C-terminal citrullinated peptide alters antigen-specific APC:T cell interactions leading to breach of immune tolerance.

In rheumatoid arthritis, the emergence of anti-citrullinated autoimmunity is associated with HLA-antigen-T cell receptor complexes. The precise mechanisms underpinning this breach of tolerance are not well understood. Porphyromonas gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination with potential to generate citrullinated autoantigens. Here we document how C-terminal citrullination of ovalbumin peptide323-339 alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. These data reveal that C-terminal citrullination is sufficient to breach T cell peripheral tolerance in vivo and reveal the potential of C-terminal citrullination to lower the threshold for T cell activation. Finally, we demonstrate a role for the IL-2/STAT5/CD25 signalling axis in breach of tolerance. Together, our data identify a tractable mechanism and targetable pathways underpinning breach of tolerance in rheumatoid arthritis and provide new conceptual insight into the origins of anti-citrullinated autoimmunity.

Understanding the Prevalence of Prediabetes and Diabetes in Patients With Cancer in Clinical Practice: A Real-World Cohort Study.

BACKGROUND: This study aimed to understand the prevalence of prediabetes (preDM) and diabetes mellitus (DM) in patients with cancer overall and by tumor site, cancer treatment, and time point in the cancer continuum. METHODS: This cohort study was conducted at Huntsman Cancer Institute at the University of Utah. Patients with a first primary invasive cancer enrolled in the Total Cancer Care protocol between July 2016 and July 2018 were eligible. Prevalence of preDM and DM was based on ICD code, laboratory tests for hemoglobin A1c, fasting plasma glucose, nonfasting blood glucose, or insulin prescription. RESULTS: The final cohort comprised 3,512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n=1,724) were female. At cancer diagnosis, the prevalence of preDM and DM was 6.0% (95% CI, 5.3%-6.8%) and 12.2% (95% CI, 11.2%-13.3%), respectively. One year after diagnosis the prevalence was 16.6% (95% CI, 15.4%-17.9%) and 25.0% (95% CI, 23.6%-26.4%), respectively. At the end of the observation period, the prevalence of preDM and DM was 21.2% (95% CI, 19.9%-22.6%) and 32.6% (95% CI, 31.1%-34.2%), respectively. Patients with myeloma (39.2%; 95% CI, 32.6%-46.2%) had the highest prevalence of preDM, and those with pancreatic cancer had the highest prevalence of DM (65.1%; 95% CI, 57.0%-72.3%). Patients who underwent chemotherapy, radiotherapy, or immunotherapy had a higher prevalence of preDM and DM compared with those who did not undergo these therapies. CONCLUSIONS: Every second patient with cancer experiences preDM or DM. It is essential to foster interprofessional collaboration and to develop evidence-based practice guidelines. A better understanding of the impact of cancer treatment on the development of preDM and DM remains critical.

Modeling the Effects of Future Hydroclimatic Conditions on Microbial Water Quality and Management Practices in Two Agricultural Watersheds.

Anticipated future hydroclimatic changes are expected to alter the transport and survival of fecally-sourced waterborne pathogens, presenting an increased risk of recreational water quality impairments. Managing future risk requires an understanding of interactions between fecal sources, hydroclimatic conditions and best management practices (BMPs) at spatial scales relevant to decision makers. In this study we used the Hydrologic Simulation Program FORTRAN to quantify potential fecal coliform (FC - an indicator of the potential presence of pathogens) responses to a range of mid-century climate scenarios and assess different BMP scenarios (based on reduction factors) for reducing the risk of water quality impairment in two, small agricultural watersheds - the Chippewa watershed in Minnesota, and the Tye watershed in Virginia. In each watershed, simulations show a wide range of FC responses, driven largely by variability in projected future precipitation. Wetter future conditions, which drive more transport from non-point sources (e.g. manure application, livestock grazing), show increases in FC loads. Loads typically decrease under drier futures; however, higher mean FC concentrations and more recreational water quality criteria exceedances occur, likely caused by reduced flow during low-flow periods. Median changes across the ensemble generally show increases in FC load. BMPs that focus on key fecal sources (e.g., runoff from pasture, livestock defecation in streams) within a watershed can mitigate the effects of hydroclimatic change on FC loads. However, more extensive BMP implementation or improved BMP efficiency (i.e., higher FC reductions) may be needed to fully offset increases in FC load and meet water quality goals, such as total maximum daily loads and recreational water quality standards. Strategies for managing climate risk should be flexible and to the extent possible include resilient BMPs that function as designed under a range of future conditions.

