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Environmental sustainability in sport is an increasingly important issue. In this paper, we want to highlight a specific phenomenon, namely artificially constructed landscapes and the outdoor sport activities that take place therein. More specifically, we are interested in the logics that govern peoples' practice of sport in such artificial landscapes and what challenges with regards to environmental sustainability that follow from these logics. The purpose of this paper is to identify what individual athletes perceive as meaningful logics when practicing sport in artificial landscapes and to analyse and discuss potential environmental consequences of these logics. The sports we focus on are cross-country skiing and canoe slalom, two sports that historically have been dependent on specific geographies and contexts. We build on two research questions: What logics of practice govern individual athletes' practice of sport in artificial landscapes? And what environmental challenges are potential consequences of the logics that are expressed by the athletes? Our findings indicate that the logic of performance is dominant for the sport practitioners who train in artificial landscapes, at the expense of perspectives such as nature experience and environmental sustainability. If performance is key, then the role of the training landscape is also first and foremost to present the best possible conditions for performance. But if the athlete/exerciser see their training as a means of experiencing nature, then other values than performance and comparability can become more important. When the environmental impact of individual athletes and of the artificial landscapes in which they do their training come under increased scrutiny, the role of logics of practice in the sport and movement culture needs further attention. Being aware of nature and the environment is also a logic that could be found meaningful in the process of making sports more sustainable.

Does nature still matter in sport? In the balancing between natural and scientific training, Swedish upper-secondary ski schools have played an important role. This paper deals with specific landscape features for testing at three Swedish ski schools: Hallstatestet in Sollefteå, Hovfjällsracet in Torsby, and Stoltjonastestet in Järpen. The following questions will be addressed: How do the coaches at each school use local tests to analyze performance? How is the importance of local tests articulated, and what roles do history and nature play in this process? The paper concludes that the use of local landscapes to articulate elite performance connects ideas of measurability and scientization to the lingering tradition of natural training. Local landscapes thereby become a mediator between scientific and experiential knowledge about sport performance and point out how local sport heritage can be used for addressing environmental issues in sport. [ABSTRACT FROM AUTHOR]

Since the introduction of a national system for upper-secondary sport schools in Sweden in the 1970s, these institutions have been an important environment for developments in training and coaching. This is particularly true for cross-country skiing, where these schools quickly became an obligatory passage point. Coaches at the sport schools, often formally employed as PE teachers, were among the first professionalized endurance sport coaches in Sweden. This article examines how communities of practice have influenced the professionalization process of XC ski coaches at Swedish sport schools. The results show how being part of this community is conditioned on personal experience of active learning, historically as a skier yourself and currently as a coach who participates in the everyday work. The strong communities of practice have enabled coaches to maintain a high degree of self--governance and ensured that experiential knowledge remain important in relation to scientific knowledge. [ABSTRACT FROM AUTHOR]

This study adopts a testimonial approach to bullying victimisation, and aims to create a deeper understanding of the experiences and effects of being a bullying target. Four written narratives about being subjected to school bullying were analysed according to interpretative phenomenological analysis. From the analysis, four themes were constructed, which represented different elements of victimhood: (1) "Self-blame" in which victims view themselves as the cause of the bullying, (2) "Abandonment" in which victims describe feelings of standing alone in their exposed situation, (3) "Turning points" in which the victims recount a variety of restorative events, and (4) "Continued victimhood" in which the victims relate how the feeling of victimhood and vulnerability continues even though the bullying has ended. In conclusion, school bullying is something that continues to affect the individual adversely long after it has stopped, although stable friendship relations might have a mitigating influence. Through such relations, victimhood can be neutralised and a more positive self-image develop. Moreover, as numerous other kinds of victims emphasise, an essential part of the rehabilitation process is to finally be able to tell one's story, to lay bare one's difficult knowledge to a wider audience.

