loss was observed at 8 weeks postoperatively. Subchondral bone remodeling was found to be dominated by bone resorption accompanied by increases in the levels of RANKL, CXCL12 and NFATc1 during the first 4 weeks. DHA was found to delay OA progression by inhibiting osteoclast formation and bone resorption during the early phase of OA. Taken together, the results of the present study demonstrated that the mechanism through which DHA could inhibit osteoclast activation may be associated with the NF-κB, MAPK and NFATc1 signaling pathways, thereby indicating a potential novel strategy for OA treatment.

The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas is now playing a significant role in biosensing applications, especially when the trans-cleavage activity of several Cas effectors is discovered. Taking advantages of both CRISPR/Cas and the enzyme-linked immunosorbent assay (ELISA) in analytical and clinical investigations, CRISPR/Cas-powered ELISA has been successfully designed to detect a spectrum of analytes beyond nucleic acid. Herein, we developed a CRISPR/Cas12a-assisted new immunoassay (CANi) for detection of salivary insulin as an example. Specifically, factors (antibody selection, temperature, and assay time) affecting the CRISPR/Cas-based ELISA system’s performance were investigated. It was observed that the concentration of blocking solution, selection of the capture antibody pairs, and the sequences of triggering ssDNA and guiding RNA affected this immunoassay sensitivity. In contrast, the preincubation of CRISPR/Cas12a working solution and pre-mixture of detection antibody with anti-IgG–ssDNA did not show influence on the performance of CANi for the detection of insulin. Under optimized conditions, the sensitivity for detection of salivary insulin was 10 fg/ml with a linear range from 10 fg/ml to 1 ng/ml.

Accumulating evidence has shown that circular RNA (circRNA) dysregulation is involved in various types of cancer, including osteosarcoma (OS). Nevertheless, the role and mechanism of circRNAs in OS progression and chemoresistance remain elusive. We found that a novel doxorubicin-induced circular RNA, hsa_circ_0004674, screened by whole total transcriptome RNA sequencing in our previous study, was upregulated in OS chemoresistant cell lines and tissues and also connected with patients’ poor prognosis. Circ_0004674 knockdown remarkably suppressed OS cell chemoresistance, proliferation, migration, invasion, OS tumor growth, and enhanced cell cycle arrest and apoptosis in vitro and in vivo through control the expression of the antiapoptotic protein MCL1, a member of the Bcl-2 gene family. Further online bioinformatics analysis revealed that miR-142-5p had potential binding sites that can bind circ_0004674 and the 3′UTR of MCL1 mRNA. Moreover, the expression and function of miR-142-5p were conversely correlated with circ_0004674 in vitro. RIP, pull-down, luciferase assay, and RNA FISH demonstrated that circ_0004674 could compete with MCL1 for miR-142-5p binding to counteract miR-142-5p-mediated repression of MCL1 at the post-transcriptional level. To sum up, our study sheds light on the critical role of the oncogenic circ_0004674/miR-142-5p/MCL1 axis in OS progression and chemoresistance, providing a novel potential target for OS therapy.

Background: It remains uncertain whether vitamin D3 (vitD3) supplementation is beneficial for remission of Crohn's disease (CD). The influence of vitD3 supplementation on Infliximab (IFX) effectiveness was analyzed in Chinese CD patients.Methods: In this retrospective cohort study, moderate-to-severe CD patients, who were bio-naïve and prescribed with IFX treatment for at least 54 weeks, were recorded from January 2014 to December 2019. VitD3 supplementation was defined as patients additionally took oral vitD3 (125 IU/d) within 3 days after the first infusion and persisted in the whole follow-up period. Disease activity was assessed using Harvey-Bradshaw Index (HBI). Serum cytokine profiles (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were quantitatively analyzed in a subset of all patients at baseline and 54-week after intervention.Results: Among 73 enrolled patients, 37 took vitD3 regularly (D3-patients), the others (non-D3-patients) did not. At 54-week, the mean 25-hydroxyvitaminD level increased in D3-patients (20.33 vs. 15.07 ng/mL, P < 0.001). The clinical remission rate was higher in D3-patients compared to non-D3-patients (83.8 vs. 61.6%, P = 0.030). The decrease of HBI from baseline to 54-week was more in D3-patients than non-D3-patients (7.41 ± 3.0 vs. 6.28 ± 2.75, P = 0.023). Furthermore, vitD3 supplementation was independently related to the increase of remission rate at 54-week in D3-patients (β = −1.667, P = 0.015). The benefit of vitD3 supplementation was significant only in patients with deficient vitD3 (all P < 0.05), but not in non-deficient vitD3. A total of nine patients (four non-D3-patients and five D3-patients) were selected to determine serum cytokine profiles after 54-week IFX treatment. In non-D3-patients, the decreases of TNF-α and IL-6 at 54-week were more obvious than at baseline (P = 0.032, 0.022, respectively). In D3-patients, however, only IL-10 increased at 54-week compared with its baseline value (P = 0.037).Conclusions: VitD3 supplementation could improve IFX effectiveness in CD patients, especially for patients with vitD3 deficiency. This beneficial effect of vitD3 supplementation probably arose from the up-regulation of IL-10.Trial Registration: NCT04606017.

