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Abstract Background and objective Progranulin (PGRN), a multifunctional growth factor, plays indispensable roles in the regulation of cancer, inflammation, metabolic diseases, and neurodegenerative diseases. Nevertheless, its immune regulatory role in periodontitis is insufficiently understood. This study attempts to explore the regulatory effects of PGRN on macrophage polarization in periodontitis microenvironment. Methods Immunohistochemical (IHC) and multiplex immunohistochemical (mIHC) stainings were performed to evaluate the expression of macrophage-related markers and PGRN in gingival samples from periodontally healthy subjects and periodontitis subjects. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were polarized towards M1 or M2 macrophages by the addition of LPS or IL-4, respectively, and were treated with or without PGRN. Real-time fluorescence quantitative PCR (qRT-PCR), immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), and flow cytometry were used to determine the expressions of M1 and M2 macrophage-related markers. Co-immunoprecipitation was performed to detect the interaction between PGRN and tumor necrosis factor receptor 2 (TNFR2). Neutralizing antibody was used to block TNFR2 to confirm the role of TNFR2 in PGRN-mediated macrophage polarization. Results The IHC and mIHC staining of human gingival slices showed a significant accumulation of macrophages in the microenvironment of periodontitis, with increased expressions of both M1 and M2 macrophage markers. Meanwhile, PGRN was widely expressed in the gingival tissue of periodontitis and co-expressed mainly with M2 macrophages. In vitro experiments showed that in RAW264.7 cells and BMDMs, M1 markers (CD86, TNF-α, iNOS, and IL-6) substantially decreased and M2 markers (CD206, IL-10, and Arg-1) significantly increased when PGRN was applied to LPS-stimulated macrophages relatively to LPS stimulation alone. Besides, PGRN synergistically promoted IL-4-induced M2 markers expression, such as CD206, IL-10, and Arg1. In addition, the co-immunoprecipitation result showed the direct interaction of PGRN with TNFR2. mIHC staining further revealed the co-localization of PGRN and TNFR2 on M2 macrophages (CD206+). Blocking TNFR2 inhibited the regulation role of PGRN on macrophage M2 polarization. Conclusions In summary, PGRN promotes macrophage M2 polarization through binding to TNFR2 in both pro- and anti-inflammatory periodontal microenvironments.

Abstract Background Biallelic pathogenic variants in PIP5K1C (MIM #606,102) lead to lethal congenital contractural syndrome 3 (LCCS3, MIM #611,369), a rare autosomal recessive genetic disorder characterized by small gestational age, severe multiple joint contractures and muscle atrophy, early death due to respiratory failure. Currently, 5 individuals with LCCS3 were reported and 5 pathogenic variants in PIP5K1C were identified. Here, we reported the two fetuses in a Chinese pedigree who displayed multiple joint contractures and other congenital anomalies. Methods Trio-based whole-exome sequencing (WES) was performed for the parents and the recent fetus to detect the genetic cause for fetus phenotype. Results A novel variant, NM_012398.3: c.949_952dup, p.S318Ifs*28 and a previously reported variant, c.688_689del, p.G230Qfs*114 (ClinVar database) in PIP5K1C, were detected in the individuals, and these variants were inherited from the mother and father, respectively. We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers, which have not been delineated detailedly in previously reported LCCS3 individuals. Furthermore, novel phenotype, bilateral dilated lateral ventricles, was revealed in one fetus. Conclusions These findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features of LCCS3, which will help with the prenatal diagnosis and genetic counseling for this family.

