the leaf blower war or the anti-'woke' backlash World Subscribers only Germany's Friedrich Merz is embracing pragmatism World Subscribers only Trump-Carney meeting: Canada seeks reconciliation World Subscribers only Friedrich Merz bets on two private sector converts to revive the German economy and reform the state World Subscribers only Founder of Sant'Egidio community fears next pope could undo Francis's legacy Opinion Subscribers only 'Russian gas and Europe is an old story that ended badly Economy Subscribers only Europe's steel industry flattened by crisis World Subscribers only How European countries plan to fund defense efforts France Subscribers only Macron announces citizens' convention on school schedules France Subscribers only 21 charged over French prison attacks as investigation narrows in on drug traffickers France Subscribers only French mosque stabber was driven by 'morbid fascination,' prosecutor says France Subscribers only At the trial of Kim Kardashian's robbers Videos World expos: From Paris 1855 to Osaka 2025 Videos How the Trump administration is attacking scientific research in the US Videos Tesla cars set on fire in Las Vegas as calls to boycott Musk's company grow worldwide Videos Can France's nuclear deterrent protect Europe Opinion Subscribers only 'The American dream is dying' Opinion Subscribers only 'It is pointless to imagine a significant wave of American academics leaving' Opinion Subscribers only 'The trade war creates new opportunities for Europeans and France' Magazine Subscribers only Tracking down the pianos taken from French Jews during the Nazi Occupation Magazine Subscribers only Eve Rodsky the American helping couples balance the mental load Magazine Subscribers only Desecration or more glory Joan Didion's private diaries are revealed Magazine Subscribers only For Jewish cartoonist Joann Sfar 2025."> Pixels Subscribers only Golden Owl solution is revealed but leaves players of 31-year hunt disappointed Pixels Subscribers only Secrets of decades-long Golden Owl treasure hunt to be revealed Lifestyle Inside Chanel's French leather workshops Culture Subscribers only The marvelous bronzes of Angkor on display at the Musée Guimet in Paris InvestigationLocalized data from popular apps including Candy Crush Vinted and Grindr appear in a data sample obtained and analyzed by Le Monde and its partners These data enable the tracking of users' habits and movements Dozens of the most widely used apps in France share their users' whereabouts in an opaque advertising market This situation has long been denounced by experts and defenders of online privacy It has now been confirmed and demonstrated with the examination of an exclusive database from one of these personal data brokers that make a profession of selling and exchanging personal information for advertising purposes The sample is one shared for commercial presentation purposes by one of these brokers The Florida-based company provides its customers with data to help them target advertising campaigns more effectively we examined the file along with eight other media organizations – netzpolitik.org and Bayerischer Rundfunk (Germany) BNR Nieuwsradio (Netherlands) and Dagens Nyheter (Sweden) You have 80.7% of this article left to read Lecture du Monde en cours sur un autre appareil Vous pouvez lire Le Monde sur un seul appareil à la fois Ce message s’affichera sur l’autre appareil Parce qu’une autre personne (ou vous) est en train de lire Le Monde avec ce compte sur un autre appareil Vous ne pouvez lire Le Monde que sur un seul appareil à la fois (ordinateur En cliquant sur « Continuer à lire ici » et en vous assurant que vous êtes la seule personne à consulter Le Monde avec ce compte Que se passera-t-il si vous continuez à lire ici Ce dernier restera connecté avec ce compte Vous pouvez vous connecter avec votre compte sur autant d’appareils que vous le souhaitez mais en les utilisant à des moments différents Nous vous conseillons de modifier votre mot de passe Votre abonnement n’autorise pas la lecture de cet article merci de contacter notre service commercial a Nazi sign and words mocking the Holocaust were painted on a tombstone at the Garden of Remembrance in the cemetery in Champagne-au-Mont-d'Or France has been shocked by incidents of anti-Semitic vandalism in the last couple weeks including 80 tombstones in a Jewish cemetery painted with graffiti and swastikas earlier this month French President Emmanuel Macron has said France and other Western democracies are experiencing a "resurgence of anti-Semitism unseen since World War II." One effort to counter the hate brought about 150 French women together from different religious ethnic and economic backgrounds to go to a notorious symbol of terror and genocide from that war: Auschwitz Together they wanted to learn more about the Holocaust in the hopes of bringing a message of greater understanding back to France "Women can transmit and educate — to their children, to the rest of society," said Samia Essabbaa, a high school teacher who is president of the diverse group Langage de Femmes The group started their tour at the Judenrampe women and children from around Europe disembarked from trains to go straight to the gas chambers Members of a group of French women from diverse religious and ethnic backgrounds lay a wreath near the Auschwitz gas chambers earlier this month After learning more about the horrors of the Holocaust they hoped to bring greater understanding to their country riven by new acts of anti-Semitism A 94-year-old Holocaust survivor named Ginette Kolinka described what it was like Kolinka was deported to Auschwitz from France in April 1944 "After we got down from the rail cars and had assembled on the platform we were told to go to the left or the right," she said "This was the selection — whether we were to live or die The Judenrampe was the last place she saw