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Urban land surface processes need to be represented to inform future urban climate and building energy projections. Here, the single layer urban canopy model Town Energy Balance (TEB) is coupled to the Weather Research and Forecasting (WRF) model to create WRF‐TEB. The coupling method is described generically, implemented into software, and the code and data are released with a Singularity image to address issues of scientific reproducibility. The coupling is implemented modularly and verified by an integration test. Results show no detectable errors in the coupling. Separately, a meteorological evaluation is undertaken using observations from Toulouse, France. The latter evaluation, during an urban canopy layer heat island episode, shows reasonable ability to estimate turbulent heat flux densities and other meteorological quantities. We conclude that new model couplings should make use of integration tests as meteorological evaluations by themselves are insufficient, given that errors are difficult to attribute because of the interplay between observational errors and multiple parameterization schemes (e.g., radiation, microphysics, and boundary layer). Plain Language Summary: With increasing urbanization and climate change, estimates of possible future urban climate and building energy scenarios are needed. Weather models (e.g., Weather Research and Forecasting; WRF) provide the state of the atmosphere, and urban land surface models (e.g., Town Energy Balance; TEB) allow the interactions and feedbacks of people—buildings—atmosphere to be investigated. WRF‐TEB is a free and open‐source model aimed at the urban climate and energy community to investigate applications such as the energy consumption associated with air conditioners, or the generation of solar energy in cities. Key Points: WRF‐TEB accounts for urban canopy energy exchanges, building energy demand, and neighborhood vegetationCoupled weather model development and scientific reproducibility are demonstratedThe coupling is verified through an integration test and evaluated with meteorological observations [ABSTRACT FROM AUTHOR]

The National Centre for Environmental Prediction (NCEP) Climate Forecast System (CFS) is being used for operational monsoon prediction over the Indian region. Recent studies indicate that the moist convective process in CFS is one of the major sources of uncertainty in monsoon predictions. In this study, the existing simple cloud microphysics of CFS is replaced by the six-class Weather Research Forecasting (WRF) single moment (WSM6) microphysical scheme. Additionally, a revised convective parameterization is employed to improve the performance of the model in simulating the boreal summer mean climate and intraseasonal variability over the Indian summer monsoon (ISM) region. The revised version of the model (CFSCR) exhibits a potential to improve shortcomings in the seasonal mean precipitation distribution relative to the standard CFS (CTRL), especially over the ISM region. Consistently, notable improvements are also evident in other observed ISM characteristics. These improvements are found to be associated with a better simulation of spatial and vertical distributions of cloud hydrometeors in CFSCR. A reasonable representation of the subgrid-scale convective parameterization along with cloud hydrometeors helps to improve the convective and large-scale precipitation distribution in the model. As a consequence, the simulated low-frequency boreal summer intraseasonal oscillation (BSISO) exhibits realistic propagation and the observed northwest-southeast rainband is well reproduced in CFSCR. Additionally, both the high and low-frequency BSISOs are better captured in CFSCR. The improvement of low and high-frequency BSISOs in CFSCR is shown to be related to a realistic phase relationship of clouds. [ABSTRACT FROM AUTHOR]

Reason for performing study To provide evidence to support recommendations regarding the co-administration of drugs with mesenchymal stem cell ( MSC) therapy. Objectives To determine the influence of sedatives, local anaesthetic and corticosteroids on MSC viability and proliferation, in comparison to somatic cells derived from tendon ( TDCs). Study design In vitro cell culture. Materials and methods MSCs (n = 3) and TDCs (n = 2) were cultured in media containing a clinically relevant dose range of xylazine, romifidine, detomidine and butorphanol, mepivacaine, methylprednisolone, or triamcinolone acetonide. Cell viability in suspension culture was assessed at intervals up to 4 h using the trypan blue dye assay. MSCs in monolayer culture were exposed to the highest concentrations of drug and proliferation was measured using the alamarBlue fluorescence assay. Results Exposure to romifidine or mepivacaine did not significantly affect viability or proliferation rate of MSCs or TDCs at any of the dosages tested. At the highest concentration of detomidine and butorphanol, MSC viability was significantly reduced compared to controls. Although xylazine exposure caused a significant (P < 0.001), dose-dependent reduction in MSC viability compared to controls, overall population viability remained good. Conversely, both methylprednisolone and triamcinolone resulted in the rapid death of significant numbers of MSCs (P < 0.001). Conclusions Clinicians can sedate horses and administer nerve blocks to assist in intratendinous or intrathecal injection of MSCs with confidence that these drugs will not impact the viability of implanted cells. However, the concomitant use of corticosteroids is likely to have a severely detrimental effect on cell viability and should not be performed. Similarly, steroid administration into the sheath of a damaged tendon is not recommended. [ABSTRACT FROM AUTHOR]