BackgroundIdentification is the first step for treatment of hypertension. However, the awareness rate of hypertension was not high globally. This study aimed to examine the potential role of health insurance for early-identifying hypertension among urban older residents in China.MethodsIn this cross-sectional study, urban residents aged 60+ years were chosen from Nanjing municipality of China in 2018. The outcome measure was hypertension status (“no hypertension,” “diagnosed hypertension” or “un-diagnosed hypertension”). Independent variable was health insurance (“Urban Employee Basic Medical Insurance scheme, UEBMI” or “Urban Resident Basic Medical Insurance scheme, URBMI”). Logistic regression models were introduced to estimate odds ratio (OR) and 95% confidence interval (CI) to examine the association between health insurance and hypertension.ResultsTotally, 19,742 participants completed the study. Among overall, URBMI and UEBMI participants, 47.2% (95%CI = 46.5, 47.9%), 38.4% (95%CI = 37.3, 39.6%) and 52.1% (95%CI = 51.2, 53.0%), separately, were diagnosed with hypertension, while the prevalence of un-diagnosed hypertension was 12.7% (95%CI = 12.2, 13.2%), 18.5% (95%CI = 17.6, 19.4%) and 9.6% (95%CI = 9.1, 10.1%), respectively. For overall participants, those with UEBMI were more likely to have hypertension identified (OR = 1.20; 95%CI = 1.11, 1.29) and at lower odds to experience un-diagnosed hypertension (OR = 0.68; 95%CI = 0.61, 0.76) compared to their counterparts with URBMI after control for potential confounders. Moreover, such associations of health insurance with diagnosed and un-diagnosed hypertension were also observed among participants stratified by age and gender.ConclusionFavorable health insurance may be a pathway for identifying hypertension among urban older residents in China. This study has important public health implications that hypertension may be identified early through favorable health insurance policies for older residents in China.

Abstract Aims To investigate the association between the triglyceride glucose (TyG) index and all-cause and cause-specific mortality in middle age and elderly population. Methods and results A total of 9,254 participants with age ≥ 45 years were enrolled from the National Health and Nutrition Examination Survey cycle of 1999–2014. The TyG index was determined as ln [fasting triglycerides (mg/dL) x fasting glucose (mg/dL)/2]. Primary outcomes were all-cause mortality and cause-specific mortality (cardiovascular diseases and malignant neoplasms). The association between the levels of TyG and the risk of mortality was explored with Cox regression models. After a median follow-up of 7.6 years, 1,774 all-cause death occurred. Univariate analysis showed that the TyG was associated with all-cause mortality (hazard ratio [HR] 1.18, 95% confidence interval [CI] [1.11,1.26]; p

Abstract Background Homozygous or compound heterozygous variants in the KLHL40 gene cause nemaline myopathy 8 (NEM8), a severe autosomal recessive muscle disorder characterized by prenatal polyhydramnios, fetal akinesia or hypokinesia, joint contractures, fractures, respiratory failure and dysphagia. Currently, 46 individuals with NEM8 have been described in the literature, and 30 variants in KLHL40 have been identified. Results Here, we reported five individuals from four unrelated Chinese families who presented common features of nemaline myopathy and infrequent clinical characteristics. Whole-exome sequencing (WES) was used to identify the causative gene. WES identified a recurrent missense variant c.1516A>C (p.Thr506Pro) and a novel frameshift variant c.543del (p.Ser182Profs*17) in KLHL40 in patient 1, a nonsense variant c.602G>A (p.Trp201*) and a missense variant c.1516A>C (p.Thr506Pro) in KLHL40 in patient 2, and homozygous variant c.1516A>C (p.Thr506Pro) in KLHL40 in patient 3 and both siblings (patients 4 and 5), all of which were confirmed by Sanger sequencing. Next, we estimated the incidence of this disorder in the southern and northern Chinese population to be 4.59/106 and 2.95/106, respectively, based on the cumulative allele frequency of pathogenic variants in internal database. Conclusion The results of our study expand the mutation spectrum of KLHL40 and enrich our understanding of the clinical characteristics of NEM8. Genetic counseling was provided for the four families involved in this study. Given the severity and the relatively high incidence of this condition, we strongly suggest that KLHL40 be incorporated into a carrier screening panel for the Chinese population.

