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Identifying climate refugia is key to effective biodiversity conservation under a changing climate, especially for mountain-specialist species adapted to cold conditions and highly threatened by climate warming. We combined species distribution models (SDMs) with climate forecasts to identify climate refugia for high-elevation bird species (Lagopus muta, Anthus spinoletta, Prunella collaris, Montifringilla nivalis) in the European Alps, where the ecological effects of climate changes are particularly evident and predicted to intensify. We considered future (2041-2070) conditions (SSP585 scenario, four climate models) and identified three types of refugia: (1) in-situ refugia potentially suitable under both current and future climate conditions, ex-situ refugia suitable (2) only in the future according to all future conditions, or (3) under at least three out of four future conditions. SDMs were based on a very large, high-resolution occurrence dataset (2901-12,601 independent records for each species) collected by citizen scientists. SDMs were fitted using different algorithms, balancing statistical accuracy, ecological realism and predictive/extrapolation ability. We selected the most reliable ones based on consistency between training and testing data and extrapolation over distant areas. Future predictions revealed that all species (with the partial exception of A. spinoletta) will undergo a range contraction towards higher elevations, losing 17%-59% of their current range (larger losses in L. muta). We identified ~15,000 km

Aim: The aim of this study is to evaluate long-term durability and effectiveness of the adjustable transobturator male system (ATOMS). Materials and methods: The retrospective multicenter Iberian ATOMS study (n = 215) was updated to evaluate long-term continence status, complications, explants, and secondary treatments. Mean follow-up from surgery to March 2020 was 60.6 ± 18.4 months (range, 39-91). Eleven patients deceased of an unrelated causes. Kaplan-Meier curves were performed to evaluate device durability and incontinence free of recurrence interval. The multivariate analysis defined the population at risk of device explant. Results: A total of 155 patients were dry at the last follow-up visit (72.1%); 99 (46%) used no pads and 56 (26%) used a security pad/day with urine loss less than 10 mL; 96% of dry patients after adjustment remained free of incontinence 1 year later, 93.6% 2 years later, 91.1% 3 years later, 89.2% 5 years later, and 86.7% 8 years later. Complications during follow-up occurred in 43 of 215 (20%). In total, 25 (11.6%) devices were explanted and causes were inefficacy 11 (44%), inefficacy and pain 3 (12%), port erosion 10 (40%), and wound infection 1 (4%). The secondary implant was performed in 11 (5.1%) cases, 6 artificial urinary sphincter and 5 repeated ATOMS. Time to explant was associated to complications (P < .0001), baseline stress urinary incontinence (SUI) severity (P = .01), and former irradiation (P = .03). Multivariate analysis revealed complications (hazard ratio [HR] = 8.71; 3.83-19.82), baseline SUI severity (>5 compared to 1-2 pads/day; HR = 14.9; 1.87-125), and irradiation before ATOMS (HR = 2.26; 1.02-5.18) predicted earlier ATOMS explant. Three cases received radiation after implant without complication. Conclusions: ATOMS device is efficacious and safe in the long term. Determinants for device explant include complications, baseline severity of incontinence, and previous irradiation. Currently, the durability of the device after 5 years is reassuring. Sin financiación 2.696 JCR (2020) Q3, 50/89 Urology & Nephrology 0.918 SJR (2020) Q1, 27/107 Urology No data IDR 2020 UEM

IL-15 has emerged as a potentially relevant target in the IL-17 response in psoriasis. However, its mechanism is poorly characterized in humans. IL-15 and IL-23 are constitutively expressed in the psoriatic lesion. Also, IL-15 is considered a susceptibility-associated gene in psoriasis, as are IL-23R, and HLACW6. Here, we studied the effect of IL-15 and IL-23 stimulation on the cytokine response of CLA+/CLA- T cells from 9 psoriasis patients and 3 healthy control subjects. To this end, CLA + and CLA- T cells from blood samples were cultured with epidermal cells from skin biopsies and treated with IL-15 and IL-23. After five days of culture, cytokines in supernatant were measured by ELISA or fluorescent bead-based immunoassay. There was a statistically significant increase in IL-17F and IL-17A production (P < .001) in cocultures of psoriasis skin-homing CLA + T cells with epidermal cells when stimulated with IL-15 and IL-23, but this effect was not observed in the cells of healthy controls. Interestingly, this response was reduced by around 50 to 80% by blocking HLA class I and II molecules. Our results point to the synergic action of IL-15 and IL-23 selectively for CLA + cells in psoriasis, leading to the induction of Th17 cell-related cytokines.

