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In this paper, we briefly discuss the historical issues concerning the Biological and Toxin Weapons Convention (BTWC) and analyse the current situation after the COVID-19 pandemic with emphasis on the new developments at 9th Review Conference of the BTWC. In particular, we discuss the mission of the new working group agreed at the review conference to identify, examine, and develop specific and effective measures, including possible legally binding measures and to make recommendations to strengthen and institutionalise the Convention in all its aspects, and compare it with productive activities associated with the Chemical Weapons Convention (CWC) and the World Health Organisation (WHO). The enhanced role for civil society in support of the BTWC is then proposed with some solid examples from our own recent projects. We hope this analysis will help to facilitate new thinking about strengthening BTWC in coming years.

Abstract Intervertebral disc degenerative disease (IDD), which usually causes lower back and neck pain, is one of the most widespread musculoskeletal disorders and often causes a low quality of life. However, the surgical and conservative treatments commonly used in clinical practice are not effective. Previous studies have identified curcumin (Cur) as a potential therapeutic agent. However, its development in this regard has been limited due to its low dissolution, instability in water, and rapid metabolism. In this study, we developed a novel anti-inflammatory composite hydrogel scaffold with curcumin encapsulated in solid lipid nanoparticles and mixed it with gelatin methacrylate (GelMA) hydrogel to treat IDD. The hydrogel scaffold, denoted Cur-solid lipid nanoparticles (SLNs)/GelMA, promoted the restoration of Collagen type II (Col II) and aggrecan expression levels in vivo, indicating that the regeneration of the intervertebral discs was effective. Combined in vitro studies showed that Cur-SLNs inhibited the expression of the inflammatory factors TNF-α and IL-6. Additionally, immunofluorescence and western blotting experiments verified that Cur-SLNs regulated the recovery of Col II and aggrecan in an inflammatory environment and promoted the metabolic homeostasis of the extramedullary cell matrix. In conclusion, this study provides a new strategy to promote IDD regeneration, which brings new application prospects.

The number of failures serves as a critical indicator that dynamically impacts the reliability of self-announcing failure products, making it highly practical to incorporate the failure count into reliability management throughout the entire product life cycle. This paper investigates comprehensive methodologies for effectively managing the reliability of self-announcing failure products throughout both the warranty and post-warranty stages, taking into account factors such as the failure count, mission cycles, and limited time duration. Three renewable warranty strategies are introduced alongside proposed models for post-warranty replacements. By analyzing variables like the failure number, mission cycles, and time constraints, these proposed warranties provide practical frameworks for efficient reliability management during the warranty stage. Additionally, the introduced warranties utilize cost and time metrics to extract valuable insights that inform decision making and enable effective reliability management during the warranty stage. Moreover, this study establishes cost and time metrics for key post-warranty replacements, facilitating the development of individual cost rates and model applications in other post-warranty scenarios. Analyses of the renewable free-repair–replacement warranties demonstrate that establishing an appropriate number of failures as the replacement threshold can effectively reduce warranty-servicing costs and extend the coverage duration.

How to ensure the safe, effective, and ethical use of emerging biotechnologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing, is a global challenge. The occurrence of the “CRISPR babies” in 2018 publicly brought this issue into sharp focus, and led to comprehensive regulatory reforms in China and various countries around the world. The current article analyzes this event-driven regulatory reform in China by elaborating the most salient provisions designed to prevent risk and protect individual rights, public health, and social morality relating to human genome editing in four important sectors of law: biosecurity law, civil code, criminal law and patent law. It highlights that, although regulation is being undertaken, the gaps between the law and advancing technology remain discernible, at both a national and transnational level (i.e., the “double-pacing problem”). Further attention and collaboration will be required to address the ongoing challenges associated with the use of human genome editing.

It is not easy to be optimistic about international security at the present time, but 9th Review Conference of the Biological Weapons Convention in December 2022 agreed a renewed effort to strengthen the Convention after decades of stagnation. In March 2023 an agreement was also reached on an agenda and timetable for this effort over the next 2 years. Scientists have a long history of providing valuable input to such meetings, in this paper, we discuss how such input might best be provided with complicated challenges now facing the BWC and concluded that there is much that could be done, but greater coordination amongst scientists is needed.