ABSTRACT The spread of a dense gas in the atmosphere is a phenomenon that occurs widely with natural (and anthropogenic) causes and is often associated with high impact and hazardous events. In this study a method of simulating the spread of dense gases in a numerical weather prediction model is presented. This approach has the advantage that dense gases can be simulated in regions of complex terrain using realistic forcings (in terms of both the driving meteorological fields and the representation of surface characteristics). The model formulation is tested against semi-idealized gravity-current-type experiments and similar modelling studies. As an example application, the Lake Nyos disaster of 1986, where a dense CO2 cloud spread through a mountainous region of Cameroon, is simulated. The predicted spread of CO2 agrees (qualitatively) very well with the observations. The method provides a means of determining a potential 'safe height' above which simulated concentrations are not hazardous, and thus the height above which refuge should be taken during similar future events. The simulation demonstrates a novel application which can be rapidly applied to other scenarios. [ABSTRACT FROM AUTHOR]

OBJECTIVES Human carriers of hypertrophic cardiomyopathy associated sarcomeric mutations have abnormal collagen metabolism before overt left ventricular hypertrophy is detectable. This study investigated whether differences in collagen biomarkers were present in blood samples of ragdoll cats positive for the MYBPC3: R820W mutation compared with negative controls. MATERIALS AND METHODS Cats were recruited for hypertrophic cardiomyopathy screening using echocardiography and genotyping. Circulating markers of collagen turnover (C-terminal telopeptide of type I collagen [ CITP; type I collagen degradation] and N-terminal propeptide of type III procollagen [type III collagen synthesis]) and cardiac biomarkers (N-terminal B-type natriuretic peptide and cardiac troponin I) were measured. Correlation between concentrations of collagen biomarkers and echocardiographic variables was analysed, and collagen biomarker concentrations were compared between MYBPC3 mutation positive and negative cats, without left ventricular hypertrophy. RESULTS Linear regression analyses showed that genotype was independently associated with CITP concentration. CITP was higher in mutation carriers (25 · 4 µg/L, interquartile range 16 · 0-29 · 2 µg/L) than non-carriers (14 · 6 µg/L, interquartile range 9 · 38-19 · 2 µg/L; P = 0 · 024). CLINICAL SIGNIFICANCE Circulating CITP was higher in MYBPC3-positive ragdoll cats than negative controls and may indicate altered collagen metabolism. Further studies are necessary to determine whether alterations in circulating collagen biomarker concentration relate to an early stage of hypertrophic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Summary Reasons for performing study: Mesenchymal stem (progenitor; stromal) cell (MSC) therapy has gained popularity for the treatment of equine tendon injuries but without reports of long-term follow-up. Objectives: To evaluate the safety and reinjury rate of racehorses after intralesional MSC injection in a large study of naturally occurring superficial digital flexor tendinopathy and to compare these data with those published for other treatments. Methods: Safety was assessed clinically, ultrasonographically, scintigraphically and histologically in a cohort of treated cases: 141 client-owned treated racehorses followed-up for a minimum of 2 years after return to full work. Reinjury percentages were compared to 2 published studies of other treatments with similar selection criteria and follow-up. The number of race starts, discipline, age, number of MSCs injected and interval between injury and treatment were analysed. Results: There were no adverse effects of the treatment with no aberrant tissue on histological examination. The reinjury percentage of all racehorses with follow-up (n = 113) undergoing MSC treatment was 27.4%, with the rate for flat (n = 8) and National Hunt (n = 105) racehorses being 50 and 25.7%, respectively. This was significantly less than published for National Hunt racehorses treated in other ways. No relationship between outcome and age, discipline, number of MSCs injected or injury to implantation interval was found. Conclusions: Whilst recognising the limitations of historical controls, this study has shown that MPC implantation is safe and appears to reduce the reinjury rate after superficial digital flexor tendinopathy, especially in National Hunt racehorses. Potential relevance: This study has provided evidence for the long-term efficacy of MSC treatment for tendinopathy in racehorses and provides support for translation to human tendon injuries. [ABSTRACT FROM AUTHOR]

