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Although renewing pro-rate replacement warranty (RPRW) can help producers obtain some compensation from users, there seldom exists a two-dimensional random RPRW with a refund (2D-RRPRW with R) where a refund can guarantee the fairness of users. In addition, although random periodic replacement last (RPRL) can extend the service span after the expiry of the warranty, RPRL considering preventive maintenance (PM) has been seldom modeled to further lengthen the service span after the expiry of the warranty. In view of these, a 2D-RRPRW with R is devised to guarantee the fairness of users by integrating the limited job cycles and a refund into RPRW. Under the case where 2D-RRPRW with R warrants products with job cycles, a RPRL with PM is modeled to further lengthen the service span after the expiry of the warranty and reduce the failure frequency. It shows that to shorten the warranty period can makes the warranty cost of 2D-RRPRW with R to be less than the warranty cost of classic RPRW; and the performance of RPRL with PM outperforms the performance of classic RPRL.

PurposeThe study aims to design the limited number of random working cycle as a warranty term and propose two types of warranties, which can help manufacturers to ensure the product reliability during the warranty period. By extending the proposed warranty to the consumer's post-warranty maintenance model, besides the authors investigate two kinds of random maintenance policies to sustain the post-warranty reliability, i.e. random replacement first and random replacement last. By integrating depreciation expense depending on working time, the cost rate is constructed for each random maintenance policy and some special cases are provided by discussing parameters in cost rates. Finally, sensitivities on both the proposed warranty and random maintenance policies are analyzed in numerical experiments.Design/methodology/approachThe working cycle of products can be monitored by advanced sensors and measuring technologies. By monitoring the working cycle, manufacturers can design warranty policies to ensure product reliability performance and consumers can model the post-warranty maintenance to sustain the post-warranty reliability. In this article, the authors design a limited number of random working cycles as a warranty term and propose two types of warranties, which can help manufacturers to ensure the product reliability performance during the warranty period. By extending a proposed warranty to the consumer's post-warranty maintenance model, the authors investigate two kinds of random replacement policies to sustain the post-warranty reliability, i.e. random replacement first and random replacement last. By integrating a depreciation expense depending on working time, the cost rate is constructed for each random replacement and some special cases are provided by discussing parameters in the cost rate. Finally, sensitivities to both the proposed warranties and random replacements are analyzed in numerical experiments.FindingsIt is shown that the manufacturer can control the warranty cost by limiting number of random working cycle. For the consumer, when the number of random working cycle is designed as a greater warranty limit, the cost rate can be reduced while the post-warranty period can't be lengthened.Originality/valueThe contribution of this article can be highlighted in two key aspects: (1) the authors investigate early warranties to ensure reliability performance of the product which executes successively projects at random working cycles; (2) by integrating random working cycles into the post-warranty period, the authors is the first to investigate random maintenance policy to sustain the post-warranty reliability from the consumer's perspective, which seldom appears in the existing literature.

Advanced sensors and measuring technologies make it possible to monitor the product working cycle. This means the manufacturer’s warranty to ensure reliability performance can be designed by monitoring the product working cycle and the consumer’s post-warranty maintenance to sustain the post-warranty reliability can be modeled by tracking the product working cycle. However, the related works appear seldom in existing literature. In this article, we incorporate random working cycle into warranty and propose a novel warranty ensuring reliability performance of the product with random working cycles. By extending the proposed warranty to the post-warranty maintenance, besides we investigate the postwarranty random maintenance policies sustaining the post-warranty reliability, i.e., replacement last (first) with preventive maintenance (PM). The cost rate is constructed for each post-warranty random maintenance policy. Finally, sensitivity of proposed warranty and investigated polices is analyzed. We discover that replacement last (first) with PM is superior to replacement last (first).

Vegetation phenology is one of the key agroclimatic indices that is sensitive to climate change. Analyzing the variation in plant phenology under a changing environment can provide reference information to assess the impact of climate change on ecosystems and agricultural management. In this study, we focused on the thermal growth season, an important phenology index. We defined four growing season indices based on the surface temperature to quantify the changes in thermal growth season and analyze their association with atmospheric circulation in China. The results showed that the start date of the growing season exhibited a significant advanced trend (P