Modulating a favorable inflammatory microenvironment that facilitates the recovery of degenerated discs is a key strategy in the treatment of intervertebral disc (IVD) degeneration (IDD). More interestingly, well-mechanized tissue-engineered scaffolds have been proven in recent years to be capable of sensing mechanical transduction to enhance the proliferation and activation of nucleus pulposus cells (NPC) and have demonstrated an increased potential in the treatment and recovery of degenerative discs. Additionally, existing surgical procedures may not be suitable for IDD treatment, warranting the requirement of new regenerative therapies for the restoration of disc structure and function. In this study, a light-sensitive injectable polysaccharide composite hydrogel with excellent mechanical properties was prepared using dextrose methacrylate (DexMA) and fucoidan with inflammation-modulating properties. Through numerous in vivo experiments, it was shown that the co-culture of this composite hydrogel with interleukin-1β-stimulated NPCs was able to promote cell proliferation whilst preventing inflammation. Additionally, activation of the caveolin1-yes-associated protein (CAV1-YAP) mechanotransduction axis promoted extracellular matrix (ECM) metabolism and thus jointly promoted IVD regeneration. After injection into an IDD rat model, the composite hydrogel inhibited the local inflammatory response by inducing macrophage M2 polarization and gradually reducing the ECM degradation. In this study, we propose a fucoidan-DexMA composite hydrogel, which provides an attractive approach for IVD regeneration.

In order to effectively implement the Tianjin Biosecurity Guidelines for Codes of Conduct for Scientists, biosecurity awareness-raising and education are essential because if these are not in place scientists will not understand the need for biosecurity codes of conduct. In an effort to assist in the implementation of the guidelines, a small-scale survey was carried out in early 2022 of biosecurity awareness-raising and education projects that have been developed over the last two decades to discoverwhat resources and experience have been accumulated. It is argued that the survey demonstrates that much of what is needed to implement the guidelines effectively has been developed, but that there are specific deficiencies that need to be remedied quickly. In particular, an updated teaching resource covering the core issues related to the Biological and Toxin Weapons Convention (BTWC) and the problem of dual use in scientific research needs to be made widely available and translated into at least the six official United Nations (UN) languages. Additionally, more specialists from the Humanities with expertise in ethics need to become involved in biosecurity awareness-raising and education activities. While advantage should be taken now of the available national, regional and international networks of people involved in related activities, it is suggested that in the longer term cooperation in biosecurity awareness-raising and education will benefit from the development of an equivalent organisation to the International Nuclear Security Education Network (INSEN) organised through the International Atomic Energy Agency (IAEA).

The aim of this study was as follows: 1) to investigate the effects of graded levels of N-carbamylglutamate (NCG) on performance, blood biochemical indexes, carcass traits and related indicators in growing-finishing pigs, and 2) to determine the optimal supplemental level. The toxicity of high-dose (much higher than recommended levels) NCG was assessed by routine blood tests and blood biochemical and histopathologic examinations of the heart, liver, spleen, lung, kidney and stomach. One hundred and forty-four growing-finishing pigs (Duroc × Large White × Landrace, 32.24 ± 1.03 kg) were used in a 74-d experiment and each treatment was replicated 6 times with 4 pigs (2 barrows and 2 gilts) per replicate. The dietary treatments were a corn-soybean meal basal diet supplemented with 0% (control), 0.05%, 0.1%, 0.15%, 0.2% or 1% NCG. The first 5 groups were used to explore the optimal supplemental level of NCG, while the control, 0.1% and 1% NCG groups were used to explore the safety of high-dose NCG. Compared with the normal control group, the final body weight and average daily gain tended to be higher in the 0.1% group (P = 0.08), the lean percentage tended to be higher in the 0.05% group (P = 0.07), the levels of free amino acids in the blood significantly increased in the 0.1% group (P

Abstract Globozoospermia (OMIM: 102530) is a rare type of teratozoospermia ( A; p.R1224Q) in the patient. This variant significantly reduced the protein expression of SSFA2. Immunofluorescence staining showed positive SSFA2 expression in the acrosome of human sperm. Liquid chromatography–mass spectrometry/mass spectrometry (LC–MS/MS) and Coimmunoprecipitation (Co-IP) analyses identified that GSTM3 and Actin interact with SSFA2. Further investigation revealed that for the patient, regular intracytoplasmic sperm injection (ICSI) treatment had a poor prognosis. However, Artificial oocyte activation (AOA) by a calcium ionophore (A23187) after ICSI successfully rescued the oocyte activation failure for the patient with the SSFA2 variant, and the couple achieved a live birth. This study revealed that SSFA2 plays an important role in acrosome formation, and the homozygous c.3671G > A loss-of-function variant in SSFA2 caused globozoospermia. SSFA2 may represent a new gene in the genetic diagnosis of globozoospermia, especially the successful outcome of AOA-ICSI treatment for couples, which has potential value for clinicians in their treatment regimen selections.

The devastating effects of the COVID-19 pandemic have acutely shown the need for maintaining robust international and national systems for biological security and ensuring that life sciences are used only for peaceful purposes. Life science stakeholders can play an important role in safeguarding scientific and technological advances in biology and related fields against accidental or deliberate misuse, not least because they are on the frontlines of driving innovation. In this paper, we argue that enhancing awareness and understanding of the risk of deliberate disease is essential for effective biological security. We first discuss the issue of ‘dual use’ in science and technology as it relates to disarmament and non-proliferation of weapons of mass destruction. Second, we review how scientist engagement with dual-use risks has been addressed in the context of the Biological and Toxin Weapons Convention (BTWC). Third, we report on the development of an innovative awareness-raising tool, a cartoon series, that can be used for engaging life science stakeholders with BTWC issues. Finally, we outline a set of practical considerations for promoting sustainable life science engagement with the BTWC.