Summary Reasons for performing the study: Highly prevalent superficial digital flexor tendon (SDFT) injury results in compromised tendon function through fibrosis and high frequency of re-injury due to altered biomechanical function. This study investigated the consequences of SDF tendinopathy on limb mechanics in relation to the mechanical properties of injured tendon. Objectives: To develop and validate a noninvasive in vivo assessment of tendon mechanics to investigate the effect of recent SDFT injury on limb stiffness index, providing an objective method to assess quality of healing. Hypotheses: Limb stiffness index would reduce as a consequence of SDFT injury and progressively increase during tendon healing and correlate with in vitro mechanical properties of the respective SDFTs. Methods: Kinematic analysis was performed at walk in 10 horses that had sustained career-ending SDFT injury. Stiffness index was derived from limb force recorded via a series of force plates and measurement of change in metacarpophalangeal joint angle using 3D motion analysis software. Horses were subjected to euthanasia 7 months after injury, the SDFTs removed and subjected to nondestructive in vitro mechanical testing. Results: Limb stiffness index was reduced following SDFT injury in comparison with the contralateral limb and increased during the convalescent period, approximating that of the contralateral limb by 7 months post injury. There was a significant positive correlation between in vivo limb stiffness index and in vitro SDFT stiffness. Clinical relevance: The ability to assess and monitor SDFT mechanical competence through limb stiffness measurement techniques in horses recovering from SDFT injury and the possibility of corroborating this with functional tendon healing may permit a more objective and accurate assessment of optimal tendon repair in the horse. This technique may be a useful method for assessing the efficacy of treatment regimens for tendinopathy and could be utilised to predict time to safe return to performance or re-injury. [ABSTRACT FROM AUTHOR]

Briston, L., Dudhia, J., Lees, P. Age-related differences in prostaglandin E2 synthesis by equine cartilage explants and synoviocytes. J. vet. Pharmacol. Therap. 33, 268–276. Time- and concentration-related actions of lipopolysaccharide (LPS) on the synthesis of prostaglandin E2 (PGE2) were investigated in cartilage explants and synoviocytes harvested from 3 age groups of horses, all with clinically normal joint function: group A <10 years; group B 11–20 years and group C >20 years. Cartilage explants from group A horses were least and those from group C were most sensitive to LPS. Significant increases in PGE2 concentration ( P ≤ 0.01) were obtained in group C horses in response to LPS concentrations of 1.0 μg/mL (and higher) after exposure for 24, 36 and 48 h, whereas explants from group A horses failed to respond to LPS at concentrations up to 100 μg/mL after exposure times up to 48 h. In contrast, synoviocytes from group A horses were most and those from group C horses were least sensitive to LPS stimulation. Synoviocytes from group A horses responded to LPS concentrations of 1 μg/mL (and higher) with significantly increased concentrations of PGE2 at 24 and 36 h. Significant but numerically smaller increases in PGE2 concentration were induced by LPS in synoviocytes from groups B and C. As the effects of high PGE2 concentrations are catabolic for cartilage, these observations suggest that both synoviocytes and chondrocytes might exert roles in the degenerative changes which occur in cartilage in horses with osteoarthritis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: A hallmark of rheumatoid arthritis (RA) is invasion of the synovial pannus into cartilage, and this process requires degradation of the collagen matrix. The aim of this study was to explore the role of one of the collagen-degrading matrix metalloproteinases (MMPs), membrane type 1 MMP (MT1-MMP), in synovial pannus invasiveness. METHODS: The expression and localization of MT1-MMP in human RA pannus were investigated by Western blot analysis of primary synovial cells and immunohistochemical analysis of RA joint specimens. The functional role of MT1-MMP was analyzed by 3-dimensional (3-D) collagen invasion assays and a cartilage invasion assay in the presence or absence of tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, or GM6001. The effect of adenoviral expression of a dominant-negative MT1-MMP construct lacking a catalytic domain was also examined. RESULTS: MT1-MMP was highly expressed at the pannus-cartilage junction in RA joints. Freshly isolated rheumatoid synovial tissue and isolated RA synovial fibroblasts invaded into a 3-D collagen matrix in an MT1-MMP-dependent manner. Invasion was blocked by TIMP-2 and GM6001 but not by TIMP-1. Invasion was also inhibited by the overexpression of a dominant-negative MT1-MMP, which inhibits collagenolytic activity and proMMP-2 activation by MT1-MMP on the cell surface. Synovial fibroblasts also invaded into cartilage in an MT1-MMP-dependent manner. This process was further enhanced by removing aggrecan from the cartilage matrix. CONCLUSION: MT1-MMP serves as an essential collagen-degrading proteinase during pannus invasion in human RA. Specific inhibition of MT1-MMP-dependent invasion may represent a novel therapeutic strategy for RA. [ABSTRACT FROM AUTHOR]