Background Low dietary fiber intake has been shown to disturb the gut microbiome community, damage the mucus barrier, and promote pathogen susceptibility. However, little is known about the temporal response of the gut microbiome to dietary fiber deprivation and the recovery induced by dietary fiber inclusion in pigs. Objective In the present study, temporal responses of ileal and fecal microbiota to dietary fiber deprivation were profiled using an ileum cannulated growing pig model. In addition, the potential of dietary-resistant starch, β-glucan, and xylan to alleviate gut dysbiosis throughout the gastrointestinal tract, as well as its possible mechanisms were investigated. Methods Six cannulated growing pigs were fed a fiber deprivation diet for 35 days. Ileal digesta and feces were collected at days 0, 7, 21, and 35 for 16S rRNA sequencing and short-chain fatty acid (SCFA) determination. Another twenty-four healthy growing pigs were assigned to one of four dietary treatments including (1) fiber-free diet, (2) resistant starch diet, (3) β-glucan diet, and (4) xylan diet. These twenty-four pigs were fed a corresponding diet for 35 days and slaughtered. Gut microbiome and SCFA concentration were profiled along the gastrointestinal tract. Results Dietary fiber deprivation-induced consistent microbiota extinction, mainly Bifidobacterium and Lactobacillus, and decreased SCFA concentrations in both ileum and feces. The community structure partially recovered at day 35 compared with baseline while SCFA concentrations remained low. Xylan supplementation alleviated gut dysbiosis by selectively promoting Bifidobacterium pseudocatenulatum within the large intestine. SCFA concentration increased significantly after xylan supplementation and exhibited a positive association with B. pseudocatenulatum abundance. An elevated abundance of xylan degradation-related enzyme genes was also observed in the gut microbiome after xylan supplementation. In vitro growth assay further verified the xylan utilization capacity of B. pseudocatenulatum. Conclusions Dietary fiber deprivation could induce probiotic extinction and loss of the SCFA production while potential pathogen was promoted. Xylan intervention could partially restore dietary fiber deprivation-induced gut dysbiosis through selectively promoting B. pseudocatenulatum and therefore normalizing the gut environment. These findings collectively provide evidence that dietary fiber-driven microbiota metabolism bridges the interplay between microbiome and gut health.

Purpose: \ud To investigate molecular pathogenesis of congenital ectopia lentis accompanied by various ophthalmic manifestations. \ud \ud Methods: \ud Three female siblings, their spouse and offspring underwent ophthalmic and general medical examinations. Genetic variants were screened with whole exome sequencing and analyzed in either dominant or recessive inheritance manner. Gene mutations were ascertained with the Sanger sequencing after polymerase chain reaction. \ud \ud Results: \ud All three female siblings were diagnosed as the Ectopia lentis et pupillae (ELeP) through combination of clinical examination and genetic analysis. No characteristic pathological changes of skeletal, metabolic and cardiac abnormalities were observed. Novel compound heterozygous mutations (p.Ser264LeufsX37/ p.Gly757ValfsX62) in ADAMTSL4 were discreetly identified in this ELeP pedigree. The skin problem of three patients was recalled, and current symptom of the proband was observed further when we re-investigated after we identified the relevant variants. The molecular etiology of skin problem of three female siblings might be due to variants including ALOX15B, TRBV3-1, and NUDT18.\ud \ud Conclusions: \ud Novel compound heterozygous ADAMTSL4 variants are responsible for ELeP in autosomal recessive inheritance manner in the current pedigree. Correlation between ADAMTSL4 variants and ELeP was firstly established based on our 12 years follow-up studies and previous reports of ELeP and ADAMTSL4–related eye disorders. The primary phenotypes caused by ADAMTSL4 variants include EL, EP, poor pupillary dilation, and axial elongation. Varying phenotypes including glaucoma, high myopia retinapathy, and poor vision and so on, may be secondary impairments. All these secondary impairments may be improved if proper clinical interventions are implemented in time.

To date, the controversy surrounding the unknown risks and consequences of heritable genome editing has grown, with such work raising biosafety and ethical concerns for future generations. However, the current guideline of global governance is limited. In the context of the new framework for the governance of human genome editing developed by the World Health Organization (WHO) committee, this paper presents further analysis by highlighting predicaments of governance on germline engineering that merit the most attention: (1) building a scientific culture informed by a broader set of values and considerations in the internal scientific community at large, such as codes of ethics, and education, in addition to awareness-raising measures; and (2) reflecting on and institutionalizing policies in grassroots practice according to local conditions in external governance, such as the experimentalist governance, which is a multi-layered model of governance that establishes an open-ended framework from the top and offers stakeholders the freedom of discussion. The key to achieving these goals is more democratic deliberation between the public and the inclusive engagement of the global scientific community, which has been extensively used in the Biological and Toxin Weapons Convention (BTWC). On a global scale, we believe that practicing heritable human genome editing in accordance with the WHO and BTWC appears to be a good choice.

Multidrug resistant (MDR) bacterial infection has emerged, raising concerns about untreatable infections, and posing the highest health risks. Antimicrobial peptides (AMPs) are thought to be the best remedy for this problem. Here, we showed biosynthetic microcin J25 (MccJ25) exhibited excellent bactericidal activity against standard and clinically relevant veterinary MDR strains with high stability, no cytotoxicity, and no increase in drug resistance. Analysis of antimicrobial mechanism possessed by sensitive enterotoxigenic Escherichia coli (ETEC) based on electron microscopy and Sytox Green methods was carried out. Results showed excellent activity against ETEC was due to permeabilizing bacterial membranes and strong affinity. MccJ25 exhibited high endotoxin-neutralizing activity in both in vivo and in vitro environments, and mice exposed to lipopolysaccharide (LPS) showed decreased plasma LPS levels and improved survival after administration of MccJ25. In an LPS-treated mouse septicemia model, MccJ25 treatment significantly alleviated inflammatory responses by inhibiting proinflammatory factor secretion and expression. In a mouse E. coli infection model, administration of MccJ25 effectively improved host defense against clinically source cocktail of multidrug-resistant E. coli strains induced intestinal inflammation and bacteria dissemination. Results of studies on anti-inflammatory mechanisms showed that MccJ25 downregulated nuclear factor kappa B kinase and mitogen-activated protein kinase, thereby reducing the production of toll-like receptor 4, myeloid differentiation factor 88 and decreasing the key proinflammatory cytokines. These findings clarify MccJ25 may be an ideal antibacterial/antiendotoxic drug candidate that has the potential to further guide the development of anti-inflammatory and/or antimicrobial agents in the war against MDR bacterial infection.