Microscopic and spectroscopic analyses were conducted on steel/bentonite interface samples removed from four in situ experiments that were carried out in three underground research laboratories at different temperatures and under different hydraulic and geochemical conditions. The results provide valuable information about the corrosion processes occurring in high‐level radioactive waste repositories. Systematic patterns can be deduced from the results, irrespective of carbon steel grade, type of bentonite and its degree of compaction, geochemical environment or experimental setup. Thus, a clear dependence of the corrosion rates on temperature and exposure period, as well as on the availability of H2O and O2 provided by the surrounding bentonite buffer, is observed. Furthermore, Fe(II) ions released by corrosion interact with the structural Fe in the clay. Recent developments highlight the usefulness of reactive transport modelling in understanding the coupled corrosion and Fe–clay interaction processes. [ABSTRACT FROM AUTHOR]

Sport has often had an important role in times of crisis, but the Covid-19 pandemic is another matter. Sport was heavily affected world-wide on all levels. In Sweden, gathering people for endurance events conflicted with the Covid-19 restrictions. Some events were cancelled, but many tried to adapt. What adaptation strategies to Covid-19 have Swedish event organizers used? What role have digital tools played in their adaptation? What economic impacts did these events experience? We argue that the challenges posed by Covid-19 have accelerated the digitization of endurance events and highlighted the tensions between commercial and non-commercial actors in sports due to the differences in financial structure and eligibility for economic support. We thereby contribute to the growing research on how sport events in general have been impacted by the Covid-19 pandemic, and specifically in the context of Sweden's somewhat exceptional response to the pandemic. [ABSTRACT FROM AUTHOR]

The findings also indicate that athletes in individual sports were less likely to engage in digital training than athletes in team sports and that older athletes are more likely to participate in virtual competitions than younger athletes. Female athletes were more likely to participate in online training than male athletes, while male athletes were more likely to participate in virtual sports competitions than female athletes. On a global scale, the different national approaches to Covid-19 led to radically different conditions for sport and physical activity athletes, exercisers, sport managers, event organizers, supporters and others. [Extracted from the article]

The Alternative Buffer Material ABM5 experiment is an in situ medium-scale experiment performed at Äspö Hard Rock Laboratory (HRL) conducted by SKB in Sweden with the aim of analysing the long-term stability of bentonites used as an engineering barrier for a high-level radioactive waste repository (HLWR). In this work, four different ring-shaped Ca- and Na-bentonite blocks, which were piled around a carbon steel cylindrical heater, subjected to a maximum temperature of 250 °C and hydrated with saline Na-Ca-Cl Äspö groundwater (0.91 ionic strength), were characterized after dismantling. This work allowed us to identify the main geochemical processes involved, as well as the modifications in the physico-chemical properties and pore water composition after 4.4 years of treatment. No significant modifications in mineralogy were observed in samples close to the heater contact, except an increase in Fe content due to C-steel corrosion, carbonate dissolution/precipitation (mainly calcite and siderite) and Mg increase. No magnetite and a low amount of Fe(II) inside the clay mineral structure were detected. No modifications were observed in the smectite structure, except a slight increase in total and tetrahedral charge. A decrease in external surface area and cation exchange capacity (CEC) was found in all samples, with lower values being detected at the heater contact. As a consequence of the diffusion of the infiltrating groundwater, a modification of the composition at clay mineral exchange sites occurred. Ca-bentonites increased their Na content at exchange sites, whereas Na-bentonite increased their Ca content. Exchangeable Mg content decreased in all bentonites, except in MX-80 located at the bottom part of the package. A salinity gradient is observed through the bentonite blocks from the granite to the heater contact due to anions are controlled by diffusion and anion exclusion. The pore water chemistry of bentonites evolved as a function of the diffusion transport of the groundwater, the chemical equilibrium of cations at exchange sites and mineral dissolution/precipitation processes. These reactions are in turn dependent on temperature and water vapor fluxes. [ABSTRACT FROM AUTHOR]

Can walking trails be understood not only as routes to history and heritage, but also as heritage in and of themselves? The paper explores the articulation of trails as a distinct landscape and mobility heritage, bridging the nature-culture divide and building on physical and intellectual movements over time. The authors aim to contribute to a better understanding of the geography of trails and trailscapes by analysing the emergence of the Swedish-Norwegian trail Finnskogleden. The trail is situated in the border region spanning the former county of Hedmark in present-day Innlandet County, south-eastern Norway, and Värmland County in mid-western Sweden, a forested area where Finnish-speaking immigrants settled from the 16th century to the early 20th century. Archives, literature, interviews, and field visits were used to analyse the emergence and governance of the trail. The main finding is the importance of continuous articulation work by local and regional stakeholders, through texts, maps, maintenance, and mobility. In conclusion, the Finn forest trailscape and its mobility heritage can be seen as an articulation of territory over time, a multilayered process drawing on various environing technologies, making the trail a transformative part of a trans-border political geography. [ABSTRACT FROM AUTHOR]

