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OBJECTIVE: To characterize aspects of triiodothyronine (T3) induced chondrocyte terminal maturation within the molecular osteoarthritis pathophysiology using the previously established T3 human ex vivo osteochondral explant model. DESIGNS: RNA-sequencing was performed on explant cartilage obtained from OA patients (n = 8), that was cultured ex vivo with or without T3 (10 ng/ml), and main findings were validated using RT-qPCR in an independent sample set (n = 22). Enrichment analysis was used for functional clustering and comparisons with available OA patient RNA-sequencing and GWAS datasets were used to establish relevance for OA pathophysiology by linking to OA patient genomic profiles. RESULTS: Besides the upregulation of known hypertrophic genes EPAS1 and ANKH, T3 treatment resulted in differential expression of 247 genes with main pathways linked to extracellular matrix and ossification. CCDC80, CDON, ANKH and ATOH8 were among the genes found to consistently mark early, ongoing and terminal maturational OA processes in patients. Furthermore, among the 37 OA risk genes that were significantly affected in cartilage by T3 were COL12A1, TNC, SPARC and PAPPA. CONCLUSIONS: RNA-sequencing results show that metabolic activation and recuperation of growth plate morphology are induced by T3 in OA chondrocytes, indicating terminal maturation is accelerated. The molecular mechanisms involved in hypertrophy were linked to all stages of OA pathophysiology and will be used to validate disease models for drug testing.

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Environmental conditions and available forage on pastures greatly differ between different farming systems, which can affect the behaviour of grazing cattle. The interplay between environment-, forage-, and animal-related variables may affect the use of feed and water resources in grazing-based systems. Hence, our objectives were (i) to study the differences between grazing-based systems and seasons in environment- and pasture-related variables as well as the behaviour, feed intake, performance, and water productivity of Nellore heifers, and (ii) to understand the interrelationships between these variables. The measurements were performed in a conventional grazing system (CON), an integrated crop-livestock (ICL), and a crop-livestock-forestry (ICLF) systems in the Brazilian Cerrado during the rainy and dry seasons. Ambient temperature and relative air humidity were hourly measured in both seasons. Forage biomass and sward height were determined every month. Forage samples were taken to determine the proportions of alive leaves, alive stems, and dead plant material and to analyse their nutritive value. Forage intake, drinking water intake, and liveweight changes were quantified in 12 Nellore heifers per system and season. Feeding behaviour was recorded by chewing sensors on nine continuous days in each season. Drinking water intake was measured by water meters attached to drinking water troughs, whereby trial cameras at the troughs recorded the frequency of drinking events of individual animals. Feed conversion efficiency and water productivity were estimated. The ICLF reduced the exposure time to high ambient temperatures so that heifers even grazed during the hottest hours. Forage biomass in ICL and CON had greater proportions of stem and dead plant material than in ICLF. Forage intake rate was greater and grazing events were longer for animals in ICLF than those in CON, whereas the daily number of grazing events was greater in CON. Feed conversion efficiency and water productivity were greater in integrated systems than in CON. Amongst studied variables, thermal environment and forage canopy structure with its proportions of dead plant material are the main driving factors for animal behaviour, forage intake rate, and animal performance. These variables reduce feed conversion efficiency and water productivity in grazing cattle. Further research should analyse strategies for promoting thermal comfort for the animals, increasing the proportions of alive biomass, and enhancing the nutritional value of pastures for more efficient use of forage and water resources in grazing-based systems.

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BACKGROUND: Microplastics comprise a significant group of emerging environmental contaminants with the capacity to adsorb several contaminants. These, in turn, undergo bioaccumulation and biomagnification processes throughout aquatic trophic chains. METHODS: Glitter, a microplastic powder composed of a combination of polymers, and raw glitter materials were investigated herein concerning metal and metalloid content, bioavailability, and sorption processes by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Metal and metalloid concentrations were higher in glitter than in raw glitter materials, but all were below the limits established by the Brazilian National Health Surveillance Agency. Elements present in glitter originate mainly from pigments and, thus, depend on glitter color. The bioavailability of the determined elements concerning human skin was assessed. Low desorbed concentrations in solution indicate that glitter does not represent a health risk through dermal contact concerning metal and metalloid contamination. However, several elements were shown to undergo significant desorption and adsorption processes. CONCLUSION: The findings reported herein indicate seemingly low human health risks from dermal glitter contact but reinforce glitter risks as aquatic environment metal and metalloid transport vectors.