Misoprostol is superior to combined omeprazole-sucralfate for the treatment of equine gastric glandular disease.

BACKGROUND: Previous studies have demonstrated a poor response to healing of gastric glandular lesions with oral omeprazole and other medications. OBJECTIVES: To evaluate the efficacy of two novel treatments (misoprostol [M] and combined omeprazole-sucralfate [OS]) in horses for gastric glandular disease. STUDY DESIGN: Prospective, clinical study. METHODS: Sixty-three sports horses with grade >1/4 glandular disease were identified by gastroscopy. Horses received either 5 µg/kg of misoprostol per os BID 1 h prior to feeding or a combination of 4 mg/kg enteric coated omeprazole per os SID and 12 mg/kg sucralfate per os BID where drugs were given 1 h prior to feeding and sucralfate given 60 min after omeprazole; allocation was dependent upon centre. Gastroscopy was repeated at 28-35 days. Evaluators of the gastroscopy images were blinded to the treatments the horses received and images were reviewed independently. RESULTS: The most common presenting sign in both treatment groups was poor performance (Overall - 65.1%; M - 60.5% and OS - 75%). Overall healing (P<0.001; OR = 11 [2.8-45]) and improvement (P = 0.006; OR = 11 [1.9-59]) of lesions were associated with resolution of clinical signs. Misoprostol was shown to be superior to combined omeprazole-sucralfate both for healing (M - 72% [95% CI 43-67] and OS - 20% [95% CI 7-41]; P<0.001) and improvement (M - 98% [95% CI 90-100] and OS - 65% [95% CI 43-83]; P<0.001). MAIN LIMITATIONS: Relatively small, clinical study, reliance on client questionnaire data, clients not blinded to the treatments the horse received, diet could have affected drug pharmacodynamics although mimics clinical practice and no validated scoring system available for glandular lesions. CONCLUSIONS: These results suggest that gastric glandular disease does indeed result in clinical signs. In this population of horses, misoprostol was superior to omeprazole and sucralfate and warrants further evaluation in a large scale, multi-centre trial.

AGRICULTURAL BEST MANAGEMENT PRACTICE SENSITIVITY TO CHANGING AIR TEMPERATURE AND PRECIPITATION.

Agricultural best management practices (BMPs) reduce non-point source pollution from cropland. Goals for BMP adoption and expected pollutant load reductions are often specified in water quality management plans to protect and restore waterbodies; however, estimates of needed load reductions and pollutant removal performance of BMPs are generally based on historic climate. Increasing air temperatures and changes in precipitation patterns and intensity are anticipated throughout the U.S. over the 21st century. The effects of such changes on agricultural pollutant loads have been addressed by several authors, but how these changes will affect the performance of widely promoted BMPs has received limited attention. We use the Soil and Water Assessment Tool (SWAT) to investigate potential changes in the effectiveness of conservation tillage, no-till, vegetated filter strips, grassed waterways, nutrient management, winter cover crops, and drainage water management practices under potential future temperature and precipitation patterns. We simulate two agricultural watersheds in the Minnesota Corn Belt and the Georgia Coastal Plain with different hydro-climatic settings, under recent conditions (1950-2005) and multiple potential future mid-century (2030-2059) and late-century (2070-2099) climate scenarios. Results suggest future increases in agricultural source loads of sediment, nitrogen and phosphorous. Most BMPs continue to reduce loads, but removal efficiencies generally decline due to more intense runoff events, biological responses to changes in soil moisture and temperature, and exacerbated upland loading. The coupled effects of higher upland loading and reduced BMP efficiencies suggest that wider adoption, resizing, and/or combining practices may be needed in the future to meet water quality goals for agricultural lands.

Enrichment of Innate Lymphoid Cell Populations in Gingival Tissue.