How is an elite sports education introduced in a political context like 1970s Sweden, where egalitarian ideas about education and sport for all were the norm and anything hinting at special treatment for talented youths was potentially controversial? This article analyzes the history of how Sweden designed and implemented a nationwide system for elite sport education, and how different actors negotiated the balance between elite sport and education. The Swedish sport schools were initiated in 1972 to solve the issue with the growing importance of elite sport, in parallel with the increasing importance of upper-secondary education. One innovation in these schools was the introduction of a school subject called Special sport. Starting with two schools and 80 students in the early 1970s, there are now more than 50 schools and 1200 students. Since the very beginning, these schools have had a dual mission – produce more and better elite athletes and give sport talents a full education to fall back on should they not become professional athletes. The introduction of sport schools in 1970s Sweden was part of a broader sportification process and has in some sports become the only realistic path toward an elite career. [ABSTRACT FROM AUTHOR]

The number of national reference populations that are whole-genome sequenced are rapidly increasing. Partly driving this development is the fact that genetic disease studies benefit from knowing the genetic variation typical for the geographical area of interest. A whole-genome sequenced Swedish national reference population (n = 1000) has been recently published but with few samples from northern Sweden. In the present study we have whole-genome sequenced a control population (n = 300) (ACpop) from Västerbotten County, a sparsely populated region in northern Sweden previously shown to be genetically different from southern Sweden. The aggregated variant frequencies within ACpop are publicly available (DOI 10.17044/NBIS/G000005) to function as a basic resource in clinical genetics and for genetic studies. Our analysis of ACpop, representing approximately 0.11% of the population in Västerbotten, indicates the presence of a genetic substructure within the county. Furthermore, a demographic analysis showed that the population from which samples were drawn was to a large extent geographically stationary, a finding that was corroborated in the genetic analysis down to the level of municipalities. Including ACpop in the reference population when imputing unknown variants in a Västerbotten cohort resulted in a strong increase in the number of high-confidence imputed variants (up to 81% for variants with minor allele frequency < 5%). ACpop was initially designed for cancer disease studies, but the genetic structure within the cohort will be of general interest for all genetic disease studies in northern Sweden. [ABSTRACT FROM AUTHOR]

The antimicrobial peptide LL‐37 is active against oral bacteria and has been demonstrated to be present in human saliva, but its distribution in different fractions of saliva is not known. LL‐37 is formed from its intracellular pro‐form, hCAP18, in an extracellular enzymatic reaction catalyzed by proteinase 3 and kallikrein 5. Here, we prepared cell‐containing and cell‐free fractions of unstimulated human whole saliva by centrifugation after depolymerization of mucins with dithiothreitol, and measured the levels of hCAP18/LL‐37 in these fractions using ELISA. Cellular expression of hCAP18/LL‐37 was determined by western blotting and immunocytochemistry. The ELISA analyses demonstrated that both cells and cell‐free saliva contained hCAP18/LL‐37. Western blot analysis of cell‐pellet homogenates showed a strong band corresponding to hCAP18 at the correct molecular weight and a weak band corresponding to LL‐37. Phase‐contrast and light microscopy revealed that the cells consisted of desquamated epithelial cells. These cells expressed cytoplasmic immunoreactivity for hCAP18/LL‐37. The peripheral part of the cytoplasm, corresponding to the plasma membrane, was particularly rich in hCAP18/LL‐37 immunoreactivity. No immunoreactivity was observed after omission of the primary antibody. We conclude that desquamated epithelial cells of human whole saliva contain antimicrobial hCAP18/LL‐37, suggesting that these cells may take part in the innate immune system by harboring and releasing these peptides. [ABSTRACT FROM AUTHOR]

Byline: Lars Taxen, Daniel Svensson With the deregulation of the markets and the introduction of new technologies, the need to manage diversification, change and complexity in product development has become crucial. To cope with this situation, an alternative foundation for PLM is needed in which social issues are considered alongside with more traditional, technical ones. Such a major re-orientation of PLM needs to be informed by a theoretical perspective, which integrates social and technical issues into a coherent sociotechnical framework. To this end, we propose the Activity Domain Theory. This theory has been used as a guide at the Ericsson telecommunication company in order to suggest an alternative foundation for PLM. Preliminary results are the enhancement of the organisational language with the construct of activity domains, a clean-up of fundamental categories in information management, a multi-domain product structure concept, an alternative business process model, an information system managing core information elements and a strategy towards balancing centralised and decentralised control.

