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The contamination of aquatic environments with heavy metals is an important issue, and in turn, it is crucial to study remediation techniques that can be applied in situ. In this work, the use of a containment system with macrophytes Limnobium laevigatum is explored in the laboratory to evaluate the remotion of Cr in contaminated sediments. The roots of the plants were placed in contact with the bottom sediment through a containment system. The concentration of Cr in macrophyte and sediment samples exposed to different exposure times (1, 4 and 7 days) was determined by laser-induced breakdown spectroscopy technique. The initial concentration of Cr in the sediment was 112 ± 5 mg/kg and decreased by 65% to the control (p < 0.05) after 24 h of exposure. The removal continued throughout the study time until reaching values of 23 ± 1 mg/kg. In macrophytes, the Cr concentration increased from 20 ± 5 mg/kg to 2066 ± 216 mg/kg after seven days of exposure. The correlation coefficient between Cr concentrations in both matrices was −0.96. Finally, the bioaccumulation factor of Cr in L. laevigatum was 95.22 ± 8.51. Therefore, the system studied could be a potential tool to remedy the bottom sediments of streams and lakes contaminated with heavy metals in situ. [ABSTRACT FROM AUTHOR]

Theories of adult brain development, based on neuropsychological test results and structural neuroimaging, suggest differential rates of age‐related change in function across cortical and subcortical sub‐regions. However, it remains unclear if these trends also extend to the aging dopamine system. Here we examined cross‐sectional adult age differences in estimates of D2‐like receptor binding potential across several cortical and subcortical brain regions using PET imaging and the radiotracer [18F]Fallypride in two samples of healthy human adults (combined N = 132). After accounting for regional differences in overall radioligand binding, estimated percent difference in receptor binding potential by decade (linear effects) were highest in most temporal and frontal cortical regions (~6–16% per decade), moderate in parahippocampal gyrus, pregenual frontal cortex, fusiform gyrus, caudate, putamen, thalamus, and amygdala (~3–5%), and weakest in subcallosal frontal cortex, ventral striatum, pallidum, and hippocampus (~0–2%). Some regions showed linear effects of age while many showed curvilinear effects such that binding potential declined from young adulthood to middle age and then was relatively stable until old age. Overall, these data indicate that the rate and pattern of decline in D2 receptor availability is regionally heterogeneous. However, the differences across regions were challenging to organize within existing theories of brain development and did not show the same pattern of regional change that has been observed in gray matter volume, white matter integrity, or cognitive performance. This variation suggests that existing theories of adult brain development may need to be modified to better account for the spatial dynamics of dopaminergic system aging. [ABSTRACT FROM AUTHOR]

Rationale: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed.Objectives: Here, we sought to investigate sex differences in dopamine release after oral D-amphetamine administration.Methods: We used [18F]fallypride positron emission tomography (PET) to measure the change in dopamine D2/3 receptor availability (%ΔBPND, an index of dopamine release) between placebo and D-amphetamine sessions in two independent datasets containing a total of 39 females (on either hormonal birth control n = 18, postmenopausal n = 10, or studied in the first 10 days of their menstrual cycle n = 11) and 37 males.Results: Using both a priori anatomical regions of interest based on previous findings and voxelwise analyses, we failed to consistently detect broad sex differences in D-amphetamine-induced dopamine release. Nevertheless, there was limited evidence for greater right ventral striatal dopamine release in young adult males relative to similarly aged females, but this was not consistently observed across samples. Plasma estradiol did not correlate with dopamine release and this measure did not differ in females on and off hormonal birth control.Conclusions: While our finding in young adults from one dataset of greater %ΔBPND in males is partially consistent with a previously published study on sex differences in D-amphetamine-induced dopamine release, our data do not support the presence of consistent widespread sex differences in this measure of dopamine release. [ABSTRACT FROM AUTHOR]