Innate lymphoid cells (ILCs) are a population of lymphocytes that act as the first line of immunologic defense at mucosal surfaces. The ILC family in the skin, lungs, and gastrointestinal tissues has been investigated, and there are reports of individual subsets of ILCs in the oral tissues. We sought to investigate the whole ILC population (group 1, 2, and 3 subsets) in the murine gingivae and the lymph nodes draining the oral cavity. We show that ILCs made up a greater proportion of the whole CD45+ lymphocyte population in the murine gingivae (0.356% ± 0.039%) as compared with the proportion of ILCs in the draining lymph nodes (0.158% ± 0.005%). Cytokine profiling of the ILC populations demonstrated different proportions of ILC subsets in the murine gingivae versus the regional lymph nodes. The majority of ILCs in the draining lymph nodes expressed IL-5, whereas there were equal proportions of IFN-γ- and IL-5 expressing ILCs in the oral mucosa. The percentage of IL-17+ ILCs was comparable between the murine gingivae and the oral draining lymph nodes. These data suggest an enrichment of ILCs in the murine gingivae, and these ILCs reflect a cytokine profile discrepant to that of the local draining lymph nodes. These studies indicate diversity and enrichment of ILCs at the oral mucosal surface. The function of ILCs in the oral cavity remains to be determined; here, we provide a premise of ILC populations that merits future consideration in investigations of mouse models and human tissues.

Mast Cells Contribute to Porphyromonas gingivalis-induced Bone Loss.

Periodontitis is a chronic inflammatory and bone-destructive disease. Development of periodontitis is associated with dysbiosis of the microbial community, which may be caused by periodontal bacteria, such as Porphyromonas gingivalis Mast cells are sentinels at mucosal surfaces and are a potent source of inflammatory mediators, including tumor necrosis factors (TNF), although their role in the pathogenesis of periodontitis remains to be elucidated. This study sought to determine the contribution of mast cells to local bone destruction following oral infection with P. gingivalis Mast cell-deficient mice (Kit(W-sh/W-sh)) were protected from P. gingivalis-induced alveolar bone loss, with a reduction in anti-P. gingivalis serum antibody titers compared with wild-type infected controls. Furthermore, mast cell-deficient mice had reduced expression of Tnf, Il6, and Il1b mRNA in gingival tissues compared with wild-type mice. Mast cell-engrafted Kit(W-sh/W-sh) mice infected with P. gingivalis demonstrated alveolar bone loss and serum anti-P. gingivalis antibody titers equivalent to wild-type infected mice. The expression of Tnf mRNA in gingival tissues of Kit(W-sh/W-sh) mice was elevated following the engraftment of mast cells, indicating that mast cells contributed to the Tnf transcript in gingival tissues. In vitro, mast cells degranulated and released significant TNF in response to oral bacteria, and neutralizing TNF in vivo abrogated alveolar bone loss following P. gingivalis infection. These data indicate that mast cells and TNF contribute to the immunopathogenesis of periodontitis and may offer therapeutic targets.

The effects of downscaling method on the variability of simulated watershed response to climate change in five U.S. basins.

Simulations of future climate change impacts on water resources are subject to multiple and cascading uncertainties associated with different modeling and methodological choices. A key facet of this uncertainty is the coarse spatial resolution of GCM output compared to the finer-resolution information needed by water managers. To address this issue, it is now common practice to apply spatial downscaling techniques, using either higher-resolution regional climate models or statistical approaches applied to GCM output to develop finer-resolution information for use in water resources impacts assessments. Downscaling, however, can also introduce its own uncertainties into water resources impacts assessments. This study uses watershed simulations in five U.S. basins to quantify the sources of variability in streamflow, nitrogen, phosphorus, and sediment loads associated with the underlying GCM compared to the choice of downscaling method (both statistically and dynamically downscaled GCM output). We also assess the specific, incremental effects of downscaling by comparing watershed simulations based on downscaled and non-downscaled GCM model output. Results show that the underlying GCM and the downscaling method each contribute to the variability of simulated watershed responses. The relative contribution of GCM and downscaling method to the variability of simulated responses varies by watershed and season of the year. Results illustrate the potential implications of one key methodological choice in conducting climate change impacts assessments for water - the selection of downscaled climate change information.