Objective: The human host defense peptide LL‐37 both shows antimicrobial effects and modulates host cell properties. Here, we assess the effects of synthesized LL‐37 on lipopolysaccharide (LPS)‐induced inflammation in human periodontal ligament (PDL) cells and investigates underlying mechanisms. Background: LL‐37 has been detected in the periodontal tissues, but its functional importance for PDL cell innate immune responses is not known. Methods: Human PDL cells were obtained from premolars extracted on orthodontic indications. Cellular pro‐inflammatory monocyte chemoattractant protein‐1 (MCP‐1) mRNA expression was determined using quantitative real‐time RT‐PCR. MCP‐1 protein production was assessed by western blot and ELISA. Internalization of LL‐37 by PDL cells was visualized by immunocytochemistry. Nuclear factor kappa‐light‐chain‐enhancer of activated B‐cell (NF‐κB) activity was assessed by western blot of phosphorylated p65, phosphorylated p105, and IκBα proteins. Binding of LL‐37 to PDL cell DNA was determined by isolation and purification of DNA and dot blot for LL‐37 immunoreactivity. Results: Treatment with LL‐37 (1 µmol/L) for 24 hours prevented LPS‐induced stimulation of MCP‐1 expression analyzed both on transcript and on protein levels. Stimulation with LL‐37 (1 µmol/L) for 24 hours had no effect on toll‐like receptor (TLR)2 and TLR4 transcript expression, suggesting that LL‐37 acts downstream of the TLRs. Preincubation with LL‐37 for 60 minutes followed by stimulation with LPS for 24 hours in the absence of LL‐37 completely prevented LPS‐evoked MCP‐1 transcript expression, implying that LL‐37 acts intracellularly and not via binding and neutralization of LPS. In PDL cells stimulated with LL‐37 for 60 minutes, the peptide was internalized as demonstrated by immunocytochemistry, suggesting an intracellular mechanism of action. LL‐37 immunoreactivity was observed both in the cytosol and in the nucleus. Downregulation of LPS‐induced MCP‐1 by LL‐37 was not mediated by reduction in NF‐κB activity as shown by unaltered expression of phosphorylated p65, phosphorylated p105, and IκBα NF‐κB proteins in the presence of LL‐37. Immunoreactivity for LL‐37 was observed in PDL cell DNA treated with but not without 0.1 and 1 µmol/L LL‐37 for 60 minutes in vitro. Conclusion: LL‐37 abolishes LPS‐induced MCP‐1 production in human PDL cells through an intracellular, NF‐κB‐independent mechanism which probably involves direct interaction between LL‐37 and DNA. [ABSTRACT FROM AUTHOR]

In The Pasteurization of France, Bruno Latour argued that the rise of hygiene was dependent on collaboration between Pasteur, the hygiene movement, scientists and others. He also pointed at the importance of obligatory passage points such as the Pasteurian laboratory, to ensure the scientization and rationalization of hygiene. This article argues that there has been a similar process in elite sports, a 'physiologization' where scientists, sport organizations and specialized coaches have transformed training from a deeply personal and experiential matter to something universal and scientific. Physiologists made the test lab an obligatory passage point for athletes who wanted to compete on the highest level. Through theories of sportification and science and technology studies this paper analyses the scientization of endurance sports. [ABSTRACT FROM AUTHOR]

Contemporary images of desirable work (for example at gaming companies or at one of the tech giants) foregrounds creativity and incorporates and idealises elements of play. Simultaneously, becoming one of the best in some particular leisure activity can require many long hours of hard, demanding work. Between on the one hand work and on the other hand leisure and play, we enter the domain of games and sports. Most classical sports originally developed from physical practices of moving the human body and these practices were, through standardization, organization and rationalization, turned into sports. Many sport researchers, (sport) historians and (sport) sociologists have pointed out that sports have gone through a process of "sportification". Cross-country skiing is an example of an activity that has gone through a historical process of sportification, over time becoming progressively more managed and regulated. Computer games are today following a similar trajectory and have gone from being a leisure activity to becoming a competitive activity, "esports", with professional players, international competitions, and live streams that are watched by tens of millions of viewers. [ABSTRACT FROM AUTHOR]

