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SETD2 catalyzes methylation at lysine 36 of histone H3 and it has many disease connections. We investigated the substrate sequence specificity of SETD2 and identified nine additional peptide and one protein (FBN1) substrates. Our data showed that SETD2 strongly prefers amino acids different from those in the H3K36 sequence at several positions of its specificity profile. Based on this, we designed an optimized super-substrate containing four amino acid exchanges and show by quantitative methylation assays with SETD2 that the super-substrate peptide is methylated about 290-fold more efficiently than the H3K36 peptide. Protein methylation studies confirmed very strong SETD2 methylation of the super-substrate in vitro and in cells. We solved the structure of SETD2 with bound super-substrate peptide containing a target lysine to methionine mutation, which revealed better interactions involving three of the substituted residues. Our data illustrate that substrate sequence design can strongly increase the activity of protein lysine methyltransferases., Deutsche Forschungsgemeinschaft (German Research Foundation), German Academic Exchange Service (DAAD), Egyptian Ministry of Higher Education, Projekt DEAL

Manufacturing companies operate in an environment characterized as increasingly volatile, uncertain, complex and ambiguous. At the same time, their customer orientation makes it increasingly important to ensure high delivery reliability. Manufacturing sites within a supply network must therefore be resilient against events from the supply network. This requires deeper integration between the supply network and manufacturing control. Therefore, this article presents a concept to connect supply network and manufacturing more closely by integrating events from the supply network into manufacturing control’s decisions. In addition to the requirements, the concept describes the structure of the system as a control loop, a reinforcement learning-based controlling element as the central decision-making component, and the integration into the existing production IT landscape of a company as well as with latest internet of things (IoT) devices and cyber-physical systems. The benefits of the concept were elaborated in expert workshops. In summary, this approach enables an effective and efficient response to events from the supply network through smarter manufacturing control, and thus more resilient manufacturing.

In the field of food packaging, the addition of exfoliated layered silicates in polymers has been established to improve the polymers&rsquo, gas barrier properties. Using these polymers as coatings to protect smart textiles from oxidation and corrosion while maintaining their textile properties should significantly extend their lifetime and promote their market penetration. The aim of this study was to print new polymer dispersions containing layered silicates to protect screen-printed conductive structures, and to test the resulting samples. For this, appropriate printing parameters were determined by statistical design of experiments. According to these results, conductive structures were printed and protected with the selected coating. The abrasion resistance and the continuity of the protective layer of the printed samples were then measured. A continuous protective coating of approximately 70&ndash, 80 &micro, m thickness was applied on a conductive structure. The printed samples showed a very high resistance to abrasion (unchanged by 85,000 abrasion cycles) while remaining flexible and presenting a lower water vapor permeability (&lt, 2.5 g/m&sup2, d) than the coatings commonly used in the textile field.

Building Information Modeling (BIM) and Virtual reality (VR) have attracted growing attention within the architecture, engineering, and construction (AEC) industry in recent years. Integration of BIM and VR technology can develop workflow efficiency through enhanced common understanding and prepare students in architecture and engineering programs to become leaders of the AEC industry. However, the current shortage of AEC professionals trained in BIM and VR is still a barrier to collaborative working practice in this industry. This paper reviews previous work on the BIM, VR, and BIM-into-VR in AEC education/training to bridge this gap. It also presents an advanced framework to clarify creating and using the BIM model into VR workflow in the AEC industry through the integrated definition function (IDEF0) model. The authors further evaluated the BIM-into-VR applications in literature and real-life by surveying students’ learning performance in terms of eight characteristics relevant to the VR environment and students’ performance within two projects, one involving the “NASA Mars Habitat Project” and the other involving the “Norris Center Project” at Northwestern University. The results confirmed that BIM-into-VR usability and efficiency in improving students’ main learning performance characteristics: Learnability, Interoperability, Visualization, Real-world, Interaction, Creativity, Motivation, and Comfort. This study addresses the advantages of using BIM-into-VR in AEC programs. It also offers suggestions to AEC educators and students in implementing BIM-into-VR in different courses and creating a roadmap for their future as professionals in the AEC industry.

(1) Background: Epithelial&ndash, mesenchymal plasticity (EMP) is a dynamic process whereby epithelial carcinoma cells reversibly acquire morphological and invasive characteristics typical of mesenchymal cells. Identifying the methylation differences between epithelial and mesenchymal states may assist in the identification of optimal DNA methylation biomarkers for the blood-based monitoring of cancer. (2) Methods: Methylation-sensitive high-resolution melting (MS-HRM) was used to examine the promoter methylation status of a panel of established and novel markers in a range of breast cancer cell lines spanning the epithelial&ndash, mesenchymal spectrum. Pyrosequencing was used to validate the MS-HRM results. (3) Results: VIM, DKK3, and CRABP1 were methylated in the majority of epithelial breast cancer cell lines, while methylation of GRHL2, MIR200C, and CDH1 was restricted to mesenchymal cell lines. Some markers that have been used to assess minimal residual disease such as AKR1B1 and APC methylation proved to be specific for epithelial breast cell lines. However, RASSF1A, RAR&beta, TWIST1, and SFRP2 methylation was seen in both epithelial and mesenchymal cell lines, supporting their suitability for a multimarker panel. (4) Conclusions: Profiling DNA methylation shows a distinction between epithelial and mesenchymal phenotypes. Understanding how DNA methylation varies between epithelial and mesenchymal phenotypes may lead to more rational selection of methylation-based biomarkers for circulating tumour DNA analysis.

Objective Tegaserod is a 5-hydroxytryptamine type 4 (5-HT4) receptor agonist, formerly used in treating constipation predominant irritable bowel syndrome, which desensitizes 5-HT4 receptors in rat oesophagus and colon in vitro. Desensitization of 5-HT4 receptors is regulated by G-protein coupled receptor kinases. This study was designed to assess the effect of 5-HT4 receptor activation on the expression of GRK2 and GRK6 in the rat oesophagus and distal colon by acute administration of tegaserod. Results Rats were treated with a single dose of tegaserod (5 mg/kg) and tissue samples of the oesophagus and distal colon were prepared and level of GRK2 and GRK6 protein expression was determined using western blotting. The immunodensity of GRK2 and GRK6 was normalized against the loading control β-actin and compared with control animals. Acute administration of tegaserod for 1, 2, 3, 4, 6, and 8 h did not change significantly the immunodensity of GRK2 or GRK6 in the oesophagus or GRK2 in the distal colon when compared with control animals. This may indicate that the basal level of GRK2 and GRK6 expression is sufficient to regulate the desensitization of 5-HT4 receptors in acute drug treatment.

Objective Dichelobacter nodosus is the causative agent of footrot in sheep. Ovine footrot is a major problem in Australia that results in large economic losses and a represents a very significant animal welfare issue. D. nodosus is divided into 10 serogroups (A–I, M), based on sequence variation in the type IV fimbriae gene, fimA. Control of the bacteria is possible through use of serogroup-specific vaccination, however traditional identification of the serogroups of D. nodosus on infected sheep is time-consuming and costly. With the aim of reducing time and cost, a PCR assay was used to identify serogroups of D. nodosus directly from foot swabs of infected sheep in Victoria. Results It was shown that serogroup B was most common (10 locations), followed by A, G and H (4 locations), I and C (2 locations), D, E and F (1 location). Infections with multiple serotypes were observed in 50% of farms, with the remaining 50% having only a single serogroup detected. The ability to identify serogroups quickly and cheaply direct from foot swabs will aid the understanding of the epidemiology of D. nodosus and support control programs. Electronic supplementary material The online version of this article (10.1186/s13104-018-3229-5) contains supplementary material, which is available to authorized users.

© 2016 The Authors. Antimicrobial resistance (AMR) is an acknowledged crisis for humanity. Its genetic origins and dire potential outcomes are increasingly well understood. However, diagnostic techniques for monitoring the crisis are currently largely limited to enumerating the increasing incidence of resistant pathogens. Being the end-stage of the evolutionary process that produces antimicrobial resistant pathogens, these measurements, while diagnostic, are not prognostic, and so are not optimal in managing this crisis. A better test is required. Here, using insights from an understanding of evolutionary processes ruling the changing abundance of genes under selective pressure, we suggest a predictive framework for the AMR crisis. We then discuss the likely progression of resistance for both existing and prospective antimicrobial therapies. Finally, we suggest that by the environmental monitoring of resistance gene frequency, resistance may be detected and tracked presumptively, and how this tool may be used to guide decision-making in the local and global use of antimicrobials.

Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the diaminopimelate pathway of bacteria, yielding amino acids required for cell wall and protein biosyntheses. The essentiality of the enzyme to bacteria, coupled with its absence in humans, validates DHDPS as an antibacterial drug target. Conventional drug design efforts have thus far been unsuccessful in identifying potent DHDPS inhibitors. Here, we make use of contemporary molecular dynamics simulation and Markov state models to explore the interactions between DHDPS from the human pathogen Staphylococcus aureus and its cognate substrate, pyruvate. Our simulations recover the crystallographic DHDPS-pyruvate complex without a priori knowledge of the final bound structure. The highly conserved residue Arg140 was found to have a pivotal role in coordinating the entry of pyruvate into the active site from bulk solvent, consistent with previous kinetic reports, indicating an indirect role for the residue in DHDPS catalysis. A metastable binding intermediate characterized by multiple points of intermolecular interaction between pyruvate and key DHDPS residue Arg140 was found to be a highly conserved feature of the binding trajectory when comparing alternative binding pathways. By means of umbrella sampling we show that these binding intermediates are thermodynamically metastable, consistent with both the available experimental data and the substrate binding model presented in this study. Our results provide insight into an important enzyme-substrate interaction in atomistic detail that offers the potential to be exploited for the discovery of more effective DHDPS inhibitors and, in a broader sense, dynamic protein-drug interactions., Author Summary Interactions between proteins and ligands underpin many important biological processes, such as binding of substrates to their cognate enzymes in the process of catalysis. These interactions are complex, often requiring several intermediate steps to fully transition into the bound state. Here, we have used computational simulation to study binding of pyruvate to Dihydrodipicolinate synthase (DHDPS), an enzyme in the bacterial diaminopimelate pathway. In bacteria, such as the human pathogen S. aureus, DHDPS functions to make building blocks necessary for protein and bacterial cell wall biosyntheses. As the enzyme is absent in humans, yet essential for bacterial growth, DHDPS is a valid target for broad-range antibiotics. However, known DHDPS inhibitors show poor potency. One avenue that has not yet been taken into consideration for inhibitor design is the dynamics of DHDPS’s interaction with its reaction substrates (e.g. pyruvate). Using molecular dynamics simulation, we find that pyruvate binding to DHDPS must pass through a transition intermediate ‘hotspot’ in which the substrate is held in place by a dense network of noncovalent bonds. Given that many of the protein residues involved in this interaction are also shared by DHDPS from many pathogenic bacteria, this binding intermediate ‘hotspot’ may help in development of better broad-range DHDPS inhibitors.

The Trypanosoma brucei Hsp70/J-protein machinery plays an essential role in survival, differentiation, and pathogenesis of the protozoan parasite, and is an emerging target against African Trypanosomiasis. This study evaluated a set of small molecules, inspired by the malonganenones and nuttingins, as modulators of the chaperone activity of the cytosolic heat inducible T. brucei Hsp70 and constitutive TbHsp70.4 proteins. The compounds were assessed for cytotoxicity on both the bloodstream form of T. b. brucei parasites and a mammalian cell line. The compounds were then investigated for their modulatory effect on the aggregation suppression and ATPase activities of the TbHsp70 proteins. A structure−activity relationship for the malonganenone-class of alkaloids is proposed based upon these results.

Background Wind strongly impacts plant growth, leaf traits, biomass allocation, and stem mechanical properties. However, whether there are common whole-plant wind responses among different plant species is still unclear. We tested this null hypothesis by exposing four eudicot steppe species to three different wind treatments in a field experiment: reduced wind velocity using windbreaks, ambient wind velocity, and enhanced wind velocity through a novel methodology using wind-funneling baffles. Results Across the four species, wind generally decreased plant height, projected crown area, and stepwise bifurcation ratio, and increased root length and stem base diameter. In contrast, the response patterns of shoot traits, especially mechanical properties, to wind velocity were idiosyncratic among species. There was no significant difference in total biomass among different treatments; this might be because the negative effects on heat dissipation and photosynthesis of low wind speed during hot periods, could counteract positive effects during favorable cooler periods. Conclusions There are common wind response patterns in plant-size-related traits across different steppe species, while the response patterns in shoot traits vary among species. This indicates the species-specific ways by which plants balance growth and mechanical support facing wind stress. Our new field wind manipulation methodology was effective in altering wind speed with the intended magnitude. Especially, our field wind-funneling baffle system showed a great potential for use in future field wind velocity enhancement. Further experiments are needed to reveal how negative and positive effects play out on whole-plant performance in response to different wind regimes, which is important as ongoing global climatic changes involve big changes in wind regimes.

Objective With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the 3 months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone. Results For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (

The course of infection by SARS-CoV-2 frequently includes a long asymptomatic period, followed in some individuals by an immune dysregulation period that may lead to complications and immunopathology-induced death. This course of disease suggests that the virus often evades detection by the innate immune system. We suggest a novel therapeutic approach to mitigate the infection's severity, probability of complications and duration. We propose that priming an individual's innate immune system for viral attack shortly before it is expected to occur may allow pre-activation of the preferable trajectory of immune response, leading to early detection of the virus. Priming can be carried out, for example, by administering a standard vaccine or another reagent that elicits a broad anti-viral innate immune response. By the time that the expected SARS-CoV-2 infection occurs, activation cascades will have been put in motion and levels of immune factors needed to combat the infection will have been elevated. The infection would thus be cleared faster and with less complication than otherwise, alleviating adverse clinical outcomes at the individual level. Moreover, priming may also mitigate population-level risk by reducing need for hospitalizations and decreasing the infectious period of individuals, thus slowing the spread and reducing the impact of the epidemic. In view of the latter consideration, our proposal may have a significant epidemiological impact even if applied primarily to low-risk individuals, such as young adults, who often show mild symptoms or none, by shortening the period during which they unknowingly infect others. The proposed view is, at this time, an unproven hypothesis. Although supported by robust bio-medical reasoning and multiple lines of evidence, carefully designed clinical trials are necessary.

Background Numerous functional genomics approaches have been developed to study the model organism yeast, Saccharomyces cerevisiae, with the aim of systematically understanding the biology of the cell. Some of these techniques are based on yeast growth differences under different conditions, such as those generated by gene mutations, chemicals or both. Manual inspection of the yeast colonies that are grown under different conditions is often used as a method to detect such growth differences. Results Here, we developed a computerized image analysis system called Growth Detector (GD), to automatically acquire quantitative and comparative information for yeast colony growth. GD offers great convenience and accuracy over the currently used manual growth measurement method. It distinguishes true yeast colonies in a digital image and provides an accurate coordinate oriented map of the colony areas. Some post-processing calculations are also conducted. Using GD, we successfully detected a genetic linkage between the molecular activity of the plant-derived antifungal compound berberine and gene expression components, among other cellular processes. A novel association for the yeast mek1 gene with DNA damage repair was also identified by GD and confirmed by a plasmid repair assay. The results demonstrate the usefulness of GD for yeast functional genomics research. Conclusion GD offers significant improvement over the manual inspection method to detect relative yeast colony size differences. The speed and accuracy associated with GD makes it an ideal choice for large-scale functional genomics investigations.

Background The most frequently used tools in bioinformatics are those searching for similarities, or local alignments, between biological sequences. Since the exact dynamic programming algorithm is quadratic, linear-time heuristics such as BLAST are used. Spaced seeds are much more sensitive than the consecutive seed of BLAST and using several seeds represents the current state of the art in approximate search for biological sequences. The most important aspect is computing highly sensitive seeds. Since the problem seems hard, heuristic algorithms are used. The leading software in the common Bernoulli model is the SpEED program. Findings SpEED uses a hill climbing method based on the overlap complexity heuristic. We propose a new algorithm for this heuristic that improves its speed by over one order of magnitude. We use the new implementation to compute improved seeds for several software programs. We compute as well multiple seeds of the same weight as MegaBLAST, that greatly improve its sensitivity. Conclusion Multiple spaced seeds are being successfully used in bioinformatics software programs. Enabling researchers to compute very fast high quality seeds will help expanding the range of their applications.