SAMHD1 is an enzyme with phosphohydrolase activity. Mutations in SAMHD1 have been linked to the development of Aicardi-Goutières syndrome in humans. This enzyme also has the capacity to restrict HIV virus replication in macrophages. Here, we report that Samhd1 is highly expressed in murine macrophages and is regulated by proinflammatory (IFN-γ and LPS) but not by anti-inflammatory (IL-4 or IL-10) activators. The induction of Samhd1 follows the pattern of an intermediate gene that requires protein synthesis. In transient transfection experiments using the Samhd1 promoter, we found that a fragment of 27 bps of this gene, falling between -937 and -910 bps relative to the transcription start site, is required for IFN-γ-dependent activation. Using EMSAs, we determined that IFN-γ treatment led to the elimination of a protein complex. Chromatin immunoprecipitation assays and siRNA experiments revealed that IRF1 is required for IFN-γ- or LPS-induced Samhd1 expression. Therefore, our results indicate that Samhd1 is stimulated by proinflammatory agents IFN-γ and LPS. Moreover, they reveal that these two agents, via IRF1, eliminate a protein complex that may be related to a repressor, thereby, triggering Samhd1 expression.

Antibody-mediated enzyme formation is a phenomenon first described in 1968 and further studied by molecular Immunologists and Biochemists over the following five decades. The present review is made mainly by analyzing the 27 articles concerned with AMEF that appeared over the course of 47 years, commenting 16 original figures selected to be re-printed in AMEF's Legacy. We, the reviewers, started by revisiting our own "insider's" experience of discovery, and followed by considering all results, our own and of members of other AMEF Labs. We had planned to conclude the review by correlating the various AMEF mutants to a detailed knowledge of the consensus betaGal structure. However, we became aware of several "robust" papers, published between 1989 and 2014, by authors outside of AMEF Labs. We familiarly called this surge: "The Second Wave" and adorned it with a doodle in Hokusai style. We were thrilled and happy to take them on board and properly examined their data. A team of this second wave had imagined unique uses for AMEF, and new doors to modern biotechnology. Another one had used AMEF as Tool and Marker to attain high levels of crystallography, solving puzzles of conformation, and ultimate structure. Together, they doubled our motivation to review AMEF. Serendipity gives us back the pleasure of finding, a treat at any age.

AIM We aimed to measure the effectiveness and quality of life (QoL) 10 years after transobturator suburethral tape surgery. METHODS We carried out a prospective observational study of 42 women assessed 10 years after surgical intervention with the transobturator technique. The main outcome measures were subjective and objective cure or improvement, complications, and changes in QoL. RESULTS The median abdominal leak point pressure had been 92 (82-113) mL H2 O prior to surgery. Thirty-six women (85.7%) remained cured (negative cough test) and 13 (31%) reported urine leakage during physical activity, percentages which were similar to those at a previous assessment at the 5th year. Urgency urinary incontinence was reported by 18 women (42.9%), 16 of whom required the use of anticholinergic drugs. Nineteen women had undergone some form of surgical pelvic reconstruction concomitantly with the TOT procedure, four of whom presented with relapse. The QoL tests indicated that cure and improvement persisted in 85.7% (n = 36, Urogenital Distress Inventory-6) and 92.9% (n = 39, Incontinence Impact Questionnaire-7) of the 42 evaluable women, respectively. CONCLUSION Rates of objective and subjective effectiveness remained stable after 10 years of surgery and QoL did not deteriorate significantly during that interval. The increase in urgency incontinence needs to be further investigated.