It is generally believed that cells that are unable to downregulate glucose transport are particularly vulnerable to hyperglycemia. Yet, little is known about the relation between expression of glucose transporters and acute toxic effects of high glucose exposure. In the present ex vivo study of rat renal cells, we compared the apoptotic response to a moderate increase in glucose concentration. We studied cell types that commonly are targeted in diabetic kidney disease (DKD): proximal tubule cells, which express Na+-dependent glucose transporter (SGLT)2, mesangial cells, which express SGLT1, and podocytes, which lack SGLT and take up glucose via insulin-dependent glucose transporter 4. Proximal tubule cells and mesangial cells responded within 4-8 h of exposure to 15 mM glucose with translocation of the apoptotic protein Bax to mitochondria and an increased apoptotic index. SGLT downregulation and exposure to SGLT inhibitors abolished the apoptotic response. The onset of overt DKD generally coincides with the onset of albuminuria. Albumin had an additive effect on the apoptotic response. Ouabain, which interferes with the apoptotic onset, rescued from the apoptotic response. Insulin-supplemented podocytes remained resistant to 15 and 30 mM glucose for at least 24 h. Our study points to a previously unappreciated role of SGLT-dependent glucose uptake as a risk factor for diabetic complications and highlights the importance of therapeutic approaches that specifically target the different cell types in DKD. [ABSTRACT FROM AUTHOR]

Whole-genome sequencing is a promising approach for human autosomal dominant disease studies. However, the vast number of genetic variants observed by this method constitutes a challenge when trying to identify the causal variants. This is often handled by restricting disease studies to the most damaging variants, e.g. those found in coding regions, and overlooking the remaining genetic variation. Such a biased approach explains in part why the genetic causes of many families with dominantly inherited diseases, in spite of being included in whole-genome sequencing studies, are left unsolved today. Here we explore the use of a geographically matched control population to minimize the number of candidate disease-causing variants without excluding variants based on assumptions on genomic position or functional predictions. To exemplify the benefit of the geographically matched control population we apply a typical disease variant filtering strategy in a family with an autosomal dominant form of colorectal cancer. With the use of the geographically matched control population we end up with 26 candidate variants genome wide. This is in contrast to the tens of thousands of candidates left when only making use of available public variant datasets. The effect of the local control population is dual, it (1) reduces the total number of candidate variants shared between affected individuals, and more importantly (2) increases the rate by which the number of candidate variants are reduced as additional affected family members are included in the filtering strategy. We demonstrate that the application of a geographically matched control population effectively limits the number of candidate disease-causing variants and may provide the means by which variants suitable for functional studies are identified genome wide. [ABSTRACT FROM AUTHOR]

Background: Ambrosia arborescens has been used in Andean traditional medicine to reduce problems associated with various inflammatory diseases and conditions, although the underlying mechanism is unknown.Hypothesis/purpose: The sesquiterpene lactones (SLs) coronopilin and damsin, which are major secondary metabolites of A. arborescens, have anti-inflammatory activity by attenuation of IL-6 and MCP-1 expression and inhibition of NF-κB in human dermal fibroblasts (HDFa) and human keratinocytes (HaCaT).Study Design: In order to confirm a high concentration of damsin and coronopilin in the plant material, a quantitative method was developed. The effect of the pure compounds on cytokine and NF-κB expression was examined, as well as their effects on HDFa and HaCaT cell morphology and viability.Methods: Coronopilin and damsin were quantified by HPLC-DAD analysis, from EtOAc extracts of the aerial parts of A. arborescens. Cell morphology was investigated by phase-contrast microscopy and cell viability by the MTT assay. IL-6 and MCP-1 cytokine gene expression was assessed by quantitative real-time RT-PCR in LPS stimulated cells. The NF-κB pathway was studied through western blotting of the phosphorylated forms of p65 and p50/p105, as well as the non-phosphorylated IκB. Dexamethasone was used as positive control.Results: Dry aerial parts contained 12.3  mg/g and 13.4  mg/g of coronopilin and damsin, respectively. Treatment with either compound (1-10 µM) for 24  h attenuated LPS-induced mRNA expression of the pro-inflammatory cytokine IL-6 and the chemokine MCP-1 in HDFa cells. The down-regulation of MCP-1 mRNA induced by coronopilin and damsin was confirmed on the protein level. Damsin reduced phosphorylated p65 and p105 subunits in HDFa cells. Neither coronopilin nor damsin affected HDFa cell morphology and viability within the used concentration range (1-10 µM). Also, in HaCaT cells, treatment with damsin (1-10 µM) for 24  h inhibited the MCP-1 expression, and damsin thereby attenuated cytokine expression both in HDFa and HaCaT cells.Conclusion: We show that coronopilin and damsin from A. arborescens inhibit pro-inflammatory IL-6 and MCP-1 expression in human skin cells via NF-κB inhibition, suggesting that they may be useful for antagonizing inflammatory conditions of the human skin. [ABSTRACT FROM AUTHOR]