Few would argue that science is better done in silos, with no transparency or sharing of methods and resources. Yet scientists and scientific stakeholders (e.g., academic institutions, funding agencies, journals) alike continue to find themselves at a relative impasse in the implementation of open science practices, slowing advancement and inadvertently perpetuating ongoing crises surrounding reproducibility. The present commentary draws attention to critical gaps in the current scientific ecosystem that perpetuate closed science practices and divide the community on how to best move forward. It also challenges scientists as individuals to improve the quality of their science by incorporating open practices in their everyday work, and provides a starter list of steps that any researcher can take to be the change they seek.

Neuronal responses characterized by regular tuning curves are typically assumed to arise from structured synaptic connectivity. However, many responses exhibit both regular and irregular components. To address the relationship between tuning curve properties and underlying circuitry, we analyzed neuronal activity recorded from primary motor cortex (M1) of monkeys performing a 3D arm posture control task and compared the results with a neural network model. Posture control is well suited for examining M1 neuronal tuning because it avoids the dynamic complexity of time-varying movements. As a function of hand position, the neuronal responses have a linear component, as has previously been described, as well as heterogeneous and highly irregular nonlinearities. These nonlinear components involve high spatial frequencies and therefore do not support explicit encoding of movement parameters. Yet both the linear and nonlinear components contribute to the decoding of EMG of major muscles used in the task. Remarkably, despite the presence of a strong linear component, a feedforward neural network model with entirely random connectivity can replicate the data, including both the mean and distributions of the linear and nonlinear components as well as several other features of the neuronal responses. This result shows that smoothness provided by the regularity in the inputs to M1 can impose apparent structure on neural responses, in this case a strong linear (also known as cosine) tuning component, even in the absence of ordered synaptic connectivity., Author Summary Relationships between the activity of single neurons and experimental parameters are often characterized by functions called tuning curves. Regular tuning-curve shapes are typically assumed to arise from structure in the synaptic inputs to each neuron. We found that the activities of neurons in primary motor cortex during an arm posture task exhibit both a regular component that fits a well-known tuning curve description, and heterogeneous irregular components that do not. Such complex components are often assumed to reflect residual noise. However, both the regular and irregular components are needed to optimally decode the commands that guide the muscles used in the task. We then asked what type of input structure was needed to generate neuronal responses with both regular and irregular elements. We constructed and analyzed a mathematical model, based on known physiology of the relevant brain regions that replicates the full spectrum of recorded neuronal responses. Surprisingly, the synaptic connectivity in this model is completely random.

Extravascular lung water (EVLW) is a basic symptom of congestive heart failure and other conditions. Computed tomography (CT) is standard to assess EVLW, but it requires ionizing radiation and radiology facilities. Lung ultrasound reverberation artifacts called B-lines have been used to assess EVLW. However, B-line artifact analysis relies on visual interpretation and subjects to inter-observer variability. We developed lung ultrasound surface wave elastography (LUSWE) to measure lung surface wave speed. This research aims to develop LUSWE to measure the change of lung surface wave speed due to lung water in an ex vivo swine lung model. The surface wave speeds of a fresh ex vivo swine lung were measured at four frequencies of 100 Hz, 200 Hz, 300 Hz, and 400 Hz. An amount of water was then filled into the lung through its trachea. Ultrasound imaging was used to guide the water filling until significant changes were visible on the imaging. The lung surface wave speeds were measured. An additional 120 ml of water was then filled into the lung. The lung surface wave speeds were then measured again. The results demonstrated that the lung surface wave speed decreased with respect to water content.

Summary Tumor-associated macrophages (TAMs) play an important role in tumor immunity and comprise of subsets that have distinct phenotype, function, and ontology. Transcriptomic analyses of human medulloblastoma, the most common malignant pediatric brain cancer, showed that medulloblastomas (MBs) with activated sonic hedgehog signaling (SHH-MB) have significantly more TAMs than other MB subtypes. Therefore, we examined MB-associated TAMs by single-cell RNA sequencing of autochthonous murine SHH-MB at steady state and under two distinct treatment modalities: molecular-targeted inhibitor and radiation. Our analyses reveal significant TAM heterogeneity, identify markers of ontologically distinct TAM subsets, and show the impact of brain microenvironment on the differentiation of tumor-infiltrating monocytes. TAM composition undergoes dramatic changes with treatment and differs significantly between molecular-targeted and radiation therapy. We identify an immunosuppressive monocyte-derived TAM subset that emerges with radiation therapy and demonstrate its role in regulating T cell and neutrophil infiltration in MB.

Therapeutic approaches for musculoskeletal tissue regeneration commonly employ growth factors (GFs) to influence neighboring cells and promote migration, proliferation, or differentiation. Despite promising results in preclinical models, the use of inductive biomacromolecules has achieved limited success in translation to the clinic. The field has yet to sufficiently overcome substantial hurdles such as poor spatiotemporal control and supraphysiological dosages, which commonly result in detrimental side effects. Physiological presentation and retention of biomacromolecules is regulated by the extracellular matrix (ECM), which acts as a reservoir for GFs via electrostatic interactions. Advances in the manipulation of extracellular proteins, decellularized tissues, and synthetic ECM-mimetic applications across a range of biomaterials have increased the ability to direct the presentation of GFs. Successful application of biomaterial technologies utilizing ECM mimetics increases tissue regeneration without the reliance on supraphysiological doses of inductive biomacromolecules. This review describes recent strategies to manage GF presentation using ECM-mimetic substrates for the regeneration of bone, cartilage, and muscle., Graphical abstract Image 1, Highlights • The contribution of growth factors during endogenous formation and repair of bone, cartilage, and muscle is reviewed. • The application and challenges of growth factors in clinical applications is discussed. • Carriers for growth factors are described, with an emphasis on the native extracellular matrix (ECM) and its constituents. • Frontiers in growth factor delivery are highlighted.

Biodegradable elastomers are important emerging biomaterials for biomedical applications, particularly in the area of soft-tissue engineering in which scaffolds need to match the physicochemical properties of native tissues. Here, we report novel fast photocurable elastomers with readily tunable mechanical properties, surface wettability, and degradability. These elastomers are prepared by a 5-min UV-irradiation of thiol-ene reaction systems of glycerol tripentenoate (GTP; a triene) or the combination of GTP and 4-pentenyl 4-pentenoate (PP; a diene) with a carefully chosen series of di- or tri-thiols. In the subsequent application study, these elastomers were found to be capable of overcoming delamination of myotubes, a technical bottleneck limiting the in vitro growth of mature functional myofibers. The glycerol-based elastomers supported the proliferation of mouse and human myoblasts, as well as myogenic differentiation into contractile myotubes. More notably, while beating mouse myotubes detached from conventional tissue culture plates, they remain adherent on the elastomer surface. The results suggest that these elastomers as novel biomaterials may provide a promising platform for engineering functional soft tissues with potential applications in regenerative medicine or pharmacological testing., Graphical abstract Image 1, Highlights • Biocompatible elastomers are formed by thiol-ene UV-curing within 5 min. • Tunable wettability, mechanical properties, and degradability of the elastomers. • The elastomers remarkably promote myogenic differentiation of myoblasts. • Myotubes on the elastomers exhibit enhanced attachment and beating frequency.