Background: Previous studies have proved that the aberrant expressions of PFDNs (Prefoldin) family proteins were correlated with several human cancer. However, the specific functions of PFDNs in liver hepatocellular carcinoma(LIHC) remain unknown. The study aimed to identify the prognostic biomarkers and independent indicators among PFDN1/2/3/4/5/6 in liver hepatocellular carcinoma.Methods: We used these databases including Oncomine, Ualcan, GEPIA2, Human Protein Atlas, The Cancer Genome Atlas, Kaplan-Meier plotter, cBioPortal, STRI-NG and TIMER and the software of Cytoscape in our study.Results: PFDN1/2/3/4/5/6 were highly expressed in LIHC tissues. The mRNA expression levels of PFDN1/2/3/4/5/6 were relevant to tumor grades.PFDN1/3/4/5 expressions significantly changed in different cancer stages. The protein expression levels of PFDNs were higher in LIHC tissue than normal liver tissue. Moreover, High mRNA expressions of PFDN1/2/3/4 were associated with shorter OS of LIHC patients. In multivariate analysis,high expressions of PFDN1/2/4 were independently correlated with poorer OS of LIHC patients. In our findings,55% of patients with LIHC had genetic mutations on PFDNs. Besides, there were significant associations between the expressions of PFDN1/2/3/4/5 and six types of infiltrated immune cells(B cells, CD4+T cells, CD8+T cells, neutrophil, macrophage, and dendritic cells).Conclusions:PFDN1/2/3/4 were potential prognostic markers to suggest poor OS of LIHC patients. In addition, high PFDN1/2/4 expressions were independent prognostic factors in OS for LIHC patients.

Leukopenia is a common manifestation of many diseases, including global outbreak SAS-CoV-2 infection. Granulocyte-macrophage colony-stimulating factor (GM -CSF) has been proved to be effective in promoting lymphocyte regeneration, but adverse immunological effects have also emerged. This study aim to investigate the effect of GM -CSF on BCR heavy chain CDR3 repertoire while promoting lymphocyte regeneration. Cyclophosphamide (CTX) and GM -CSF were used to inhibit and stimulate bone marrow hematopoiesis, respectively. High throughput sequencing was applied to detect the characteristics of BCR CDR3 repertoire in controls, CTX group and GM -CSF group. The white blood cells (WBCs) were quickly reduced (P

