Search

Introduction and aims Skin fibrosis, a common fibrotic condition that currently has no specific treatments or cures, is caused by persistent activation of skin fibroblasts after tissue injury that Results in excessive scarring, can cause severe disability and seriously affect morbidity. This study aims to uncover the specific fibroblast subsets and molecular pathways that are integral to this sustained fibroblast activation using a bleomycin-induced skin fibrosis mouse model that accurately recapitulates the human disease. Methods We have successfully shown that 2 weeks (early) and 4 weeks (advanced) of bleomycin injections Results in an increasing severity of skin fibrosis characteristics. Following this treatment, we performed single-cell RNA sequencing (scRNA-Seq) using control, early and advanced fibrotic tissue and identified fibroblast subclusters and specific gene signatures that are altered across the time course and may play a role in the fibrotic phenotype we observe. The use of advanced scRNA-Seq analysis techniques such as SCENIC and regulon analysis has allowed us to further characterize the changes in fibroblast states during fibrosis. Results Our scRNA-Seq data show a loss of fibroblast heterogeneity alongside the emergence of two main subclusters with distinct gene signatures in the advanced fibrotic state. While proliferation is minimal, RNA velocity analysis indicates that the increase in cell count is due to the convergence of neighbouring fibroblast subclusters. The pronounced profibrotic gene expression point to its key role in driving skin fibrosis and we are now exploring the therapeutic potential of chemically or genetically targeting this subcluster. Conclusions Our novel skin fibrosis time course scRNA-Seq dataset allows us to compare the cellular and molecular changes in early and advanced fibrotic lesions in order to identify the key fibroblast subpopulations, molecular regulators and connective tissue alterations promoting fibrotic tissue repair. Our findings will support the development of new fibroblast-targeted fibrosis therapies in skin and potentially in other organs. [ABSTRACT FROM AUTHOR]

Introduction and aims Junctional epidermolysis bullosa (JEB) is a devastating hereditary skin disorder characterized by severe fragility of skin and mucus membrane, emerges as blistering with little or no trauma. The major classification of JEB includes JEB intermediate and JEB severe; the latter is the most common subtype, which is the result of loss of function mutations in the skin basement membrane protein laminin-332. Lacking this protein impairs basement membrane adhesion of epidermal keratinocytes and leads to deregulated epidermal–dermal crosstalk. The skin dermis is composed of multiple fibroblast subpopulations with different functions in skin homeostasis and repair; however, their specific involvement in skin diseases is largely unknown. Here, we investigate how fibroblast subpopulations, namely papillary and reticular fibroblasts, impact JEB disease progression and skin regeneration. Methods Three-dimensional (3D) organotypic (OT) combining healthy (control) and diseased (JEB) keratinocytes cells with distinct fibroblast subpopulations from different anatomical sites were developed and analysed by immunohistochemistry and RNA-Seq. Results JEB OTs with papillary fibroblasts showed increased epidermal growth, invagination of basal layer and deregulated differentiation compared with reticular fibroblasts. RNA-Seq analysis revealed altered activity in key signalling including immune, cytokine, gap junction, mitogen-activated protein kinase and remodelling of keratinization and ECM proteins, particularly in JEB OT cultured with papillary fibroblast. JEB OTs and cells also demonstrated variation in cell proliferation and activation of transforming growth factor-β1 and immune cell signalling. Currently, we are targeting identified signalling pathways in our two-dimensional and 3D cell culture models and identifying druggable targets, before testing selected candidates in our JEB mouse disease model for further preclinical validation. Conclusions By dissecting the pathological signalling interactions between keratinocytes and distinct fibroblast subpopulations, our goal is to identify new therapeutic target to improve the skin health and regeneration in patients with JEB. [ABSTRACT FROM AUTHOR]