ObjectiveTo explore the clinical characteristics and risk factors of common systemic rheumatism concomitant with tuberculosis (TB).MethodsA total of 3,906 patients of RA, SLE, and SS diagnosed in the People's Hospital of Sichuan Province from January 2007 to January 2017 were collected. One hundred and five patients with TB were included as TB group, including 42 RA, 41 SLE, and 22 SS patients. In the non-TB group, 84 RA, 82 SLE, and 44 SS patients were randomly selected during the same period.ResultsFever was the most common symptom among RA, SLE, and SS patients with TB, accounting for 83.3%, 92.7%, and 68.2%, respectively. Cough, weight loss or fatigue were the next common. RA patients with TB were mostly pulmonary TB (PTB), accounting for 64.3%. The proportion of PTB for SLE and SS were 46.3%, 59.01%, respectively. In TB group, 59% RA, 57% SLE, and 62% SS with PTB had two or more chest CT findings. There were 48 TB cases received both Interferon Gamma Release Assay (IGRA) and Tuberculin skin test (TST) with positive rates of 91.8%, 45.8%, respectively. The daily average dose of glucocorticoids within 1 year in TB group was higher than that in non-TB group of SLE patients, lower counts of CD4+ T cell count were found in TB group (P < 0.05), while no such differences were found in RA and SS patients.ConclusionRA patients with TB are mainly pulmonary TB. For SLE and SS patients, the chance of PTB and extrapulmonary tuberculosis is similar. Daily average dose of glucocorticoids within 1 year may be a common risk factor for RA, SLE and SS patients developing TB. Decreased CD4+ T cell count may also be a risk factor for SLE patients with TB. Symptoms of RA, SLE, SS with TB, are similar with the primary disease or other infection. It is recommended to conduct both TST and IGRA to help diagnose TB.

Rheumatoid arthritis (RA) is a chronic, systemic disease of unknown etiology. The primary manifestation of RA is inflammatory synovitis, which eventually leads to deformity and functional loss. Ferroptosis is a non-apoptosis form of cell death that depends on intracellular iron accumulation. This leads to an increase in reactive oxygen species (ROS) induced-lipid peroxidation. The underlying mechanisms of ferroptosis are System Xc- and Glutathione metabolism, regulation of glutathione peroxidase 4 activity, and ROS generation. Recent studies have shown an association between the pathogenesis of RA and ferroptosis, suggesting the involvement of ferroptosis in the onset and progression of RA. In this review, we have focused on the mechanism of ferroptosis and its association with RA pathogenesis. Further, we discuss the status of therapeutics targeting ferroptosis in the treatment of patients with RA. Targeting ferroptosis could be a potential therapeutic approach for RA treatment.

Abstract Background The aim of this study was to characterize patients who ingested multiple rare-earth magnets, reveal the harm of rare-earth magnet foreign bodies in the digestive tract, and develop a clinical management algorithm. Methods This was a retrospective review of patients with rare-earth magnet foreign bodies in the digestive tract admitted to a university-affiliated pediatric medical center in China, between January 2016 and December 2019; the subset of medical data evaluated included clinical symptoms, signs, treatments and outcomes. Results A total of 51 cases were included in this study, including 36(70.6%) males and 15(29.4%) females. The magnets were passed naturally in 24(47.1%) patients and removed by intervention in 27(52.9%) patients, including 5(9.8%) cases by endoscopy and 22(43.1%) cases by surgery. Twenty-two (43.1%)cases had gastrointestinal obstruction, perforation, and fistula. Compared with the non-surgical group, the time of the surgical group from ingestion to arriving at the hospital was longer([80(5–336) vs 26(2–216)]hours, p