Objectives: To construct a simplified prognostic risk model to predict overall survival after adjuvant radiotherapy for parotid gland carcinoma patients with stage T1-4aN1-3M0. Materials and Methods: We evaluated 879 patients who were pathological diagnosed as stage T1-4aN1-3M0 parotid gland cancer. Those eligible patients treated with parotidectomy and neck lymph node dissection between 2004 and 2015 in the Surveillance Epidemiology and End Results database. All cases received adjuvant radiotherapy. Independent prognostic factors included in the original model were identified by Cox regression analysis. The primary endpoint was overall survival. The model’s prediction power was evaluated by the concordance index. The entire cohort was categorized into new low- and high-risk groups using X-tile software according to the results of prognostic model. Kaplan-Meier method was used to depict the survival curves. And the statistical significance was determined by log-rank test. Besides, a heat map was visually described the association between the survival time and 2 most significant prognostic factors. Results: In the univariable and multivariate analyses, 4 independent factors for overall survival were age, tumor size, pTNM stage, and the number of positive lymph nodes, which were all selected in the parsimonious prognostic model. The concordance indices of the prognostic model and pTNM stage were 0.652 and 0.565, respectively. Patients in the low-risk group had better overall survival over patients in the high-risk group [unadjusted hazard ratio = 2.578, 95% confidence interval 2.095-3.172, P < 0.001]. The results of the heat map revealed that patients with smaller tumor size and fewer positive lymph nodes had much longer survival time. Conclusions: This parsimonious prognostic model could estimate the long-term survival after adjuvant radiotherapy for parotid gland carcinoma with stage T1-4aN1-3N0M0. The tools may be valuable to guide multidisciplinary team in making treatment decisions.

lncRNA RHPN1-AS1 (RHPN1-AS1) has been confirmed to promote tumor progression in multiple cancers and is upregulated in prostate cancer (PCa), but whether it has an effect on PCa progression remains unclear. In this study, we found that PCa patients with high RHPN1-AS1 expression had a shorter survival time, and RHPN1-AS1 was significantly upregulated in PCa tissues and cells. Based on informatics analysis we predicted that miR-7-5p binds to 3’UTR of RHPN1-AS1 and epidermal growth factor receptor (EGFR) and verified it by luciferase reporter gene assay. Subsequently, we transfected PCa cells with RHPN1-AS1 overexpression vector (RHPN1-AS1), knockdown plasmids (sh-RHPN1-AS1) and/or miR-7-5p mimics or inhibitor and/or overexpression vector (EGFR) or small interfering RNA of EGFR (si-EGFR) or its control, and found that overexpression of RHPN1-AS1 inhibited miR-7-5p expression and promoted EGFR expression, silencing RHPN1-AS1 inhibited proliferation and invasion and induced G2/M arrest, apoptosis and autophagy in PCa cells. 3MA (an inhibitor of autophagy)-mediated autophagy inhibition attenuated RHPN1-AS1 inhibition-induced apoptosis. Overexpression miR-7-5p or silencing EGFR promoted LC3-I to LC3-II conversion, enhanced autophagy activity, induced cleaved-caspase-3 expression and apoptosis in PCa cells. Furthermore, we found that overexpression of RHPN1-AS1 promoted phosphorylation of phosphatidylinositol 3-kinase (PI3K), AKT and mTOR, inhibited LC3-I to LC3-II conversion and reduced apoptosis in PCa cells, while GSK2126458 (an inhibitor of PI3K) reversed the effect of RHPN1-AS1 on PCa cells. In summary, RHPN1-AS1 acted as a ceRNA of miR-7-5p to upregulate EGFR expression, silencing RHPN1-AS1 suppressed PCa tumor progression by inducing autophagy and apoptosis in PCa cells through the miR-7-5p/EGFR/PI3K/AKT/mTOR pathway.