Introduction and aims Fibroblasts, the major cell population in connective tissue, are the guardians of the extracellular matrix homeostasis. In adult tissue they exist in a quiescent state that can persist for years, but upon tissue injury, they become rapidly activated and re-enter the cell cycle, followed by deposition and reorganization of the dermal matrix. The fundamental mechanism by which fibroblasts can maintain quiescence and be primed for prompt activation is currently unknown. Deregulations of this process in the skin and other organs is associated with several pathologies including fibrosis or chronic wounds. Notably, rapid fibroblast state switching is also observed during skin development, where a tightly controlled change from a highly proliferative state to a quiescent state promotes extracellular matrix deposition and maturation of the dermal architecture. Understanding the shared mechanisms and differences between development and wound healing will help in the development of tissue regenerative therapies. Methods Using dermal development as a model for fibroblast state switching, we integrated several single-cell RNA-Seq and assay for transposase-accessible chromatin-Seq datasets of whole skin during embryonic and postnatal growth. Our novel integrated multiomics single-cell dataset can recapitulate skin developmental changes observed in vivo and reveal the major regulatory networks. Results We identified the activating protein (AP)-1 member cJun as the key regulator of fibroblast state switching in skin development and wound repair. Mechanistically, in quiescent adult fibroblasts cJun is highly transcribed, but the protein is constantly ubiquitinated and degraded, priming fibroblasts for rapid activation when needed. Upon injury cJun ubiquitination is reduced, allowing an accumulation of cJun leading to a change in AP-1 dimer composition at the chromatin level, inhibiting fibroblast quiescence and promoting proliferation and activation. Conclusions In normal wounds cJun accumulation is inhibited during the advanced (remodelling) wounding phase; however, chronic wounds and fibrotic disease conditions show a continuous and pathological cJun stabilization, which can be targeted through pharmacological intervention. [ABSTRACT FROM AUTHOR]

Partial volume effects (PVE) present a source of confound for the analysis of functional imaging data. Correction for PVE requires estimates of the partial volumes (PVs) present in an image. These estimates are conventionally obtained via volumetric segmentation, but such an approach may not be accurate for complex structures such as the cortex. An alternative is to use surface-based segmentation, which is well-established within the literature. Toblerone is a new method for estimating PVs using such surfaces. It uses a purely geometric approach that considers the intersection between a surface and the voxels of an image. In contrast to existing surface-based techniques, Toblerone is not restricted to use with any particular structure or modality. Evaluation in a neuroimaging context has been performed on simulated surfaces, simulated T1-weighted MRI images and finally a Human Connectome Project test-retest dataset. A comparison has been made to two existing surface-based methods; in all analyses Toblerone’s performance either matched or surpassed the comparator methods. Evaluation results also show that compared to an existing volumetric method (FSL FAST), a surface-based approach with Toblerone offers improved robustness to scanner noise and field non-uniformity, and better inter-session repeatability in brain volume. In contrast to volumetric methods, a surface-based approach negates the need to perform resampling which is advantageous at the resolutions typically used for neuroimaging. [ABSTRACT FROM AUTHOR]

Studies the electron spin resonance of AlO, GaO and InO. Observation of hyperfine interactions; Pulsed laser vaporization of the metals; All-electron CI calculations.

Discusses techniques for establishing a list of periodicals in academic libraries. Recommendation for conducting studies on collection use; Implementation of bibliographic instruction programs; Articulation of a collection development policy; Measurement of the efficiency of the list in assisting researchers.

Skin fibrosis, a common scarring condition that currently has no curative treatments, is caused by persistent activation of fibroblasts after tissue injury or inflammation that results in excessive connective tissue deposition, leading to severe disability, organ malfunction and increased morbidity. This study aims to uncover the early and advanced changes in different fibroblast subsets and molecular pathways that are integral to pathological fibroblast activation using a bleomycin-induced skin fibrosis mouse model that recapitulates well the human disease. We have shown that 2 weeks (early) and 4 weeks (advanced) of subcutaneous bleomycin injections result in an increasing severity of skin fibrosis, characterized by increased dermal thickness, collagen deposition, inflammation, and loss of dermal fibroblasts and adipocytes. We performed single-cell RNA sequencing and successfully isolated 14 944 control, 16 344 early and 6860 advanced fibrotic cells. We identified the changes in fibroblast subclusters and gene signatures that are altered across the time course. Using CellChat, we are dissecting the specific signalling crosstalk between different fibroblast subpopulations and other skin cells, promoting a profibrotic phenotype and locking fibroblasts in an activated state. Furthermore, we are intersecting our novel data set with publicly available wound healing transcriptomic data, allowing us to examine how fibroblast subpopulations, behaviour and key signalling pathways vary in healthy wounding healing and pathological scarring. To understand the impact that changes in extracellular matrix biomechanics elicit on profibrotic fibroblast fate, we are correlating our histological and transcriptomic analysis with nanoindentation atomic force microscopy imaging throughout the fibrotic time course. This novel multidisciplinary approach allows us to compare the cellular and molecular changes in early and advanced fibrotic lesions, identifying the key fibroblast subpopulations, molecular regulators and connective tissue alterations promoting fibrotic tissue repair. Our findings will support the development of new fibroblast-targeted fibrosis therapies in skin and potentially other organs. [ABSTRACT FROM AUTHOR]