Microcin C7 (McC) as a viable form of antimicrobial has gained substantial attention due to its distinctive antimicrobial activity, by targeting aspartyl tRNA synthetase. McC can be a potential solution against pathogenic microbial infections in the postantibiotic era. However, considering that degradation by digestive enzymes can disrupt the function of this peptide in the gastrointestinal tract, in this study, we attempt to design McC variants to overcome several barriers that may affect its stability and biological activity. The mccA gene encoding the McC peptide precursor was mutated and 12 new McC variants with trypsin resistance were found. The Yej+rimL− strain was used as an indicator to determine the minimum inhibitory concentrations (MICs). The results showed that three variants, including R2A, R2T and R2Q, among 12 variants formed by the replacement of the second arginine of the McC peptide with different amino acids, were resistant to trypsin and had an outstanding antimicrobial ability, with MIC values of 12.5, 25, and 25 μg/mL, respectively. Taken together, our findings show that the engineering of the site-directed mutagenesis of McC significantly enhances McC trypsin resistance and maintains a great antimicrobial activity.

The involvement of alterations in gut microbiota composition due to the use of antibiotics has been widely observed. However, a clear picture of the influences of gentamicin, which is employed for the treatment of bacterial diarrhea in animal production, are largely unknown. Here, we addressed this problem using piglet models susceptible to enterotoxigenic Escherichia coli (ETEC) F4, which were treated with gentamicin. Gentamicin significantly alleviated diarrhea and intestinal injury. Through 16s RNS sequencing, it was found that gentamicin increased species richness but decreased community evenness. Additionally, clear clustering was observed between the gentamicin-treated group and the other groups. More importantly, with the establishment of a completely different microbial structure, a novel metabolite composition profile was formed. KEGG database annotation revealed that arachidonic acid metabolism and vancomycin resistance were the most significantly downregulated and upregulated pathways after gentamicin treatment, respectively. Meanwhile, we identified seven possible targets of gentamicin closely related to these two functional pathways through a comprehensive analysis. Taken together, these findings demonstrate that gentamicin therapy for diarrhea is associated with the downregulation of arachidonic acid metabolism. During this process, intestinal microbiota dysbiosis is induced, leading to increased levels of the vancomycin resistance pathway. An improved understanding of the roles of these processes will advance the conception and realization of new therapeutic and preventive strategies.

Driven by the wide application of industrial software integrated with digital technologies, the real information of task cycles for some products in the real world can be monitored in real time and transmitted to the management center. Monitored task cycles hide consumers’ usage characteristics, which are signals of the products’ usage heterogeneity because they vary from one consumer to another consumer. By classifying monitored task cycles into different categories, this paper customizes two random maintenance models to ensure the life cycle reliability of the product with monitored task cycles on the basis of usage categories. The first model is customized using usage categories, the key objective of which is, from the perspective of heterogeneity, to ensure warranty-stage reliability. In view of using minimal repair service, the first model is named a random free repair warranty with heterogeneity (RFRW-H), which is modeled from the viewpoints of cost and time measures. By calculating the limits of cost and time measures, some specific cases are presented to model other warranties. The second model is customized using the same usage categories, which aims to ensure post-warranty-stage reliability. In view of using each of ‘whichever occurs first/last’, the second model is named a customized random periodic replacement first (CRPRF) model or a customized random periodic replacement last (CRPRL) model, respectively, which are modeled from the viewpoint of the cost rate function. By calculating the limits of the cost rate function, the cost rate functions of other maintenance models are obtained. Finally, from the numerical viewpoint, some of the features of the customized models are mined, and the performances are compared.

The recent global COVID-19 pandemic has had profound economic and social impacts on the world. It has highlighted an urgent need to strengthen existing international biosecurity governance mechanisms to prevent the misuse and malicious abuse of life science research and maintain international biological arms control norms. Biologists are at the front line of biotechnology development and are key to maintaining biosecurity awareness and moral self-discipline. As an important first step, biologists need to actively participate in the formulation and implementation of relevant biosecurity policies and measures to ensure their effectiveness and sustainability. Furthermore, efforts should be made to advocate for and promote the establishment of an ethical code of conduct for biologists to share safety responsibilities for global biosecurity. To maximize the impact of this ethical code of conduct, an effective approach to implementing codes of conduct for biologists at both national and international levels should be established under the framework of the Biological and Toxin Weapons Convention (BTWC).