Background Osteoarthritis (OA) is a chronic degenerative disease that suppresses middle-aged and older people worldwide. Silent information regulator 1(SIRT-1) is associated with several age-related diseases, such as cardiovascular diseases, neurodegenerative diseases and tumors, etc. The protective role of SIRT-1 in bone and joint diseases has become increasingly well known. Objective To explore the relationship between SIRT-1 and its related factors in OA. Methods Fresh tibial plateau specimens were collected from 30 patients with knee OA who underwent total knee arthroplasty. According to the results of Safranin O Fast Green Staining, hematoxylin–eosin staining and the OARSI grade developed by the International Association for the Study of Osteoarthropathy, the specimens were divided into the mild group, moderate group and severe group, and the damage of cartilage was evaluated. SIRT-1 protein levels in cartilage samples were analyzed by immunohistochemistry. Then, take 60 8-week-old female C57BL/6 J mice and apply the Destabilization of the medial meniscus (DMM) to induce OA. Mice were randomly divided into normal group (sham), model group (model), and post-modeling drug administration group (srt), and each group was further divided into 2 weeks after modeling (2 W) and 8 weeks after modeling (8 W) according to the time after surgery. The degenerative degree of a knee joint in mouse knee cartilage samples was evaluated using Safranin O Fast Green Staining and OARSI grade. Immunohistochemical techniques assessed the protein levels of SIRT-1, β-catenin, LEF-1, MMP-13 and Collagen II in cartilage samples. The protein levels of β-catenin, LEF-1 and MMP-13 in the samples were assessed by the immunohistofluorescence technique. The mRNA expression of SIRT-1 and LEF-1 in mouse cartilage samples was evaluated by real-time quantitative polymerase chain reaction (qPCR). Results In the human cartilage samples, according to the results of Safranin O Fast Green Staining, compared with the mild group, the moderate group and the severe group showed damage cartilage layer structure, the number of chondrocytes decreased, the cell hypertrophic, the cartilage surface discontinuous, and the OARSI grade increased. The severe group had severe cartilage injury and the highest OARSI grade. In the mice cartilage samples, according to immunohistochemical analysis, the protein levels of β-catenin, LEF-1 and MMP-13 in cartilage specimens of model 2 W and model 8 W groups were significantly increased than the sham 2 W and sham 8 W groups. The protein levels of SIRT-1 and Collagen II were significantly decreased (P Conclusion SRT-1720, as a specific activator of SIRT-1, does increase the protein level of SIRT-1. SIRT-1 may play a protective role in cartilage by regulating the expression of LEF-1 and related inflammatory factors in OA.

Regulating surface wrinkles have received considerable attention because of their potential applications in stretchable electronics, microfluidics, bionics, sensors, stamps, optical devices and smart materials. In this work, optical microscopy and atomic force microscopy revealed that tunable film thickness and substrate stiffness effectively regulate localized wrinkle patterns in metal films deposited on soft polymer substrates. Theoretical analysis and numerical simulation found that the high tensile stress developed during the film deposition leads to channel cracks in the film and creates a stripe-like plastic zone around each crack. The subsequently developed compressive stress in the plastic zone is anisotropic, resulting in the formation of localized straight wrinkles perpendicular to the crack. The width of the wrinkle is consistent with the size of the plastic zone, which decreases with increasing the film thickness or substrate stiffness, in good agreement with the experimental observations. The report in this work not only elucidates how the subtle correlation among crack, plasticity and buckle leads to such localized wrinkling pattern but also demonstrates an efficient way to produce crack-network-guided localized wrinkle patterns.

The current study aimed to examine the anticancer activity of HTF-1, a cardiac glycoside (CG) isolated from Helleborus thibetanus Franch, using a cell-based model and to discover the underlying mechanisms with specific focus on autophagy. We found that HTF-1 was able to potently decrease the viability of several cancer cell lines especially for HeLa cervical carcinoma cells. It was discovered that HTF-1 dose dependently induced overproduction of ROS in HeLa cells, and the cell viability can be rescued when adding ROS scavenger N-acetyl-l-cysteine (NAC). More, we found that HTF-1 induced ROS-independent autophagy in concentration- and time-dependent manners in HeLa cells. This can be collectively verified by LC3-II and p62 abundance and also eGFP-LC3 puncta assay, bafilomycin clamp experiment, and acidotropic dye fluorescent labeling experiment. Additionally, TEM examination showed more autophagic vacuoles for HTF-1-treated HeLa cells. In HeLa cells, pretreatment with wortmannin (an inhibitor of the initial stages of autophagy to block autophagosome formation, thus, it should weaken the autophagy induction effect of HTF-1) decreased the autophagic flux and partially antagonized cell death induced by HTF-1, indicating that autophagy induced by HTF-1 played a cancer-suppressing role. Furthermore, coadministration of BAF (as a distal inhibitor of autophagy) with HTF-1 demonstrated a synergistic anticancer effect against HeLa cells. We believe that our work will enrich the understanding of CGs and especially anticarcinoma activity, also, pave the way for natural-product-based anticancer drug development.

