Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. However, molecular mechanisms contributing to the pathogenesis of DFUs ...remain poorly understood. We use next-generation sequencing to generate a human dataset of pathogenic DFUs to compare to transcriptional profiles of human skin and oral acute wounds, oral as a model of "ideal" adult tissue repair due to accelerated closure without scarring. Here we identify major transcriptional networks deregulated in DFUs that result in decreased neutrophils and macrophages recruitment and overall poorly controlled inflammatory response. Transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, are inhibited in DFUs. Moreover, inhibition of FOXM1 in diabetic mouse models (STZ-induced and db/db) results in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. Our data underscore the role of a perturbed, ineffective inflammatory response as a major contributor to the pathogenesis of DFUs, which is facilitated by FOXM1-mediated deregulation of recruitment of neutrophils and macrophages, revealing a potential therapeutic strategy.
The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small-molecule FGF receptor (FGFR) kinase inhibitors are currently in ...clinical development; however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here, we report the pharmacologic profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2, and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR-related effects were observed, confirming the in vivo FGFR selectivity of AZD4547. Taken together, our findings show that AZD4547 is a novel selective small-molecule inhibitor of FGFR with potent antitumor activity against FGFR-deregulated tumors in preclinical models. AZD4547 is under clinical investigation for the treatment of FGFR-dependent tumors.
The strategic reduction and remediation of degraded land is a global environmental priority. This is a particular priority in the Great Barrier Reef catchment area, Australia, where gully erosion a ...significant contributor to land degradation and water quality deterioration. Urgent action through the prioritisation and remediation of gully erosion sites is imperative to safeguard this UNESCO World Heritage site. In this study, we analyze a comprehensive dataset of 22,311 mapped gullies within a 3480 km2 portion of the lower Burdekin Basin, northeast Australia. Utilizing high-resolution lidar datasets, two independent methods - Minimum Contemporary Estimate (MCE) and Lifetime Average Estimate (LAE) – were developed to derive relative erosion rates. These methods, employing different data processing approaches and addressing different timeframes across the gully lifetime, yield erosion rates varying by up to several orders of magnitude. Despite some expected divergence, both methods exhibit strong, positive correlations with each other and additional validation data. There is a 43% agreement between the methods for the highest yielding 2% of gullies, although 80.5% of high-yielding gullies identified by either method are located within a 1 km proximity of each other. Importantly, distributions from both methods independently reveal that ∼80% of total volume of gully erosion in the study area is produced from only 20% of all gullies. Moreover, the top 2% of gullies generate 30% of the sediment loss and the majority of gullies do not significantly contribute to the overall catchment sediment yield. These results underscore the opportunity to achieve significant environmental outcomes through targeted gully management by prioritising a small cohort of high yielding gullies. Further insights and implications for management frameworks are discussed in the context of the characteristics of this cohort. Overall, this research provides a basis for informed decision-making in addressing gully erosion and advancing environmental conservation efforts.
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•Two independent methods for determining erosion rates are presented for a large dataset of gullies.•The methods have strong, positive correlations in derived rates.•Over 80% of the total gully sediment loss is generated from <20% of the gullies.•Only 2% of gullies are generating ∼30% of the sediment loss.•These methods enable effective targeting and prioritisation for gully remediation.
Despite over a century of investigations into gullies and gully erosion, the characterization and categorization of gullies and the varied definitions, nomenclatures and terminology used has caused ...some confusion in understanding and communicating the relationships of gully forms and processes around the world. We firstly review the gully literature and highlight how a lack of consistency in gully definition and characterization prevents unifying theory from being developed within this important field of research, since it is often unclear whether different landscape features being discussed are comparable. We propose that conventionally employed qualitative planform and cross‐sectional characteristics of gullies alone are inadequate to define gully types, yet both these features remain central to most modern gully descriptions. We discuss the need to revise and augment these basic characteristics with clearly defined morphogenetic attributes such as landscape context, soil material characteristics, erosion processes, hydrological integrity, modes of development, and head/side‐wall morphology for an effective, practicable, generic gully classification scheme. Central to a gully classification scheme is the need for a clear definition of what a gully is – and is not – for which geomorphological criteria are proposed to differentiate a ‘gully’ from other ‘incisional land surface forms’. This gully definition hinges largely on the identification of a retreating head scarp and the internal erosion by mass‐movement and other sidewall slope erosion processes, coupled with the transport of the soil materials from the gully void. By defining a gully and synthesizing descriptions of gully ‘types’ from the literature and our own experience, we propose key morphogenetic attributes of gullies necessary to form a framework for a systematic gully classification scheme. An initial, eclectic classification framework is presented as both a summation and a synthesis of the literature review, and as a progenitor to a dynamic generic classification scheme that is proposed in a follow‐up article.