Abstract 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. Video abstract

The ISSCR recently released new guidelines that relaxed the 14-day rule taking away the tough barrier, and this has rekindled relevant ethical controversies and posed a fresh set of challenges to each nation’s legislations and policies directly or indirectly. To understand its broad implications and the variation and impact of China’s relevant national policies, we reviewed and evaluated Chinese laws, administrative regulations, departmental rules, and normative documents on fundamental and preclinical research involving human embryos from 1985 to 2022 in this paper. We have historically examined whether these regulations, including a 14-day rule, had restrictions on human embryo research, and whether and how these policies affected human embryo and embryoid research in China. We also discussed and assessed the backdrop in which China has endeavored to handle such as the need for expanding debates among justice practice, academia, and the public, and the shifting external environment influenced by fast-developing science and technology and people’s culture and religions. In general, Chinese society commonly opposes giving embryos or fetuses the legal status of humans, presumably due to the Chinese public not seeming to have any strong religious beliefs regarding the embryo. On this basis, they do not strongly oppose the potential expansion of the 14-day rule. After the guidelines to strengthen governance over ethics in science, and technology were released by the Chinese government in 2022, Chinese policymakers have incorporated bioethics into the national strategic goals using a “People-Centered” approach to develop and promote an ecological civilization. Specifically, China follows the “precautionary principle” based on ethical priority as it believes that if scientific research carries any potential technological and moral risks on which no social ethical consensus has been attained, there would be a need to impose oversight for prevention and precaution. At the same time, China has adopted a hybrid legislative model of legislation and ethical regulations with criminal, civil and administrative sanctions and a 14-day limit specified within its national hESCs guidelines. This would certainly be a useful example for other countries to use when considering the possibility of developing a comprehensive, credible and sustainable regulatory framework.

The dual-use risk of infectious disease research using enhanced potential pandemic pathogens (ePPP), particularly gain-of-function (GOF) research, has been debated since 2011. As of now, research is supported on the condition that the research plan is reviewed and the actual experiment is supervised. However, the kinds of research conducted and what benefits they have brought to our society have not been adequately verified. Nevertheless, due to the COVID-19 pandemic that began at the end of 2019 and caused numerous deaths and wide economic disruption, the importance of infectious disease control from an international perspective has been recognized. Although complete control of the pandemic is still far off, positive signs include generating epidemiological trends based on genome analysis, therapeutic drug and vaccine development, clinical patient management, and public health policy interventions. In this context, the time has come to reconsider the true significance of GOF research on ePPP and the state of research governance in the post-COVID-19 era. In particular, the risks of such research are clearer than before, whereas its benefits seem less apparent. In this paper, we summarize the history of discussions on such GOF research, its significance in the light of the current COVID-19 pandemic, and the direction we shall take in the future.

In this paper, we systematically investigated and assessed China’s evolving medical biotechnology legislative and regulatory regime. 89 laws, rules, measures, guidelines, and views from 1985 to 2022 were systematically analogized and 28 were found to be involved in medical biotechnology legislation, including the recently passed Biosecurity Law. We classified the legislations and performed a comparative analysis for their legal binding based on the legal subject and extent of application, then further analyzes some of the legislative challenges in governing medical biotechnology risks in the context of China’s upgrading its regulatory and legal regime in the last 3 years. We concluded that policymakers in China have now incorporated medical biotechnology-related biosafety and biosecurity into the national strategic goals of a “People-Centered” approach to establish and foster an ecological civilization, particularly in the aftermath of the “He Jiankui affair.” Instead of relying on a patchwork of existing regulations and measures relating to the emerging field of medical biotechnology, China is attempting to integrate a patchwork of existing regulations and measures into a comprehensive legal framework, such as the constitution, National Security Law, Biosecurity Law, administrative regulations, departmental and local rules, and has begun to use the Civil Code and Criminal Law to explicitly identify actions relating to medical biotechnology. In general, China follows the “precautionary principle” as it thinks that uncertainty in science and technology should not be used to justify delaying the adoption of measures to prevent injuries or dangers, stating that whoever advances biotechnology must face the burden of proof of no harm. There would be a need to impose oversight for prevention and precaution if any biotechnology breakthrough that carries risks on which no scientific consensus has been reached. We argued that the “top-down” formulation of general objectives by the active political leadership and “bottom-up” innovation in the implementation are the keys to achieving these goals. Given the rapid advancements in medical biotechnology, countries all over the world must examine the governance landscape around biosafety and biosecurity and quickly consider options for their own comprehensive, credible, and long-lasting regulatory frameworks and experiences learned from China’s governance will help chart a scalable future roadmap.