Aim Human-induced climate change requires conservation strategies incorporating its potential effects on species and communities. Key components of population persistence can be attributed to resistance (the capacity to remain unaffected) or resilience (capacity to absorb and recover) to climate change. In situ climatic refugia can act as resistant distribution units, and ex situ climatic refugia and the corridors to reach them may enhance resilience. We develop a novel approach selecting conservation priorities, resistant units and resilient areas according to structural connectivity and future distribution, to identify strategies that maximize the chances of species persistence in a changing climate. Location Italian Alps. Methods Conservation priorities were defined across species according to the regional conservation status and the level of threat from climate change, and across sites according to their suitability for target species and their related potential for population persistence (in situ climatic refugia, i.e., resistant units) or redistribution (ex situ climatic refugia and main corridors according to current and future connectivity, i.e., resilient units). Results Models suggested a marked loss of suitable area for all species by 2050 (ranging from ~50% for pygmy owl and water pipit, to 84% for snowfinch in the worst scenario), and a general loss of connectivity, which was particularly marked for pygmy owl and snowfinch. The approach applied to Alpine birds of different habitats led to a spatially explicit definition of conservation priorities. Main conclusions The spatial definition of conservation priorities according to species (regional importance and level of threat), resistance and resilience refines the definition of management/conservation priorities (including protected area definition), complementing the existing approaches to address climate change-induced threats in planning conservation and ecological networks.

Foam cells are lipid-loaded macrophages that are generated from the massive uptake of modified low-density lipoproteins and the intracytoplasmatic accumulation of cholesteryl esters. Foam cells are present in all stages of atherosclerosis and participate in inflammatory responses and tissue remodelling within the arterial intima. Foam cells can also be generated as a consequence of infection by persistent pathogens, such as Mycobacterium, Chlamydia and Toxoplasma. These pathogens meet nutritional advantages by residing within cells that accumulate lipids. When the immune system is unable to eliminate substances perceived as foreign, it produces a granuloma, composed mostly of macrophages, attempting to wall off the nonself-material. This article reviews the processes that lead to the regulation of foam cell formation in atherosclerosis and infection. Key Concepts: Foam cells are lipid-loaded macrophages. Foam cells are generated from the massive uptake of modified low-density lipoproteins and the intracytoplasmatic accumulation of cholesteryl esters. Foam cells are present in several diseases as atherosclerosis and as result of different infections. Foam cells participate in inflammatory responses and tissue remodelling. Endothelial transmigration of monocytes is the first step in the development of atherosclerosis. Once monocytes have taken residence in the arterial wall intima, they undergo phenotypic transformation into macrophages, and can internalise large amounts of modified LDLs and become foam cells. Liver X receptors (LXR) and the retinoid X receptors (RXR) heterodimers directly upregulate the expression of a number of genes involved in lipid and lipoprotein homeostasis. When the immune system is unable to eliminate substances that it perceives as foreign it attempts to wall off the nonself-material by producing granulomas; a ball-like structures composed of immune cells, mostly activated macrophages, that are surrounded by lymphocytes predomintantly of the TH1 type. Keywords: foam cells; granuloma; low-density lipoproteins; liver X receptors (LXRs); macrophages; nuclear receptors; peroxisome proliferator-activated receptors (PPARs); retinoid X receptors (RXR); tuberculosis

The distribution of seabirds at sea is influenced by physical, ecological and anthropogenic factors such as sea depth, prey distribution, intra-specific competition and commerical fishing activities. We quantified the foraging habitat preferences of Scopoli's Shearwater Calonectris diomedea in the Mediterranean Sea. We analysed habitat preferences in relation to a suite of physical and ecological variables including sea depth, net primary production and distance to other colonies (as a proxy of intra-specific competition). Since the Mediterranean is heavily impacted by commercial fisheries, we also incorporated the distance to fishing harbours in our analyses as a proxy of the availability of discards which are a potential feeding source for Scopoli's Shearwater. Foraging birds preferred shallower waters and avoided areas close to other colonies, thereby reducing interactions with conspecifics. We also found that long-distance trips were undertaken to areas close to fishing harbours, suggesting that these represented particularly profitable locations to compensate for the greater travelling costs involved. No differences in foraging between the sexes were recorded. This study improves our understanding of the at-sea distribution and habitat preference of a seabird inhabiting the over-exploited Mediterranean Sea. Our results support growing evidence that seabirds exhibit complex relationships with commerical fishing activities, which must be considered when planning conservation programmes.