This work studies the combined effect of resistance spot welding and post-welding sensitization on the pitting corrosion behavior of AISI 304 (UNS S30400) by using cyclic potentiodynamic polarization tests. The combined effect of welding and post-welding sensitization give rise to worse pit nucleation resistances and better repassivation capacities than those of the state without prior welding. This behavior is caused by the weld metal zone, a cast dendritic microstructure with δ-ferrite in interdendritic regions, whose microstructural regeneration kinetics is faster than that of HAZ and that of the parent metal and where the chromium-rich phases are more homogeneously distributed than in the parent metal. [ABSTRACT FROM AUTHOR]

Introduction: The goal of this study is to determine whether Advanced glycosylated end-products (AGE), Advanced oxidation protein products (AOPP) and Matrix metalloproteinase 7 (MMP7) could be used as differential biomarkers for idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated interstitial lung disease (CTD-ILD). Method: Seventy-three patients were enrolled: 29 with IPF, 14 with CTD-ILD, and 30 healthy controls. The study included a single visit by participants. A blood sample was drawn and serum was analysed for AGE using spectrofluorimetry, AOPP by spectrophotometry, and MMP7 using sandwich-type enzyme-linked immunosorbent assay. Results: AGE, AOPP and MMP7 serum levels were significantly higher in both IPF and CTD-ILD patients versus healthy controls; and AGE was also significantly elevated in CTD-ILD compared to the IPF group. AGE plasma levels clearly distinguished CTD-ILD patients from healthy participants (AUC = 0.95; 95% IC 0.86–1), whereas in IPF patients, the distinction was moderate (AUC = 0.78; 95% IC 0.60–0.97). Conclusion: In summary, our results provide support for the potential value of serum AGE, AOPP and MMP7 concentrations as diagnostic biomarkers in IPF and CTD-ILD to differentiate between ILD patients and healthy controls. Furthermore, this study provides evidence, for the first time, for the possible use of AGE as a differential diagnostic biomarker to distinguish between IPF and CTD-ILD. The value of these biomarkers as additional tools in a multidisciplinary approach to IPF and CTD-ILD diagnosis needs to be considered and further explored. Multicentre studies are necessary to understand the role of AGE in differential diagnosis. [ABSTRACT FROM AUTHOR]

The critical factor in restoration and conservation of urban streams and their catchments is the human population, however the most of studies of urban ecosystems do not present social descriptors as concrete variables of analysis. The objective of this study is to perform an environmental diagnosis from a social-ecological perspective by considering both ecological and urban development descriptors of an urban basin. We selected 12 sampling sites of the Langueyú upper basin where social and ecological descriptors were determined. We arranged sampling sites according to their physicochemical characteristics (pre-urban, urban and post-urban sites). An ecological index was defined from habitat and biological descriptors: vegetation cover, richness and total density of invertebrates and organic matter. The index determined that urban and post-urban sites showed similar characteristics, and pre-urban sites presented the best habitat and biological conditions. An urbanisation index was defined from urban development descriptors: distance to the stormwater drainage network, number of industries, distance to a house without sewage, impervious surface and housing density. The results showed that the pre-urban and post-urban sites share a greater similarity in relation to the urban descriptors but with different impact in ecological quality. The headwaters in the hills (pre-urban zone) still presents a very good ecological condition (although threatened by urbanisation and tourism); however, once it crosses the dense urban area, no >5 km distance, the environmental degradation is alarming. We were able to determine that the structural measures associated with greater urbanisation, added to illegally connected sewer pipes and illegally industrial connections, produce the ecological degradation of the stream. This environmental diagnosis allowed us a deep understanding of the urbanisation impact on the ecological integrity of an urban stream in a developing country which, like many others, doesn't have monitoring programs or an integrated vision of water resources. Unlabelled Image • We used an integral approach that analyzes urban and ecological descriptors. • From these descriptors, we make urbanisation and ecological indexes. • The indexes allowed us to define the environmental status of an urban basin. • Structural measures added to illegally connected produce ecological degradation. • The environmental diagnosis is fundamental in developing countries without monitoring. [ABSTRACT FROM AUTHOR]