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. Tremendous progress has been made in the prevention and treatment of CVD; however, there are still lots of limitations and new technology is needed. Nanoparticles have been studied recently for CVD due to their nanoscale size and unique properties, and hold a potential to be a novel therapy for the treatment. To test the safety and effectiveness of drug-loaded nanoparticles for CVD prior to human studies, animal disease models are unavoidably needed. This review summarized the animal models used in the research of nanoparticles for CVD and provided a generic picture of current use of CVD animal models according to the different types of diseases which should be prioritized when considering the application of nanoparticles in treating CVD. This review would be useful resources not only for life science researchers and clinicians but also for those from chemistry and materials sciences background who may not have a systematic knowledge about CVD animal models.

Scope. Implantation loss is a considerable cause of early pregnancy loss in humans and mammalian animals. It is not addressed how proliferative uterine defects implicate in implantation loss. Methods and Results. Herein, a comprehensive proteomic analysis was conducted on proliferative endometria from sows with low and normal reproductive performance (LRP and NRP, respectively). Enrichment analysis of differentially expressed proteins revealed alterations in endometrial remodeling, substance metabolism (mainly lipid, nitrogen, and retinol metabolism), immunological modulation, and insulin signaling in LRP sows. Importantly, aberrant lipid metabolite accumulation and dysregulation of insulin signaling were coincidently confirmed in endometria of LPR sows, proving an impaired insulin sensitivity. Furthermore, established high-fat diet- (HFD-) induced insulin-resistant mouse models revealed that uterine insulin resistance beginning before pregnancy deteriorated uterine receptivity and decreased implantation sites and fetal numbers. Mitochondrial biogenesis and fusion were decreased, and reactive oxygen species was overproduced in uteri from the HFD group during the implantation period. Ishikawa and JAR cells directly demonstrated that oxidative stress compromised implantation in vitro. Conclusions. This study demonstrated that uterine insulin sensitivity impairment beginning before pregnancy resulted in implantation and fetal loss associated with oxidative stress induced by mitochondrial dysfunction.

The interactions between cells and nanoparticles has been the focus of recent research in the area. The effects of AgNPs on skin cell lines for further potential biological applications are highlighted. This study aimed to investigate the mechanism of cytotoxic and genotoxic effects of AgNPs nanoparticles on human skin keratinocytes (HaCaT). Genocytotoxic effects of AgNPs was assessed using changes in various cellular parameters of HaCaT cells involving viability, superoxide anion radical production, lactate dehydrogenase release and the levels of the antioxidant enzymes, namely, Catalase, Glutathione peroxidase (GPX) and Superoxide Dismutase (SOD). Superoxide anion was detected using nitroblue tetrazolium NBT reduction assay. LDH levels was evaluated using the standard kit, and activity of antioxidant enzymes such as catalase (CAT), glutathione peroxidase 1 (GPX-1) and superoxide dismutase 1 (SOD-1) were quantified using qPCR. Our results indicated that AgNPs caused severe HaCaT oxidative damage, accompanied by increased the production of superoxide anion levels as well as significant decrease in endogenous antioxidant enzyme of SOD, CAT, GPX expression involved in HaCat cells in vitro. Our study suggests that AgNPs exposure increased oxidative stress levels. Moreover; the low cytotoxic effect observed on human HaCaT keratinocytes suggested that these nano-compounds have a potential toxic effect at the skin level only after long-term exposure.

The limited number of human hematopoietic stem cells (HSCs) has restrained their widespread clinical application. Despite great efforts in recent years, the in vitro expansion of HSCs remains a challenge due to incomplete understanding of the signaling networks underlying HSC self-renewal. Here, we show that culturing human cord blood (CB) CD34+ cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 3.88-fold increase in cell number. These cultured CD34+ cells repopulated recipient mice for 21 weeks and can form secondary engraftment that lasted for more than 21 weeks. Knockdown of c-Jun, a major downstream target in the JNK pathway, promoted the expansion of hematopoietic stem and progenitor cells (HSPCs). Our findings demonstrate a critical role of the JNK pathway in regulating HSC expansion, provide new insights into HSC self-renewal mechanism, and may lead to improved clinical application of HSCs.

In recent years, tremendous progress has been made in the treatment of acute myocardial infarction, but pathological ventricular remodeling often causes survivors to suffer from fatal heart failure. Currently, there is no effective therapy to attenuate ventricular remodeling. Recently, nanoparticle-based drug delivery systems are widely applied in biomedicine especially in cancer and liver fibrosis, owing to its excellent physical, chemical and biological properties. Therefore, the use of nanoparticles as delivery vehicles of small molecules, polypeptides, etc. to improve postinfarct ventricular remodeling is expected. In this review, we summarize the updated researches in this fast-growing area and suggest further works needed.