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In the scope of a research program with the goal of developing treatments for inflammatory diseases, the pharmacological evaluation of LQFM291, designed by molecular hybridization from butylated hydroxytoluene and paracetamol, was described. The antioxidant profile of LQFM291 was evaluated by electrochemical measurement. Also, acute or repeated treatments with equimolar doses to paracetamol were used to evaluate the antinociceptive and/or anti-inflammatory activities of LQFM291 in animal models. The toxicologic potential of LQFM291 was also evaluated and compared to paracetamol through biochemical and histopathological analysis after the repeated treatment schedule. As a result of the acute treatment, paracetamol showed a similar antinociceptive effect in formalin test compared to LQFM291. Whereas, after the repeated treatment, when carrageenan-induced hyperalgesia and edema tests were performed, paracetamol showed a delayed antinociceptive and anti-inflammatory effect compared to LQFM291. Furthermore, as other advantages the LQFM291 showed a high redox capacity, a gastroprotective activity and a safety pharmacological profile without any liver or kidney damage. These effects can be related to the prevention of oxidative stress by reduction of protein and lipid peroxidation in gastric tissue, maintenance of glutathione levels in hepatic homogenate, and a systemic reduction of pro-inflammatory cytokine levels, which may characterize the LQFM291 as a more viable and effective alternative to relief pain and inflammatory signs in patients with chronic disorders.

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OBJECTIVE: To explore the co-expression network of the osteoarthritis (OA) risk gene WWP2 in articular cartilage and study cartilage characteristics when mimicking the effect of OA risk allele rs1052429-A on WWP2 expression in a human 3D in vitro model of cartilage. METHOD: Co-expression behavior of WWP2 with genes expressed in lesioned OA articular cartilage (N = 35 samples) was explored. By applying lentiviral particle mediated WWP2 upregulation in 3D in vitro pellet cultures of human primary chondrocytes (N = 8 donors) the effects of upregulation on cartilage matrix deposition was evaluated. Finally, we transfected primary chondrocytes with miR-140 mimics to evaluate whether miR-140 and WWP2 are involved in similar pathways. RESULTS: Upon performing Spearman correlations in lesioned OA cartilage, 98 highly correlating genes (|ρ| > 0.7) were identified. Among these genes, we identified GJA1, GDF10, STC2, WDR1, and WNK4. Subsequent upregulation of WWP2 on 3D chondrocyte pellet cultures resulted in a decreased expression of COL2A1 and ACAN and an increase in EPAS1 expression. Additionally, we observed a decreased expression of GDF10, STC2, and GJA1. Proteomics analysis identified 42 proteins being differentially expressed with WWP2 upregulation, which were enriched for ubiquitin conjugating enzyme activity. Finally, upregulation of miR-140 in 2D chondrocytes resulted in significant upregulation of WWP2 and WDR1. CONCLUSIONS: Mimicking the effect of OA risk allele rs1052429-A on WWP2 expression initiates detrimental processes in the cartilage shown by a response in hypoxia associated genes EPAS1, GDF10, and GJA1 and a decrease in anabolic markers, COL2A1 and ACAN.

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The approaches developed for studying the polarization of molecules and the dynamics of ions in dielectric materials are usually considered separately. The two effects are often believed to take place in different frequency ranges. The low frequency response is usually dominated by ionic migration, whereas the high frequency response is played by molecular polarization. The goal here is to clarify the interplay between free and bound charge densities and their influences on permittivity and impedance profiles by proposing a version of the Poisson-Nernst-Planck (PNP) model that allows to include the effect of a frequency-dependent (and thus not instantaneous) polarizability.