In the present academic and engineering fields, every measure function of product reliability is modeled and estimated from the statistical perspective. These indicate that there universally exist differences in the reliabilities of new identical products that survive the burn-in test. On the basis of the differences in the reliabilities of new identical products, designing through-life maintenance models for managing the different reliabilities is a very practical topic for engineering fields. In this study, a random warranty model and a random maintenance model are designed by screening product reliabilities to manage the through-life reliabilities of products. In the random warranty model, the coverage areas of the warranty are set as the different areas for applying flexibility to them to control the warranty costs of new identical products with different reliabilities, and thus this warranty is called a flexible random free repair warranty (FRFRW) model. In the random maintenance model, two random replacement actions are customized by setting different replacement ranges for controlling maintenance costs and lengthening service life. This random maintenance model is called a customized random replacement (CRR), which is used to manage product reliabilities after the FRFRW expiration. These two random models are characterized from the mathematical perspective, and some derivatives of both are provided to model other maintenance problems. The characteristics of every model and the performance of the CRR are explored and illustrated through numerical experiments. The results show that the CRR is superior to random age replacement.

Assimilation of atlas is a rare skeletal malformation causing nerve compression with high risk of fatal. However, the genetic etiology of assimilation of atlas AOA is currently lacking. In this paper, the whole-exome sequencing (WES) analysis was employed to study a Chinese family having a sporadic proband son of assimilation of atlas AOA but other healthy family members. We identified a novel variant in ciliary rootlet coiled-coil gene (NM_014675.5 (CROCC): c.4702C>T (r.4702c>u, p.(Arg1568Cys)). The variant had different genotypes between the proband and healthy family members but with high conservations of “damage” to protein structure based on MutationTaster and SIFT prediction. CROCC gene can be obtained in both healthy (n=220) and non-mutated assimilation of atlas AOA patient samples (n=68) but absented in five sporadic patients with the novel variant. Furthermore, abnormal of cilia was observed after editing the target sequence on CROCC using CRISPR-Cas9. These results suggested that assimilation of atlas AOA might be caused by the mutation of CROCC: c.4702C>T (r.4702c>u, p.(Arg1568Cys)). With strong amino acid conservation and interaction regulation, the variant mutation could cause the signal disorder of skeletal development which may lead to the defective bone formation and finally cause the development of assimilation of atlas AOA.

In this report, we identify some of the key technical and political challenges currently facing the broader Chemical and Biological Weapon (CBW) regime- with a particular emphasis on major forthcoming diplomatic meetings. Most significantly the Ninth Review Conference of the Biological and Toxins Weapons Convention (1972) (BTWC) which will take place in 2022 and preparations for the Fifth Review Conference of the Chemical Weapons Convention (1993) (CWC), expected in 2023. This report is an output of an ongoing project, designed to stimulate thinking and discussion about these issues, within relevant stakeholder communities. The report provides an introduction to this issue area for the general reader before surveying key issues and developing a series of practical policy suggestions for further consideration.

With the help of advanced digital technologies, product managers can use monitored mission cycles to sustain product reliability. In this study, a random warranty model and a random replacement next (RRN) model are designed to sustain the through-life reliability of the product with monitored mission cycles. The designed random warranty, called a two-stage two-dimensional free repair warranty (2DFRW), can be carried out to sustain the reliability of the product during the warranty stage. In this warranty, ‘whichever occurs first and last’ is used to distinguish the coverage ranges of the latter stage warranties, which is to maintain the warranty fairness by removing the inequity of the former stage warranty. The RRN can be performed to sustain post-warranty reliability, which defines that if the limited number of mission cycles is completed before a working time, then the product will be replaced at next mission cycle completion to extend remaining service life; otherwise, the product will be replaced at a working time. Under the case of the two-stage 2DFRW, the cost rate of the RRN is constructed based on the renewable reward theorem. By simplifying the parameters, some derivative models of the cost rate are presented. Numerical analysis is performed to explore characteristics.

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.

Microcin C7 is an antimicrobial peptide produced by Escherichia coli, composed of a heptapeptide with a modified adenosine monophosphate. This study was performed to evaluate the effects of Microcin C7 as a potential substrate to traditional antibiotics on growth performance, immune functions, intestinal barrier, and cecal microbiota of broilers. In the current study, 300 healthy Arbor Acres broiler chicks were randomly assigned to one of five treatments including a corn–soybean basal diet and basal diet supplemented with antibiotic or 2, 4, and 6 mg/kg Microcin C7. Results showed that Microcin C7 significantly decreased the F/G ratio of broilers; significantly increased the levels of serum cytokine IL-10, immunoglobulins IgG and IgM, and ileal sIgA secretion; significantly decreased the level of serum cytokine TNF-α. Microcin C7 significantly increased villus height and V/C ratio and significantly decreased crypt depth in small intestine of broilers. Microcin C7 significantly increased gene expression of tight junction protein Occludin and ZO-1 and significantly decreased gene expression of pro-inflammatory and chemokine TNF-α, IL-8, IFN-γ, Toll-like receptors TLR2 and TLR4, and downstream molecular MyD88 in the jejunum of broilers. Microcin C7 significantly increased the number of Lactobacillus and decreased the number of total bacteria and Escherichia coli in the cecum of broilers. Microcin C7 also significantly increased short-chain fatty acid (SCFA) and lactic acid levels in the ileum and cecum of broilers. In conclusion, diet supplemented with Microcin C7 significantly improved growth performance, strengthened immune functions, enhanced intestinal barrier, and regulated cecal microbiota of broilers. Therefore, the antimicrobial peptide Microcin C7 may have the potential to be an ideal alternative to antibiotic.