Primary ovarian insufficiency (POI) is an ovarian dysfunction that affects more than 1 % of women and is characterized by hormone imbalances that afflict women before the age of 40. The typical perimenopausal symptoms result from abnormal levels of sex hormones, especially estrogen. The most prevalent treatment is hormone replacement therapy (HRT), which can relieve symptoms and improve quality of life. However, HRT cannot restore ovarian functions, including secretion, ovulation, and fertility. Recently, as part of a developing field of regenerative medicine, stem cell therapy has been proposed for the treatment of POI. Thus, we recapitulate the literature focusing on the use of stem cells and biomaterials for POI treatment, and sum up the underlying mechanisms of action. A thorough understanding of the work already done can aid in the development of guidelines for future translational applications and clinical trials that aim to cure POI by using regenerative medicine and biomedical engineering strategies., Graphical abstract Graphical abstract: Multiple sources of MSCs and their roles in improving ovarian functions. MSCs isolated from various kinds of tissues and organs, such as bone marrow, adipose tissue, placenta, endometrium, and umbilical cord have been used as treatments for POI to stimulate follicle growth and improve oocyte quality, ovulation, and fertility.Image 1, Highlights • This paper illustrates the in-vivo, in-vitro, and cell-free treatments for POI using stem cells and biomaterials. • We provide basic theories and suggestions for future research and clinical therapy translation. • This review can help researcher to develop guidelines on stem cells treating POI.

Developmental engineering strategy needs the biomimetic composites that can integrate the progenitor cells, biomaterial matrices and bioactive signals to mimic the natural bone healing process for faster healing and reconstruction of segmental bone defects. We prepared the gelatin-reduced graphene oxide (GOG) and constructed the composites that mimicked the procallus by combining the GOG with the photo-crosslinked gelatin hydrogel. The biological effects of the GOG-reinforced composites could induce the bi-differentiation of bone marrow stromal cells (BMSCs) for rapid bone repair. The proper ratio of GOG in the composites regulated the composites' mechanical properties to a suitable range for the adhesion and proliferation of BMSCs. Besides, the GOG-mediated bidirectional differentiation of BMSCs, including osteogenesis and angiogenesis, could be activated through Erk1/2 and AKT pathway. The methyl vanillate (MV) delivered by GOG also contributed to the bioactive signals of the biomimetic procallus through priming the osteogenesis of BMSCs. During the repair of the calvarial defect in vivo, the initial hypoxic condition due to GOG in the composites gradually transformed into a well-vasculature robust situation with the bi-differentiation of BMSCs, which mimicked the process of bone healing resulting in the rapid bone regeneration. As an inorganic constituent, GOG reinforced the organic photo-crosslinked gelatin hydrogel to form a double-phase biomimetic procallus, which provided the porous extracellular matrix microenvironment and bioactive signals for the bi-directional differentiation of BMSCs. These show a promised application of the bio-reduced graphene oxide in biomedicine with a developmental engineering strategy., Graphical abstract Image 1, Highlights • The gelatin-reduced graphene oxide (GOG) was used to reinforce the photo-crosslinked gelatin hydrogel. • The GOG reinforced composite hydrogel was constructed to mimic the procallus for bone regeneration. • The bi-differentiation of bone marrow stromal cells (BMSCs) could be induced by the composite hydrogel.

Severe ischemic stroke damages neuronal tissue, forming irregular-shaped stroke cavities devoid of supporting structure. Implanting biomaterials to provide structural and functional support is thought to favor ingrowth of regenerated neuronal networks. Injectable hydrogels capable of in situ gelation are often utilized for stroke repair, but challenged by incomplete gelation and imprecise control over end-macrostructure. Injectable shape-memory scaffolds might overcome these limitations, but are not explored for stroke repair. Here, we report an injectable, photoluminescent, carbon-nanotubes-doped sericin scaffold (CNTs-SS) with programmable shape-memory property. By adjusting CNTs' concentrations, CNTs-SS′ recovery dynamics can be mathematically calculated at the scale of seconds, and its shapes can be pre-designed to precisely match any irregular-shaped cavities. Using a preclinical stroke model, we show that CNTs-SS with the customized shape is successfully injected into the cavity and recovers its pre-designed shape to well fit the cavity. Notably, CNTs-SS’ near-infrared photoluminescence enables non-invasive, real-time tracking after in vivo implantation. Moreover, as a cell carrier, CNTs-SS not only deliver bone marrow mesenchymal stem cells (BMSCs) into brain tissues, but also functionally promote their neuronal differentiation. Together, we for the first time demonstrate the feasibility of applying injectable shape-memory scaffolds for stroke repair, paving the way for personalized stroke repair., Graphical abstract Image 1, Highlights • A customized stroke cavity repairing strategy using preformed sericin-based scaffold with programmable shape-memory properties. • Injectability facilitates its' in vivo delivery and minimizes implantation injury. • Embedded CNTs endowing this biomaterial neuro-differentiation-promoting activity.

The tumor development and metastasis are closely related to the structure and function of the tumor microenvironment (TME). Recently, TME modulation strategies have attracted much attention in cancer immunotherapy. Despite the preliminary success of immunotherapeutic agents, their therapeutic effects have been restricted by the limited retention time of drugs in TME. Compared with traditional delivery systems, nanoparticles with unique physical properties and elaborate design can efficiently penetrate TME and specifically deliver to the major components in TME. In this review, we briefly introduce the substitutes of TME including dendritic cells, macrophages, fibroblasts, tumor vasculature, tumor-draining lymph nodes and hypoxic state, then review various nanoparticles targeting these components and their applications in tumor therapy. In addition, nanoparticles could be combined with other therapies, including chemotherapy, radiotherapy, and photodynamic therapy, however, the nanoplatform delivery system may not be effective in all types of tumors due to the heterogeneity of different tumors and individuals. The changes of TME at various stages during tumor development are required to be further elucidated so that more individualized nanoplatforms could be designed., Graphical abstract Image 1, Highlights • In responsive to the changes in TME, nanoparticles target tumor microenvironment and enhance the therapeutic effect. • Nanoparticles modulate the activation and maturation of DC. • Nanoparticles could reprogram polarization of TAM and relieve hypoxia. • Nanoparticles could transfer the immunosuppressive TME to immunosupportive.

Sea squirt, as a highly invasive species and main biofouling source in marine aquaculture, has seriously threatened the biodiversity and aquaculture economy. On the other hand, a conductive biomaterial with excellent biocompatibility, and appropriate mechanical property from renewable resources is urgently required for tissue engineering patches. To meet these targets, we presented a novel and robust strategy for sustainable development aiming at the marine pollution via recycling and upgrading the waste biomass-sea squirts and serving as a renewable resource for functional bio-scaffold patch in tissue engineering. We firstly demonstrated that the tunic cellulose derived natural self-conductive scaffolds successfully served as functional cardiac patches, which significantly promote the maturation and spontaneous contraction of cardiomyocytes both in vitro and enhance cardiac function of MI rats in vivo. We believe this novel, feasible and “Trash to Treasure” strategy to gain cardiac patches via recycling the waste biomass must be promising and beneficial for marine environmental bio-pollution issue and sustainable development considering the large-scale consumption potential for tissue engineering and other applications., Graphical abstract Image 1, Highlights • Fouling sea squirts used as scaffold materials can effectively solve the pollution problem of marine aquaculture. • The natural electrical conductivity of the sea squirts derived scaffold is similar to that of natural myocardial tissue. • Cellulose scaffold from sea squirts has a good orientation, and its structure is similar to natural myocardial tissue. • Sea squirts cellulose derived natural self-conductive scaffolds were successfully served as the functional cardiac patches.

The mechanical environment and anisotropic structure of the heart modulate cardiac function at the cellular, tissue and organ levels. During myocardial infarction (MI) and subsequent healing, however, this landscape changes significantly. In order to engineer cardiac biomaterials with the appropriate properties to enhance function after MI, the changes in the myocardium induced by MI must be clearly identified. In this review, we focus on the mechanical and structural properties of the healthy and infarcted myocardium in order to gain insight about the environment in which biomaterial-based cardiac therapies are expected to perform and the functional deficiencies caused by MI that the therapy must address. From this understanding, we discuss epicardial therapies for MI inspired by the mechanics and anisotropy of the heart focusing on passive devices, which feature a biomaterials approach, and active devices, which feature robotic and cellular components. Through this review, a detailed analysis is provided in order to inspire further development and translation of epicardial therapies for MI., Graphical abstract In this paper, we review cardiac mechanostructure and epicardial devices for cardiac support and relate their design to biological remodeling and heart function after myocardial infarction. Reprinted from Ref. [1] with permission from Elsevier (left panel); reproduced with permission of SynCardia, © 2020 (middle panel). All rights reserved; reprinted from Ref. [2] with permission (right panel); the publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers.Image 1, Highlights • Mechanics and structure, two key factors in cardiac function, significantly change during MI and subseqent healing. • Epicardial restraint devices have been explored clinically as a way to mechanically reinforce the ventricular wall post- MI. • Current research demonstrates the potential of epicardial devices to preserve heart function post-MI.