Bladder denervation and bladder outlet obstruction are urological conditions that cause bladder growth. Transcriptomic surveys in outlet obstruction have identified differentially expressed genes, but similar studies following denervation have not been done. This was addressed using a rat model in which the pelvic ganglia were cryo-ablated followed by bladder microarray analyses. At 10 days following denervation, bladder weight had increased 5.6-fold, and 2,890 mRNAs and 135 micro-RNAs (miRNAs) were differentially expressed. Comparison with array data from obstructed bladders demonstrated overlap between the conditions, and 10% of mRNAs changed significantly and in the same direction. Many mRNAs, including collagen triple helix repeat containing 1 (Cthrc1), Prc1, Plod2, and Dkk3, and miRNAs, such as miR-212 and miR-29, resided in the shared signature. Discordantly regulated transcripts in the two models were rare, making up for <0.07% of all changes, and the gene products in this category localized to the urothelium of normal bladders. These transcripts may potentially be used to diagnose sensory denervation. Western blotting demonstrated directionally consistent changes at the protein level, with increases of, e.g., Cthrc1, Prc1, Plod2, and Dkk3. We chose Cthrc1 for further studies and found that Cthrc1 was induced in the smooth muscle cell (SMC) layer following denervation. TGF-1 stimulation and miR30d-5p inhibition increased Cthrc1 in bladder SMCs, and knockdown and overexpression of Cthrc1 reduced and increased SMC proliferation. This work defines common and distinguishing features of bladder denervation and obstruction and suggests a role for Cthrc1 in bladder growth following denervation. [ABSTRACT FROM AUTHOR]

This paper discusses the emergence of Swedish women's football through the case of pioneering team Öxabäcks IF, from a rural village of about 900 inhabitants. From the start in 1966 until the dissolving of the team due to financial problems in 1999, Öxabäck was one of the top Swedish football clubs. They won seven Swedish Championships and six Swedish Cups, and played an important role in advancing national and international women's football through exhibition matches and tours. How was this possible in a small rural village? We will analyze the strategies used by the Öxabäck players to convince the Swedish Football Association, the press, and the public that their ambition to play football was serious and should be supported. What aspects of sportification did they try to achieve, as Swedish women's football went through a rapid sportification process in the late 1960s and early 1970s? We argue that concepts related to sportification, such as rational training and organization, were used to further the cause of women's football. The experiences from the Öxabäck case are important to shed light on similar processes in currently emerging sports today. [ABSTRACT FROM AUTHOR]

The protein gC1qR (globular C1q receptor), also named p33, was originally identified as a binding partner of the globular heads of C1q in the complement system. gC1qR/p33 is abundantly expressed in many cell types, but the functional importance of this protein is not completely understood. Here, we investigate the impact of gC1qR/p33 on the production and function of the pathophysiologically important chemokine monocyte chemoattractant protein-1 (MCP-1) and the underlying molecular mechanisms. Knockdown of gC1qR/p33 negatively regulated the production of MCP-1, but had no effect on the expression of transcript for MCP-1 in human periodontal ligament cells, suggesting a translational/post-translational mechanism of action. Laser scanning confocal microscopy showed considerable cytosolic co-localization of gC1qR/p33 and MCP-1, and co-immunoprecipitation disclosed direct physical interaction between gC1qR/p33 and MCP-1. Surface plasmon resonance analysis revealed a high-affinity binding (KD = 10.9 nM) between gC1qR/p33 and MCP-1. Using a transwell migration assay, we found that recombinant gC1qR/p33 enhances MCP-1-induced migration of human THP-1 monocytes, pointing to a functional importance of the interaction between gC1qR/p33 and MCP-1. An in vitro assay revealed a rapid turnover of the MCP-1 protein and that gC1qR/p33 stabilizes MCP-1, hence preventing its degradation. We propose that endogenous gC1qR/p33 physically interacts with MCP-1 causing stabilization of the MCP-1 protein and stimulation of its activity in human periodontal ligament cells, suggesting a novel gC1qR/p33-mediated pro-inflammatory mechanism of action. [ABSTRACT FROM AUTHOR]