Vortex shedding within laminar separation bubbles forming over the suction side of a NACA 0018 airfoil is studied through a combination of high-speed flow visualization and boundary layer measurements. Wind tunnel experiments are performed at a chord-based Reynolds number of 100,000 and four angles of attack. The high-speed flow visualization is complemented by quantitative velocity and surface pressure measurements. The structures are shown to originate from the natural amplification of small-amplitude disturbances, and the shear layer roll-up is found to occur coherently across the span. However, significant cycle-to-cycle variations are observed in vortex characteristics, including shedding period and roll-up location. The formation of the roll-up vortices precedes the later stages of transition, during which these structures undergo significant deformations and breakdown to smaller scales. During this stage of flow development, vortex merging is also observed. The results provide new insight into the development of coherent structures in separation bubbles and their relation to the overall bubble dynamics and mean bubble topology. [ABSTRACT FROM AUTHOR]

Tendinopathy of the Achilles tendon contributes to a large range of disorders, including mechanical damage and degenerative diseases. Glycosaminoglycans (GAGs), are thought to play a role in the mechanical strength of tendons by forming cross-links between collagen molecules and allowing the transmission of forces between fibrils. This study assessed the response of GAG-depleted tendons to damage induced by fatigue loading, investigating the mechanical damage (stiffness, hysteresis and maximum load), macrostructural changes (tenocyte morphology, fiber anisotropy and waviness) assessed by confocal imaging and nanostructural changes (fibril D-periodicity length) within the same non-viable intact tendons. Changes in fiber waviness and tenocyte shape are strongly correlated to mechanical and nano-structural (D-periodicity elongation) properties in both Control and GAG-depleted tendons. This study supports firstly, the vital role GAGs play as mechanical connectors facilitating the load transfer between the fibrils and their hydrophilic role in facilitating fibril sliding. Secondly, that observed changes in tenocyte shape and fiber waviness correlate with tendon stiffness and other mechanical profiles. [ABSTRACT FROM AUTHOR]

The response of white New Zealand rabbit Achilles tendons to load was assessed using mechanical measures and confocal arthroscopy (CA). The progression of fatigue-loading-induced damage of the macro- (tenocyte morphology, fiber anisotropy and waviness), as well as the mechanical profile, were assessed within the same non-viable intact tendon in response to prolonged cyclic and static loading (up to four hours) at different strain levels (3%, 6% and 9%). Strain-mediated repeated loading induced a significant decline in mechanical function (p < 0.05) with increased strain and cycles. Mechanical and structural resilience was lost with repeated loading (p < 0.05) at macroscales. The lengthening of D-periodicity correlated strongly with the overall tendon mechanical changes and loss of spindle shape in tenocytes. This is the first study to provide a clear concurrent assessment of form (morphology) and function (mechanics) of tendons undergoing different strain-mediated repeated loading at multiple-scale assessments. This study identifies a variety of multiscale properties that may contribute to the understanding of mechanisms of tendon pathology. [ABSTRACT FROM AUTHOR]

Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their role in remodelling the extracellular matrix, however more recently they have been recognised as a functionally highly diverse cell population that constantly responds and adapts to their environment. Biological memory is the process of a sustained altered cellular state and functions in response to a transient or persistent environmental stimulus. While it is well established that fibroblasts retain a memory of their anatomical location, how other environmental stimuli influence fibroblast behaviour and function is less clear. The ability of fibroblasts to respond and memorise different environmental stimuli is essential for tissue development and homeostasis and may become dysregulated in chronic disease conditions such as fibrosis and cancer. Here we summarise the four emerging key areas of fibroblast adaptation: positional, mechanical, inflammatory, and metabolic memory and highlight the underlying mechanisms and their implications in tissue homeostasis and disease. [ABSTRACT FROM AUTHOR]