Trans-catheter arterial embolization (TAE) plays an important role in treating various diseases. The available embolic agents lack X-ray visibility and do not prevent the reflux phenomenon, thus hindering their application for TAE therapy. Herein, we aim to develop a multifunctional embolic agent that combines the X-ray radiopacity with local procoagulant activity. The barium sulfate nanoparticles (BaSO4 NPs) were synthesized and loaded into the polyvinyl alcohol/chitosan (PVA/CS) to prepare the radiopaque BaSO4/PVA/CS microspheres (MS). Thereafter, thrombin was immobilized onto the BaSO4/PVA/CS MS to obtain the thrombin@BaSO4/PVA/CS MS. The prepared BaSO4/PVA/CS MS were highly spherical with diameters ranging from 100 to 300 μm. In vitro CT imaging showed increased X-ray visibility of BaSO4/PVA/CS MS with the increased content of BaSO4 NPs in the PVA/CS MS. The biocompatibility assessments demonstrated that the MS were non-cytotoxic and possessed permissible hemolysis rate. The biofunctionalized thrombin@BaSO4/PVA/CS MS showed improved hemostatic capacity and facilitated hemostasis in vitro. Additionally, in vivo study performed on a rabbit ear embolization model confirmed the excellent X-ray radiopaque stability of the BaSO4/PVA/CS MS. Moreover, both the BaSO4/PVA/CS and thrombin@BaSO4/PVA/CS MS achieved superior embolization effects with progressive ischemic necrosis on the ear tissue and induced prominent ultrastructural changes in the endothelial cells. The findings of this study suggest that the developed MS could act as a radiopaque and hemostatic embolic agent to improve the embolization efficiency., Graphical abstract Image 1, Highlights • Excellent in vitro and in vivo visibility of BaSO4/PVA/CS MS. • Excellent cytocompatibility and hemocompatibility of BaSO4/PVA/CS MS. • Enhanced hemostatic capacity and hemostasis of thrombin@BaSO4/PVA/CS MS. • Potential application of thrombin@BaSO4/PVA/CS MS for in vivo embolization.

Poly(α-l-lysine) (PLL) is a class of water-soluble, cationic biopolymer composed of α-l-lysine structural units. The previous decade witnessed tremendous progress in the synthesis and biomedical applications of PLL and its composites. PLL-based polymers and copolymers, till date, have been extensively explored in the contexts such as antibacterial agents, gene/drug/protein delivery systems, bio-sensing, bio-imaging, and tissue engineering. This review aims to summarize the recent advances in PLL-based nanomaterials in these biomedical fields over the last decade. The review first describes the synthesis of PLL and its derivatives, followed by the main text of their recent biomedical applications and translational studies. Finally, the challenges and perspectives of PLL-based nanomaterials in biomedical fields are addressed., Graphical abstract Image 1, Highlights • Focusing on biomedical applications of PLL-based nanomaterials. • Discussing antibacterial agents, delivery systems, bio-sensing, bio-imaging, and tissue engineering in detail. • Addressing perspectives of PLL-based nanomaterials in biomedical fields.

As an important phenomenon to monitor disease development, cell signaling usually takes place at the interface between organisms/cells or between organisms/cells and abiotic materials. Therefore, finding a strategy to build the specific biomedical interfaces will help regulate information transmission and produce better therapeutic results to benefit patients. In the past decades, plasmas containing energetic and active species have been employed to construct various interfaces to meet biomedical demands such as bacteria inactivation, tissue regeneration, cancer therapy, and so on. Based on the potent functions of plasma modified surfaces, this mini-review is aimed to summarize the state-of-art plasma-activated interfaces and provide guidance to researchers to select the proper plasma and processing conditions to design and prepare interfaces with the optimal biological and related functions. After a brief introduction, plasma-activated interfaces are described and categorized according to different criteria including direct plasma-cells interfaces and indirect plasma-material-cells interfaces and recent research activities on the application of plasma-activated interfaces are described. The authors hope that this mini-review will spur interdisciplinary research efforts in this important area and expedite associated clinical applications., Graphical abstract Image 1, Highlights • The Interfaces between organisms/cells and abiotic materials are crucial for cell signaling. • Plasmas containing energetic and active species are potent tool to construct biomedical interfaces. • The objective here is to summarize recent plasma-activated interfaces to spur interdisciplinary efforts for clinical applications.

Tissue engineering provides a promising avenue for treating cartilage defects. However, great challenges remain in the development of structurally and functionally optimized scaffolds for cartilage repair and regeneration. In this study, decellularized cartilage extracellular matrix (ECM) and waterborne polyurethane (WPU) were employed to construct WPU and WPU-ECM scaffolds by water-based 3D printing using low-temperature deposition manufacturing (LDM) system, which combines rapid deposition manufacturing with phase separation techniques. The scaffolds successfully achieved hierarchical macro‐microporous structures. After adding ECM, WPU scaffolds were markedly optimized in terms of porosity, hydrophilia and bioactive components. Moreover, the optimized WPU-ECM scaffolds were found to be more suitable for cell distribution, adhesion, and proliferation than the WPU scaffolds. Most importantly, the WPU-ECM scaffold could facilitate the production of glycosaminoglycan (GAG) and collagen and the upregulation of cartilage-specific genes. These results indicated that the WPU-ECM scaffold with hierarchical macro‐microporous structures could recreate a favorable microenvironment for cell adhesion, proliferation, differentiation, and ECM production. In vivo studies further revealed that the hierarchical macro‐microporous WPU-ECM scaffold combined with the microfracture procedure successfully regenerated hyaline cartilage in a rabbit model. Six months after implantation, the repaired cartilage showed a similar histological structure and mechanical performance to that of normal cartilage. In conclusion, the hierarchical macro‐microporous WPU-ECM scaffold may be a promising candidate for cartilage tissue engineering applications in the future.

Skin wounds can lead to numerous complications with dangerous health consequences. In this work, magnetite nanoparticles were doped with different concentrations of antimicrobial silver (Ag) ions and incorporated into the electrospun nanofibrous ε-polycaprolactone (PCL) scaffolds. Nanoparticles and scaffolds with various Ag contents were characterized using a range of physicochemical techniques. Ag entered magnetite as cations and preferentially positioned at tetrahedral sites, introducing lattice distortions and topographic irregularities. Amorphization of the structure due to accommodation of Ag expanded the lattice in the bulk and contracted it on the surface, where broadened distribution of Fe–O coordinations was detected. Promoting spin canting and diminishing the double exchange interaction through altered distribution of ferric and ferrous ions, Ag softened the magnetism of magnetite. By making the nanoparticle structure more defective, Ag modified the interface with the polymer and promoted the protrusion of the nanoparticles from the surface of the polymeric nanofibers, thus increasing their roughness and hydrophilicity, with positive repercussions on cell adhesion and growth. Both the viability of human melanocytes and the antibacterial activity against E. coli and S. aureus increased with the concentration of Ag in the magnetite phase of the scaffolds. Skin wound healing rate in rats also increased in direct proportion with the concentration of Ag in the magnetite phase, and no abnormalities in the dermal and epidermal tissues were visible on day 10 in the treatment group. These results imply an excellent potential of these composite nanofibrous scaffolds for use as wound dressings and in other reconstructive skin therapies., Graphical abstract Image 1, Highlights • Electrospun nanofibrous polymeric wound dressings interspersed with magnetite nanoparticles doped with Ag ions were fabricated. • Detailed physicochemical characterization is provided with aid of diffractometric, spectroscopic and microscopic techniques. • Both the viability of melanocytes and the antibacterial activity increased with the addition of Ag ions. • Skin wound healing rate in rats increased to 51 and 92 % on day 10 for dressings without and with Ag, respectively, relative to control. • Animals treated with Ag-doped dressings displayed no atrophy of sebaceous glands and necrosis of hair follicles of control animals.