The human cathelicidin peptide LL-37 has antimicrobial and anti-biofilm functions, but LL-37 may also damage the host by triggering inflammation and exerting a cytotoxic effect, thereby reducing host cell viability. Human plasma mitigates LL-37-induced host cell cytotoxicity but the underlying mechanisms are not completely understood. Apolipoprotein A-I (ApoA-I) is a plasma protein endowed with atheroprotective effects. Here, we investigate the interaction between ApoA-I and LL-37 by biochemical techniques, and furthermore assess if ApoA-I protects against LL-37-evoked cytotoxicity in human umbilical vein endothelial cells (HUVEC). Our results demonstrated that ApoA-I effectively binds LL-37. The binding of ApoA-I to LL-37 resulted in a structural rearrangement of the protein, but this interaction did not cause lower ApoA-I stability. Recombinant ApoA-I protected against LL-37-induced cytotoxicity in HUVEC and endogenous ApoA-I knockdown in HepG2 cells made the cells more sensitive to LL-37-evoked cytotoxicity. We conclude that ApoA-I physically interacts with LL-37 and antagonizes LL-37-induced down-regulation of endothelial cell viability suggesting that this mechanism counteracts endothelial cell dysfunction. [ABSTRACT FROM AUTHOR]

Modulation from contractile to synthetic phenotype of vascular smooth muscle cells is a central process in disorders involving compromised integrity of the vascularwall. Phenotypemodulation has been shown to include transition from voltage-dependent toward voltage-independent regulation of the intracellular calcium level, and inhibition of non-voltage dependent calcium influx contributes to maintenance of the contractile phenotype. One possible mediator of calcium-dependent signaling is the FAK-family non-receptor protein kinase Pyk2, which is activated by a number of stimuli in a calcium-dependent manner. We used the Pyk2 inhibitor PF-4594755 and Pyk2 siRNA to investigate the role of Pyk2 in phenotype modulation in rat carotid artery smooth muscle cells and in cultured intact arteries. Pyk2 inhibition promoted the expression of smooth muscle markers at the mRNA and protein levels under stimulation by FBS or PDGF-BB and counteracted phenotype shift in cultured intact carotid arteries and balloon injury ex vivo. During long-term (24-96 hr) treatment with PF-4594755, smooth muscle markers increased before cell proliferation was inhibited, correlating with decreased KLF4 expression and differing from effects of MEK inhibition. The Pyk2 inhibitor reduced Orai1 and preserved SERCA2a expression in carotid artery segments in organ culture, and eliminated the inhibitory effect of PDGF stimulation on L-type calcium channel and largeconductance calcium-activated potassium channel expression in carotid cells. Basal intracellular calcium level, calcium wave activity, and store-operated calcium influx were reduced after Pyk2 inhibition of growth-stimulated cells. Pyk2 inhibition may provide an interesting approach for preserving vascular smooth muscle differentiation under pathophysiological conditions. [ABSTRACT FROM AUTHOR]

The human host-defence peptide (HDP) LL-37 not only displays anti-microbial activity but also immune-modulating properties that trigger intracellular signalling events in host cells. Since the cytolytic activity of high LL-37 concentrations affects cell viability, the function of LL-37 requires tight regulation. Eukaryotic cells therefore benefit from protective measures to prevent harmful effects of LL-37. p33, also known as globular C1q receptor (gC1qR), is reported to act as an LL-37 antagonist by binding the peptide, thereby reducing its cytotoxic activity. In the present report, we show that high levels of endogenous p33 correlate with an increased viability in human cells treated with LL-37. Sub-cellular localization analysis showed p33 distribution at the mitochondria, the plasma membrane and in the cytosol. Strikingly, cytosolic overexpression of p33 significantly antagonized detrimental effects of LL-37 on cell fitness, whereas the reverse effect was observed by siRNA-induced downregulation of p33. However, modulation of p33 expression had no effect on LL-37-induced plasma membrane pore forming capacity pointing to an intracellular mechanism. A scavenging function of intracellular p33 is further supported by co-immunoprecipitation experiments, showing a direct interaction between intracellular p33 and LL-37. Thus, our findings support an important role of intracellular p33 in maintaining cell viability by counteracting LL-37-induced cytotoxicity. [ABSTRACT FROM AUTHOR]