(1) Background: The impact of SARS-CoV-2 has been variable over the time course of the pandemic and in different populations. The aim was to analyze the impact of COVID-19 infection in a known population of hemodialysis (HD) patients and professionals in Spain at different times of the pandemic. (2) Methods: We conducted an observational, descriptive study with a follow-up from 3 March 2020 to 23 April 2022 (776 days), using in average of 414 professionals and 1381 patients from 18 HD units in Spain. The data from the positive PCR or the rapid antigen detection test (RADT) subject were analyzed and segmented into six periods (waves). (3) Results: Of 703 positive COVID-19 tests, 524 were HD patients (74.5%), and 179 were HD professionals (25.5%). Overall, 38% of staff and 43% of patients were affected. Differences were observed in regard to incidence (21% vs. 13%), mortality (3.5% vs. 0%), and symptomatology between the patients and professionals and throughout the pandemic. (4) Conclusions: COVID-19 severity varied during different pandemic waves, with a greater impact seen in the first wave. HD professionals and patients had similar infection rates, but patients had higher mortality rates. Community transmission was the primary route of infection.

After their application in agricultural areas, pesticides are dispersed throughout the environment, causing contamination problems. In Argentina, the main promoter of transgenic biotechnology in the region, the total consumption of agrochemicals has increased significantly in recent years. Most chemicals dumped near surface waters eventually end up in bottom sediments and can be toxic to the organisms that live there. However, published data on the mixing of pesticides in this compartment is still scarce. The objective of this work was to detect and quantify pesticide residues in the sediment of rural streams in the Pampas region and to carry out acute and chronic risk assessment in these aquatic ecosystems. The study area comprises the mountainous system of Tandilia, located in one of the most productive agricultural areas in the country. The concentration of atrazine, acetochlor, chlorpyrifos, cypermethrin, and 2,4-D in the sediment of four rural streams was determined in three different seasons, and the toxic units (TU) and the risk ratios (RQ) were calculated. All the compounds analyzed were detected in most of the sampling seasons and study sites, at concentrations higher than those established in the national and international quality guidelines for the protection of aquatic biota in surface waters and for human consumption. Chlorpyrifos, cypermethrin, and acetochlor were the main pesticides contributing to the TU and RQ values, representing a medium or high ecological risk in most of the sites. Therefore, the evaluation of these pesticides in the bottom sediments could be a decisive factor in assessing the risk to the aquatic environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Cytotoxic T lymphocytes take on a leading role in many immune-related diseases. They function as key effector immune cells fighting cancer cells, but they are also considerably involved in autoimmune diseases. Common to both situations, CD8 + T cells need to adapt their metabolism and effector function to the harsh and nutrient-deprived conditions of the disease-associated microenvironment., Methods: We used an in vitro starvation as well as rapamycin treatment protocol mimicking nutrient deprivation to generate CD8 Low versus CD8 High T cells and performed FACS-Sorting followed by transcriptomic profiling of the cytotoxic T cell subsets. Prominent markers identified in the CD8 Low versus the CD8 High T cells were then used to investigate the presence of these cell subsets in immune-related human diseases. Employing cancer tissue microarrays and PhenOptics multispectral imaging as well as flow cytometry, we studied these CD8 + T cell subsets in cancer and relapsing-remitting multiple sclerosis patients., Results: Starvation induced a decreased expression of CD8, yielding a CD8 Low T cell subpopulation with an altered transcriptomic signature and reduced effector function. CD8 Low T cell showed enhanced ST2L and IL6ST (CD130) expression compared to CD8 High T cells which expressed elevated KLRD1 (CD94) and granzyme B levels within the tumour microenvironment (TME). Spatial analysis revealed the presence of CD8 High T cells in close proximity to tumour cells, while the CD8 Low T cells resided at the tumour boundaries. Importantly, the number of tumour-infiltrating CD8 Low T lymphocytes correlated with a poor prognosis as well as with enhanced cancer progression in human mammary carcinoma. We also found a reduced frequency of CD8 Low T lymphocytes in a cohort of relapse (disease active) multiple sclerosis patients compared to healthy subjects during immune cell starvation in vitro., Conclusions: In summary, our data show that functionally distinct cytotoxic T lymphocytes can be identified based on their expression of CD8. Indicating a more general role in CD8 T cell immunity, these cells may play opposing roles in the TME, and also in the pathophysiology of autoimmune diseases such as multiple sclerosis., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Purpose: The aim of this study was to evaluate the antioxidant potential, antimicrobial activity, the in vitro anticancer effect (tested on MCF-7 breast cancer cell line), as well as the antiangiogenic and immunomodulatory potential of Populus nigra L. bud (Pg) extract collected from the western part of Romania., Results: Populus nigra L. bud extract presents an important antioxidant activity, due to the rich phytochemical composition. Regarding the biological activity, results have shown that poplar bud extract presents a significant inhibitory activity against Gram-positive bacteria and a dose-dependent decrease of MCF-7 tumor cell viability with an IC 50 of 66.26 μg/mL, while not affecting healthy cells. Phenomena of early apoptotic events at the maximum concentration tested (150 μg/mL) were detected by Annexin V-PI double staining. The extract induced G0/G1 phase cell cycle arrest. In addition, Pg extract showed antiangiogenic potential on the chorioallantoic membrane. Also, at the highest concentration (150 μg/mL), good tolerability and no signs of toxicity upon vascular plexus were observed. Moreover, in low concentrations, the Pg extract had immunomodulatory activity on primary human dendritic cells by upregulating IL-12 and IL-23 subunits., Conclusion: The study concludes that poplar bud extract elicited antioxidant activity, antitumor properties on the breast cancer cell line, followed by an antiangiogenic effect and an immunomodulatory potential on human primary dendritic cells. The biological activity of Populus nigra L. buds extract may open new directions of research on the topic addressed., (© 2022. The Author(s).)