Butyltins (BTs) contaminate the environment and are found in human blood. BTs, tributyltin (TBT) and dibutyltin (DBT), diminish the cytotoxic function and levels of key proteins of human natural killer (NK) cells. NK cells are an initial immune defense against tumors, virally-infected cells and antibody-coated cells and thus critical to human health. The signaling pathways that regulate NK cell functions include mitogen-activated protein kinases (MAPKs). Studies have shown that exposure to BTs leads to the activation of specific MAPKs and MAPK kinases (MAP2Ks) in human NK cells. MAP2K kinases (MAP3Ks) are upstream activators of MAP2Ks, which then activate MAPKs. The current study examined if BT-induced activation of MAP3Ks was responsible for MAP2K and thus, MAPK activation. This study examines the effects of TBT and DBT on the total levels of two MAP3Ks, c-Raf and ASK1, as well as activating and inhibitory phosphorylation sites on these MAP3Ks. In addition, the immediate upstream activator of c-Raf, Ras, was examined for BT-induced alterations. Our results show significant activation of the MAP3K, c-Raf, in human NK cells within 10 minutes of TBT exposure and the MAP3K, ASK1, after one hour exposures to TBT. In addition, our results suggest that both TBT and DBT are impacting the regulation of c-Raf.

T lymphocytes expressing the CLA antigen constitute a subset of effector memory lymphocytes that are functionally involved in T-cell-mediated cutaneous diseases. Skin-seeking lymphocytes recirculate between inflamed skin and blood during cutaneous inflammation. Many studies in different T-cell- mediated inflammatory cutaneous diseases have clearly related their pathologic mechanisms to CLA+ T cells. Based on common features of these cells in different cutaneous disorders mediated by T cells, we propose that circulating CLA+T cells could constitute very useful peripheral cellular biomarkers for T-cell-mediated skin diseases.

BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT1A autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT1A receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT1A autoreceptors. However, it is unclear whether 5-HT1A receptor antagonists not discriminating between pre- and post-synaptic 5-HT1A receptors would be clinically effective. EXPERIMENTAL APPROACH We characterized the pharmacological properties of the 5-HT1A receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT1A receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT1A receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT1A receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS DU-125530 is an excellent pre- and post-synaptic 5-HT1A receptor antagonist. However, blockade of post-synaptic 5- HT1A receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.

The amount of arginine available at inflammatory loci is a limiting factor for the growth of several cells of the immune system. IL-4-induced activation of macrophages produced arginase-1, which converts arginine into ornithine, a precursor of polyamines and proline. Trichostatin A (TSA), a pan-inhibitor of histone deacetylases (HDACs), inhibited IL-4-induced arginase-1 expression. TSA showed promoter-specific effects on the IL-4-responsive genes. While TSA inhibited the expression of arginase-1, fizz1, and mrc1, other genes, such as ym,1 mgl1, and mgl2, were not affected. The inhibition of arginase-1 occurred at the transcriptional level with the inhibition of polymerase II binding to the promoter. IL-4 induced STAT6 phosphorylation and binding to DNA. These activities were not affected by TSA treatment. However, TSA inhibited C/EBPβ DNA binding. This inhibitor induced acetylation on lysine residues 215-216, which are critical for DNA binding. Finally, using macrophages from STAT6 KO mice we showed that STAT6 is required for the DNA binding of C/EBPβ. These results demonstrate that the acetylation/deacetylation balance strongly influences the expression of arginase-1, a gene of alternative activation of macrophages. These findings also provide a molecular mechanism to explain the control of gene expression through deacetylase activity.

The rearing of astacid crayfishes under controlled conditions requires the addition of live zooplankton to basal dry diets. To investigate the possibility of minimizing the labor and costs involved in providing live feed, a 180-d experiment that focused on reducing the brine shrimp Artemia spp. supply period was carried out with stage 2 signal crayfish Pacifastacus leniusculus. From the onset of exogenous feeding, juvenile crayfish were fed a dry diet (formulated for salmonids) that was supplemented with live Artemia nauplii. Five treatments were implemented, varying the time at which the Artemia supplement was withdrawn (at days 80, 100, 120, or 160, or no withdrawal). No significant differences in survival, growth, or cheliped loss were found among groups throughout the trial. Survival rates at the end of the experiment (180 d) ranged from 62.3% to 66.7%, final carapace length averaged 20.6 mm, and final weight averaged 2.29 g. The results presented here indicate that juvenile astacid crayfishe...