Clinical Research Abstracts of the British Equine Veterinary Association Congress 2015.

REASONS FOR PERFORMING STUDY: Equine gastric glandular disease (EGGD) is a common condition, for which the underlying pathophysiology is undetermined. Endoscopic mucosal biopsies have been proposed as a method for adapting therapy. OBJECTIVES: To evaluate diagnostic information obtained from endoscopic mucosal biopsies. STUDY DESIGN: Prospective, experimental study. METHODS: Twenty-one horses undergoing elective humane slaughter were subjected to gross examination of the glandular mucosa. Glandular pathology was graded using EGUS Council guidelines from digital camera images. Mucosal biopsies were obtained using a 'single-bite' (1.8 mm; A and 2.4 mm; B) or 'double bite' technique (2.4 mm; C) using endoscopic biopsy instruments. Tissue was formalin fixed, processed and stained using standard protocols. Inflammatory infiltrates visualised histologically were graded (mild, moderate or severe) and compared with ulcer grade. Full thickness biopsies were also obtained adjacent to the biopsy site and of other visual lesions and inflammatory cell counts were compared with mucosal biopsies using ICC. RESULTS: Full thickness samples were artefact free and allowed visualisation of all layers. Mucosal biopsy samples contained mucosa in all samples, submucosa in 55% (C), 61% (A) and 66% (B) of samples and glands in 50% (B), 66% (A) and 100% (C). Samples from A were too small for histological assessment (33%) and tissue damage was commonly seen in A and B (n = 8 and n = 10) when compared with C (n = 3). Horses with normal glandular appearance (grade 0; n = 7) mostly demonstrated mild gastritis (n = 5). Severe gastritis was identified in mild EGGD (grade 1/2), whilst mild and moderate gastritis was identified in all EGGD grades. There was no histological evidence of ulceration or erosion. There was poor agreement between cell numbers and sampling techniques (ICC<0.29). CONCLUSIONS: These data show lack of ulcerative pathology and instead inflammation in EGGD. Lesion appearance is a poor indicator of underlying severity. Mucosal biopsies offer limited value in predicting underlying disease. Ethical animal research: This study was approved by the University of Nottingham Ethics and Welfare Committee. The study was performed on material collected at an abattoir. SOURCE OF FUNDING: None. Competing interests: None declared.

IL-33 Exacerbates Periodontal Disease through Induction of RANKL.

Cytokines mediate the balance between protective and destructive immunity in periodontitis. We sought to investigate the role of IL-33 in periodontitis. The expression of IL-33 in gingival tissue from healthy controls (n = 10) and patients with chronic periodontitis (n = 17) was investigated. Based on a murine model of periodontal disease, the function of IL-33 was determined first by administration of exogenous IL-33 and second by inhibition of IL-33 signaling using mice deficient in the IL-33 receptor ST2. Alveolar bone level, serum antibody, and lymphocyte responses were assessed in the murine model. Expression of IL-33 and ST2 was elevated in gingival tissues from patients with chronic periodontitis as compared with healthy tissues (P < 0.05). Similarly, Il33 expression was higher in periodontal tissues of Porphyromonas gingivalis-infected mice as compared with sham-infected controls (P < 0.05). IL-33 treatment of P. gingivalis-infected mice significantly exacerbated alveolar bone loss when compared with infection or IL-33 treatment alone (P < 0.001). Conversely, P. gingivalis infection-induced alveolar bone loss was attenuated in mice lacking ST2. The percentages of T and B lymphocytes expressing nuclear factor κB ligand (RANKL) in the gingival tissues and T lymphocytes expressing RANKL in the cervical draining lymph nodes were higher in IL-33-treated P. gingivalis-infected mice versus phosphate buffered saline-treated P. gingivalis-infected controls (all P < 0.001). Targeting the RANKL pathway by osteoprotegerin administration abrogated periodontal bone destruction in P. gingivalis-infected, IL-33-treated mice. These data demonstrate a previously unrecognized role for IL-33 in exacerbating bone loss in a RANKL-dependent manner in the context of bacterial infection and suggest that this pathway may be amenable to manipulation as a novel therapeutic target in periodontitis.