Receptor conversion in breast cancer occurs in up to 32% of patients, resulting in ineffective therapy in the absence of corresponding biomarkers. We report a case of a middle-aged woman who presented with a 2-month history of hoarseness. Laryngoscopy demonstrated right vocal cord paralysis. Whole body positron emission tomography-CT (PET-CT) scan showed a hypermetabolic cervical lymph node, worrisome for metastasis. Biopsy of the cervical lymph node was consistent with metastatic carcinoma of the breast (GATA3 and mammaglobin positive, oestrogen receptor (OR)-positive, progesterone receptor-negative and human epidermal growth factor receptor 2 (HER2)-positive). She underwent targeted therapy with ado-trastuzumab emtansine every 3 weeks. Repeat PET-CT scan after 6 months showed stable disease. Reassessment of receptor status in metastatic breast cancer is encouraged to rule out receptor conversion. There is significant cross-talk between OR and HER2 signalling pathways, leading to treatment resistance. Close collaboration and teamwork among various subspecialties facilitate prompt management of patients with suspected metastatic breast cancer., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Although the human immune response to cancer is naturally potent, it can be severely disrupted as a result of an immunosuppressive tumor microenvironment. Infiltrating regulatory T lymphocytes contribute to this immunosuppression by inhibiting proliferation of cytotoxic CD8 + T lymphocytes, which are key to an effective anti-cancer immune response. Other important contributory factors are thought to include metabolic stress caused by the local nutrient deprivation common to many solid tumors. Interleukin-33 (IL-33), an alarmin released in reaction to cell damage, and sphingosine-1-phosphate (S1P) are known to control cell positioning and differentiation of T lymphocytes. In an in vitro model of nutrient deprivation, we investigated the influence of IL-33 and S1P receptor 4 (S1P 4 ) on the differentiation and migration of human CD8 + T lymphocytes. Serum starvation of CD8 + T lymphocytes induced a subset of CD8 Low and IL-33 receptor-positive (ST2L + ) cells characterized by enhanced expression of the regulatory T cell markers CD38 and CD39. Both S1P 1 and S1P 4 were transcriptionally regulated after stimulation with IL-33. Moreover, expression of the chemokine receptor CXCR4 was increased in CD8 + T lymphocytes treated with the selective S1P 4 receptor agonist CYM50308. We conclude that nutrient deprivation promotes CD8 Low T lymphocytes, contributing to an immunosuppressive microenvironment and a poor anti-cancer immune response by limiting cytotoxic effector functions. Our results suggest that S1P 4 signaling modulation may be a promising target for anti-CXCR4 cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Burkard, Dreis, Herrero San Juan, Huhn, Weigert, Pfeilschifter and Radeke.)