From reviewing the gully erosion literature for definitions, terminology, and categorization we conclude that a systematic classification of gullies is necessary to overcome the apparent disorder. Thus, we propose key morphogenetic attributes of gullies to form a framework for a generic gully classification scheme. An initial classification framework is presented as both a summation and a synthesis of the literature, and as a progenitor to a dynamic classification scheme that is proposed in a follow up article.
The number of cattle herds placed under movement restrictions in Great Britain (GB) due to the suspected presence of bovine tuberculosis (bTB) has progressively increased over the past 25 years ...despite an intensive and costly test-and-slaughter control program. Around 38% of herds that clear movement restrictions experience a recurrent incident (breakdown) within 24 months, suggesting that infection may be persisting within herds. Reactivity to tuberculin, the basis of diagnostic testing, is dependent on the time from infection. Thus, testing efficiency varies between outbreaks, depending on weight of transmission and cannot be directly estimated. In this paper, we use Approximate Bayesian Computation (ABC) to parameterize two within-herd transmission models within a rigorous inferential framework. Previous within-herd models of bTB have relied on ad-hoc methods of parameterization and used a single model structure (SORI) where animals are assumed to become detectable by testing before they become infectious. We study such a conventional within-herd model of bTB and an alternative model, motivated by recent animal challenge studies, where there is no period of epidemiological latency before animals become infectious (SOR). Under both models we estimate that cattle-to-cattle transmission rates are non-linearly density dependent. The basic reproductive ratio for our conventional within-herd model, estimated for scenarios with no statutory controls, increases from 1.5 (0.26-4.9; 95% CI) in a herd of 30 cattle up to 4.9 (0.99-14.0) in a herd of 400. Under this model we estimate that 50% (33-67) of recurrent breakdowns in Britain can be attributed to infection missed by tuberculin testing. However this figure falls to 24% (11-42) of recurrent breakdowns under our alternative model. Under both models the estimated extrinsic force of infection increases with the burden of missed infection. Hence, improved herd-level testing is unlikely to reduce recurrence unless this extrinsic infectious pressure is simultaneously addressed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cardiac hypertrophy and heart failure are associated with metabolic dysregulation and a state of chronic energy deficiency. Although several disparate changes in individual metabolic pathways have ...been described, there has been no global assessment of metabolomic changes in hypertrophic and failing hearts in vivo. Hence, we investigated the impact of pressure overload and infarction on myocardial metabolism.
Male C57BL/6J mice were subjected to transverse aortic constriction or permanent coronary occlusion (myocardial infarction MI). A combination of LC/MS/MS and GC/MS techniques was used to measure 288 metabolites in these hearts. Both transverse aortic constriction and MI were associated with profound changes in myocardial metabolism affecting up to 40% of all metabolites measured. Prominent changes in branched-chain amino acids were observed after 1 week of transverse aortic constriction and 5 days after MI. Changes in branched-chain amino acids after MI were associated with myocardial insulin resistance. Longer duration of transverse aortic constriction and MI led to a decrease in purines, acylcarnitines, fatty acids, and several lysolipid and sphingolipid species but a marked increase in pyrimidines as well as ascorbate, heme, and other indices of oxidative stress. Cardiac remodeling and contractile dysfunction in hypertrophied hearts were associated with large increases in myocardial, but not plasma, levels of the polyamines putrescine and spermidine as well as the collagen breakdown product prolylhydroxyproline.
These findings reveal extensive metabolic remodeling common to both hypertrophic and failing hearts that are indicative of extracellular matrix remodeling, insulin resistance and perturbations in amino acid, and lipid and nucleotide metabolism.
Achieving change through gully erosion research Wilkinson, Scott N.; Rutherfurd, Ian D.; Brooks, Andrew P. ...