Here, evodiamine (EVO) and the photosensitizer indocyanine green (ICG) were integrated into a liposomal nanoplatform for noninvasive diagnostic imaging and combinatorial therapy against oral squamous cell carcinoma (OSCC). EVO, as an active component extracted from traditional Chinese medicine, not only functioned as an antitumor chemotherapeutic agent but was also capable of 68Ga-chelation, thus working as a contrast agent for positron emission tomography/computed tomography (PET/CT) imaging. Moreover, EVO could exhibit peroxidase-like catalytic activity, converting endogenous tumor H2O2 into cytotoxic reactive oxygen species (ROS), enabling Chemo catalytic therapy beyond the well-known chemotherapy effect of EVO. As proven by in vitro and in vivo experiments, guided by optical imaging and PET/CT imaging, we show that the theragnostic liposomes have a significant inhibiting effect on in situ tongue tumor through photodynamic therapy combined with chemodynamic chemotherapy., Graphical abstract Image 1, Highlights • Proposing water-soluble nanoliposomes to solve the problem of drug insoluble in water. • Evodiamine is found to have HRP mimic catalase activity. • EI@lipo displays photodynamic/chemodynamic/chemo therapy abilities. • Ei@Lipo significantly inhibits tongue tumor through in situ.

Mesoporous bioactive glasses (MBGs) are promising materials for regenerative medicine, due to their favorable properties including bioactivity and degradability. These key properties, but also their surface area, pore structure and pore volume are strongly dependent on synthesis parameters and glass stoichiometry. However, to date no systematic study on MBG properties covering a broad range of possible compositions exists. Here, 24 MBG compositions in the SiO2–CaO–P2O5 system were synthesized by varying SiO2 (60–90 mol %), CaO and P2O5 content (both 0 to 40 mol-%), while other synthesis parameters were kept constant. Mesopore characteristics, degradability and bioactivity were analysed. The results showed that, within the tested range of compositions, mesopore formation required a molar SiO2 content above 60% but was independent of CaO and P2O5 content. While mesopore size did not depend on glass stoichiometry, mesopore arrangement was influenced by the SiO2 content. Specific surface area and pore volume were slightly altered by the SiO2 content. All materials were degradable; however, degradation as well as bioactivity, i.e. the ability to form a CaP mineral on the surface, depended on stoichiometry. Major differences were found in early surface reactions in simulated body fluid: where some MBGs induced direct hydroxyapatite crystallization, high release of calcium in others resulted in calcite formation. In summary, degradation and bioactivity, both key parameters of MBGs, can be controlled by glass stoichiometry over a broad range while leaving the unique structural parameters of MBGs relatively unaffected. This allows targeted selection of material compositions for specific regenerative medicine applications., Graphical abstract Image 1, Highlights • Mesoporous bioactive glasses can be obtained over a broad range of compositions. • In the SiO2/CaO/P2O5 system up to 15 mol-% P2O5 allow ordered porosity. • In SiO2/P2O5 glasses, up to 30 mol-% P2O5 are possible. • Bioactivity and degradation can be tailored by controlling stoichiometry.

Macrophage-mediated inflammation compromises bone repair in diabetic patients. Electrical signaling cues are known to regulate macrophage functions. However, the biological effects of electrical microenvironment from charged biomaterials on the immune response for regulating osteogenesis under diabetic conditions remain to be elucidated. Herein the endogeneous electrical microenvironment of native bone tissue was recapitulated by fabricating a ferroelectric BaTiO3/poly (vinylidene fluoridetrifluoroethylene) (BTO/P(VDF-TrFE)) nanocomposite membrane. In vitro, the polarized BaTiO3/poly (vinylidene fluoridetrifluoroethylene) (BTO/P(VDF-TrFE)) nanocomposite membranes inhibited high glucose-induced M1-type inflammation, by effecting changes in cell morphology, M1 marker expression and pro-inflammatory cytokine secretion in macrophages. This led to enhanced osteogenic differentiation of human bone marrow mesenchymal stem cells (BM-MSCs). In vivo, the biomimetic electrical microenvironment recapitulated by the polarized nanocomposite membranes switched macrophage phenotype from the pro-inflammatory (M1) into the pro-healing (M2) phenotype, which in turn enhanced bone regeneration in rats with type 2 diabetes mellitus. Mechanistic studies revealed that the biomimetic electrical microenvironment attenuated pro-inflammatory M1 macrophage polarization under hyperglycemic conditions by suppressing expression of AKT2 and IRF5 within the PI3K-AKT signaling pathway, thereby inducing favorable osteo-immunomodulatory effects. Our study thus provides fundamental insights into the biological effects of restoring the electrical microenvironment conducive for osteogenesis under DM conditions, and offers an effective strategy to design functionalized biomaterials for bone regeneration therapy in diabetic patients., Graphical abstract Within the restored electrical microenvironment mediated by polarized ferroelectric nanocomposite membrane, macrophages exhibit suppressed M1 polarization and enhanced M2 polarization. The restored electrical microenvironment downregulates AKT2-IRF5 signaling that induces macrophages to the M2 phenotype, which indicates a favorable osteo-immunomodulatory effects. Hence mimicking the endogeneous electrical microenvironment promotes osteogenic differentiation of BM-MSCs mediated by macrophages, thereby improving bone regeneration.Image 1, Highlights • Electrical microenvironment recapitulated by BTO membranes switched pro-inflammatory M1 into pro-healing M2 phenotype. • The macrophage phenotype transformation from M1 to M2 promotes bone regeneration in rats with type 2 diabetes mellitus. • Restored electrical microenvironment attenuated M1 macrophage polarization via downregulation of AKT2-IRF5.

The deep burn skin injures usually severely damage the dermis with the loss of hair follicle loss, which are difficult to regenerate. Furthermore, severe burns often accompanied with large amount of wound exudates making the wound moist, easily infected, and difficult to heal. Therefore, it is of great clinical significance to develop wound dressings to remove wound exudates and promote hair follicle regeneration. In this study, a sandwich-structured wound dressing (SWD) with Janus membrane property was fabricated by hot compression molding using hydrophilic zinc silicate bioceramics (Hardystonite, ZnCS) and hydrophobic polylactic acid (PLA). This unique organic/inorganic Janus membrane structure revealed excellent exudate absorption property and effectively created a dry wound environment. Meanwhile, the incorporation of ZnCS bioceramic particles endowed the dressing with the bioactivity to promote hair follicle regeneration and wound healing through the release of Zn2+ and SiO32− ions, and this bioactivity of the wound dressing is mainly attributed to the synergistic effect of Zn2+ and SiO32− to promote the recruitment, viability, and differentiation of hair follicle cells. Our study demonstrates that the utilization of the Janus membrane and synergistic effect of different type bioactive ions are effective approaches for the design of wound dressings for burn wound healing., Graphical abstract Image 1, Highlights • A sandwich-structured wound dressing is constructed using ZnCS ceramic powder and PLA fiber membrane (ZnCS-SWD). • ZnCS-SWD has Janus membrane property to absorb wound exudate unidirectionally from wound bed to the dressing. • The combination of Zn2+ and SiO32- ions is found to have a synergistic effect to promote burn wound healing.

A close relationship has been reported to exist between cadherin-mediated cell–cell adhesion and integrin-mediated cell mobility, and protein tyrosine phosphatase 1B (PTP1B) may be involved in maintaining this homeostasis. The stable residence of mesenchymal stem cells (MSCs) and endothelial cells (ECs) in their niches is closely related to the regulation of PTP1B. However, the exact role of the departure of MSCs and ECs from their niches during bone regeneration is largely unknown. Here, we show that the phosphorylation state of PTP1B tyrosine-152 (Y152) plays a central role in initiating the departure of these cells from their niches and their subsequent recruitment to bone defects. Based on our previous design of a PTP1B Y152 region-mimicking peptide (152RM) that significantly inhibits the phosphorylation of PTP1B Y152, further investigations revealed that 152RM enhanced cell migration partly via integrin αvβ3 and promoted MSCs osteogenic differentiation partly by inhibiting ATF3. Moreover, 152RM induced type H vessels formation by activating Notch signaling. Demineralized bone matrix (DBM) scaffolds were fabricated with mesoporous silica nanoparticles (MSNs), and 152RM was then loaded onto them by electrostatic adsorption. The DBM-MSN/152RM scaffolds were demonstrated to induce bone formation and type H vessels expansion in vivo. In conclusion, our data reveal that 152RM contributes to bone formation by coupling osteogenesis with angiogenesis, which may offer a potential therapeutic strategy for bone defects., Graphical abstract Image 1, Highlights • PTP1B plays a dual regulatory role in cadherin- and integrin-related pathways. • Inhibition of PTP1B Y152 phosphorylation enhances the departure of MSCs from the stem cell niche. • DBM-MSN/152RM scaffolds coordinate the recruitment of MSCs and ECs. • DBM-MSN/152RM scaffolds promote bone regeneration and angiogenesis in bone defects.