Risk-taking behaviors of adult bedridden patients in neurosurgery are frequent, however little analyzed. We aimed to estimate from the literature and our clinical experience the incidence of the different clinical pictures. Risk-taking behaviors seem to be more frequent than reported. They are often minor, but they can lead to death, irrespective of the prescription of physical or chemical constraints. We also aimed to contextualize the risks, and to describe the means reducing the consequences for the patients. Two main conditions were identified, the loss of awareness of risk-taking behaviors by the patient, and uncontrolled body motions. Besides, current experience feedback analyses and new non-exclusive technological solutions could limit the complications, while improving prevention with wearable systems, neighborhood sensors, or room monitoring and service robots. Further research is mandatory to develop efficient and reliable systems avoiding complications and saving lives. Ethical and legal issues must also be accounted for, notably concerning the privacy of patients and caregivers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lemaire, Chaix, Sontheimer, Coste, Cousseau, Dubois, San Juan, Massa, Raynaud, Usclade, Pontier, El Ouadih, Abdelouahab, Maggiani and Berry.)

Background: Reduction of the Sphingosine-1-phosphate (S1P) degrading enzyme S1P lyase 1 (SGPL1) initiates colorectal cancer progression with parallel loss of colon function in mice. We aimed to investigate the effect of SGPL1 knockout on the stem cell niche in these mice., Methods: We performed immunohistochemical and multi-fluorescence imaging on tissue sections of wildtype and SGPL1 knockout colons under disease conditions. Furthermore, we generated SGPL1 knockout DLD-1 cells (SGPL1 -/-M.Ex1 ) using CRISPR/Cas9 and characterized cell cycle and AKT signaling pathway via Western blot, immunofluorescence, and FACS analysis., Results: SGPL1 knockout mice were absent of anti-Ki-67 staining in the stem cell niche under disease conditions. This was accompanied by an increase of the negative cell cycle regulator FOXO3 and attenuation of CDK2 activity. SGPL1 -/-M.Ex1 cells show a similar FOXO3 increase but no arrest of proliferation, although we found a suppression of the PDK1/AKT signaling pathway, a prolonged G1-phase, and reduced stem cell markers., Conclusions: While already established colon cancer cells find escape mechanisms from cell cycle arrest, in vivo SGPL1 knockout in the colon stem cell niche during progression of colorectal cancer can contribute to cell cycle quiescence. Thus, we propose a new function of the S1P lyase 1 in stemness.