MODELING STREAMFLOW AND WATER QUALITY SENSITIVITY TO CLIMATE CHANGE AND URBAN DEVELOPMENT IN 20 U.S. WATERSHEDS.

Watershed modeling in 20 large, United States (U.S.) watersheds addresses gaps in our knowledge of streamflow, nutrient (nitrogen and phosphorus), and sediment loading sensitivity to mid-21st Century climate change and urban/residential development scenarios. Use of a consistent methodology facilitates regional scale comparisons across the study watersheds. Simulations use the Soil and Water Assessment Tool. Climate change scenarios are from the North American Regional Climate Change Assessment Program dynamically downscaled climate model output. Urban and residential development scenarios are from U.S. Environmental Protection Agency's Integrated Climate and Land Use Scenarios project. Simulations provide a plausible set of streamflow and water quality responses to mid-21st Century climate change across the U.S. Simulated changes show a general pattern of decreasing streamflow volume in the central Rockies and Southwest, and increases on the East Coast and Northern Plains. Changes in pollutant loads follow a similar pattern but with increased variability. Ensemble mean results suggest that by the mid-21st Century, statistically significant changes in streamflow and total suspended solids loads (relative to baseline conditions) are possible in roughly 30-40% of study watersheds. These proportions increase to around 60% for total phosphorus and total nitrogen loads. Projected urban/residential development, and watershed responses to development, are small at the large spatial scale of modeling in this study.

Periodontitis in the absence of B cells and specific anti-bacterial antibody.

Periodontitis (PD) results from complex interactions between a dysbiotic oral microbiota and a dysregulated host immune response. The inflammatory infiltrate in the gingiva of PD patients includes an abundance of B cells, implicating these cells in the immunopathology. We sought to investigate the role of B cells in PD using a murine model. Wild-type or B-cell-deficient (µMT) mice were orally infected with Porphyromonas gingivalis. One or six weeks following infection, lymphocyte populations in the gingiva and cervical draining lymph nodes (dLN) were analysed by flow cytometry; serum anti-P. gingivalis IgG antibody titers were measured by enzyme-linked immunosorbent assay, and alveolar bone loss was determined. In wild-type mice, the percentage of gingival B cells expressing receptor activator of nuclear factor-κB ligand (RANKL) was significantly increased 1 week post-infection (5.36% control versus 11% PD, P < 0.01). The percentage of Fas(+) GL7(+) germinal centre B cells in the dLN was significantly increased at both 1 week (2.03% control versus 6.90% PD, P < 0.01) and 6 weeks (4.45% control versus 8.77% PD, P < 0.05) post-infection. B-cell-deficient mice were protected from P. gingivalis-induced alveolar bone loss, with a lack of B-cell proliferation and lack of CD4(+) CD44(+) CD62L(-) T-cell generation in the dLN, and absence of serum anti-P. gingivalis antibodies. Our data imply a pathological role for B cells in PD, and that selective targeting of this immune axis may have a role in treating severe periodontal disease.

Evaluation of a capacity building clinical educational model for oral health clinicians treating very young children.

OBJECTIVE: There are significant levels of dental caries in Australian school-aged children, with children aged five years having a mean dmft of 1.3. It has also been identified that, in general, oral health clinicians lack confidence to treat very young children and this study aimed to increase capacity of public sector oral health clinicians to treat preschool children. BASIC RESEARCH DESIGN: An educational program was developed, implemented and evaluated for its capability to increase the confidence and knowledge of oral health clinicians and dental assistants in providing oral care for children aged 12 months to 5 years. RESULTS: In 2011 and 2012, the course was delivered to 36 clinicians (22 dentists, 12 dental therapists, and two oral health therapists) and showed increases in their confidence and knowledge for participants when providing dental procedures to preschool children. CONCLUSIONS: The educational program that was developed and implemented has met its objective of increasing the knowledge and confidence of practicing oral health clinicians and dental assistants in the management of preschool children. Strategies to further enhance the outcomes of this educational program have been proposed.

Development of UK recommendations on treatment for post-surgical erectile dysfunction.