Introduction: The collagen structure in the superficial zone of articular cartilage is critical to the tissue's durability. Early osteoarthritis is often characterized with fissures on the articular surface. This is closely related to the disruption of the collagen network. However, the traditional histology can not offer visualization of the collagen structure in articular cartilage because it uses conventional optical microscopy that does not have insufficient imaging resolution to resolve collagen from proteoglycans in hyaline articular cartilage. This study examines the 3D collagen network of articular cartilage scored from 0 to 2 in the scoring system of International Cartilage Repair Society, and aims to develop a 3D histology for assessing early osteoarthritis. Methods: Articular cartilage was visually classified into five physiological groups: normal cartilage, aged cartilage, cartilage with artificial and natural surface disruption, and fibrillated. The 3D collagen matrix of the cartilage was acquired using a 3D imaging technique developed previously. Traditional histology was followed to grade the physiological status of the cartilage in the scoring system of International Cartilage Repair Society. Results: Normal articular cartilage contains interwoven collagen bundles near the articular surface, approximately within the lamina splendens. However, its collagen fibres in the superficial zone orient predominantly in a direction spatially oblique to the articular surface. With age and disruption of the articular surface, the interwoven collagen bundles are gradually disappeared, and obliquely oriented collagen fibres change to align predominantly in a direction spatially perpendicular to the articular surface. Disruption of the articular surface is well related to the disappearance of the interwoven collagen bundles. Conclusion: A 3D histology has been developed to supplement the traditional histology and study the subtle changes in the collagen network in the superficial zone during early physiological alteration of articular cartilage. The fibre confocal imaging technology used in this study has allowed developing confocal arthroscopy for in vivo studying the chondrocytes in different depth of articular cartilage. Therefore, the current study has potential to develop an in vivo 3D histology for diagnosis of early osteoarthritis. [ABSTRACT FROM AUTHOR]

The theoretical framework developed in a companion paper (Part I) is used to derive estimates of mechanical response of two meniscal cartilage specimens. The previously developed framework consisted of a constitutive model capable of incorporating confocal image-derived tissue microstructural data. In the present paper (Part II) fibre and matrix constitutive parameters are first estimated from mechanical testing of a batch of specimens similar to, but independent from those under consideration. Image analysis techniques which allow estimation of tissue microstructural parameters form confocal images are presented. The constitutive model and image-derived structural parameters are then used to predict the reaction force history of the two meniscal specimens subjected to partially confined compression. The predictions are made on the basis of the specimens' individual structural condition as assessed by confocal microscopy and involve no tuning of material parameters. Although the model does not reproduce all features of the experimental curves, as an unfitted estimate of mechanical response the prediction is quite accurate. In light of the obtained results it is judged that more general non-invasive estimation of tissue mechanical properties is possible using the developed framework. [ABSTRACT FROM AUTHOR]

Current development of a laser scanning confocal arthroscope within our school will enable 3D microscopic imaging of joint tissues in vivo. Such an instrument could be useful, for example, in assessing the microstructural condition of the living tissues without physical biopsy. It is envisaged also that linked to a suitable microstructural constitutive formulation, such imaging could allow non-invasive patient-specific estimation of tissue mechanical performance. Such a procedure could have applications in surgical planning and simulation, and assessment of engineered tissue replacements, where tissue biopsy is unacceptable. In this first of two papers the development of a suitable constitutive framework for generating such estimates is reported. A microstructure-based constitutive formulation for cartilaginous tissues is presented. The model extends existing fibre composite-type models and accounts for strain-rate sensitivity of the tissue mechanical response through incorporation of a viscoelastic fibre phase. Importantly, the model is constructed so as to allow direct incorporation of structural data from confocal images. A finite element implementation of the formulation suitable for incorporation within commercial codes is also presented. [ABSTRACT FROM AUTHOR]

Focuses on commercial rivalry between port of Livorno and territorial state of Genoa. Success of the Genoese free port for grain of the 1590s; Gradual restriction of free-port privileges; Livorno's capacity to draw traffic away from Genoa; Establishment of Genoese maritime policy; Change in the nature of the Mediterranean trade; Impact of the epidemic of bubonic plague.

Since the spring of 1973, Michigan's EPSDT program has screened more than 300,000 children. The Department of Social Services contracted with the Department of Public Health to design the screening and referral parts of the program; in turn, the Department of Public Health contracts with local health departments to do screening with one or more teams composed of a nurse, two technicians, and a clerk. The 72 teams screen 10.000 clients each month. More treatment. The highest percentage (27 per cent) of referrals is for dental care; the second highest (26 per cent) is for immunization. Participation in the program of state and local social services departments, local health departments, and all groups of health providers had been excellent. There continues to be a high no-show for screening and a moderate no-show rate to providers for diagnosis and treatment. Evaluation of the program elements is needed. [ABSTRACT FROM AUTHOR]