Dünya üzerinde bulunan bitkilerin çoğunun hem yaraların iyileşme sürecini hızlandırmada hem de yaralanmaya bağlı enfeksiyonların tedavisinde etkili maddelere sahip oldukları bilinmektedir. Bilim insanları tarafından yapılan daha önceki çalışmalar, karayosunlarının ve ciğerotlarının da çeşitli bakteri ve mantarlara karşı antimikrobiyal ve antifungal aktiviteye sahip olduklarını göstermiştir. Bu çalışmada Philonotis seriata Mitt, Porella arboris-vitae (With.) Grolle, Porella platyphylla (L.) Pfeiff, Syntrichia calcicola J.J.Amann türlerinin etil alkol ekstraktlarının 8 gram pozitif, 9 gram negatif bakteri ve 1 maya olan toplam 18 suş üzerindeki antimikrobiyal aktivitelerinin analizi yapılmıştır. Yapılan analiz sonucunda tüm karayosunu ve ciğerotu örneklerinin birkaç suşa karşı antimikrobiyal aktiviteye sahip olduğu ve özellikle gram pozitif olan Staphylococcus aureus ve gram negatif olan Klebsiella pneumoniae üzerinde belirgin bir antimikrobiyal etki gösterdiği belirlenmiştir.

The aim of this study is to reveal the current taxa list of liverwort flora for the Kastamonu province by examining the previous floristic studies which were done within the boundaries of the province. As a result of assessing the literature data floristic studies, 1 hornwort (Anthoceratophyta) taxon and 73 liverwort (Marchantiophyta) taxa belonging 29 families were listed. The richest Familia is Scapaniaceae with 9 taxa., Bu çalışmada; Kastamonu ili sınırları içerisinde gerçekleştirilmiş ciğerotu florası araştırmaları incelenerek, ilin ciğerotu florasının güncel takson listesinin hazırlanması amaçlanmıştır. Buna göre alanda yapılan çalışmaların incelenmesi neticesinde Kastamonu ilinde 1 boynuzotu (Anthoceratophyta) taksonu ile 29 familyaya ait 73 ciğerotu (Marchantiophyta) taksonu bulunduğu tespit edilmiştir. Scapaniaceae familyası 9 takson ile en zengin familya konumundadır.

Stable integration of hydrogel implants with host tissues is of critical importance to cartilage tissue engineering. Designing and fabricating hydrogels with high adhesive strength, stability and regeneration potential are major challenges to be overcome. This study fabricated injectable adhesive hyaluronic acid (HA) hydrogel modified by aldehyde groups and methacrylate (AHAMA) on the polysaccharide backbone with multiple anchoring mechanisms (amide bond through the dynamic Schiff base reaction, hydrogen bond and physical interpenetration). AHAMA hydrogel exhibited significantly improved durability and stability within a humid environment (at least 7 days), together with higher adhesive strength (43 KPa to skin and 52 KPa to glass), as compared to commercial fibrin glue (nearly 10 KPa) and HAMA hydrogel (nearly 20 KPa). The results showed that AHAMA hydrogel was biocompatible and could be easily and rapidly prepared in situ. In vitro cell culture experiments showed that AHAMA hydrogel could enhance proliferation (1.2-folds after 3 days) and migration (1.5-folds after 12 h) of bone marrow stem cells (BMSCs), as compared to cells cultured in a culture dish. Furthermore, in a rat osteochondral defect model, implanted AHAMA hydrogel significantly promoted integration between neo-cartilage and host tissues, and significantly improved cartilage regeneration (modified O'Driscoll histological scores of 16.0 ± 4.1 and 18.3 ± 4.6 after 4 and 12-weeks of post-implantation in AHAMA groups respectively, 12.0 ± 2.7 and 12.2 ± 2.8 respectively in HAMA groups, 9.8 ± 2.4 and 11.5 ± 2.1 respectively in untreated groups). Hence, AHAMA hydrogel is a promising adhesive biomaterial for clinical cartilage regeneration and other biomedical applications., Graphical abstract Image 1, Highlights • Adhesive hydrogel composed of single natural polymer component. • The single component enhance stable and easy to use in surgical operation of hydrogel. • Adhesive hydrogel exhibited strong adhesive strength through multiple anchoring mechanisms. • Adhesive hydrogel promoted integration between neo-cartilage and host tissues, drastically improved cartilage regeneration.

Magnesium metal (Mg) is a promising material for stent applications due to its biocompatibility and ability to be resorbed by the body. Manufacturing of stents by laser cutting has become an industry standard. Our alternative approach uses photo-chemical etching to transfer a pattern of the stent onto a Mg sheet. In this study, we present three stages of creating and validating a stent prototype, which includes design and simulation using finite element analysis (FEA), followed by fabrication based on AZ31 alloy and, finally, in vivo testing in peripheral arteries of domestic pigs. Due to the preliminary character of this study, only six stents were implanted in two domestic farm pigs weighing 25–28 kg and they were evaluated after 28 days, with an interim follow-up on day 14. The left and right superficial femoral, the left iliac, and the right renal artery were selected for this study. The diameters of the stented artery segments were evaluated at the time of implantation, on day 14 and then, finally, on day 28, by quantitative vessel analysis (QVA) using fluoroscopic imaging. Optical Coherence Tomography (OCT) imaging displayed some malposition, breaks, stacking, and protrusion into the lumen at the proximal, distal, and mid-sections of the stented arteries. The stents degraded with time, but simultaneously became embedded in the intima. After 28 days, the animals were euthanized, and explanted vessels were fixed for micro-CT imaging and histology studies. Micro-CT imaging revealed stent morphological and volumetric changes due to the in-body degradation. An in vivo corrosion rate of 0.75 mm/year was obtained by the CT evaluation. The histology suggested no-life threatening effects, although moderate injury, inflammation, and endothelialization scores were observed., Graphical abstract Image 1

In the field of bone defect repair, 3D printed scaffolds have the characteristics of personalized customization and accurate internal structure. However, how to construct a well-structured vascular network quickly and effectively inside the scaffold is essential for bone repair after transplantation. Herein, inspired by the unique biological structure of “lotus seedpod”, hydrogel microspheres encapsulating deferoxamine (DFO) liposomes were prepared through microfluidic technology as “lotus seeds”, and skillfully combined with a three-dimensional (3D) printed bioceramic scaffold with biomimetic “lotus” biological structure which can internally grow blood vessels. In this composite scaffold system, DFO was effectively released by 36% in the first 6 h, which was conducive to promote the growth of blood vessels inside the scaffold quickly. In the following 7 days, the release rate of DFO reached 69%, which was fundamental in the formation of blood vessels inside the scaffold as well as osteogenic differentiation of bone mesenchymal stem cells (BMSCs). It was confirmed that the composite scaffold could significantly promote the human umbilical vein endothelial cells (HUVECs) to form the vascular morphology within 6 h in vitro. In vivo, the composite scaffold increased the expression of vascularization and osteogenic related proteins Hif1-α, CD31, OPN, and OCN in the rat femoral defect model, significantly cutting down the time of bone repair. To sum up, this “lotus seedpod” inspired porous bioceramic 3D printed scaffold with internal vascularization functionality has broad application prospects in the future., Graphical abstract A lotus seedpod-inspired internal vascularized 3D printed bioceramic scaffold with internal vascularization and osteogenesis functionalities was successfully constructed. Bioceramic scaffold takes the role of the lotus “coat” while the DFO-liposome-loaded injectable hydrogel microspheres as “lotus seeds”. The “lotus seeds” are injected directly into the scaffold to construct an internally vascularized bioceramic scaffold to promote the repair bone defects.Image 1, Highlights • 3D printed bioceramic scaffold with biomimetic structure for blood vessels. • Well-structured vascular network quickly and effectively inside the scaffold. • Promoting the growth of blood vessels inside the scaffold quickly. • Increased the expression of vascularization and osteogenic related proteins Hif1-α.