Myopia, which is the result of the uncoordinated development of the eyeball, has become a major public health focus worldwide. Laser in situ keratomileusis (LASIK) and small-incision lenticule extraction (SMILE) have been successfully used in modern corneal refractive surgery. However, there are still controversies about postoperative results of LASIK and SMILE. In this study, a three-dimensional finite element model of the cornea was constructed based on the elevation and pachymetry data of a female volunteer. Surgical parameters, magnitudes of myopic correction, and intraocular pressure (IOP) were varied. Furthermore, an iterative algorithm was applied to retrieve the free-stress state of the intact corneal model, LASIK model, and SMILE model. To better evaluate the differences between LASIK and SMILE procedures, the displacement and Von Mises stress on the anterior and posterior corneal surface along the x- and y-axes were analyzed. Results for the zero-pressure model showed larger displacement compared to the image-based corneal model, suggesting that the initial corneal pre-stress stiffens the response of the cornea, both in the intact cornea and under refractive surgery. In addition, the displacement on the corneal surface in LASIK (both zero-pressure and image-based model) was obviously higher than that of the SMILE model. In contrast, SMILE increased Von Mises stress in the corneal cap and reduced Von Mises stress in the residual stromal bed compared with the LASIK model. However, the maximum Von Mises stress in the SMILE model was still smaller than that of the LASIK model. Moreover, the displacement and Von Mises stress on the residual stromal bed increased linearly with IOP. Overall, LASIK and SMILE refractive surgery could change biomechanical behaviors of the cornea. Compared to LASIK refractive surgery, SMILE may present a lower risk of ectasia. Creating a corneal cap rather than a corneal flap may have an advantage in improving corneal biomechanical stability.

Background: Verbascoside (VB), as an active component of multiple medicinal plants, has been proved to exert anti-oxidative, anti-aging and neuroprotective effects. This study was designed to investigate whether VB could play a cardioprotective role in septic heart injury. Methods: Mice were injected with lipopolysaccharide (LPS; 10 mg/kg) to induce sepsis. The treatment group received an intraperitoneally injection of VB (20 mg/kg) before LPS challenge. Transthoracic echocardiography, ELISA, immunofluorescence, and qPCR were performed to assess the effect of VB on heart function, oxidative stress, inflammation and apoptosis. Transmission electronic microscopy and immunoblotting were used to evaluate the mitochondrial morphology and biogenesis of the septic heart. In vitro experiments were also performed to repeat above-mentioned assays. Results: Compared with LPS group, the VB treatment group showed improved cardiac function in sepsis. VB alleviated oxidative stress and inflammatory cell infiltration, as well as cardiomyocyte apoptosis. Specifically, VB could restore sepsis-induced mitochondrial alterations via regulating mitochondrial biogenesis. These results were also confirmed in in vitro experiments. Conclusion: Verbascoside could protected from sepsis-induced cardiomyopathy by inhibiting oxidative stress, inflammation, and apoptosis, as well as promoting mitochondrial biogenesis.

Abstract Background Macrophage M1 polarization plays a pivotal role in inflammatory diseases. Progranulin (PGRN) has potential anti-inflammation action, however, the effect of PGRN on macrophage M1 polarization has been poorly studied. Our study aimed to investigate the effect of PGRN on lipopolysaccharide (LPS)-induced macrophage M1 polarization and clarify the underlying mechanisms. Methods RAW264.7 cells were polarized to M1 macrophage by LPS with or without recombinant PGRN (rPGRN) and tumor necrosis factor alpha antibody (anti-TNF-α). A cell counting kit-8 assay (CCK-8), flow cytometry, Quantitative Real-Time PCR assay (q-PCR), Western blot assay and enzyme-linked immunosorbent assay (ELISA) were used to determine the effect of different treatments on cell proliferation, expression of surface phenotype marker and expressions and secretion of inflammatory cytokines. The activation of NF-κB/mitogen-activated protein kinase (MAPK) pathways and the nuclear translocation of NF-κB p65 were detected by Western blot and immunofluorescence respectively. THP-1 and primary bone marrow-derived monocytes (BMDMs) were also used to demonstrate effect of PGRN on expressions and secretion of inflammatory cytokines induced by LPS. Results In RAW264.7 cells, rPGRN at concentrations below 80 ng/ml significantly promoted cell proliferation in dose dependent fashion. rPGRN significantly inhibited LPS-induced change of phenotype (CD86/CD206 ratio) and function (tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) expressions). LPS-stimulated secretion of TNF-α and activated phosphorylation of IKKα/β, IкBα, p65, JNK and p38 and the nucleus translocation of NF-кB p65 were also significantly downregulated by rPGRN. In addition, recombinant TNF-α (rTNF-α) significantly boosted TNF-α and iNOS expression vs the control group. Moreover, anti-TNF-α significantly inhibited LPS-induced TNF-α and iNOS expression. In THP-1 and BMDM cells, reversing effect of rPGRN on LPS-enhanced expressions of TNF-α and iNOS and secretion of TNF-α was further demonstrated. Conclusions PGRN down-regulates LPS-induced macrophage M1 polarization in phenotype and function via NF-κB/MAPK signaling pathways.