The aim of the present work was to study the effect of the pyrethroid cypermethrin (CYP) on the non-target freshwater snail Chilina parchappi. Initially, the sensitivity of adult snails to CYP was evaluated via the 96-h LC 50 test. Then, snails were exposed to subtethal CYP concentrations (0.1 and 10 mg/l) for 1, 4 and 10 days and the digestive glands were dissected for biomarkers analyses. Enzymatic activity of catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST), as well as total glutathione reduced (GSH) levels, were determined. Histological analyses of morphology, intracellular accumulation of lipofucsins and neutral lipids accumulation in the digestive gland were also evaluated. As compared to other molluscs, C. parchappi showed high resistance to CYP exposure evidenced by the 96-h LC 50 value (44.59 mg/l). Snails exposed to sublethal CYP concentrations showed a statistically significant increase (p < 0.01) in GST (79-116%) and GPx (45-190%) activities with respect to controls. However, CAT activity showed a tendency to decrease with CYP treatment but was not statistically significantly different compared to control. Only high CYP concentration caused a statistically significant increase (p < 0.01) in GSH content (95-196%). There was evidence of structural changes in the digestive gland of snails exposed to CYP, showing a dose-dependent response. In exposed snails, some of the main symptoms included a reduction in the thickness of the epithelium, vacuolisation of the digestive cells and an increase in the number of excretory cells. Accumulation of lipofuscins (933-1006%) and neutral lipids (403%) were statistically significantly higher (p < 0.05) in snails exposed to CYP compared to control. This study showed that C. parchappii is quite tolerant to CYP exposure and that at sublethal concentrations, GSH metabolism could play a protective role against the pesticide harm in snails. Therefore, it would be interesting to study the response of this organism to other environmental stressors to assess its potential use in monitoring programs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A role of sphingolipids for inflammatory bowel disease and cancer is evident. However, the relative and separate contribution of sphingolipid deterioration in inflammation versus carcinogenesis for the pathophysiology of colitis-associated colon cancer (CAC) was unknown and therefore examined in this study. We performed isogenic bone marrow transplantation of inducible sphingosine-1-phosphate (S1P) lyase knockout mice to specifically modulate sphingolipids and associated genes and proteins in a compartment-specific way in a DSS/AOM mediated CAC model. 3D organoid cultures were used in vitro. S1P lyase (SGPL1) knockout in either immune cells or tissue, caused local sphingolipid accumulation leading to a dichotomic development of CAC: Immune cell SGPL1 knockout (I-SGPL -/- ) augmented massive immune cell infiltration initiating colitis with lesions and calprotectin increase. Pathological crypt remodeling plus extracellular S1P-signaling caused delayed tumor formation characterized by S1P receptor 1, STAT3 mRNA increase, as well as programmed cell death ligand 1 expression, accompanied by a putatively counter regulatory STAT1 S727 phosphorylation. In contrast, tissue SGPL1 knockout (T-SGPL -/- ) provoked immediate occurrence of epithelial-driven tumors with upregulated sphingosine kinase 1, S1P receptor 2 and epidermal growth factor receptor. Here, progressing carcinogenesis was accompanied by an IL-12 to IL-23 shift with a consecutive development of a T h 2/GATA3-driven, tumor-favoring microenvironment. Moreover, the knockout models showed distinct lymphopenia and neutrophilia, different from the full SGPL1 knockout. This study shows that depending on the initiating cellular S1P source, the pathophysiology of inflammation-induced cancer versus cancer-induced inflammation develops through separate, discernible molecular steps.

Systemic sclerosis (SSc) is a rare multi-organ autoimmune disease characterized by progressive skin fibrosis. Inflammation, type 2 immunity, and fibrogenic processes are involved in disease development and may be affected by sphingolipids. However, details about early-stage pathophysiological mechanisms and implicated mediators remain elusive. The sphingolipid sphingosine-1-phosphate (S1P) is elevated in the sera of SSc patients, and its receptor S1P5 is expressed in skin tissue. Nevertheless, almost nothing is known about the dermatological contribution of S1P5 to inflammatory and pro-fibrotic processes leading to the pathological changes seen in SSc. In this study, we observed a novel effect of S1P5 on the inflammatory processes during low-dose bleomycin (BLM)-induced fibrogenesis in murine skin. By comparing 2-week-treated skin areas of wild-type (WT) and S1P5-deficient mice, we found that S1P5 is important for the transcriptional upregulation of the Th2 characteristic transcription factor GATA-3 under treatment-induced inflammatory conditions, while T-bet (Th1) and FoxP3 (Treg) mRNA expression was regulated independently of S1P5. Additionally, treatment caused a regulation of S1P receptor 1 and S1P receptor 3 mRNA as well as a regulation of long-chain ceramide profiles, which both differ significantly between the genotypes. Despite S1P5-dependent differences regarding inflammatory processes, similar macroscopic evidence of fibrosis was detected in the skin histology of WT and S1P5-deficient mice after 4 weeks of subcutaneous BLM treatment. However, at the earlier 2-week point in time, the mRNA data of pro-collagen type 1 and SMAD7 indicate a pro-fibrotic S1P5 contribution in the applied SSc mouse model. In conclusion, we propose that S1P5 plays a role as a novel modulator during the early phase of BLM-caused fibrogenesis in murine skin. An immediate relationship between dermal S1P5 expression and fibrotic processes leading to skin alterations, such as formative for SSc pathogenesis, is indicated but should be studied more profound in further investigations. Therefore, this study is an initial step in understanding the role of S1P5-mediated effects during early stages of fibrogenesis, which may encourage the ongoing search for new therapeutic options for SSc patients.