Antimicrobial peptide (AMP) can be a promising alternative in various domains. However, further risk information is required. In this study, mice were orally administrated different dosages of recombinant AMP microcin J25 (4.55, 9.1, and 18.2 mg/kg; MccJ25) for 1 week, and the toxicity risk impacts were examined. We evidenced that middle-dosage administration mice had a lower inflammation, better body weight, and ameliorated mucosal morphology, accompanied by reduced intestinal permeability and tighter intestinal barrier. Fecal microbiota composition analysis in middle- or low-dosage mice revealed the Bifidobacterium count was increased and the coliform bacteria count was decreased, and increased in short-chain fatty acid levels. Unexpectedly, there was a risk that high-dosage mice increased intestinal permeability and imbalance of intestinal bacteria. Taken together, these data indicated a safe threshold for usage of MccJ25 in clinical practice. Such studies can effectively enhance the safety of various aspects such as food preservative and drug.

Alterations of Endothelial cells (ECs) play a critical role in different pathogenesis of many serious human diseases, and dysfunction of the vascular endothelium is an indicator for human disorders. Endothelial dysfunction is considered to be an early indicator for atherosclerosis, which is characterised by overexpression of adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Hydrogen peroxide (H2O2) released via neutrophils is an important mediator of endothelial cell function. Ambient production of superoxide anion (O2−) and subsequently H2O2 at low levels is critical for regulating endothelial cell functions and proliferation. In this study, we investigated the effects of H2O2 on the expression of adhesion molecules VCAM-1 and ICAM-1 in cultured human umbilical vein endothelial cells (HUVECs). Intracellular superoxide anion production was detected by using p-Nitro Blue Tetrazolium (NBT) assay. Our results showed that administration of 100μM of H2O2 on HUVECs for 2, 6, 12 and 24 h induced a time-dependent increase in ICAM-1 and VCAM-1 mRNA and protein expression levels with a significant increase observed from 6 h. HUVECs exposed to H2O2 exhibit increased O2−, suggesting that H2O2 induced oxidative stress may be a reasonable for atherosclerosis. This increase can be reduced by the flavonoid, N-acetyl cysteine (NAC). The modulation of endothelial cell function through this mechanism may underlie the contribution of H2O2 to the development of vascular disease.

Background: \ud Sperm DNA fragmentation and its adverse impact on outcomes of assisted reproductive techniques (ART) in globozoospermic infertile patients has been previously reported. However, the association of Zinc element with DNA damage and intracytoplasmic sperm injection (ICSI) outcome in globozoospermic infertile patients remain unclear.\ud \ud Methods: \ud Using Flame Atomic Absorption Spectrophotometer and Superoxide Dismutase Assay, the levels of Cu, Fe, Mn, Zn and SOD activities in seminal plasma from both globozoospermic infertile patients and fertile volunteers were tested respectively. Using Sperm chromatin dispersion (SCD) test and Comet assay, the DNA damages in their semen samples from the two groups was detected. In addition, using Aniline Blue staining, their sperm nucleus maturations were also examined.\ud \ud Results: \ud The levels of seminal Zinc and SOD activities were lower in the globozoospermic infertile patients and the double-stranded break DFI (DSB-DFI) were significantly higher than that in the fertile controls. Antioxidative insufficiency of SOD with a low Zn level might be responsible for oxidative stress, which may lead to DNA damage in globozoospermic spermatozoa. Zn deficiency might also have influence on the chromatin stabilization of globozoospermic spermatozoa during spermiogenesis, causing its more vulnerable to oxidative attack.\ud \ud Conclusions: \ud Serious DSBs in globozoospermia and antioxidative insufficiency due to Zinc element deficiency in spermatozoa might be responsible for the failure of ICSI in globozoospermia.

Glucagon-like peptide-2 (GLP-2) is secreted from enteroendocrine L-type cells of the gut and also released from preproglucagonergic (PPG) neurons in the nucleus tractus solitarius (NTS) and adjacent medial reticular nucleus of the brain stem. The neurons in the NTS express GLP-2, and the neurons send extensive projections to the hypothalamus. Recent studies show that the intracerebroventricular administration of GLP-2 significantly suppresses food intake in animals and some evidence suggest that the melanocortin receptor-4 (MC4-R) signaling in the hypothalamus is required for intracerebroventricular GLP-2-mediated inhibition of feeding. There is proopiomelanocortin (POMC) positive neurons expressing MC4-R in the NTS. Suppression of MC4-R expressing neurons in the brain stem inhibits gastric emptying. In this study, we tested the effects of NTS GLP-2R activation and blockade on feeding behavior and evaluated the endogenous melanocortin system's role in the NTS in mediating effects of GLP-2 on feeding behavior in fed and fasted rats. Our results demonstrated that microinjection of GLP-2 into the NTS suppressed food intake in fasted-refeeding rats but did not affect food intake in free-feeding rats, and this inhibition was blocked by pretreatment of either Exendin (9-39) or SHU 9119, suggesting the GLP-2 system in the NTS exerts an inhibitory action on food intake. MC4-R mediates this action in the NTS.