Citrullination and homocitrullination are stress induced post‐translational modifications (siPTMs) which can be recognized by T cells. Peripheral blood mononuclear cells isolated from healthy donors and rheumatoid arthritis (RA) patients were stimulated with nine siPTM‐peptides. CD45RA/CD45RO depletion was employed to determine if peptide‐specific responses are naïve or memory. Human leucocyte antigen (HLA)‐DP4 and HLA‐DR4 transgenic mice were immunized with siPTM‐peptides and immune responses were determined with ex vivo ELISpot assays. The majority (24 out of 25) of healthy donors showed CD4 T cell‐specific proliferation to at least 1 siPTM‐peptide, 19 to 2 siPTM‐peptides, 14 to 3 siPTM‐peptides, 9 to 4 siPTM‐peptides, 6 to 5 siPTM‐peptides and 4 to 6 siPTM‐peptides. More donors responded to Vim28‐49cit (68%) and Bip189‐208cit (75%) compared with Vim415‐433cit (33%). In RA patients, the presentation of citrullinated epitopes is associated with HLA‐SE alleles; however, we witnessed responses in healthy donors who did not express the SE allele. The majority of responding T cells were effector memory cells with a Th1/cytotoxic phenotype. Responses to Vim28‐49cit and Eno241‐260cit originated in the memory pool, while the response to Vim415‐433cit was naïve. In the HLA‐DP4 and HLA‐DR4 transgenic models, Vim28cit generated a memory response. Peptide‐specific T cells were capable of Epstein–Barr virus transformed lymphoblastoid cell line recognition suggesting a link with stress due to infection. These results suggest siPTM‐peptides are presented under conditions of cellular stress and inflammation and drive cytotoxic CD4 T cell responses that aid in the removal of stressed cells. The presentation of such siPTM‐peptides is not restricted to HLA‐SE in both humans and animal models. [ABSTRACT FROM AUTHOR]

Reactive laser vaporization conditions have been employed to generate various isotopic combinations of the new radical species, BNH, for neon matrix electron-spin-resonance (ESR) study. The BNH radical was found to have a linear geometry with an X 2Σ electronic ground state, in agreement with ab initio theoretical calculations, which were conducted as part of this experimental investigation. ESR results for the nuclear hyperfine interactions (A tensor) indicate that the electronic structure of BNH is quite similar to that of the isoelectronic BO radical. Results of a detailed reinvestigation of the 11,10B 16,17O radicals trapped in neon matrices are reported which now show excellent agreement with earlier gas-phase microwave spectroscopic measurements of the dipolar boron hyperfine interaction. The 17O A tensor for BO has been fully resolved for the first time into its isotropic and anisotropic components. A new ultracold neon trapping procedure is described which was used to produce matrix samples of randomly oriented and nonrotating radicals in order to measure the full extent of the dipolar nuclear hyperfine interaction. The neon matrix magnetic parameters for 11B 14NH are g||=2.0020(5) and g⊥=2.0010(5), A||=1089(1) and A⊥=1013(1) MHz for 11B, A||=49(1) and A⊥=37(1) MHz for 14N, and A||=29(1) and A⊥=23(1) MHz for H. [ABSTRACT FROM AUTHOR]

Pays tribute to Michael John Murtagh, chair of the Brookhaven National Laboratory's physics department who died on July 12, 2001 in Stony Brook, New York. Cause of death; His Educational and career background; Achievements and awards received.

Editorial. Focuses on the importance of networking in library systems in the United States. Role of librarians in assisting researchers; Network with customers; Confusion to the amount of information and modes of access; Development of new access tools; Involvement of other information professionals; Diversity of libraries.

The purpose of this study was to mechanically test a novel Unthreaded Expandable Fastener (UEF), manufactured using Selective Laser Melting, which was designed for fixation in the cervical lateral mass. The pull-out strength and stiffness of the prototype UEFs was evaluated in a non-osteoporotic ovine bone model against equivalent screws. The prototype UEF demonstrated a 41% increase in failure force and a 60% reduction in failure force standard deviation compared to the screws. All bone samples were micro CT-scanned and no significant differences in bone microstructural properties was found between the screw and UEF sample sets, indicating that the UEFs may be less sensitive to bone quality variation. This increased performance can potentially translate into improved surgical outcome and reduced surgical risk for lateral mass fixation. With further design optimisation, additional improvement in performance over screws may be possible in future studies. [ABSTRACT FROM AUTHOR]

The depth distributions of refractive index (RI) in normal and early degenerated articular cartilage (AC) were measured and correlated to the pathological statuses. Utilizing a confocal microscope, the depth distribution of RI was determined with an interval of 50 µm from the articular surface and approximated as a smooth curve. The fluctuation of RI was quantified with a specially defined coefficient and the proteoglycan (PG) loss was quantified with histological images. The overall RI of the AC collected from the femoral condyles of mature sheep was 1.4444. Significant differences existed in the refractive indices of different cartilage samples or even in the different depths of the same sample. The RI of normal cartilage distributed as a regular ramp or arch curve with depth and peaked in the middle-deep zone. The cartilage samples detected with high PG losses were coupled with severe fluctuations of RI. The fluctuating level was increased with pathological progress. The coefficient of RI fluctuation can distinguish the normal cartilage from the initially degenerated one, which potentially provides an indicator to detect the pathological development of AC. [ABSTRACT FROM AUTHOR]