Objective: To investigate the differential expression of the thymic stromal lymphopoietin isoforms, short and long, and discern their biological implications under eosinophilic gastroenteritis. Methods: The expression of thymic stromal lymphopoietin and its two isoforms in tissues was assessed by quantitative RT‐PCR in healthy controls (n = 24) and patients with eosinophilic gastroenteritis (n = 17). Results: Thymic stromal lymphopoietin mRNA was significantly reduced in eosinophilic gastroenteritis when compared with healthy controls (p

Abstract Background X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease characterized by haemophagocytic lymphohistiocytosis, recurrent splenomegaly and inflammatory bowel disease (IBD). The only curative treatment is haematopoietic stem cell transplant (HSCT). Case presentation Here, we report the case of a 22-month-old male with a long history of abdominal distension and anaemia. Clinical and laboratory findings were consistent with eosinophilic colitis. To identify the underlying disease, we performed exome sequencing, which showed an unreported frameshift mutation in the XIAP gene. Conclusion We present eosinophilic colitis as the initial manifestation of XIAP deficiency for the first time in this article, which expands the mutation spectrum and phenotype of this disease.

The aim of the study was to develop an automatic segmentation approach to optical coherence tomography (OCT) images and to investigate the changes in epithelial and stromal thickness profile and radius of curvature after the use of orthokeratology (Ortho-K) contact lenses. A total of 45 right eyes from 52 participants were monitored before, and after one month of, uninterrupted overnight Ortho-K lens wear. The tomography of their right eyes was obtained using optical OCT and rotating Scheimpflug imaging (OCULUS Pentacam). A custom-built MATLAB code for automatic segmentation of corneal OCT images was created and used to assess changes in epithelial thickness, stromal thickness, corneal and stromal profiles and radii of curvature before, and after one month of, uninterrupted overnight wear of Ortho-K lenses. In the central area (0–2 mm diameter), the epithelium thinned by 12.8 ± 6.0 µm (23.8% on average, p < 0.01) after one month of Ortho-K lens wear. In the paracentral area (2–5 mm diameter), the epithelium thinned nasally and temporally (by 2.4 ± 5.9 µm, 4.5% on average, p = 0.031). The stroma thickness increased in the central area (by 4.8 ± 16.1 µm, p = 0.005). The radius of curvature of the central corneal anterior surface increased by 0.24 ± 0.26 mm (3.1%, p < 0.01) along the horizontal meridian and by 0.34 ± 0.18 mm (4.2%, p < 0.01) along the vertical meridian. There were no significant changes in the anterior and posterior stromal radius of curvature. This study introduced a new method to automatically detect the anterior corneal surface, the epithelial posterior surface and the posterior corneal surface in OCT scans. Overnight wear of Ortho-K lenses caused thinning of the central corneal epithelium. The anterior corneal surface became flattered while the anterior and posterior surfaces of the stroma did not undergo significant changes. The results are consistent with the changes reported in previous studies. The reduction in myopic refractive error caused by Ortho-K lens wear was mainly due to changes in corneal epithelium thickness profile.