BACKGROUND: When people require medical treatment, many risk factors including adverse medical events, economic burdens, and social–psychological consequences may contribute to their hesitation to seek medical help. Therefore, a reliable and valid instrument that can comprehensively assess the risk perception of medical help-seeking behavior among ordinary Chinese adults should be developed. METHODS: The basic dimensions of the scale were determined based on literature review and in-depth interviews with patients. Then, an item pool with 32 items and six dimensions was developed. After the item reduction process based on item and factor analyses, a three-factor, 16-item scale was established. From March 2019, this scale was distributed among 639 healthy adults, outpatients, or inpatients in 20 provinces and municipalities in the mainland of China by convenience sampling. Then, the reliability and validity of the scale were examined. RESULTS: The scale consists of three dimensions (treatment risks, burden risks, and stigma risks) and 16 items. The root-mean-square error of approximation, comparative fit index, and Tucker-Lewis index of this model were 0.069, 0.925, and 0.910, respectively. The internal consistency reliability of the scale was 0.893, and the test-retest reliability was 0.784. The criterion-related validity was 0.720 (P

Treating serious bone trauma with an osteo-inductive agent such as bone morphogenetic proteins (BMPs) has been considered as an optimized option when delivered via a collagen sponge (CS). Previous works have shown that the BMP concentration and release rate from approved CS carriers is difficult to control with precision. Here we presented the fabrication of a recombinant fusion protein from recombinant human-like collagen (HLC) and human BMP-2 (hBMP2). The fusion protein preserved the characteristic of HLC allowing the recombinant protein to be expressed in Yeast (such as Pichia pastoris GS115) and purified rapidly and easily with mass production after methanol induction. It also kept the stable properties of HLC and hBMP2 in the body fluid environment with good biocompatibility and no cytotoxicity. Moreover, the recombinant fusion protein fabricated a vertical through-hole structure with improved mechanical properties, and thus facilitated migration of bone marrow mesenchymal stem cells (MSCs) into the fusion materials. Furthermore, the fusion protein degraded and released hBMP-2 in vivo allowing osteoinductive activity and the enhancement of utilization rate and the precise control of the hBMP2 release. This fusion protein when applied to cranial defects in rats was osteoinductively active and improved bone repairing enhancing the repairing rate 3.5- fold and 4.2- fold when compared to the HLC alone and the control, respectively. There were no visible inflammatory reactions, infections or extrusions around the implantation sites observed. Our data strongly suggests that this novel recombinant fusion protein could be more beneficial in the treatment of bone defects than the simple superposition of the hBMP2/collagen sponge.

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is rising constantly all over the world. However, current medical treatments are not universally practical. Microcin J25 (MccJ25), a member of the lasso peptides class, has excellent antimicrobial activity both in vitro and in vivo. Here, we assessed the anti-inflammatory effects of MccJ25 through DSS-induced UC mouse model. MccJ25 significantly ameliorated the UC-associated parameters such as decreased body weight, increased disease activity index (DAI) and shortened colon length. MccJ25 also provides barrier protection by preserving structural integrity and reducing inflammatory infiltrates of colon epithelium. The underlying mechanism may be associated with gut microbiota. To test this uncertainty, co-housing experiment was performed, and results indicate homogenized microbiota could relief the inflammatory. Meanwhile, we also proved the prominent role of the possible targets of MccJ25, namely genus Lactobacillus, Bacteroides and Akkermansia (as well as the possible strains related to the important OTUs) in inflammation status through comprehensive analysis. In conclusion, MccJ25 effectively attenuates inflammation and improves disrupted barrier function, and the MccJ25-modified gut microbiota plays a central role in this process.

Glucagon-like peptide 2 (GLP-2), a member of Glucagon peptide family involved in regulating energy metabolism, can be produced and secreted by preproglucagonergic (PPG) neurons in the brain. GLP-2 reduces food intake but at which brain sites GLP-2 exerts its feeding-suppress effects are still unclear. In this study, we used the stereological microinjection technique and behavioral test to examine the functions of locally delivered GLP-2 into DMH on feeding behavior. We compared effects of different concentration of GLP-2 on the food intake behavior in free-feeding rats and fasted-refeeding rats. We found that GLP-2 inhibited food intake in fasted rats after a short-term intervention in a dose-dependent manner. Importantly, the effects of locally delivered GLP-2 can be blocked by specific GLP-1 receptor antagonist Exendin

Natural animal collagen and its recombinant collagen are favorable replacements in human tissue engineering due to their remarkable biomedical property. However, this exploitation is largely restricted due to the potential of immunogenicity and virus contamination. Exploring new ways to produce human collagen is a fundamental key to its biomedical and clinical application. All human fibrillar collagen molecules have three polypeptide chains constructed from a repeating Gly-Xaa-Yaa triplet, where Xaa and Yaa represent one random amino acid. Using cDNA techniques to modify several repeat sequences of the cDNA fragment, a novel human collagen named recombinant human-like collagen (HLC), with low immunogenicity and little risk from hidden virus can be engineered and notably tailored to specific applications. HLC was initially used as a coating to modify the tissue engineering scaffold, and then used as the scaffold after cross link agents were added to increase its mechanical strength. Due to its good biocompatibility, low immunogenicity, stabilised property and the ability of mass production, HLC has been widely considered to use in skin injury treatments, vascular scaffolds engineering, cartilage, bone defect repair, skincare, haemostatic sponge, and drug delivery including coating with medical nanoparticles. In this review, we symmetrically reviewed the development, recent advances in design and application of HLC, and other recombinant human collagen-based biomedicine potentials. For comparison and providing basic background information about the techniques, we start with recombinant human collagens. In the end, future improvements in using HLC are also discussed.