Solar ultraviolet radiation (UVR) is a major source of skin damage, resulting in inflammation, premature ageing, and cancer. While several UVR-induced changes, including extracellular matrix reorganisation and epidermal DNA damage, have been documented, the role of different fibroblast lineages and their communication with immune cells has not been explored. We show that acute and chronic UVR exposure led to selective loss of fibroblasts from the upper dermis in human and mouse skin. Lineage tracing and in vivo live imaging revealed that repair following acute UVR is predominantly mediated by papillary fibroblast proliferation and fibroblast reorganisation occurs with minimal migration. In contrast, chronic UVR exposure led to a permanent loss of papillary fibroblasts, with expansion of fibroblast membrane protrusions partially compensating for the reduction in cell number. Although UVR strongly activated Wnt signalling in skin, stimulation of fibroblast proliferation by epidermal ß-catenin stabilisation did not enhance papillary dermis repair. Acute UVR triggered an infiltrate of neutrophils and T cell subpopulations and increased pro-inflammatory prostaglandin signalling in skin. Depletion of CD4- and CD8-positive cells resulted in increased papillary fibroblast depletion, which correlated with an increase in DNA damage, pro-inflammatory prostaglandins, and reduction in fibroblast proliferation. Conversely, topical COX-2 inhibition prevented fibroblast depletion and neutrophil infiltration after UVR. We conclude that loss of papillary fibroblasts is primarily induced by a deregulated inflammatory response, with infiltrating T cells supporting fibroblast survival upon UVR-induced environmental stress. [ABSTRACT FROM AUTHOR]

Solar ultraviolet radiation (UVR) is a major source of skin damage, resulting in inflammation, premature ageing, and cancer. While several UVR- induced changes, including extracellular matrix reorganisation and epidermal DNA damage, have been documented, the role of different fibroblast lineages and their communication with immune cells has not been explored. We show that acute and chronic UVR exposure led to selective loss of fibroblasts from the upper dermis in human and mouse skin. Lineage tracing and in vivo live imaging revealed that repair following acute UVR is predominantly mediated by papillary fibroblast proliferation and fibroblast reorganisation occurs with minimal migration. In contrast, chronic UVR exposure led to a permanent loss of papillary fibroblasts, with expansion of fibroblast membrane protrusions partially compensating for the reduction in cell number. Although UVR strongly activated Wnt signalling in skin, stimulation of fibroblast proliferation by epidermal β-catenin stabilisation did not enhance papillary dermis repair. Acute UVR triggered an infiltrate of neutrophils and T cell subpopulations and increased pro- inflammatory prostaglandin signalling in skin. Depletion of CD4- and CD8- positive cells resulted in increased papillary fibroblast depletion, which correlated with an increase in DNA damage, pro- inflammatory prostaglandins, and reduction in fibroblast proliferation. Conversely, topical COX- 2 inhibition prevented fibroblast depletion and neutrophil infiltration after UVR. We conclude that loss of papillary fibroblasts is primarily induced by a deregulated inflammatory response, with infiltrating T cells supporting fibroblast survival upon UVR- induced environmental stress. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Hydrogel with high mechanical toughness and good fatigue resistance is investigated. • The hydrogel can recover to original shape within 300 s under NIR stimuli. • The temperature rise during shape recovery under NIR is lower than 37 °C. • A more sustained drug delivery matrix is achieved from temporary shape hydrogels. • The nontoxic hydrogel will be a promising material in biomedical applications. Abstract In this work, near-infrared (NIR)-responsive double network shape memory hydrogels were formed by chemically cross-linking Pluronic F127 diacrylate macromer (F127DA) and physical blending of poly(lactide-co-glycolide) (PLGA) with graphene oxide (GO, an energy convertor to convert NIR irradiation to thermal energy). The hydrogels were manufactured with 3D-printing technology using ultraviolet light polymerization. The morphologies and crystalline structure of the hydrogels were determined by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The NIR and thermal activated shape memory properties, mechanical toughness, and cytotoxicity were investigated. The shape memory properties were improved by incorporating GO into the hydrogels and the mechanical properties were enhanced by the addition of PLGA, which served as a second network. The cytotoxicity was assessed by the CCK-8 assay, which revealed no cytotoxicity. The nontoxicity, high mechanical toughness (3.45 MPa in the swollen state), and biosafety at the shape recovery temperature (36 ± 1 °C), which was achieved by NIR stimuli, indicates that shape memory hydrogels can be used in biomedical materials safely. The practical potential of the F127DA/PLGA/GO hydrogels was further revealed by their 3D-printing performance, their shape fixity ratio greater than 85%, and their shape recovery time under 300 s. Our results propose that F127DA/PLGA/GO hydrogels will be a promising material in biomedical applications as a drug carrier and an antibacterial scaffold. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • FA-CPSP-UA is a redox-responsive prodrug. • It can specifically deliver UA to the tumor cells. • It can arouse chemosensitizing effects by the depletion of intracellular GSH contents. • It is valid for cancer treatment. Abstract Antitumor efficacy of ursolic acid (UA) is seriously limited due to its low hydrophilicity and needy bioavailability. To overcome these obstacles, chemosensitive polyspermine (CPSP) conjugated with UA and folic acid (FA) as a novel targeted prodrug was designed and successfully synthesized in this investigation. This prodrug not only showed high aqueous solubility, GSH-triggered degradation and good biocompatibility, but also exhibited better inhibition effect on the tumor cells proliferation in comparison with free UA. FA-CPSP-UA could down-regulate the generation of GSH and manifest excellent ability in enhancing antitumor efficacy. In addition, FA-CPSP-UA could inhibit the expression of MMP-9, which led to restricting MCF-7 cells migration. Taken together, the results indicated that FA-CPSP-UA, as a carrier, can efficiently deliver UA to folate receptor positive cancer cells and improve tumor therapy of UA by Chemosensitive effect. [ABSTRACT FROM AUTHOR]