Abstract 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.

The effects and safety of dietary supplementation with Microcin C7 (C7) were evaluated in 216 weaned piglets. The pigs were given a control corn–soybean meal basal diet or C7 diet (control diet supplemented with 250, 500, 750, 1000, or 5000 mg C7/kg diets). Compared with the control group, the 500 mg/kg C7 supplementation group had better intestinal morphological indicators (p < 0.05), which may help maintain intestinal epithelial function and increase the growth performance (p < 0.05) and apparent total tract digestibility (p < 0.05). The diarrhea indexes of the 250, 500, and 750 mg/kg groups were significantly lower than that of the control group at 0–28 d (p < 0.05), and the 500 mg/kg group had the lowest diarrhea indexes (linear and quadratic, p < 0.05). A comprehensive analysis showed that microbial structure was significantly correlated with the degree of diarrhea, and the diarrhea-alleviating effect of C7 may be related to its selective regulation of specific microbial taxa. The 250 and 500 mg/kg C7 supplementation also significantly improved several immune indices of piglets (p < 0.05). Compared with the control diet, 5000 mg/kg C7 supplementation had no significant adverse effect on all parameters. Overall, the 250–500 mg/kg dose had the best effect, and the highest dose (5000 mg/kg) posed no toxicity risk. Therefore, C7 appears safe for use as an alternative to antibiotic growth promoters in weaned piglets.

Driven by digital technologies, it is possible that high-tech equipment management personnel use monitored job cycles to ensure products’ operation and maintenance over their life cycle. By means of monitored job cycles, this paper designs two categories of random maintenance policies: a two-stage two-dimensional free repair warranty (2DFRW) policy and a random hybrid periodic replacement (RHPR) policy. The 2DFRW policy is performed to ensure the product’s operation and maintenance over the warranty stage. Under such a policy, a product is minimally repaired at each failure, and regions of the second-stage warranty are set to be diverse to remove all inequities produced by limitations of the first-stage warranty. The warranty cost of two-stage 2DFRW is built and discussed. The RHPR policy is modeled to ensure the product’s operation and maintenance over the post-warranty stage. Under this policy, depending on the final expiry of the two-stage 2DFRW, a bivariate random periodic replacement (BRPR) policy and a univariate random periodic replacement (URPR) policy are skillfully used to reduce the maintenance cost over the post-warranty stage and maximally extend the residual useful time of the product through the warranty. The expected cost rate over the product’s operation and maintenance cycle is derived on the basis of renewal rewarded theorem. The optimal RHPR policy is analyzed by minimizing the cost rate. The presented models are numerically analyzed to explore hidden characteristics.

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.

Facilitated by advanced digital technologies, reliability managers can monitor system working cycles during the whole life cycle. Such a technological realization can help reliability managers ensure system reliability in real time by monitoring working cycles. In this paper, by incorporating a limited random working cycle, rebate and charge into warranty theory, a random free repair warranty with rebate and charge (RFRW-RC) is devised to ensure system reliability during the warranty stage. Under RFRW-RC, the rebate removes manufacturers’ responsibility for continuing to ensure system reliability, while the charge is a support where manufacturers continue to ensure system reliability. The warranty cost of RFRW-RC is derived, and a random discrete free repair warranty (RDFRW) is presented by simplifying RFRW-RC. By mixing random age replacement last (RARL) and classic age replacement (CAR), a random hybrid age replacement (RHAR) is designed in order to ensure system reliability during the post-warranty stage. In such an RHAR, RARL is applied to extend the replacement time during the post-warranty stage in order to maximize the remaining life of the system through warranty, and CAR is used to lower the maintenance cost of the system through warranty. The cost rate of RHAR is modeled, and the cost rate of RDFRW is offered as well by discussing parameter values. The decision variable is optimized by minimizing the cost rate model. The properties of the presented models are explored from numerical perspectives.

In this study, by integrating preventive maintenance (PM) into a two-dimensional warranty region, a two-dimensional warranty with customized PM (2D warranty with customized PM) is proposed from the manufacturer’s perspective to reduce the warranty cost. The warranty cost of a 2D warranty with customized PM is derived. The manufacturer’s tradeoff between PM cost and minimal repair cost saving is obtained by choosing the proper reliability threshold and the number of customized PMs, and the advantage of a 2D warranty with customized PM is illustrated. Second, by integrating PM into the post-warranty period, a bivariate post-warranty maintenance (BPWM) policy is proposed from the consumer’s perspective to ensure the reliability of the product through the 2D warranty with customized PM. The expected cost rate model of BPWM is derived. Optimal BPWM is obtained in the numerical experiments. It is shown that a 2D warranty with customized PM is beneficial for both the manufacturer and the consumer, since both the manufacturer’s warranty cost and the consumer’s total cost are reduced.