Acceleration of the applications of cutting edge science is often most likely in situations involving conflict and warfare between different groups. That is the focus of this paper. It asks what we know of the past, present and possible future applications of advances in our understanding of the brain in the development of chemical weapons, and what might best be done to moderate the most dangerous aspects of that process at the present time, particularly by members of civil society. The paper therefore begins by examining this possibility of hostile manipulation of the brain in some detail. It then briefly reviews the current state of the chemical and biological arms control and disarmament regime as embodied in the Biological and Toxin Weapons Convention (BTWC) and the Chemical Weapons Convention (CWC) following the 2016 8th Five Year Review Conference of the BTWC and in the lead up to the 2018 4th Five Year Review Conference of the CWC. Finally, our civil society initiative to assist in achieving a successful outcome of the 2018 CWC Review Conference is described. This initiative involves the production of a multi-authored edited book, to be published in advance of the Review Conference by the UK Royal Society of Chemistry that explores many of the critical issues facing the CWC States Parties as they seek to agree effective measures to prevent the development and use of chemical weapons, as the life and chemical sciences advance.

Due to the non-substitutability of the product, the monopoly manufacturer designs warranty to reduce maximally warranty cost. Although the monopoly manufacturer maintains responsibly produc...

Microporous carbons (MPC) with three-dimensional (3D) honeycomb-like porous structure is synthesized by a simple and convenient carbonization method using polyvinyl alcohol (PVA) as carbon source and KOH as both activating agent and template. Benefiting from its large surface area, 3D interconnected honeycomb-like porous structure and high oxygen doping, the MPC-2 electrode exhibits a high specific capacitance of 367 F g−1 at 0.5 A g−1 and excellent electrochemical stability (99.7% of its initial capacitance after 10,000 cycles) in 6.0 M KOH aqueous electrolyte. More importantly, the assembled MPC-2 symmetric supercapacitor shows an energy density of 22.4 Wh kg−1 based on the total mass of active materials of the two electrodes in 1.0 M Na2SO4 aqueous electrolyte, as well as excellent electrochemical stability. Therefore, this work provides an easy, convenient way to design and large-scale produce 3D honeycomb-like porous carbon for high performance supercapacitors.

Background Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and Ulcerative colitis (UC), are chronic and relapsing inflammation occurring among the gastrointestinal tract. Available evidence suggests that host microbiome, as well as various components of the mucosal immune system, are implicated in the pathogenesis of IBD though the exact mechanism remains unknown. Advances in DNA sequencing technologies have provided new insights on the function identification of gut microbiota. In this study, we investigated the gut microbiota response to colitis and discussed the underlying mechanisms of this alteration in combination with latest research. The function of altered microbiota was investigated through microbiota transplantation technology.Results Twenty-seven female C57BL/6J mice were fed DSS solution for 5 days and followed by 5 days normal drinking water. D 0 was considered as normal control while d 5 and d 10 were seen as disease progressive phase and recovery phase, respectively. Alpha diversity results showed that the detected microbiota composition differences among 3 phases were not due to the presence and/or absence of rare phylotypes. In IBD mouse model, community richness decreased but diversity did not change significantly. Besides, the strong negative correlation between phyla Firmicutes and Bacteroidetes decreased in IBD mouse model of which maybe one of the dysbiosis signatures. Furthermore, transplanting microbiota of IBD mouse model to antibiotic-induced microbiota depletion mice (Abx-mice) could induce inflammation similar to colitis. The proportion of the Lactobacillus, as well as other less abundant probiotic taxa, significantly increased in recovery phase, revealing the potential of these probiotic in IBD therapy.Conclusions IBD could induce proportional changes of gut microbiota, and these changes are capable of conferring pathogenicity in Abx-mice. This study provides updated comprehensions of the commensal microbiota alteration.Keywords Gut microbiota, dysbiosis, inflammation bowel disease, DSS, microbiota transplantation

Warranty policy, as a marketing strategy, has been widely studied for several decades, but warranty models incorporating condition-based maintenance are still rare. In condition monitoring, product...