To exploit a green way to produce polymer nanoparticles using biodegradable and renewable macromolecules instead of petroleum-based ones, we initiated a novel and facile method to synthesize lignin nanoparticles (LNPs). The LNPs, having a hydrodynamic diameter ranging from ca. 80 to 230 nm, were formed by self-assembly in a recyclable and non-toxic aqueous sodium p-toluenesulfonate (pTsONa) solution at room temperature, with a lowest concentration of up to 48 g/L. We eliminated the unfavorable factors of restricted processing pH and lignin species by taking advantage of the hydrotropic chemistry and the synergistic dissociation of the entrapped pTsONa and intrinsic phenolic hydroxyl and carboxylic acid moieties of the LNPs. Because of the hydrotropic system, various water-soluble or water-insoluble drugs can be dissolved and encapsulated in the LNPs with an encapsulation efficiency of up to 90%. The drug-encapsulated LNPs also showed great properties, with sustained drug-releasing capability and biocompatibility. Furthermore, the unloaded drugs and free pTsONa could be easily recycled for multiple use, thereby achieving environmental sustainability. This synthesis approach with broad processing window could realize the industrial scale-up production of LNPs and have wide potential applications, including but not limited to versatile drug/bioactive macromolecule loading in the biomedical field. [ABSTRACT FROM AUTHOR]

The Pd12CH3, Pd13CH3, and 105Pd12CH3 radicals have been generated by reactive laser vaporization and isolated in neon matrices at 4 K for electron spin resonance (ESR) investigation. Apparently no previous monomethyl metal radical has been characterized by ESR despite the importance of such species as reactive intermediates. These results allow an experimental description of the electronic structure in the valence region to be obtained. A direct electronic structure comparison between PdH and PdCH3 is also presented. A significant amount of s/d hybridization on Pd is observed which agrees with earlier calculations on the bonding in Pd(CH3)2. The magnetic parameters (MHz) for PdCH3 in neon matrices are: g⊥=2.273(1); for 105Pd, A⊥=-946(2), A||=-987(20); for H, |A|=13(1); and for 13C, |A|=10.2(4). [ABSTRACT FROM AUTHOR]