In hepatocellular carcinoma (HCC), the hypoxic tumor microenvironment can drive enhance tumor malignancy and recurrence. The microRNA (miRNA) miR-196-5p has been shown to modulate the progression of several cancer types, but its roles in HCC remain uncertain. In the present report we observed significant miR-196-5p downregulation in HCC tissues and cells, and we found that the expression of this miRNA significantly impaired the proliferation and metastatic potential of HCC in vitro and in vivo. We identified high-mobility group AT-hook 2 (HMGA2) as a miR-196-5p target gene that was associated with the ability of miR-196-5p to modulate the progression of HCC. Expression of miR-196-5p and HMGA2 were correlated with the clinical characteristics and poor outcomes in patients with HCC. Finally, we found that hypoxic conditions were linked with reduced miR-196-5p expression in the context of HCC. Together these results highlight the role for miR-196-5p as an inhibitor of the proliferation and metastasis of HCC via the targeting of HMGA2, with this novel hypoxia/miR-196-5p/HMGA2 pathway serving as a potential target for future therapeutic intervention.

Diosgenin and diosgenyl saponins as the major bioactive compounds isolated from dietary fenugreek seeds, yam roots, etc. possessed strong antitumor effects. To understand their detailed antitumor mechanisms, a fluorophore-appended derivative of diosgenin [Glc/CNHphth-diosgenin (GND)] was synthesized, starting from diosgenin and glucosamine hydrochloride in overall yields of 7-12% over 7-10 steps. Co-localization of GND with organelle-specific stains, transmission electron microscopy, and relative protein analyses demonstrated that GND crossed the plasma membrane through organic anion-transporting polypeptide 1B1 and distributed in the endoplasmic reticulum (ER), lysosome, and mitochondria. In this process, GND induced ER swelling, mitochondrial damage, and autophagosome and upregulating IRE-1α to induce autophagy and apoptosis. Furthermore, autophagy inhibitor chloroquine delayed the appearance of cleaved poly(ADP-ribose) polymerase and inhibited cleaved caspase 8, which indicated that GND induced autophagy to activate caspase-8-dependent apoptosis. These observations suggested that diosgenyl saponin was a potent anticancer agent that elicited ER stress and mitochondria-mediated apoptotic pathways in liver cancer.

Worldwide, the most prevalent metabolic disorder is diabetes mellitus (DM), an important condition that has been widely studied. Diabetic peripheral neuropathy (DPN), a complication that can occur with DM, is associated with pain and can result in foot ulcers and even amputation. DPN treatments are limited and mainly focus on pain management. There is a clear need to develop treatments for DPN at all stages. To make this progress, it is necessary to understand the molecular signaling pathways related to DPN. For this review, we aimed to concentrate on the main signaling cascades that contribute to DPN. In addition, we provide information with regard to treatments that are being explored.

Purpose: Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common disease after long-term or high-dose glucocorticoid use. The pathogenesis of GIONFH is still controversial, and abnormal bone metabolism caused by glucocorticoids may be one of the important factors. Exosomes, owing to their positive effect on bone repair, show promising therapeutic effects on bone-related diseases. In this study, we hypothesised that exosomes reduce osteocyte apoptosis in rat GIONFH via the miR-21-PTEN-AKT signalling pathway. Methods: To evaluate the effects of exosomes in GIONFH, a dexamethasone-treated or exosome-treated in vitro cell model and a methylprednisolone-treated in vivo rat model were set up. In vitro, a CCK-8 assay and 5-ethynyl-2'-deoxyuridine staining were performed to evaluate the proliferation of osteocytes. Further, a terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay, annexin V-fluorescein isothiocyanate-propidium iodide staining, and western blotting were conducted to evaluate the apoptosis of osteocytes. In vivo, we used micro-computed tomography and histological and immunohistochemical analyses to assess the effects of exosomes. Moreover, the mechanism of exosome action on osteocyte apoptosis through the miR-21-PTEN-AKT pathway was investigated by high-throughput RNA sequencing, fluorescence in situ hybridisation, luciferase reporter assays, and western blotting. Results: High-throughput RNA sequencing results showed that the AKT signalling pathway was up-regulated in the exosome group. Quantitative PCR and western blotting confirmed that the relative expression of genes in the AKT pathway was up-regulated. Western blotting revealed that AKT activated by exosomes inhibited osteocyte apoptosis. RNA fluorescence in situ hybridisation and luciferase reporter assays were performed to confirm the interaction between miR-21 and PTEN. According to the experiment in vivo, exosomes prevented GIONFH in a rat model as evidenced by micro-computed tomography scanning and histological and immunohistochemical analyses. Conclusions: Exosomes are effective at inhibiting osteocyte apoptosis (in MLO-Y4 cells) and at preventing rat GIONFH. These beneficial effects are mediated by the miR-21-PTEN-AKT signalling pathway.