AIM: To develop a management strategy (rehabilitation programme) for postsurgical erectile dysfunction (ED) among men experiencing ED associated with treatment of prostate, bladder or rectal cancer that is suitable for use in a UK NHS healthcare context. METHODS: PubMed literature searches of ED management together with a survey of 13 experts in the management of ED from across the UK were conducted. RESULTS: Data from 37 articles and completed questionnaires were collated. The results discussed in this study demonstrate improved objective and subjective clinical outcomes for physical parameters, sexual satisfaction, and rates of both spontaneous erections and those associated with ED treatment strategies. CONCLUSION: Based on the literature and survey analysis, recommendations are proposed for the standardisation of management strategies employed for postsurgical ED.

Three-dimensional printed trileaflet valve conduits using biological hydrogels and human valve interstitial cells.

Tissue engineering has great potential to provide a functional de novo living valve replacement, capable of integration with host tissue and growth. Among various valve conduit fabrication techniques, three-dimensional (3-D) bioprinting enables deposition of cells and hydrogels into 3-D constructs with anatomical geometry and heterogeneous mechanical properties. Successful translation of this approach, however, is constrained by the dearth of printable and biocompatible hydrogel materials. Furthermore, it is not known how human valve cells respond to these printed environments. In this study, 3-D printable formulations of hybrid hydrogels are developed, based on methacrylated hyaluronic acid (Me-HA) and methacrylated gelatin (Me-Gel), and used to bioprint heart valve conduits containing encapsulated human aortic valvular interstitial cells (HAVIC). Increasing Me-Gel concentration resulted in lower stiffness and higher viscosity, facilitated cell spreading, and better maintained HAVIC fibroblastic phenotype. Bioprinting accuracy was dependent upon the relative concentrations of Me-Gel and Me-HA, but when optimized enabled the fabrication of a trileaflet valve shape accurate to the original design. HAVIC encapsulated within bioprinted heart valves maintained high viability, and remodeled the initial matrix by depositing collagen and glyosaminoglycans. These findings represent the first rational design of bioprinted trileaflet valve hydrogels that regulate encapsulated human VIC behavior. The use of anatomically accurate living valve scaffolds through bioprinting may accelerate understanding of physiological valve cell interactions and progress towards de novo living valve replacements.

Artificial neural network analysis of hydrocarbon profiles for the ageing of Lucilia sericata for post mortem interval estimation.

In analytical chemistry large datasets are collected using a variety of instruments for multiple tasks, where manual analysis can be time-consuming. Ideally, it is desirable to automate this process while obtaining an acceptable level of accuracy, two aims that artificial neural networks (ANNs) can fulfil. ANNs possess the ability to classify novel data based on their knowledge of the domain to which they have been exposed. ANNs can also analyse non-linear data, tolerate noise within data and are capable of reducing time taken to classify large amounts of novel data once trained, making them well-suited to the field of analytical chemistry where large datasets are present (such as that collected from gas chromatography-mass spectrometry (GC-MS)). In this study, the use of ANNs for the autonomous analysis of GC-MS profiles of Lucilia sericata larvae is investigated, where ANNs are required to estimate the age of the larvae to aid in the estimation of the post mortem interval (PMI). Two ANN analysis approaches are presented, where the ANN correctly classified the data with accuracy scores of 80.8% and 87.7% and Cohen's Kappa coefficients of 0.78 and 0.86. Inspection of these results shows the ANN to confuse two consecutive days which are of the same life stage and as a result are very similar in their chemical profile, which can be expected. The grouping of these two days into one class further improved results where accuracy scores 89% and 97.5% were obtained for the two analysis approaches.

Quantitative optimization of solid freeform deposition of aqueous hydrogels.