The aim of the present study was to correlate the levels of COMP and aggrecan as indicators of tissue damage, in synovial fluid (sf) from carpal joints of acutely lame racehorses, with macroscopical lesions of articular cartilage (OA), osteochondral fractures and ligament tears found at arthroscopy.Sixty-three lame horses [49 Standardbred trotters (STB) and 14 Thoroughbreds (TB)] in conventional training and racing that underwent arthroscopy of their middle carpal or radiocarpal joints were included in the study. Intact as well as fragmented COMP and aggrecan released into the synovial fluid were quantified by western blot analyses and ELISA. The expression of COMP in tissues was estimated by mRNA in situ hybridisation and protein immunolocalisation in cartilage and osteochondral fractures.The concentration of sf-COMP was higher in TB with an osteochondral fracture than in STB with osteochondral fractures and TB and STB with OA. The chondrocytes in middle and deep zones of the articular cartilage of the osteochondral fragments (from a TB) expressed COMP mRNA, in contrast to the cartilage on the opposite side of the fracture where no expression was detected. In the synovial fluid from a joint (TB) with osteochondral fractures only intact COMP was present, whereas, fragmented COMP was more prominent in synovial fluid from a joint with OA. The concentration of sf-aggrecan did not differ between the two breeds, or between different lesions. The increased concentration of sf-COMP in TB with osteochondral fractures, but not in synovial fluid from equine joints with OA, is a novel finding. The results from this study indicate that elevated sf-COMP concentration in the joints of Thoroughbreds may be a useful marker for carpal joint osteochondral fragments. [Copyright &y& Elsevier]

Aims Performance horses are at high risk of injury to the superficial digital flexor tendon (SDFT). Studies have shown that autologous mesenchymal stem cells (MSCs) injected into SDFT lesions subsequently result in a significant reduction of re-injury in National Hunt racehorses; however, recent studies show that only 25% of implanted MSCs survive 24 h post injection. The reason for this loss is unclear but may relate to cell quiescence or injection-related mortality. We hypothesised that cell viability and mortality is increased with needle gauge. Methods Equine MSCs cultured in vitro were resuspended to a final suspension density of 5 x 105 cells/ml to mimic that used for implantation in clinic. The cell suspension was injected through a 19 gauge, 21 gauge (current practice in clinic) or 23 gauge needle. Mesenchymal stem cells viability and mortality was analysed over a 24 h period post injection using alamarBlue® and Annexin V (apoptosis) assays, respectively. Results There was a 25% reduction in viability (P<0.01) and mortality (P<0.01) compared with noninjected MSCs over the 24 h period post injection. All needle gauges also induced a decrease in cell metabolic activity immediately post injection but with recovery by 2 h post injection. Furthermore, 21 gauge and 23 gauge needles increased early apoptotic cells immediately post injection, whereas the 19 gauge needle showed a delayed increase in apoptosis until 2 h post injection. Conclusions The delayed apoptosis may correlate with a subpopulation of quiescent cells subsequently becoming apoptotic. The proportion of early and late apoptotic MSCs, while significant, does not account for the total cell loss reported after intra-lesional injection. Practical significance Needle gauge selection has significant implications for the survival of MSC intra-lesional injections but it may not be the sole factor implicated in post injection cell mortality. We therefore recommend a minimum diameter of 19 gauge should be used for implantation. Ethical animal research Stem cell lines were obtained from bone marrow with approval of the Institutional Ethical Committee and under UK Home Office licence. Sources of funding: Funded by the Medical Research Council and The Royal Veterinary College. Competing interests: None. [ABSTRACT FROM AUTHOR]

Age-associated and degenerative loss of functional integrity in soft tissues develops from effects of cumulative and subtle changes in their extracellular matrix (ECM). The highly ordered tendon ECM provides the tissue with its tensile strength during loading. As age and exercise collide in the high incidence of tendinopathies, we hypothesized that aged tendons fail due to cumulative damage resulting from a combination of diminished matrix repair and fragmentation of ECM proteins induced by prolonged cyclical loading, and that this is an active cell-mediated process. We developed an equine tendon explant model to examine the effect of age on the influence of prolonged cyclical loading at physiologically relevant strain rates (5% strain, 1 Hz for 24 h) on tissue mechanical properties, loss of ECM protein and matrix metalloproteinase (MMP) expression. We show significantly diminished mechanical strength of cyclically loaded tissue compared to controls (39.7 +/- 12%, P