In the colon, a sophisticated balance between immune reaction and tolerance is absolutely required. Dysfunction may lead to pathologic phenotypes ranging from chronic inflammatory processes to cancer development. Two prominent modulators of colon inflammation are represented by the closely related cytokines interleukin (IL)-12 and IL-23, which initiate adaptive Th1 and Th17 immune responses, respectively. In this study, we investigated the impact of the NADPH oxidase protein p47phox, which negatively regulates IL-12 in dendritic cells, on colon cancer development in a colitis-associated colon cancer model. Initially, we found that IL-12-/- mice developed less severe colitis but are highly susceptible to colon cancer. By contrast, p47phox-/- mice showed lower tumor scores and fewer high grade tumors than wild-type (WT) littermates. Treatment with toll-like receptor 9 ligand CpG2216 significantly enhanced colitis in p47phox-/- mice, whereas tumor growth was simultaneously reduced. In tumor tissue of p47phox-/- mice, the IL-23/IL-17 axis was crucially hampered. IL-23p19 protein expression in tumor tissue correlated with tumor stage. Reconstitution of WT mice with IL-23p19-/- bone marrow protected these mice from colon cancer, whereas transplantation of WT hematopoiesis into IL-23p19-/- mice increased the susceptibility to tumor growth. Our study strengthens the divergent role of IL-12 and IL-23 in colon cancer development. With the characterization of p47phox as a novel modulator of both cytokines our investigation introduces a promising new target for antitumor strategies.

Pesticide chemical residues in water samples and biomarker responses in transplanted fish were used to monitor environmental hazards of pesticides in Palo Verde National Park (Costa Rica). The Costarican fish, Parachromis dovii (Ciclhidae) and Poecilia gillii (Poecillidae), were selected as sentinel species. Contaminant analyses detected up to 15 different pesticide residues in water with hexachlobenzene (2261 ng l(-1)), phorate (473 ng l(-1)), epoxiconazole (314) and bromacil (117 ng l(-1)) being the compounds found in higher concentrations. Biomarker responses evidenced impacts on cholinesterase activities in transplanted fish at Barbudal site probably due to the presence of organophosphate insecticides such as phorate. High enzyme activities of glutathione S-transferase and catalase and elevated levels of lipid peroxides were also observed at a site impacted by rice fields (Cabuyo); those effects could be associated with the presence of hexachloro benzene and triazole fungicides. In general, P. dovii biomarkers were affected to a greater extent than those of P. gillii in fish transplanted to sites associated with agriculture, which suggests the former species is a good candidate for future surveys.