A monitoring system (MS) has been used to monitor products’ job cycles. It is indicated that by incorporating the job cycle into the product’s life cycle, warrantors can devise novel warranty models and consumers can define and model random maintenances sustaining the reliability of the product through warranty. In this study, by incorporating limited job cycles and a refund into the traditional free repair warranty, a two-dimensional free repair warranty with a refund (2DFRW-R) is devised for guaranteeing the product reliability to consumers. Under the condition that 2DFRW-R is planned to guarantee product reliability, a bivariate random periodic replacement (BRPR) (i.e., a random periodic replacement where the accomplishment of the Nth job cycle and the replacement time T are designed as replacement limits) is modeled to sustain the post-warranty reliability from the point of view of the consumer. From the point of view of the warrantor, the warranty cost related to 2DFRW-R is derived, and the characteristics of 2DFRW-R are explored. From the point of view of consumers, the expected cost rate related to BRPR is constructed, and the existence and uniqueness of the optimal BRPR are summarized as well. By discussing parameters, several special cases are derived. The characteristics of the proposed models are analyzed in numerical examples.

The working cycle of the products can be supervised by sensors and other measuring technologies. This fact means that by supervising the working cycle, the manufacturer can devise a warranty policy, and by continuing to supervise the post-warranty working cycle, the consumer can model the post-warranty maintenance. However, in the literature, there is no associated work. Integrating a renewing free-replacement warranty (RFRW) and the number of working cycles, this paper proposes a two-dimensional renewing free-replacement warranty policy, which can be applied to warrant the product and analyze the related warranty cost. By extending the warranty policy to the post-warranty maintenance model, we investigate two kinds of post-warranty maintenance models, including the uniform post-warranty maintenance model and the customized post-warranty maintenance model. For each post-warranty maintenance model, we provide an algorithm to seek the optimum solution. Finally, we provide some numerical experiments to demonstrate the model. The numerical results show that for the produced warranty cost, the traditional RFRW is higher than the proposed warranty policy, and the customized policy is inferior to the uniform policy.

In this article, by considering both a limited number of failure replacements and a limited number of random working cycles as warranty terms, a hybrid warranty (HW) is designed from the manufacturer’s point of view to warrant the product that does successive projects at random working cycles. The warranty cost produced by HW is derived and analyzed. By defining that HW warrants the product, two types of post-warranty replacement models are investigated from the consumer’s point of view to ensure the reliability of the product through HW, i.e., customized post-warranty replacement and uniform post-warranty replacement. Depreciation expense is integrated into each post-warranty replacement. The expected cost rate model is presented for each post-warranty replacement and some special cases are obtained by setting parameters in the expected cost rate. Finally, sensitivities on both HW and post-warranty replacements are analyzed in numerical experiments. It is shown that when a limited number of failure replacements or/and a limited number of random working cycles are introduced to a warranty, the warranty cost can be reduced; and the performance of the uniform post-warranty replacement is superior to the customized post-warranty replacement.

The fecal bacteria transplantation (FMT) technique is indispensable when exploring the pathogenesis and potential treatments for microbiota-related diseases. For FMT clinical treatments, there are already systematic guidelines for donor selection, fecal bacterial separation, FMT frequency, and infusion methods. However, only a few studies have demonstrated the use of standardized FMT procedures for animal models used in theoretical research, creating difficulties for many new researchers in this field. In the present paper, we provide a brief overview of FMT and discuss its contribution to the current understanding of disease mechanisms that relate to microbiota. This protocol can be used to generate a commonly used FMT mouse model and provides a literature reference of customizable steps.

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic and relapsing inflammation within the gastrointestinal tract. Antibiotics have been used to treat IBD, primarily utilizing metronidazole. Although there does seem to be a treatment effect, the broad-spectrum antibiotics that have been used to date are crude tools and have many adverse effects. Available evidence suggests that the host microbiome is implicated in the pathogenesis of IBD, though the key bacteria remain unknown. If the bacterial population can be modified appropriately, the use of antibiotics will have a better therapeutic effect. In this study, mice were fed dextran sodium sulfate (DSS) solution for 5 days, followed by 5 days of normal drinking water, to investigate the gut microbiota response to colitis and the initial alteration of microbiota in recovery phase. Day 0 was considered the normal control, while day 5 and day 10 were considered the colitis mouse model progressive phase and recovery phase, respectively. Results showed that inflammation could induce proportional changes in the gut microbiota. Furthermore, transplanting the microbiota in progressive phase to antibiotic-induced microbiota-depleted mice could induce inflammation similar to colitis, which proves the importance of initial alteration of the microbiota for IBD recovery and the potential of the microbiota as a target for the treatment of IBD. Meanwhile, we have also identified three possible target microorganisms in the development of colitis, namely genera Muribaculaceae (negative correlation), Turicibacter (positive correlation) and Lachnospiraceae (negative correlation) in inflammation status through comprehensive analysis.