Abstract Background The accuracy of the surgical amount of extraocular muscle (EOM) is key to the success of strabismus surgery. To establish an accurate eye movement model, it is of great theoretical value and clinical significance to determine the surgical amount of EOM. At present, only resistance and stiffness data of orbital suspension tissues with EOMs exist, while those of orbital suspension tissues without EOMs, which is critical information for eye movement modeling, have not been reported. The aim of this research is to study the resistance and stiffness of orbital suspension tissues with/without EOMs. Methods Fifteen healthy New Zealand white rabbits with body weights of 2.41 ± 0.13 kg were used in the study. Two recti (two horizontal recti of the left eye or two vertical recti of the right eye) or all EOMs were detached from each eye under general anesthesia. Then, a 5-0 silk suture was attached to the stump of the detached rectus insertion (two horizontal recti insertions of the left eye and two vertical recti insertions of the right eye) on the isolated eyeball. The 5-0 silk suture was connected to the INSTRON 5544 tester to facilitate the horizontal rotations of the left eyes and the vertical rotations of the right eyes, respectively. Results The resistance and stiffness of orbital suspension tissues with superior rectus, inferior rectus, superior oblique, and inferior oblique EOMs were obtained during horizontal eye movement. Similarly, the resistance and stiffness of orbital suspension tissues with lateral rectus, medial rectus, superior oblique, and inferior oblique EOMs were obtained during vertical eye movement. Then, the resistance and stiffness of orbital suspension tissues without EOMs were obtained during horizontal and vertical eye movements. The resistance and stiffness data of orbital suspension tissues with EOMs were compared with those of orbital suspension tissues without EOMs. The comparison results showed no significant difference in the resistance values between these two cases. In addition, the stiffness values of these two cases statistically differed. Conclusions The two horizontal recti play a major role in passive horizontal eye movement. In addition, when the eye is passively moved vertically, the two vertical recti play major roles. The stiffness of orbital suspension tissues with EOMs, which has been used in eye movement modeling, is not accurate. The results of this work may serve as a reference for improving the accuracy in eye movement modeling, and then it will be beneficial for determining the surgical amount of EOMs in clinical surgery.

Abstract Background As the optimal source of seed cells in periodontal tissue engineering, periodontal ligament stem cells (PDLSCs) have always been researched to improve cell expansion due to their limited resource and spontaneous differentiation in vitro cultivation. Fibroblast growth factor-2 (FGF-2) has been proven to stimulate bone marrow mesenchymal stem cells (BMMSCs) proliferation and maintain their pluripotency when being added to the culture medium. As a small molecule inhibitor of transforming growth factor-beta receptors (TGF-βRs), A83-01 can also promote cell proliferation. Therefore, the aim of this study was to verify whether the combined application of FGF-2 and A83-01 could augment cell quantity and quality during in vitro culture. Methods PDLSCs were preconditioned with A83-01, FGF-2, or their combination. A cell counting kit-8 (CCK8) assay, cell apoptosis assay, ALP activity assay, Alizarin Red S staining assay, RT-PCR assay, Western blot assay and ELISA were used to determine the sustained effects of different preconditioning strategies on the proliferation, apoptosis, stemness, osteogenic differentiation and paracrine action of PDLSCs. Results The combined application of FGF-2 and A83-01 significantly augmented cell expansion, reduced cell apoptosis, magnified stemness expression, promoted later osteogenic differentiation and mineralization and increased paracrine action of PDLSCs compared with the control. Moreover, the combination presented significant advantages in enhancing proliferation, stemness expression and paracrine action over FGF-2 alone. Conclusions The combined application of A83-01 and FGF-2 may be an improved strategy for PDLSCs biological behavior optimization in culture expansion and advantageous for reinforcing proliferation, stemness expression and cytokine secretion over FGF-2 alone.