BACKGROUND AND PURPOSE Intracranial epidermal cysts are benign uncommon lesions. Such lesions arise from an inclusion of an ectodermal element during neural tube closure, in which dermal elements become trapped in the suture line, diploe, meninges, or scalp. Reports have extensively demonstrated the typical magnetic resonance (MR) spectra with the presence of large lactate signals with a virtual absence of healthy brain metabolites. METHODS A 20-year-old male patient with a parietal lobe brain lesion was studied by magnetic resonance imaging and magnetic resonance spectroscopy in a 1.5-T Philips scanner. RESULTS The lesion presented atypical MR spectra with presence of alanine (1.46 ppm), lactate (1.31 ppm), and amino acids such as valine, isoleucine (0.97 ppm), and glicine (3.52 ppm). No evidence of normal parenchyma tissue metabolites (N-acetylaspartate, creatine, and choline) or succinate and acetate signals was observed. This spectral pattern was unexpected being proposed the differential diagnosis of brain abscess versus epidermoid cyst. Finally, surgical total excision biopsy confirmed the diagnosis of epidermal cyst. CONCLUSIONS In this report, we describe a case of an epidermal cyst with an unusual metabolic pattern observed by magnetic resonance spectroscopy mimicking a brain abscess.

Background and purpose: F15599, a novel 5-hydroxytryptamine (5-HT)1A receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5-HT1A heteroreceptors. Experimental approach: In vivo single unit and local field potential recordings and microdialysis in the rat. Key results: F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 µg·kg−1 i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 µg·kg−1 i.v.). Both effects were reversed by the 5-HT1A antagonist (±)WAY100635. F15599 did not alter low frequency oscillations (∼1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT1A receptors) with an ED50 of 30 µg·kg−1 i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT1A autoreceptor activation) with an ED50 of 240 µg·kg−1 i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to F15599 were prevented by administration of (±)WAY100635. Conclusions and implications: These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5-HT1A receptors in PFC rather than somatodendritic 5-HT1A autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT1A receptor agonists, which preferentially activate somatodendritic 5-HT1A autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.

MAPK phosphatase-1 (MKP-1) is a protein phosphatase that plays a crucial role in innate immunity. This phosphatase inactivates ERK1/2, which are involved in two opposite functional activities of the macrophage, namely proliferation and activation. Here we found that although macrophage proliferation and activation induce MKP-1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between −380 and −180 bp. Mutagenesis experiments of the proximal element determined that CRE/AP-1 is required for LPS- or M-CSF-induced activation of the MKP-1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c-Jun and CREB bind to the CRE/AP-1 box. The distinct kinetics shown by M-CSF and LPS correlates with the induction of JNK and c-jun, as well as the requirement for Raf-1. The signal transduction pathways that activate the induction of MKP-1 correlate kinetically with induction by M-CSF and LPS.

Macrophages are recruited from the blood stream to the inflammatory loci to carry out their functional activities. In an early phase of the cell cycle, macrophages become activated by Th1-type cytokines (i.e. IFN-gamma), thereby producing several factors (cytokines, NO, etc.) and developing pro-inflammatory activities. When bacteria and apoptotic bodies are removed, through the interaction with Th2-type cytokines (i.e. IL-4), macrophages become anti-inflammatory and repair damaged tissues. Incubation of bone-marrow-derived macrophages with IFN-gamma or IL-4 blocked their proliferation. While M-CSF withdrawal caused cell cycle arrest at the early G(1) phase, treatment of macrophages with IFN-gamma or IL-4 caused this arrest later, at the G(1)/S boundary. Proliferation arrest was not due to an induction of apoptosis. IFN-gamma and IL-4 induced the expression of the cyclin-dependent kinase (Cdk) inhibitor p21(Waf1). Using KO mice and iRNA experiments, we found that p21(Waf1)is required for IL-4- but not for IFN-gamma-dependent inhibition of macrophage proliferation. IL-4 inhibited M-CSF-dependent Cdk-2 and Cdk-4 activities, which are necessary for entry and passage through the S phase of the cell cycle. The signal transduction used to induce the expression of p21(Waf1)after interaction of IL-4 with the corresponding receptor was mediated by STAT6. Thus, IL-4 and IFN-gamma blocked M-CSF-induced macrophage proliferation through distinct mechanisms.