Poison of intestinal induce severe health problems in human infants and young animals due to contaminating foods and feedstuffs. With the emergence of public health concerns and high-speed diffuse of drug-opposition of bacteria, the adoption of antimicrobial peptides as potential candidates in treating pathogen infections raised up. Nature Microcin J25 (MccJ25), a class of lasso peptides separated from a fecal strain of E. coli, has been replied to display powerful antimicrobial behavior. Herein, the study was to assess the usefulness of biogenic MccJ25 in the prophylaxis of ETEC K88 infection in IPEC-J2 cells. In vitro antimicrobial activity against ETEC K88 and cytotoxicity of biogenic MccJ25 were determined first. To further understand how biogenic MccJ25 mediates its impact, ETEC K88 adhesion in cells, membrane permeability [as indicated by reduced release of lactate dehydrogenase (LDH)], transepithelial electrical resistance (TEER), barrier function, and proinflammatory cytokines levels were determined in IPEC-J2 cells after treatment with biogenic MccJ25 and challenge with ETEC K88. Biogenic MccJ25 had a minimum inhibitory concentration of 0.25 μg/mL against ETEC K88, decreased ETEC K88 adhesion in cells and did not cause cytotoxicity toward cells. Furthermore, biogenic MccJ25 protects against ETEC-induced barrier dysfunction by increasing the TEER, decreasing the LDH and promoting tight junction proteins (TJPs) by promoting the assembly of occludin and claudin-1 in the tight junction complex. Biogenic MccJ25 was further found to relieve inflammation responses through modulation of interleukine-6, IL-8 and tumor necrosis factor-α levels via inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor κB activation. In summary, biogenic MccJ25 can protects against ETEC K88-induced intestinal damage and inflammatory response, recommend the hidden adoption of biogenic MccJ25 as a novel prophylactic agent to reduce pathogen infection in animals, food or humans.

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.

We report an evaluation of the cytotoxicity of a series of electron-deficient (16-electron) half-sandwich precious metal complexes of ruthenium, osmium and iridium ([Os/Ru(η6-p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolato)] (1/2), [Ir(η5-pentamethylcyclopentadiene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolato)] (3), [Os/Ru(η6-p-cymene)(benzene-1,2-dithiolato)] (4/5) and [Ir(η5-pentamethylcyclopentadiene)(benzene-1,2-dithiolato)] (6)) towards RAW 264.7 murine macrophages and MRC-5 fibroblast cells. Complexes 3 and 6 were found to be non-cytotoxic. The anti-inflammatory activity of 1–6 was evaluated in both cell lines after nitric oxide (NO) production and inflammation response induced by bacterial endotoxin lipopolysaccharide (LPS) as the stimulus. All metal complexes were shown to exhibit dose-dependent inhibitory effects on LPS-induced NO production on both cell lines. Remarkably, the two iridium complexes 3 and 6 trigger a full anti-inflammatory response against LPS-induced NO production, which opens up new avenues for the development of non-cytotoxic anti-inflammatory drug candidates with distinct structures and solution chemistry from that of organic drugs, and as such with potential novel mechanisms of action.

Designing the “ideal” hydrogel/matrix which can load bone morphogenetic protein-2 (BMP-2) in a low dose and with a sustained release is the key for its successful therapeutic application to enhance osteogenesis. The current use of natural collagen sponges as hydrogel/matrix is limited due to the collagen matrix showing weak mechanical strength and unmanageable biodegradability. Furthermore, the efficiency and safe dose usage of the BMP-2 has never been seriously considered other than purely chasing the lowest dose usage and extended-release time. In this paper, we customized a novel enzymatically cross-linked recombinant human-like collagen (HLC) sponge with low immunogenicity, little risk from hidden viruses, and easy production. We obtained a unique vertical pore structure and the porosity of the HLC, which are beneficial for Mesenchymal stem cells (MSCs) migration into the HLC sponge and angiopoiesis. This HLC sponge loading with low dose BMP-2 (1 µg) possessed high mechanical strength along with a burst and a sustained release profile. These merits overcome previous limitations of HLC in bone repair and are safer and more sensitive than commercial collagens. For the first time, we identified that a 5 µg dose of BMP-2 can bring about the side effect of bone overgrowth through this sensitive delivery system. Osteoinduction of the HLC-BMP sponges was proved by an in vivo mouse ectopic bone model and a rat cranial defect repair model. The method and the HLC-BMP sponge have the potential to release other growth factors and aid other tissue regeneration. Additionally, the ability to mass-produce HLC in our study overcomes the current supply shortage, which limits bone repair in the clinic.