Objective: This study aimed to investigate the prevalence of hyperhomocysteinemia (Hhcy) and its major determinants in Chinese urban population with new-onset hypertension. Methods: A total of 574 adults (404 men and 170 women) with newly diagnosed primary hypertension were recruited from seven communities in Nanjing, China. Data on lifestyle factors, such as physical activities, current smoking and drinking status, dietary habits, and familial factors were collected in interviews, and laboratory examinations were performed by well-trained personnel. Potential factors related to the prevalence of Hhcy in this population were analyzed using a logistic regression model. Results: Of the 574 participants, 421 (73.3%) were diagnosed with Hhcy whereas the remainder were only hypertensive. The study highlighted a number of factors that were significantly correlated (p

Context: The audiological features and cochlear morphology of individuals with noise-induced hearing loss (NIHL) are well characterized. However, the molecular processes in the cochlea are not well understood. Aims: To explore the role of the endoplasmic reticulum stress (ERS) response in the guinea pig model of cochlear damage induced by exposure to intense noise. Settings and Design: A pilot case–control study. Subjects and Methods: Forty-eight guinea pigs were divided into four equal groups. At 1, 4, or 14 days (d) post-exposure, the auditory brainstem responses (ABRs) were tested before sacrificing the subjects. The expression levels of the binding immunoglobulin protein/glucose-regulated protein 78 (BiP/GRP78) and C/EBP-homologous protein/growth arrest and DNA damage-inducible gene 153 (CHOP/Gadd153) proteins were evaluated using immunohistochemistry and Western blotting. The number of cochlear hair cells with altered nuclei was counted using confocal fluorescence microscopy. Statistical analysis used: One-way analysis of variance (ANOVA) and the least squares difference (LSD) test. Results: The outer hair cells (OHCs) showed changes of apoptosis, necrosis, and loss after noise exposure. In the 1- and 4-d groups, more apoptotic cells were found than necrotic cells (P < 0.01). The level of BiP/GRP78 was significantly higher in all three experimental groups compared to the control group (P < 0.01). The level of CHOP/Gadd153 was increased at 1 d post-exposure, achieving a peak that was maintained until 4 d, after which it returned to baseline levels by 14 d post-exposure. Conclusions: ERS response was activated by inducing the expression of BiP/GRP78 to lessen the extent of the resulting cellular damage and activating the CHOP/Gadd153 pathway to eliminate the most severely damaged cells.

Previously, we reported the biocontrol effects of Saccharothrix yanglingensis strain Hhs.015 on Valsa mali. Here, we report a novel protein elicitor BAR11 from the biocontrol strain Hhs.015 and its functions in plant defense responses. Functional analysis showed that the elicitor BAR11 significantly stimulated plant systemic resistance in Arabidopsis thaliana to Pseudomonas syringae pv. tomato DC3000. In addition, systemic tissues accumulated reactive oxygen species and deposited callose in a short period post-treatment compared with the control. Quantitative RT-PCR results revealed that BAR11 can induce plant resistance through the salicylic acid and jasmonic acid signaling pathways. Further analysis indicated that BAR11 interacts with host catalases in plant cells. Taken together, we conclude that the elicitor BAR11 from the strain Hhs.015 can trigger defense responses in plants.

A supply chain contract is established using a dynamic, Nash bargaining game which determines the optimal bargaining power allocation for the manufacturer, retailer, and society in an environment affected by moral hazard and irreversible investment. The results found that the manufacturer’s choice was to hold all bargaining power; however, due to the remaining information problem, the retailer still had a profit; in contrast, the retailer was only willing to give up bargaining power if the manufacturer’s profit was reserved. The optimal bargaining power allocation was found to be strongly related to the ability to convert and monitor technology, with the bargaining power gradually shifting to the manufacturer as the technology improved. A numerical simulation is given to examine the theoretical results.