Earth surface processes and landforms,
January 2024, 2024-01-00, 20240101, Letnik:
49, Številka:
1
Journal Article
Recenzirano
Odprti dostop
This is an introduction to a special issue arising from the 8th International Conference on Gully Erosion, held in Townsville, Australia in 2019. Research has improved understanding of gully erosion ...processes and increasingly emphasizes sophisticated near‐and‐remotely sensed methods to characterize and measure gullies. These data can then be analysed using equally sophisticated models and scenarios can be simulated. These advances improve the capacity to predict gully initiation and development over time and space. It is often assumed that better prediction translates into greater impact and uptake of research to solve real world gully erosion problems. Examples of impressive associations between research programmes and major gully management programmes are evident. However, there has been little assessment of the impact of gully research. We argue for a greater focus on achieving impact including interventions that better manage and prevent gully erosion. Opportunities to deliver research impact are assessed using three indicators of progression towards impact; the practical usability of research, whether it is in use by non‐researchers, and whether it is useful in guiding improvements in management. Like other natural hazards, gully erosion is a phenomenon of the social, economic and environmental context in which it occurs. Defining the contexts and consequences of gully erosion and using these to frame further research is therefore a means to increase research impact. Enhancing collaboration between research disciplines and with practitioners who act on the research, and a greater focus on the translation of results into practice, is another avenue. Expanding the monitoring and evaluation of gully management can better demonstrate the impact of past research and enable further useful investigations. We urge gully erosion researchers to consider the potential impact of their research, including how it can more effectively inform better and more cost‐effective management and political decisions.
Following the 8th International Symposium on Gully Erosion we propose an increased focus on research impact on gully management and prevention, by defining the consequences of gully erosion, enhancing collaboration, focusing on use by practitioners, and expanding monitoring and evaluation.
Silicon (Si) is suggested to be an important/essential nutrient for bone and connective tissue health. Silicon-substituted hydroxyapatite (Si-HA) has silicate ions incorporated into its lattice ...structure and was developed to improve attachment to bone and increase new bone formation. Here we investigated the direct adsorption of silicate species onto an HA coated surface as a cost effective method of incorporating silicon on to HA surfaces for improved implant osseointegration, and determined changes in surface characteristics and osteoblast cell adhesion. Plasma-sprayed HA-coated stainless steel discs were incubated in silica dispersions of different concentrations (0-42 mM Si), at neutral pH for 12 h. Adsorbed Si was confirmed by XPS analysis and quantified by ICP-OES analysis following release from the HA surface. Changes in surface characteristics were determined by AFM and measurement of surface wettability. Osteoblast cell adhesion was determined by vinculin plaque staining. Maximum Si adsorption to the HA coated disc occurred after incubation in the 6 mM silica dispersion and decreased progressively with higher silica concentrations, while no adsorption was observed with dispersions below 6 mM Si. Comparison of the Si dispersions that produced the highest and lowest Si adsorption to the HA surface, by TEM-based analysis, revealed an abundance of small amorphous nanosilica species (NSP) of ~1.5 nm in diameter in the 6 mM Si dispersion, with much fewer and larger NSP in the 42 mM Si dispersions. 29Si-NMR confirmed that the NSPs in the 6 mM silica dispersion were polymeric and similar in composition to the larger NSPs in the 42 mM Si dispersion, suggesting that the latter were aggregates of the former. Amorphous NSP adsorbed from the 6 mM dispersion on to a HA-coated disc surface increased the surface's water contact angle by 53°, whereas that adsorbed from the 42 mM dispersion decreased the contact angle by 18°, indicating increased and decreased hydrophobicity, respectively. AFM showed an increase in surface roughness of the 6 mM Si treated surface, which correlated well with an increase in number of vinculin plaques. These findings suggest that NSP of the right size (relative to charge) adsorb readily to the HA surface, changing the surface characteristics and, thus, improving osteoblast cell adhesion. This treatment provides a simple way to modify plasma-coated HA surfaces that may enable improved osseointegration of bone implants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The stoichiometric reaction between thiols and maleimide-functional poly(ester)s is demonstrated to be a quantitative, tolerant, mild and efficient method for polymer modification.
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