The present study is based on moss specimens collected from several urban habitats in Ankara University Beşevler 10. Yıl Campus in the year 2019. As a result of identifications of 94 bryophyte specimens collected from the campus area, a total of 28 species belonging to 7 families and 17 genera were determined. Six of them are new record for B7 grid-square. Pottiaceae (9 species) and Orthotrichaceae (6 species) are the two largest families in the campus area.

Lipopolysaccharide (LPS) plays an important role in metabolic syndrome (MetS) and other gut-derived diseases, and detoxifying LPS is considered to be a fundamental approach to prevent and treat these diseases. Here, inspired by the feeding behaviour of scavenger, novel microfluidic microcapsules with alkaline phosphatase (ALP) encapsulation and the scavenger-like molecular sieve shell are presented for cleaning intestinal LPS. Benefiting from the precisely controlled of the pore size and microfluidic electrospray, the generated microcapsules were imparted with porous molecular-sieve shells and ALP encapsulated active cores. These microcapsules could continuously work as an intestinal scavenger after colonized in intestine. It has been demonstrated that the microcapsules could englobe LPS while inhibit the permeation of digestive enzyme, and this ability contributes to promising ALP's activity, protecting cells at the presence of LPS and reducing inflammation. In addition, this scavenger inspired microcapsule could effectively decrease the LPS in organs, reduce inflammation and regulating fat metabolism in vivo. These features make the ALP encapsulated microcapsules an ideal candidate for treating MetS and other LPS related diseases., Graphical abstract The proposed intestinal scavenger microcapsules fabricated by microfluidic electrospray were imparted with scavenger-like molecular sieve shell are presented for cleaning intestinal LPS. It has been demonstrated that the microcapsules could englobe LPS while inhibit the permeation of digestive enzyme, and this ability contributes to promising ALP's activity, protecting cells at the presence of LPS and reducing inflammation.Image 1, Highlights • A microfluidic electrospray microcapsule with molecular sieve shell. • Microcapsules protect the alkaline phosphatase from digestive enzyme. • Microcapsules allow the permeation of lipopolysaccharide.

Iodine ion is one of the most indispensable anions in living organisms, particularly being an important substance for the synthesis of thyroid hormones. Curcumin is a yellow-orange polyphenol compound derived from the rhizome of Curcuma longa L., which has been commonly used as a spice and natural coloring agent, food additives, cosmetics as well as Chinese medicine. However, excess curcumin may cause DNA inactivation, lead to a decrease in intracellular ATP levels, and trigger the tissue necrosis. Therefore, quantitative detection of iodine and curcumin is of great significance in the fields of food and life sciences. Herein, we develop nitrogen-doped fluorescent carbon dots (NCDs) as a multi-mechanism detection for iodide and curcumin in actual complex biological and food samples, which was prepared by a one-step solid-phase synthesis using tartaric acid and urea as precursors without adding any other reagents. An assembled NCDs-Hg2+ fluorescence-enhanced sensor for the quantitative detection of I− was established based on a fluorescence “turn-off-on” mechanism in a linear range of 0.3–15 μM with a detection limit of 69.4 nM and successfully quantified trace amounts of I− in water samples and urine sample. Meanwhile, the as-synthesized NCDs also can be used as a fluorescent quenched sensor for curcumin detection based on the synergistic internal filtration effect (IFE) and static quenching, achieving a good linear range of 0.1–20 μM with a satisfactory detection limit of 29.8 nM. These results indicate that carbon dots are potential sensing materials for iodine and curcumin detection for the good of our health., Graphical abstract Image 1, Highlights • Facile synthesis of nitrogen-doped carbon dots with tartaric acid and urea as precursors without any additives. • High-sensitive determination of I− with assembled NCDs-Hg2+ fluorescence-enhanced sensor. • Fluorescence sensor for curcumin detection with good linear response, high specificity, and high sensitivity. • Successful applications for I− and curcumin in water, urine, and foods.

Both phototherapy via photocatalysts and physical puncture by artificial nanostructures are promising substitutes for antibiotics when treating drug-resistant bacterial infectious diseases. However, the photodynamic therapeutic efficacy of photocatalysts is seriously restricted by the rapid recombination of photogenerated electron–hole pairs. Meanwhile, the nanostructures of physical puncture are limited to two-dimensional (2D) platforms, and they cannot be fully used yet. Thus, this research developed a synergistic system of Ag3PO4 nanoparticles (NPs), decorated with black urchin-like defective TiO2 (BU–TiO2-X/Ag3PO4). These NPs had a decreased bandgap compared to BU-TiO2-X, and BU-TiO2-X/Ag3PO4 (3:1) exhibited the lowest bandgap and the highest separation efficiency for photogenerated electron–hole pairs. After combination with BU-TiO2-X, the photostability of Ag3PO4 improved because the oxygen vacancy of BU-TiO2-X retards the reduction of Ag+ in Ag3PO4 into Ag0, thus reducing its toxicity. In addition, the nanospikes on the surface of BU-TiO2-X can, from all directions, physically puncture bacterial cells, thus assisting the hybrid's photodynamic therapeutic effects, alongside the small amount of Ag+ released from Ag3PO4. This achieves synergy, endowing the hybrid with high antibacterial efficacy of 99.76 ± 0.15% and 99.85 ± 0.09% against Escherichia coli and Staphylococcus aureus, respectively, after light irradiation for 20 min followed by darkness for 12 h. It is anticipated that these findings may bring new insight for developing synergistic treatment strategies against bacterial infectious diseases or pathogenic bacterial polluted environments., Graphical abstract Image 1, Highlights • BU-TiO2-X/Ag3PO4 (3:1) hybrid improved the photostability of Ag3PO4. • BU-TiO2-X/Ag3PO4 (3:1) hybrid exhibited outstanding photodynamic therapeutic effects. • The nanospikes from all directions on the BU-TiO2-X physically punctured bacterial cells. • The physical puncture combined with the Ag+ released by Ag3PO4 had long-term bacteriostatic efficacy.

Brain barrier is both a protective permeability hurdle and a limitation site where therapeutic agents are excluded to enter the target region. Designing drug vehicle to overcome this notorious barrier bottle is challenging. Herein, we construct a stimuli-responsive self-assembled nanovesicle that delivers water-soluble drugs to prevent the efflux transport of brain barriers by responding to the endogenously occurring signals in Alzheimer's disease (AD) brain microenvironment. Once stimuli-responsive vesicles are accumulated in intracerebrally, the intrinsically occurring legumain endopeptidase cleaves the Ac-Ala-Ala-Asn-Cys-Asp (AK) short peptide on the drug vesicles to expose the 1,2 thiol amino group to cyclize with the cyano groups on 2-cyano-6-aminobenzothiazole (CABT) of the chaperone vesicles, thus triggering the formation of cross-linked micrometre-scale vesicles. Such a structural alteration completely prevents further brain barriers efflux. The superior neuroprotective capacity of cross-linked vesicles is validated in senescence accelerated mouse prone 8 (SAMP8). This smart multi-drug delivery vesicle is promising to serve as a powerful system for AD treatment and can be adapted for the therapy of other central nervous system (CNS) disorders., Graphical abstract a) Responsive cross-linked of large compound vesicles formed in intracerebrally. b) Inhibition of brain barrier efflux and synergistic treatment of AD.Image 1, Highlights • Drug efflux is a bottleneck for treating many disorders, such as Alzheimer's diseases (AD). • The key to success in drug brain parenchyma anchoring is specific targeting delivery. • Functionalized vesicles provided the possibility of inhibiting the efflux transport and increasing drug brain enrichment. • Legumain-induced aggregated multi-drug delivery vesicle is promising to serve as a powerful system for AD treatment.