To ensure supply chain coordination and equitable profit allocation when there is bilateral asymmetric information, a supply chain consisting of one manufacturer with private manufacturing cost information and one retailer with private selling cost information is considered. A bilateral adverse selection model is established with a virtual altruistic principal as the coordination subject, for which the supply chain coordination conditions and an allocation rule for the supply chain surplus are then given. It was found that contract coordination depended on the costs and risk rates of both parties and market demand; that is, the lower the costs and the risk rate, the easier the supply chain coordination. Second, the trading volume distortion degree was positively correlated with production cost, sales cost, and price sensitivity and negatively correlated with the market environment parameter. Third, the allocation proportion for the supply chain surplus was determined. Finally, under a specific cost distribution assumption, a numerical example was given to simulate the contract execution and analyze the relationships between costs and profit.

Aim. The length-contractile force relationships of six human extraocular muscles (EOMs) in primary innervations should be determined during eye movement modeling and surgery of clinical EOMs. This study aims to investigate these relationships. Method. The proposal is based on the assumption that six EOMs have similar constitutive relationships, with the eye suspended in the primary position. The constitutive relationships of EOMs are obtained by optimizing from previous experimental data and the theory of mechanical equilibrium using traditional model. Further, simulate the existing experiment of resistance force, and then compare the simulated results with the existing experimental results. Finally, the mechanical constitutive relationships of EOMs are obtained. Results. The results show that the simulated resistance forces from the other four EOMs except for the horizontal recti well agree with previous experimental results. Conclusion. The mechanical constitutive relationships of six EOMs in primary innervations are obtained, and the rationality of the constitutive relationships is verified. Whereafter, the active stress-strain relationships of the six EOMs in the primary innervations are obtained. The research results can improve the eye movement model to predict the surgical amounts of EOMs before EOM surgery more precisely.

Alagille syndrome is an autosomal dominant disorder that results from defects in the Notch signaling pathway, which is most frequently due to JAG1 mutations. This study investigated the rate, spectrum, and origin of JAG1 mutations in 91 Chinese children presenting with at least two clinical features of Alagille syndrome (cholestasis, heart murmur, skeletal abnormalities, ocular abnormalities, characteristic facial features, and renal abnormalities). Direct sequencing and/or multiplex-ligation-dependent probe amplification were performed in these patients, and segregation analysis was performed using samples available from the parents. JAG1 disease-causing mutations were detected in 70/91 (76.9%) patients, including 29/70 (41.4%) small deletions, 6/70 (8.6%) small insertions, 16/70 (22.9%) nonsense mutations, 8/70 (11.4%) splice-site mutations, 6/70 (9.4%) missense mutations, and 5/70 (7.1%) gross deletions. Of the mutations detected, 45/62 (72.6%) were novel, and almost all were unique, with the exception of c.439C>T, c.439+1G>A, c.703C>T, c.1382_1383delAC, c.2698C>T, and c.2990C>A, which were detected in two cases each; three cases exhibited entire gene deletions. A majority (69.2%) of the point and frameshift mutations could be detected by the sequencing of eleven exons (exons 3, 5, 6, 11, 14, 16, 18, 21, and 23-25). The mutation detection rate was 50.0% (10/20) in atypical cases that only presented with two or three clinical features of Alagille syndrome. Segregation analysis revealed that 81.1% (30/37) of these mutations were de novo. In conclusion, JAG1 mutations are present in the majority of Chinese pediatric patients with clinical features of Alagille syndrome, and the mutations concentrate on different exons from other reports. Genetic study is important for the diagnosis of atypical Alagille syndrome in Chinese patients.

The supply chain always appears inefficient because of the different targets of members and information asymmetry, especially when upstream enterprises not only hide information about their effort levels, but also hide information about their technology level. The paper uses principal-agent theory and the theory of regulation to design the contract to realize the maximization of principal's profit on the condition that the contract satisfies the participant and incentive conditions of agent. As a result, it is obvious that the contract achieves the goal of control. In addition, it also can be concluded that the amount of rent that the manufacturer can obtain is up to the value of his information and the condition of his resource.