Dual-band electrochromic device (Db-ECD) can tune visible and near-infrared (NIR) radiation independently. The Db-ECDs have inspired considerable interest for their potential applications in smart windows and camouflage. Organic small molecules and polymers were examined carefully though, exploring organics with dual-band electrochromism is still challenging. Herein, the triazine-centered viologen analogues, 2,4,6-tri(pyridyl-4-propyl)-1,3,5-triazine bromide (TPPT) and 2,4,6-tri(pyridyl-4-benzyl)-1,3,5-triazine bromide (TPBT) show excellent dual-band electrochromic behaviors with high dynamic contrasts (66.63% at 887 nm and 50.71% at 600 nm for TPPT, and 59.79% at 900 nm and 66.90% at 600 nm for TPBT, respectively). The Db-ECDs fabricated via gel electrolyte mixed with TPPT or TPBT can work at a low driving voltage down to ∼0.6 V, rendering a high coloration efficiency (up to 230.94 cm2 C-1) in the NIR region, the absorbance difference at 1037 nm reaching up to 2.58 for TPPT. This work sets the stage for novel organic materials of dual-band electrochromic gadgets.

Ethylene-Vinyl Acetate (EVA) polymer foam was prepared using a mold for this investigation. The effect of the cell structure parameters and pore filling gas type on the sound absorption performance of the EVA foam materials were analyzed in terms of their sound absorption capability. The results show that the cell size, cell wall thickness and pore filling gas type have significant influence on the sound absorption performance. When the cell size is 71.3 μm, at low frequency (1000 Hz) the absorption coefficient was the largest at 0.487 and the absorption effect was good. With the increase of the cell wall thickness, the peak value of the sound absorption coefficient first increased and then decreased, and gradually transferred to the low frequency area. When the cell wall thicknesses were 14.3 μm, the foam material had optimal sound absorption properties. The cell filling gas was hydrogen, the EVA foam material had optimal sound absorption effect, and the sound absorption peak value was 0.553 at 800 Hz in the low frequency range (Ⅰ), the sound absorption performance of the foamed materials was ideal.

Purpose: To investigate whether systemic injection of rapamycin attenuates articular cartilage degeneration by inhibiting β-catenin in a murine model of osteoarthritis (OA). Materials and methods: Ten-week-old male C57BL/6j wild-type (WT) mice and SOST-knockout (SOST-/-) mice were randomized to a sham group, a vehicle-treated group, and a rapamycin-treated group. Mice in the vehicle-treated group underwent destabilizing of the medial meniscus (DMM) in the right knee, and were then treated with vehicle. Mice in the rapamycin treatment group underwent DMM and were treated with rapamycin. Safranin O-Fast green staining and Osteoarthritis Research Society International (OARSI) modified Mankin score were used to evaluate the histopathological features of the articular cartilage in the knee. The expression of light chain 3 (LC3) was evaluated by immunofluorescence, whereas the expression of ATG5, matrix metallopeptidase 13 (MMP-13), vascular endothelial growth factor (VEGF), sclerostin, and β-catenin were evaluated by immunohistochemistry. TUNEL staining was used to determine apoptosis of chondrocytes. Results: In vehicle-treated mice when compared with mice in the sham group, the OARSI scores, expression of MMP-13, VEGF, sclerostin, β-catenin, and chondrocyte apoptosis were significantly increased, whereas the expression of LC3 and ATG5 were significantly decreased. A systemic injection of rapamycin activated chondrocyte autophagy, which increased the expression of LC3 and ATG-5, and reduced OARSI scores, the expression of β-catenin, MMP-13, and VEGF, and chondrocyte apoptosis in rapamycin treated mice when compared with vehicle-treated mice. Conclusions: Systemic injection of rapamycin attenuated articular cartilage degeneration by inhibiting β-catenin in a murine model of OA.