The chemokine receptors CXCR3 and CXCR4 are primarily involved in memory Th1 cell-driven autoimmune diseases. Although recent studies in chronic inflammatory disease showed therapeutic success using combined blockade, details of CXCR3 and CXCR4 synergism are not understood. In this investigation, we intended to unravel the interaction of these chemokine receptors in static and dynamic cell-migration assays at both the cellular and molecular levels. Effects of combined stimulation by murine CXCL9 and CXCL12, ligands of CXCR3 and CXCR4, respectively, were analyzed using a murine central memory Th1 cell clone. Costimulation with CXCL9 desensitized the chemotaxis of Th1 cells toward CXCL12 by up to 54%. This effect was found in murine EL-4 cells, as well as in primary human T cells. Furthermore, under dynamic flow conditions CXCL12-induced crawling and endothelial transmigration of Th1 cells was desensitized by CXCL9. Subsequent experiments uncovered several molecular mechanisms underlying the heterologous cross-regulation of CXCR4 signaling by the CXCR3 ligand. CXCR4 surface expression was reduced, whereas CXCL12-induced Akt phosphorylation and intracellular Ca(2+) signals were modulated. Moreover, blockade of Rac by NSC23766 revealed differential effects on CXCL12 and CXCL9 chemotaxis and abolished the desensitizing effect of CXCL9. The desensitization of CXCR4 via CXCR3 in memory Th1 cells suggests that their in vivo homeostasis, widely regulated by CXCL12, seemed to be significantly altered by CXCR3 ligands. Our data provide a more detailed understanding for the continuing extravasation and recruitment of Th1 lymphocytes into sites of persistent inflammation.

When considering joint toxic apical effects at higher levels of biological organization, such as the growth of populations, the so-called pharmacological mode of action that relies on toxicological mechanistic effects on molecular target sites may not be relevant. Such effects on population growth rate will depend on the extent to which juvenile and adult survival rates and production rates (juvenile developmental rates and reproduction) are affected by toxic exposure and also by the sensitivity of population growth rates to life-history changes. In such cases, the ecotoxicological mode of action, defined as the crucial life-history trait processes and/or xenobiotic-life-history trait interactions underlying a toxicological effect on population growth rate, should be considered. Life-table response experiments with the crustacean Ceriodaphnia dubia exposed to single and ternary mixtures of nine compounds were conducted to test the hypothesis that joint effects on population growth rates could be predicted from the mixture constituent ecotoxicological mode of action. Joint effects of mixtures containing pharmacologically dissimilar compounds (cadmium, λ-cyhalothrin, and chlorpyrifos) that differentially affected life-history traits contributing to population growth rates were accurately predicted by the independent-action concept. Conversely, the concentration-addition concept accurately predicted joint effects of two different mixtures: one containing pharmacologically similar acting pyrethroids that also affected similarly life-history traits, the other one that included pharmacologically dissimilar compounds (3,4-dichloroaniline, sodium bromide, and fenoxycarb) acting mainly on reproduction rates. These results indicate that when assessing combined effects on population growth rate responses, selection of mixture toxicity conceptual models based on the ecotoxicological mode of action of mixture constituents provided more accurate predictions than those based on the pharmacological mode of action.

Hypoxia-inducible factor 1 (HIF-1) induces a gene expression program essential for the cellular adaptation to lowered oxygen environments. The intracellular mechanisms by which hypoxia induces HIF-1 remain poorly understood. Here we show that exposure of various cell types to hypoxia raises the intracellular level of phosphatidic acid primarily through the action of diacylglycerol kinase (DGK). Pharmacological inhibition of DGK activity through use of the specific DGK inhibitors and abrogated specifically HIF-1-dependent transcription analyzed with a HIF-1-responsive reporter plasmid. A more detailed analysis revealed that pharmacological inhibition of DGK activity prevented the hypoxia-dependent accumulation of the HIF-1alpha subunit and the subsequent HIF-1-DNA complex formation as well as hypoxia-induced activity of the HIF-1 transactivation domains localized to amino acids 530-582 and 775-826 of the HIF-1alpha subunit. Our results demonstrate for the first time that accumulation of phosphatidic acid through DGK underlines oxygen sensing and provide evidence for the involvement of this lipid kinase in the intracellular signaling that leads to HIF-1 activation.

Absorbable fixation has evolved from sutures and pins to screws. The current biomaterials available are polyparadiaxanone (PDS), polygycolide acid (PGA), and poly-L-lactic acid (PLLA). Extensive evaluation of PDS and PGA over the last several years has identified their benefits and weaknesses in reconstructive foot surgery. Future research will focus on PLLA rods and screws as they emerge as the latest advance in the search for the ideal internal fixation device.