her father and younger brother Samia Essabaa is president and co-founder of the group Langage de Femmes and they lied to us with such aplomb that we believed them," she said you will all meet up in the camp.' When we got to the camp and saw the chimneys and the smoke and were hit by the terrible odor And we quickly found out from the other prisoners the terrible secret But we could have never imagined such a thing." Between 1940 and 1945, researchers estimate at least 1.3 million people were deported to Auschwitz a complex of forced labor facilities and death camps in Nazi-occupied Poland Langage de Femmes is one of the latest interfaith groups to visit the Nazi site at a time when Europe has experienced bouts of vandalism harassment and attacks against minority groups Jewish groups and researchers in France say a new anti-Semitism has risen largely within the country's Muslim communities Several Jewish cemeteries and memorials in France have been hit with anti-Semitic vandalism in recent months two illustrations of a prominent Holocaust survivor were graffitied with swastikas in Paris who was deported to Auschwitz at age 16 and later went on to became one of France's most beloved politicians and public figures The group visiting Auschwitz peppered their tour guide with questions about Veil A rose is placed on mailboxes that were vandalized with swastikas covering the face of the late Holocaust survivor and renowned French politician the number of registered anti-Semitic acts rose to 541 in 2018 from 311 in 2017 Other minority groups are also targeted in Europe. Researchers tracking discrimination, harassment and hate crimes against Muslims have warned of a rise of Islamophobia in recent years explained how meaningful it was to visit Auschwitz with women from different backgrounds seeking to stop the hate "To bring a group of women this diverse here is very important because when we are all here no one with a job more important than another and no cultural or religious differences," she said "We are all part of one community of women whose common goal is to struggle against racism and anti-Semitism." came to Auschwitz with her 18-year-old daughter Ina Both were speechless after hearing stories from a Holocaust survivor there said they were learning about the Holocaust for the first time Mangara grew up in Mali and came on the trip with her 18-year-old daughter Ina Both women were silent after Kolinka's testimony "It must have been so horrible to live through that," Mangara said Another woman on the Auschwitz trip was Laetitia Avia a congresswoman from President Macron's party She said as a black woman from a housing project in a Parisian suburb she has dealt with discrimination her whole life Avia said her efforts to stop anti-Semitism have earned her the moniker "Negress of the Jews." But that doesn't dissuade her The 34-year-old recently introduced legislation in French parliament that would slap social media platforms like Twitter with millions of euros in fines if they don't remove hate speech within 24 hours "[Auschwitz] shows where words and acts of hatred can lead," Avia said a teacher at a high school in a Paris suburb says many of the students grow up hearing stereotypes about Jews at a young age Ibtihele Ben Amor is a high school teacher in the Paris suburb of Noisy-le-Sec. She is Muslim and wears a headscarf, which she takes off when she teaches. France's secular law prohibits wearing noticeable religious symbols or clothing in public schools and institutions Ben Amor thinks it would be wonderful to bring her students to Auschwitz She said some of them grow up hearing stereotypes about Jews from a young age "We tell them to put aside everything they were told and we try to establish reality," she said Suzanne Nakache (front) and Samia Essabaa at a ending candlelight ceremony at Auschwitz and they hope their strong friendship serves as a model for others Langage de Femmes' vice president Suzanne Nakache said for French Jews it is important that the much larger Muslim population understands the trauma of the Holocaust She believes the women on the trip now do and will share what they learned "It was very hard for some of the black and Muslim women to think what happened to the Jews here There was stunned silence as the group walked through rooms showing tens of thousands of pairs of leather shoes and eye glasses Nakache said during the tour one woman squeezed her hand while another had tears streaming down her face "They understand why you can't use insults like 'dirty Jew,' because it can end up here," she said and wishes everyone could have a relationship like theirs "Samia is my best friend and she is a Muslim," she says Become an NPR sponsor Your browser is out of date and potentially vulnerable to security risks.We recommend switching to one of the following browsers: You are using an outdated browser. Please upgrade your browser or activate Google Chrome Frame to improve your experience With recent incidents of anti-Semitic vandalism in France a group of women from different religious and ethnic backgrounds sought greater.. French Women Find Strength In Diversity At Auschwitz President Trump issued an executive order Monday banning federal funding for any research abroad that involves a field of scientific study known as "gain-of-function" research are challenging an executive order Trump signed on his first day in office pausing approvals permits and loans for all wind energy projects Square root days happen only a few times in a century and the man who brought the day fame is celebrating his sixth one more than a dozen former workers of the powerful data-mining and surveillance company say the firm's work with the Trump administration violates the company's founding principles Israel's cabinet has approved plans for Gaza that include expanding the war taking territory with the intent to keep troops