Surface wrinkles in homogeneous and heterogeneous film-substrate systems have received intense attention in both science and engineering. Understanding the wrinkling phenomena of heterogeneous systems with continuously variable features is still a challenge. In this work, we propose an unconventional strategy to prepare periodic thickness-gradient metal films on polydimethylsiloxane (PDMS) substrates by masking of copper grids which are weaved by orthometric copper wires. It is found that a periodic thickness-gradient film spontaneously forms during the sputtering process because of the specific structures of the copper grids. Surface wrinkles are strongly modulated by the copper grid structures and are position-dependent within a period. A phase diagram has been established to correlate the wrinkle morphology with the mesh size and film thickness. The film surfaces at mesh centers are evolved from labyrinth wrinkling to herringbone wrinkling and then to stripe wrinkling and finally to wrinkling-free state when the mesh size decreases and/or the film thickness increases. The morphological characteristics, evolutional behaviors, and underlying mechanisms of such wrinkling are discussed in detail based on the stress theory and numerical simulation.

We perform a meta‐analysis from published randomized controlled trials to assess the efficacy and safety of aprotinin in total hip arthroplasty (THA). The following electronic databases were searched: PubMed (1966 to December 2018), EMBASE (1974 to December 2018), the Cochrane Library (1974 to December 2018), and Web of Science (1990 to December 2018). We also used Google Search to search for more potentially eligible studies up to December 2018. The methodological quality of the included studies was assessed independently by the two reviewers described by the Cochrane Collaboration for Systematic Reviews. Data analysis was performed with STATA13.0. Four randomized controlled trials were included in the meta‐analysis. Our study indicated that intravenous aprotinin was associated with improved outcomes in terms of total blood loss, hemoglobin decline, and transfusion rates. There was no significant difference regarding the length of stay and the risk of deep venous thrombosis and pulmonary embolism. Intravenous aprotinin was effective and safe to use in reducing total blood loss after total hip arthroplasty. Further high‐quality studies are required to confirm the conclusion.

The pharmaceutical wastewater (PW) produced during the production of antibiotics has a huge impact on the ecological environment. The efficient removal of residual antibiotics from PW has become a great challenge. Here, a ZIF-8/GO composite film, a new material, was prepared by loading ZIF-8/GO nanosheets onto the surface of a polyethyleneimine- (PEI-) modified nylon microporous support. This new material can effectively remove tetracycline (TC) from PW with a removal rate of 99%. In addition, the layer of ZIF-8/GO nanosheets on the surface of the carrier had certain defect sites. This feature not only made the film have a relatively high flux (502 L·m−2·h−1·bar−1) but also overcame the disadvantages of the traditional membrane separation technology, such as the high operation pressure required by the easy plugging of micropores. More importantly, the abovementioned advantages enable the novel material to be applied on a larger scale. A probable adsorption mechanism was investigated and suggested.

Juvenile hormone (JH) regulates many physiological processes in insect development, diapause, and reproduction. Juvenile hormone binding protein (JHBP), the carrier partner protein of JH, is essential for the balance of JH titer to regulate the metamorphosis and development of insect. In this study, two JHBP genes were identified from Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae), namely HaJHBP1 and HaJHBP2. The tissue and temporal expression pattern revealed that both HaJHBP1 and HaJHBP2 were dominantly expressed in larval fat body, and their high transcription stages were detected in fourth and fifth instars. The ingestion of methoprene, a JH analogue, significantly induced the expression of HaJHBP1 and HaJHBP2. However, both HaJHBP1 and HaJHBP2 mRNA levels were significantly downregulated after treated with a JH antagonist, precocene. When subject to starvation, larvae showed a marked suppressive effect in the expression of HaJHBP1 and HaJHBP2. These results indicate that JHBP plays a part in the JH-regulated metabolism, growth, or development in reaction to different nutritional conditions.