The distribution of HLA antigens was studied in 40 patients suffering from systemic lupus erythematosus. For loci A and B, increased frequencies of A1, B8 and the presence of only one B antigen were found. Nevertheless, in relation to the number of antigens tested, this increase was not significant. For the DRw locus, DRw3 was significantly increased (P < 0.001, after correction for the 39 antigens tested). However, the patients with DRw3 did not show any correlation with a specific clinical picture or the presence in their serum of lymphocytotoxic antibodies or autoantibodies against T and B lymphocytes.

The release of 5-HT in terminal areas of the rodent brain is regulated by 5-HT1B receptors. Here we examined the role of 5-HT1B receptors in the control of 5-HT output and firing in the dorsal raphe nucleus (DR), median raphe nucleus (MnR) and forebrain of the rat in vivo. The local perfusion (30-300 microM) of the selective 5-HT1B receptor agonist CP-93,129 to freely moving rats decreased 5-HT release in the DR and more markedly in the MnR. Likewise, 300 microM CP-93,129 reduced 5-HT output in substantia nigra pars reticulata, ventral pallidum, lateral habenula and the suprachiasmatic nucleus. The effect of CP-93,129 was prevented by SB-224289, but not by WAY-100635, selective 5-HT1B and 5-HT1A receptor antagonists, respectively. SB-224289 did not alter dialysate 5-HT in any raphe nuclei. The intravenous administration of the brain-penetrant selective 5-HT1B receptor agonist CP-94,253 (0.5-2.0 mg/kg) to anesthetized rats decreased dialysate 5-HT in dorsal hippocampus and globus pallidus, increased it in MnR and left it unaltered in the DR and medial prefrontal cortex. SB-224289, at a dose known to block 5-HT1B autoreceptor-mediated effects (5 mg/kg), did not prevent the effect of CP-94,253 on MnR 5-HT. The intravenous administration of CP-94,253 (0.05-1.6 mg/kg) to anesthetized rats increased the firing rate of MnR, but not DR-5-HT neurons. The local perfusion of CP-94,253 in the MnR showed a biphasic effect, with 5-HT reductions at 0.3-3 microM and increase at 300 microM. These results suggest that 5-HT cell firing and release in midbrain raphe nuclei (particularly in the MnR) are under control of 5-HT1B receptors. The activation of 5-HT1B autoreceptors (possibly located on 5-HT nerve endings and/or varicosities within DR and MnR) reduces 5-HT release. The effects of higher concentrations of 5-HT1B receptor agonists seem more compatible with the activation of 5-HT1B heteroreceptors on inhibitory neurons.

In murine macrophages, as a result of arginine catabolism during activation, citruline is produced under the effect of IFN-gamma and LPS, and ornithine and polyamines by IL-4 and IL-10. For proliferation, arginine is required from the extracellular medium and is used for protein synthesis. During activation, most arginine (95% in 6 h) was metabolized, while under proliferation only half was incorporated into proteins. Under basal conditions, this amino acid was preferentially transported by y(+)L activity. During activation, arginine transport increased drastically (4-5-fold) through y(+) cationic amino acid transporter (CAT) activity. By contrast, M-CSF induced only a modest increase in uptake (0.5-fold). The increase in arginine transport during activation, but not proliferation, was mediated by the SLC7A2/Cat2 gene. SLC7A1/Cat1 is constitutively expressed, and is not modified by proliferating or activating agents. M-CSF-dependent proliferation was not affected in the macrophages of SLC7A2 knockout mice; however, these cells showed a drastic reduction in the production of citruline or ornithine and polyamines during activation. The data show that a large increase in a specific transport system (CAT2) is necessary for activation-induced arginine metabolism, while arginine is in excess for the requirements of proliferation and a modest increase in transport occurs.