Osteoinductive activity of the implant in bone healing and regeneration is still a challenging research topic. Therapeutic application of recombinant human bone morphogenetic protein-2 (BMP-2) is a promising approach to enhance osteogenesis. However, high dose and uncontrolled burst release of BMP-2 may introduce edema, bone overgrowth, cystlike bone formation, and inflammation. In this study, low-dose BMP-2 of 1 μg was used to design PLA-PD-BMP for functionalization of polylactic acid (PLA) implants via mussel-inspired polydopamine (PD) assist. For the first time, the binding property and efficiency of the PD coating with BMP-2 were directly demonstrated and analyzed using an antigen-antibody reaction. The obtained PLA-PD-BMP surface immobilized with this low BMP-2 dose can endow the implants with abilities of introducing strong stem cell adhesion and enhanced osteogenicity. Furthermore, in vivo osteoinduction of the PLA-PD-BMP-2 scaffolds was confirmed by a rat ectopic bone model, which is marked as the "gold standard" for the evidence of osteoinductive activity. The microcomputed tomography, Young's modulus, and histology analyses were also employed to demonstrate that PLA-PD-BMP grafted with 1 μg of BMP-2 can induce bone formation. Therefore, the method in this study can be used as a model system to immobilize other growth factors onto various different types of polymer substrates. The highly biomimetic mussel-derived strategy can therefore improve the clinical outcome of polymer-based medical implants in a facile, safe, and effective way.

Background The early-life microbiota exerts a profound and lifelong impact on host health. Longitudinal studies in humans have been informative but are mostly based on the analysis of fecal samples and cannot shed direct light on the early development of mucosa-associated intestinal microbiota and its impact on GI function. Using piglets as a model for human infants, we assess here the succession of mucosa-associated microbiota across the intestinal tract in the first 35 days after birth. Results Although sharing a similar composition and predicted functional profile at birth, the mucosa-associated microbiome in the small intestine (jejunum and ileum) remained relatively stable, while that of the large intestine (cecum and colon) quickly expanded and diversified by day 35. Among detected microbial sources (milk, vagina, areolar skin, and feces of sows, farrowing crate, and incubator), maternal milk microbes were primarily responsible for the colonization of the small intestine, contributing approximately 90% bacteria throughout the first 35 days of the neonatal life. Although maternal milk microbes contributed greater than 90% bacteria to the large intestinal microbiota of neonates upon birth, their presence gradually diminished, and they were replaced by maternal fecal microbes by day 35. We found strong correlations between the relative abundance of specific mucosa-associated microbes, particularly those vertically transmitted from the mother, and the expression levels of multiple intestinal immune and barrier function genes in different segments of the intestinal tract. Conclusion We revealed spatially specific trajectories of microbial colonization of the intestinal mucosa in the small and large intestines, which can be primarily attributed to the colonization by vertically transmitted maternal milk and intestinal microbes. Additionally, these maternal microbes may be involved in the establishment of intestinal immune and barrier functions in neonates. Our findings strengthen the notion that studying fecal samples alone is insufficient to fully understand the co-development of the intestinal microbiota and immune system and suggest the possibility of improving neonatal health through the manipulation of maternal microbiota.

Objective Interstitial fluid in extracellular matrices may not be totally fixed but partially flow through long‐distance oriented fibrous connective tissues via physical mechanisms. We hypothesized there is a long‐distance interstitial fluid transport network beyond vascular circulations. Materials and methods We first used 20 volunteers to determine hypodermic entrant points to visualize long‐distance extravascular pathway by MRI. We then investigated the extravascular pathways initiating from the point of thumb in cadavers by chest compressor. The distributions and structures of long‐distance pathways from extremity ending to associated visceral structures were identified. Results Using fluorescent tracer, the pathways from right thumb to right atrium wall near chest were visualized in seven of 10 subjects. The cutaneous pathways were found in dermic, hypodermic and fascial tissues of hand and forearm. The perivascular pathways were along the veins of arm, axillary sheath, superior vena cava and into the superficial tissues on right atrium. Histological and micro‐CT data showed these pathways were neither blood nor lymphatic vessels but long‐distance oriented fibrous matrices, which contained the longitudinally assembled micro‐scale fibres consistently from thumb to superficial tissues on right atrium. Conclusions These data revealed the structural framework of the fibrous extracellular matrices in oriented fibrous connective tissues was of the long‐distance assembled fibres throughout human body. Along fibres, interstitial fluid can systemically transport by certain driving‐transfer mechanisms beyond vascular circulations.

Additional file 5: Figure S5. β-diversity of the mucosa-associated microbiota, milk, skin, vagina and feces of sows, and environmental microbiota. PCoA of phylogenetic community composition based on weighted UniFrac (A), and taxonomic community composition based on Bray–Curtis (B).

In recent years, the reports on using nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer prevention and treatment have been on the rise. In 2017, the US Preventive Services Working Group issued primary prevention guidelines on the use of NSAIDs, especially aspirin, for cardiovascular disease and colorectal cancer, and formally established the role and status of aspirin in cancer prevention. However, the mechanism of NSAIDs on preventing cancer is still not clear. In this paper, the progress of the application of NSAIDs, especially aspirin, in the prevention and treatment of tumors in recent years is summarized, and new ideas and directions for the follow-up study are also discussed.

Glucagon-like peptide 2 (GLP-2), a member of Glucagon peptide family involved in regulating energy metabolism, can be produced and secreted by preproglucagonergic (PPG) neurons in the brain. GLP-2 reduces food intake but at which brain sites GLP-2 exerts its feeding-suppress effects are still unclear. In this study, we used the stereological microinjection technique and behavioral test to examine the functions of locally delivered GLP-2 into DMH on feeding behavior. We compared effects of different concentration of GLP-2 on the food intake behavior in free-feeding rats and fasted-refeeding rats. We found that GLP-2 inhibited food intake in fasted rats after a short-term intervention in a dose-dependent manner. Importantly, the effects of locally delivered GLP-2 can be blocked by specific GLP-1 receptor antagonist Exendin(9-39), but not the melanocortin-4 receptor antagonist SHU9119, indicating the involvement of specificity of GLP-2 signaling in regulating the feeding behavior. Taken together, our data revealed that GLP-2 peptide pharmacologically inhibited food intake in DMH and this effect could be blocked functionally by Exendin(9-39).