Many soft tissues exhibit complex anatomical geometry that is challenging to replicate for regenerative medicine applications. Solid freeform fabrication (SFF) has emerged as an attractive approach for creating 3D tissues, but a detailed understanding of how specific fabrication parameters affect accuracy and viability has not been established to date. In this study, we evaluate the effects of printing parameters of the Fab@Home 3D printing system on accuracy using alginate, photocrosslinkable polyethylene-glycol diacrylate (PEG-DA) and gelatin as commonly used model hydrogel materials. Print accuracy and resolution along the length, width and height were determined based on quantitative image analysis. The effects of extrusion parameters on cell viability were assessed using porcine aortic valve interstitial cells (PAVIC) as a model cell type. We observed that pressure, pathheight and pathspace all significantly affected print accuracy and resolution. Printing conditions did not affect PAVIC viability within the ranges applied. We predicted that optimal pressure, pathheight and pathspace values would be increased linearly with increasing nozzle diameter, and we confirmed that the predicted values generate accurate 3D geometries while poorly chosen parameters yield inaccurate, unpredictable geometries. This systematic optimization strategy therefore improves the accuracy of 3D printing platforms for biofabrication and tissue engineering applications.

Reservoir computing and extreme learning machines for non-linear time-series data analysis.

Random projection architectures such as Echo state networks (ESNs) and Extreme Learning Machines (ELMs) use a network containing a randomly connected hidden layer and train only the output weights, overcoming the problems associated with the complex and computationally demanding training algorithms traditionally used to train neural networks, particularly recurrent neural networks. In this study an ESN is shown to contain an antagonistic trade-off between the amount of non-linear mapping and short-term memory it can exhibit when applied to time-series data which are highly non-linear. To overcome this trade-off a new architecture, Reservoir with Random Static Projections (R(2)SP) is investigated, that is shown to offer a significant improvement in performance. A similar approach using an ELM whose input is presented through a time delay (TD-ELM) is shown to further enhance performance where it significantly outperformed the ESN and R(2)SP as well other architectures when applied to a novel task which allows the short-term memory and non-linearity to be varied. The hard-limiting memory of the TD-ELM appears to be best suited for the data investigated in this study, although ESN-based approaches may offer improved performance when processing data which require a longer fading memory.

Rapid 3D printing of anatomically accurate and mechanically heterogeneous aortic valve hydrogel scaffolds.

The aortic valve exhibits complex three-dimensional (3D) anatomy and heterogeneity essential for the long-term efficient biomechanical function. These are, however, challenging to mimic in de novo engineered living tissue valve strategies. We present a novel simultaneous 3D printing/photocrosslinking technique for rapidly engineering complex, heterogeneous aortic valve scaffolds. Native anatomic and axisymmetric aortic valve geometries (root wall and tri-leaflets) with 12-22 mm inner diameters (ID) were 3D printed with poly-ethylene glycol-diacrylate (PEG-DA) hydrogels (700 or 8000 MW) supplemented with alginate. 3D printing geometric accuracy was quantified and compared using Micro-CT. Porcine aortic valve interstitial cells (PAVIC) seeded scaffolds were cultured for up to 21 days. Results showed that blended PEG-DA scaffolds could achieve over tenfold range in elastic modulus (5.3±0.9 to 74.6±1.5 kPa). 3D printing times for valve conduits with mechanically contrasting hydrogels were optimized to 14 to 45 min, increasing linearly with conduit diameter. Larger printed valves had greater shape fidelity (93.3±2.6, 85.1±2.0 and 73.3±5.2% for 22, 17 and 12 mm ID porcine valves; 89.1±4.0, 84.1±5.6 and 66.6±5.2% for simplified valves). PAVIC seeded scaffolds maintained near 100% viability over 21 days. These results demonstrate that 3D hydrogel printing with controlled photocrosslinking can rapidly fabricate anatomical heterogeneous valve conduits that support cell engraftment.

Periodontitis, Porphyromonas, and the pathogenesis of rheumatoid arthritis.

Epidemiological data indicate a link between rheumatoid arthritis (RA) and periodontal disease (PD). In vitro and in vivo studies have sought to dissect potential mechanisms by which PD may contribute to initiation and progression of RA. However, these are both multifactorial, chronic diseases, and their complex etiologies and pathogenesis themselves remain incompletely understood. Could there really be an etiological link or does this simply represent a statistical coincidence muddied by common risk factors? This review seeks to provide background on these two diseases in the context of recent discoveries suggesting that their pathogenesis may be related. In particular, the process of citrullination, a post-translational protein modification, has been highlighted as a process common to both diseases. The evidence for a relationship between the diseases is explored and its potential mechanisms discussed.