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OBJECTIVES: To investigate how ANP32A, previously linked to the antioxidant response, regulates Wnt signaling as unraveled by transcriptome analysis of Anp32a-deficient mouse articular cartilage, and its implications for osteoarthritis (OA) and diseases beyond the joint. METHODS: Anp32a knockdown chondrogenic ATDC5 cells were cultured in micromasses. Wnt target genes, differentiation markers and matrix deposition were quantified. Wnt target genes were determined in articular cartilage from Anp32a-deficient mice and primary human articular chondrocytes upon ANP32A silencing, using qPCR, luciferase assays and immunohistochemistry. Co-immunoprecipitation, immunofluorescence and chromatin-immunoprecipitation quantitative PCR probed the molecular mechanism via which ANP32A regulates Wnt signaling. Anp32a-deficient mice were subjected to the destabilization of the medial meniscus (DMM) OA model and treated with a Wnt inhibitor and an antioxidant. Severity of OA was assessed by cartilage damage and osteophyte formation. Human Protein Atlas data analysis identified additional organs where ANP32A may regulate Wnt signaling. Wnt target genes were determined in heart and hippocampus from Anp32a-deficient mice, and cardiac hypertrophy and fibrosis quantified. RESULTS: Anp32a loss triggered Wnt signaling hyper-activation in articular cartilage. Mechanistically, ANP32A inhibited target gene expression via histone acetylation masking. Wnt antagonist treatment reduced OA severity in Anp32a-deficient mice by preventing osteophyte formation but not cartilage degradation, contrasting with antioxidant treatment. Dual therapy ameliorated more OA features than individual treatments. Anp32a-deficient mice also showed Wnt hyper-activation in the heart, potentially explaining the cardiac hypertrophy phenotype found. CONCLUSIONS: ANP32A is a novel translationally relevant repressor of Wnt signaling impacting osteoarthritis and cardiac disease.

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INTRODUCTION AND AIM: Overactive bladder (OAB) negatively impacts patient quality of life and may be associated with high resource use. Our aim was to describe the resource use, costs and persistence associated with mirabegron (MB) or antimuscarinic (AM) treatment in patients with OAB. MATERIALS AND METHODS: Observational retrospective study of medical records in adult patients initiating OAB treatment with MB or AM in Catalonia. Healthcare resource use (visits, hospital stays, tests, medication, absorbent pads) in the first year after treatment initiation was collected. Associated costs were estimated (є, reference year 2019), as well as treatment persistence. Treatment discontinuation was defined as the absence of prescription for at least 45 days or treatment change. RESULTS: The mean cost per patient (SD) was є 1,640.20 (є 1,227.60) with MB and є 2,159.20 (є 2,264.40) with AM; the associated healthcare resource use cost was lower with MB compared to AM, except for OAB drug costs. Persistence after 12 months of treatment initiation was higher in MB (42.1%) compared to AM (33.0%), as was the median time until treatment discontinuation: 299 (95% CI: 270-328) vs 240 days (95% CI: 230-250). CONCLUSIONS: Lower healthcare resource use was observed with MB compared to AM in the first year of index treatment, resulting in a lower mean direct cost per patient and year, despite its higher acquisition cost. Increased treatment persistence, as well as rational use of available treatments improves OAB management and, in return, patients' quality of life.

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OBJECTIVE: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin. METHODS: Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1ß; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes. RESULTS: We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression. DISCUSSION & CONCLUSIONS: Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in cartilage. The determined direct negative effect of warfarin on human explant cultures functionally underscores the previously found association between vitamin K deficiency and OA.

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Adolescence is known for its high level of risk-taking, and neurobiological alterations during this period may predispose to psychoactive drug initiation and progression into more severe use patterns. Stress is a risk factor for drug consumption, and post-weaning social isolation increases drug self-administration in rodents. This review aimed to provide an overview of the effects of adolescent social isolation on cocaine, amphetamine and nicotine use-related behaviours, highlighting the specific period when animals were submitted to stress and these drugs. We wondered if there was a specific period during adolescence that isolation stress would increase drug use vulnerability. A total of 323 publications from the Scopus, Web of Science and PubMed (Medline) electronic databases were identified using the words "social isolation" and "adolescence" and "drug" or "cocaine" or "amphetamine" or "nicotine", resulting in 24 articles after analyses criteria following the PRISMA statement. The main points raised were social isolation during adolescence increased cocaine self-administration, amphetamine and nicotine locomotor activity. We did not observe a pattern of a specific moment during the adolescent period that could lead to an increased vulnerability to drug use. The precise conditions under which adolescent social stress alters drug use parameters are complex and likely depend on several factors.