In this paper, firstly, a renewable hybrid warranty policy is proposed from the manufacturer’s perspective. By integrating the replacement depending on number of failures and preventive maintenance at the expiration of the warranty, secondly, a maintenance-replacement policy is presented from the perspective of the customer. Thirdly, the consumer’s expected cost rate model is obtained and the related special models are offered. Finally, a numerical example is used to illustrate performance of the proposed maintenance-replacement policy and to analyse sensitively. As showed in the example, performance of the proposed maintenance-replacement policy is more superior.

Developing new methods to treat heart diseases is always a focus for basic research and clinical applications. Existing drugs have strong side-effects and also require lifetime administration for patients. Recent attempts of using nanoparticles (NPs) in treating atherosclerosis in animals and some heart diseases such as heart failure and endocarditis have provided hopes for better drug delivery and reducing of drug side-effects. In this mini-review, we summarize the present applications of using gold nanoparticles (GNPs) as a new drug delivery system in diseased hearts and of the assessment of toxicity in using GNPs. We suggest that conjugating existing clinical drugs with GNPs is a favorable choice to provide "new and double-enhanced" potentiality to those existing drugs in treating heart diseases. Other applications of using NPs in the treatment of heart diseases including using drugs in nano-form and coating drugs with a surface of relevant NP are also discussed.

An introductory chapter that outlines the concepts and rationale behind the creation of this book, including holistic arms control and an outline of the role of non-governmental life science communities in the prevention of chemical weapons.

Traditional chemical weapons such as mustard gas and nerve agents remain the biggest global threat; their pathogenesis is complex, particularly mustard gas and soman poisoning, and thus there has been no suitable means of prevention and treatment developed to date. In the past 10 years, significant research progress on the mechanisms, biomarkers, and drugs for the prevention and treatment of exposure to traditional chemical weapons, such as mustard gas and soman poisoning, has been made as a result of the beneficial impact of the convergence of chemistry and biology. In this chapter, we firstly review recent advances in the mechanism of sulfur mustard (SM) damage to organs mainly involving inflammation, apoptosis, DNA damage, and oxidative stress. Secondly, the in vivo study of SM injury-related markers from two aspects of various adducts and inflammatory markers, and in vivo diagnostic biomarkers for nerve agent (NA) poisoning such as toxicant prototypes, hydrolysis products, toxin protein adducts, and other analytical detection methods, are systematically reviewed. Finally, we review research progress on drugs used in the prevention and treatment of SM and NA poisoning.

In this concluding chapter, we employ the Holistic Arms Control framework as a means of analysing the contributions of the preceding chapters and synthesising them into a proposed integrated approach which would prioritise the most appropriate and effective mechanisms to address the threats arising from the rapid advances in relevant science and technologies. Given the central importance of the Chemical Weapons Convention and the accompanying implementation and verification regime, the chapter will highlight recommendations for both States and civil society to strengthen OPCW action in these areas, at the Fourth Review Conference and beyond.

In a previous study we identified an extensive gating network within the inwardly rectifying Kir1.1 (ROMK) channel by combining systematic scanning mutagenesis and functional analysis with structural models of the channel in the closed, pre-open and open states. This extensive network appeared to stabilize the open and pre-open states, but the network fragmented upon channel closure. In this study we have analyzed the gating kinetics of different mutations within key parts of this gating network. These results suggest that the structure of the transition state (TS), which connects the pre-open and closed states of the channel, more closely resembles the structure of the pre-open state. Furthermore, the G-loop, which occurs at the center of this extensive gating network, appears to become unstructured in the TS because mutations within this region have a ‘catalytic’ effect upon the channel gating kinetics.

As an important economic insect, Bombyx mori is also a useful model organism for lepidopteran insect. Integrins are evolutionarily conserved from sponges to humans, and play vital roles in many physiological and pathological processes. To explore their diverse functions of integrins in insect, eleven integrins including six α and five β subunits were cloned and characterized from silkworm. Our results showed that integrins from silkworm own more family members compared to other invertebrates. Among those α subunits, integrins α1, α2, and the other four subunits belong to PS1, PS2, and PS3 groups, respectively. The β subunits mainly gather in the insect βν group except the β1 subunit which belongs to the insect β group. Expression profiles demonstrated that the integrins exhibited distinct patterns, but were mainly expressed in hemocytes. α1 and β2 subunits are the predominant ones either in the embryogenesis or larva stages. Interestingly, integrins were significantly up-regulated after stimulated by 20-hydroxyecdysone (20-E) in vivo. These results indicate that integrins perform diverse functions in hemocytes of silkworm. Overall, our results provide a new insight into the functional and evolutionary features of integrins.