The reactive laser vaporization of palladium metal in the presence of H2(g) has been used to generate and trap neutral and charged palladium hydride radicals in neon and argon matrices for electron spin resonance investigations. The radicals identified are: 0PdH+2, 105PdH+2, 0PdD+2, 105PdD+2, 0PdH, 0PdD, 105PdH, and 105PdD. The electron spin resonance results prove that the H atoms are equivalent in PdH+2 but it cannot be determined for certain whether a highly bent 2A1 ground state complex or a linear 2Σ state is being observed, although the evidence seems to favor the 2A1 state. The observed nuclear hyperfine properties (A and g tensors) are best accounted for by assigning the unpaired electron predominantly to 4d2z/5s orbitals on the metal in PdH+2 with only about 3% of the spin density on each H atom. Electron spin resonance results for PdH constitute the first observations for a diatomic metal hydride radical trapped in a neon matrix. The magnetic parameters (MHz) for 105PdH+2 in a neon matrix at 4 K are: g⊥=2.568(2); g||[bar_over_tilde:_approx._equal_to]1.92; A⊥(105Pd)=-713(2); A||(105Pd)=-688(15); A⊥(H)=45(1). Multireference SCF (MCSCF) and configuration interaction (CI) calculations were conducted for PdH+2 to calculate the energies and gross population distributions in the lowest-lying electronic states. The lowest of these, the 2A1 state, has a calculated stabilization energy of 9.3 kcal/mol relative to Pd+(4d9)+H2. [ABSTRACT FROM AUTHOR]

Hydrogels with shape memory behavior and internal structure have wide applications in fields ranging from tissue engineering and medical instruments to drug delivery; however, creating the hydrogels has proven to be extremely challenging. This study presents a three-dimensional (3D) printing technology to fabricate the shape memory hydrogels with internal structure (SMHs) by combining sodium alginate (alginate) and pluronic F127 diacrylate macromer (F127DA). SMHs were constituted by a dual network structure. One is a stable network which is formed by F127DA photo-crosslinking; the other one is a reversible network which is formed by Ca 2 + cross-linked alginate. SMHs recovery ratio was 98.15% in 10 min after Ca 2 + was removed in the Na 2 CO 3 solution, and the elastic modulus remains essentially stable after the shape memory cycle. It showed that the drug releasing rate is more rapid compared with traditional drug-loaded hydrogels in in vitro experiments. The viability of 3T3 fibroblasts remained intact which revealed its excellent biocompatibility. Therefore, SMHs have a huge prospect for application in drug carriers and tissue engineering scaffold. [ABSTRACT FROM AUTHOR]

Knowledge of the collagen structure of an Achilles tendon is critical to comprehend the physiology, biomechanics, homeostasis and remodelling of the tissue. Despite intensive studies, there are still uncertainties regarding the microstructure. The majority of studies have examined the longitudinally arranged collagen fibrils as they are primarily attributed to the principal tensile strength of the tendon. Few studies have considered the structural integrity of the entire three-dimensional (3D) collagen meshwork, and how the longitudinal collagen fibrils are integrated as a strong unit in a 3D domain to provide the tendons with the essential tensile properties. Using second harmonic generation imaging, a 3D imaging technique was developed and used to study the 3D collagen matrix in the midportion of Achilles tendons without tissue labelling and dehydration. Therefore, the 3D collagen structure is presented in a condition closely representative of the in vivo status. Atomic force microscopy studies have confirmed that second harmonic generation reveals the internal collagen matrix of tendons in 3D at a fibril level. Achilles tendons primarily contain longitudinal collagen fibrils that braid spatially into a dense rope-like collagen meshwork and are encapsulated or wound tightly by the oblique collagen fibrils emanating from the epitenon region. The arrangement of the collagen fibrils provides the longitudinal fibrils with essential structural integrity and endows the tendon with the unique mechanical function for withstanding tensile stresses. A novel 3D microscopic method has been developed to examine the 3D collagen microstructure of tendons without tissue dehydrating and labelling. The study also provides new knowledge about the collagen microstructure in an Achilles tendon, which enables understanding of the function of the tissue. The knowledge may be important for applying surgical and tissue engineering techniques to tendon reconstruction. [ABSTRACT FROM AUTHOR]

ABSTRACT Similar to most biological tissues, the biomechanical, and functional characteristics of the Achilles tendon are closely related to its composition and microstructure. It is commonly reported that type I collagen is the predominant component of tendons and is mainly responsible for the tissue's function. Although elastin has been found in varying proportions in other connective tissues, previous studies report that tendons contain very small quantities of elastin. However, the morphology and the microstructural relationship among the elastic fibres, collagen, and cells in tendon tissue have not been well examined. We hypothesize the elastic fibres, as another fibrillar component in the extracellular matrix, have a unique role in mechanical function and microstructural arrangement in Achilles tendons. It has been shown that elastic fibres present a close connection with the tenocytes. The close relationship of the three components has been revealed as a distinct, integrated and complex microstructural network. Notably, a 'spiral' structure within fibril bundles in Achilles tendons was observed in some samples in specialized regions. This study substantiates the hierarchical system of the spatial microstructure of tendon, including the mapping of collagen, elastin and tenocytes, with 3-dimensional confocal images. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1203-1214, 2017. [ABSTRACT FROM AUTHOR]