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Sphingoid bases encompass a group of long chain amino alcohols which form the essential structure of sphingolipids. Over the last years, these amphiphilic molecules were moving more and more into the focus of biomedical research due to their role as bioactive molecules. In fact, free sphingoid bases interact with specific receptors and target molecules and have been associated with numerous biological and physiological processes. In addition, they can modulate the biophysical properties of biological membranes. Several human diseases are related to pathological changes in the structure and metabolism of sphingoid bases. Yet, the mechanisms underlying their biological and pathophysiological actions remain elusive. Within this review, we aimed to summarize the current knowledge on the biochemical and biophysical properties of the most common sphingoid bases and to discuss their importance in health and disease.

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OBJECTIVES: To compare mini-incision donor nephrectomy (MDN) with laparoscopic donor nephrectomy (LDN) performed by the same surgical team, regarding short- and long-term outcomes. METHODS: Three hundred and five patients, who underwent donor nephrectomy in our institution, through an MDN (n = 141) between January 1998-November 2011 and LDN (n = 164) since June 2010-December 2017, were compared. RESULTS: The mean operative time for MDN (120 ± 29 minutes) was not significantly different when compared to LDN (113 ± 34 minutes), but when comparing the first 50 LDN and the 50 most recent, we found a reduction in the duration of the procedure. Laparoscopic donors had a shorter warm ischemia time (229 seconds vs 310 seconds, P = .01), particularly the 50 most recent, hospital stay (4.3 days vs 5.9 days, P < .001), and postoperative complications (P = .03). The incidence of graft acute tubular necrosis (ATN) was superior in the MDN (89% vs 25%, P < .001), although there was no significant difference regarding first-year serum creatinine (SCr) and glomerular filtration rate (GFR) (SCr 1.38 mg/dL vs SCr 1.33 mg/dL and GFR 63.7 mL/min vs 63.1 mL/min) comparing the 2 groups. Long-term graft survival did not significantly differ between groups. There was also no relationship between postoperative ATN events and long-term graft function. CONCLUSIONS: With the growing experience of the high-volume centers and with specialized teams, LDN could be considered the most suitable technique for living donor nephrectomy with better results in short-term results (warm ischemia time, hospital stay, and postoperative complications), without difference in long-term outcomes.

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Sphingoid bases encompass a group of long chain amino alcohols which form the essential structure of sphingolipids. Over the last years, these amphiphilic molecules were moving more and more into the focus of biomedical research due to their role as bioactive molecules. In fact, free sphingoid bases interact with specific receptors and target molecules, and have been associated with numerous biological and physiological processes. In addition, they can modulate the biophysical properties of biological membranes. Several human diseases are related to pathological changes in the structure and metabolism of sphingoid bases. Yet, the mechanisms underlying their biological and pathophysiological actions remain elusive. Within this review, we aimed to summarize the current knowledge on the biochemical and biophysical properties of the most common sphingoid bases and to discuss their importance in health and disease.

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Spatial confinement is known to affect molecular organizations of soft matter. We present an important manifestation of this statement for thin films of bent-core smectic liquid crystals. Prior freeze-fracture transmission electron microscopy (FFTEM) studies carried out on nitro-substituted bent-core mesogens (n-OPIMB-NO_{2}) revealed an undulated smectic layer structure with an undulation periodicity of ∼8 nm. We report cryogenic TEM measurements on ∼100 nm thick 8-OPIMB-NO_{2} films. In contrast to FFTEM results, our studies show only density modulation with periodicity b=16.2 nm, and no smectic layer undulation. We show that the discrepancy between the FFTEM and cryogenic transmission electron microscopy (cryo-TEM) results can be attributed to the different sample thicknesses used in the experiments. FFTEM monitors cracked surfaces of a relatively thick (5-10 µm) frozen sample, whereas cryo-TEM visualizes the volume of a thin (0.1 µm) film that was quenched from its partially fluid phase. These results have importance in possible photovoltaics and organic electronics applications where submicron thin films are used.

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BACKGROUND: Pemphigus foliaceus (PF) is an epidermal autoimmune disease, characterized by the presence of autoantibodies against the desmosomal protein desmoglein 1. Genetic and environmental factors contribute to PF, a complex disease that is endemic in Brazil and Colombia and neighbouring countries, and in Tunisia. Long noncoding RNAs (lncRNAs) may participate in gene regulation by interacting with DNA, proteins and other RNAs. Dysregulation of lncRNAs has recently been recognized as an important coplayer in the onset or progression of complex diseases. In addition, single-nucleotide polymorphisms (SNPs) located in lncRNA genes have been associated with differential risk to cancer, autoimmunity and infection. OBJECTIVES: Here, we aimed to investigate whether SNPs in lncRNA genes are associated with differential susceptibility to endemic PF. MATERIALS AND METHODS: We integrated data from the lncRNA SNP database with genome-wide genotype data obtained for 229 patients and 6681 controls. We tested the association between endemic PF and 2080 SNPs located in lncRNAs applying logistic regression. RESULTS: The most significantly associated SNP was rs7144332 (OR = 1·63, P = 2·8 × 10-6 ), located in the lncRNA gene AL110292·1. Results for five other SNPs were suggestive of association (P < 0·001). In silico analysis indicated that five of the six SNPs impact transcription, three may influence lncRNA's secondary structure, and three may alter microRNA-lncRNA interactions. CONCLUSIONS: We showed, for the first time, that variation in lncRNA genes may influence pemphigus pathogenesis. Our findings highlight the importance of lncRNA variation in autoimmune and possibly other complex diseases and suggest polymorphisms for functional validation.

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OBJECTIVE: To evaluate the stability of anterior open bite (AOB) treatment with bonded spurs associated with high-pull chincup (BS/HPCC). METHODS: The experimental group consisted of 25 Class I AOB patients (15 female, 10 male) treated with BS/HPCC for 1 year. Cephalograms were analysed at pre-treatment (T1), post-treatment (T2) and at the 3-year post-treatment (T3) stage with the patients mean ages of 8.10, 9.14 and 12.18 years, respectively. The control group consisted of 23 subjects (13 female, 10 male) with normal occlusion, with comparable ages at the 3 stages (8.45, 9.45 and 12.50 years at T1, T2 and T3, respectively). T tests were used for intergroup comparisons at T1 and to compare the changes during the 3-year post-treatment period (T2-T3). Intragroup comparison in the treated group was evaluated with dependent t tests between T1 and T2. Correlations between the overbite changes in the T2-T3 period, the pre-treatment AOB severity and the amount of correction achieved during treatment were evaluated with Pearson's correlation coefficient. RESULTS: No statistically significant relapse of the AOB was found at T3. Only 1 patient had a clinically significant AOB relapse. Neither the pre-treatment AOB severity nor the amount of correction was related to overbite changes during the 3-year post-treatment period. CONCLUSIONS: There was no statistically significant relapse of the AOB, and the clinical stability of AOB correction 3-year post-treatment was of 96%.

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BACKGROUND: From 2006 to 2010, France experienced two bluetongue epidemics caused by serotype 1 (BTV-1) and 8 (BTV-8) which were controlled by mass vaccination campaigns. After five years without any detected cases, a sick ram was confirmed in August 2015 to be infected by a BTV-8 strain almost identical to that circulating during the previous outbreak. By then, part of the French cattle population was expected to be still protected, since bluetongue antibodies are known to last for many years after natural infection or vaccination. The objective of this study was to estimate the proportion of cattle in France still immune to BTV-8 at the time of its re-emergence in 2015. RESULTS: We used BTV group-specific cELISA results from 8525 cattle born before the vaccination ban in 2013 and 15,799 cattle born after the ban. Samples were collected from January to April 2016 to estimate seroprevalence per birth cohort. The overall seroprevalence in cattle at national and local levels was extrapolated from seroprevalence results per birth cohort and their respective proportion at each level. To indirectly assess pre-immune status of birth cohorts, we computed prevalence per birth cohort on infected farms in autumn 2015 using 1377 RT-PCR results. These revealed limited BTV circulation in 2015. Seroprevalence per birth cohort was likely to be connected to past exposure to natural infection and/or vaccination with higher seroprevalence levels in older animals. A seroprevalence of 95% was observed for animals born before 2008, of which > 90% were exposed to two compulsory vaccination campaigns in 2008-2010. None of the animals born before 2008 were found to be infected, unlike 19% of the young cattle which had never been vaccinated. This suggests that most ELISA-positive animals were pre-immune to BTV-8. We estimated that 18% (from 12% to 32% per département) of the French cattle population was probably pre-immune in 2015. CONCLUSIONS: These results strongly suggest a persistence of antibodies for at least 5-6 years after natural infection or vaccination. The herd immunity of the French cattle population probably limited BTV circulation up to 2015, by which time more than 80% of cattle were naive.

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