there and major shifts in the way food and aid are distributed Our correspondent in Tel Aviv tells us what are in the plans and what they could mean for Gaza Production in Hollywood has been suffering But it's unclear how a 100% tariff on movies produced outside the United States would work – or who it would help The 2025 Pulitzer Prizes were announced Monday afternoon Percival Everett won the award for fiction for his novel James a powerful re-imagination of Huckleberry Finn The annual Eta Aquarid meteor shower is set to peak early on May 6 and will be viewable in the dark predawn skies the Trump administration confirmed that it terminated visa records for thousands of international students because of past brushes with law enforcement Microsoft has announced that the pioneering online video calling service that's been around for more than two decades will go offline on Monday Emmitsburg is home to the National Fire Academy The Trump administration's decision to halt classes has some townspeople pondering their votes The prison on a forbidding island off San Francisco was operated at a prohibitive cost President Trump says it's time to substantially enlarge and rebuild Alcatraz as a federal penitentiary Tuesday World Subscribers only In Zurich Here are our favorite versions of this must-have dessert for end-of-year meals By Gilbert Pytel After tasting over 100 bûches de noël across France here's our selection of the 15 best of 2024 PÂTISSERIE INTENSE World pastry champion in 2017 Bastien Girard made his dreams come true in 2020 by returning to the Ardèche department to set up his own boutique with his wife The cakes on offer vary according to the season with as much locally sourced fruit and with the most eco-friendly approach possible Our opinion: This bûche takes up the fundamentals of the paris-brest cake reworked in an ice cream version and spiced up by the peanut that replaces the hazelnut with an éclair topped with creamy peanut praline as an insert The addition of a hint of fleur de sel to the praline balances out the sweetness and gives a long finish peanut praline ice cream and peanut Chantilly cream €35 (for 6 people). Pâtisserie Intense Tournon-sur-Rhône (southeastern France); 64 You have 92.75% of this article left to read Metrics details dynamic and heterogeneous host response modulations the risk of mortality and healthcare-associated infections remains high Treatments to counterbalance immune response are under evaluation but effective biomarkers are still lacking to perform patient stratification The design of the present study was defined to alleviate the limitations of existing literature: we selected patients who survived the initial hyperinflammatory response and are still hospitalized at day 5–7 after ICU admission a fully automated RT-qPCR multiplex prototype we optimized a machine learning model combining the IPP gene expression levels for the identification of patients at high risk of worsening a composite endpoint defined as death or secondary infection This was done on 332 sepsis patients selected from two retrospective studies The IPP model identified a high-risk group comprising 30% of patients with a significant increased proportion of worsening events at day 28 compared to the low-risk group (49% vs These preliminary results underline the potential clinical application of IPP for sepsis patient stratification in a personalized medicine perspective that will be confirmed in a larger prospective multicenter study outcomes occurring within 28 days after markers measurement could be challenging to predict reliably We postulated that the prediction of an outcome in a shorter timeframe could improve the performances The aim of this study is to evaluate the performances of the IPP prototype for the identification of a subgroup of high-risk sepsis patients in a stratification perspective for a precision medicine approach we selected from two retrospective cohorts patients who survived until day 5–7 after intensive care unit (ICU) admission and who did not already develop any HAI at this time We then set up a classifier combining the expression level of the IPP gene set for the prediction of the occurrence of worsening a composite outcome combining death and HAI The study protocol was approved by the local ethics committee (Centre d’Investigation Clinique IRB# 5044) which waived the need for informed consent from patients and/or next of kin (analyses performed on leftover blood) and is in accordance with the Helsinki Declaration of 1975 patients or legal representatives were informed about the study and about their right to refuse to participate Written informed consent was obtained from each patient The study protocol was approved on December 3rd 2015 by the Institutional Review Board (Comité de Protection des Personnes Sud-Est II) under number 2015-42-2 and is in accordance with the Helsinki Declaration of 1975 RNA integrity was assessed using the RNA 6000 Nano Kit (Agilent Technologies USA) on the Agilent 2100 Bioanalyzer (Agilent Technologies) Normalized expression values were computed for each marker and used for the analyses Boxplot representation of the expression level of the 11 IPP genes according to patient status at day 28: Alive Squared brackets report comparison between groups either anova or pairwise Wilcoxon signed rank depending on the distribution A patient that dies during the measurement period receives a score of 0 A machine learning approach was implemented on the IPP gene set expression levels to predict worsening status (i.e. HAI occurrence or death; versus alive without HAI) within day 15 after ICU admission based on a linear regression that used a space dimension reduction: the partial least square-discriminant analysis (PLS-DA) regression This classification method can simultaneously manage many predictors which would hinder the identification of the features primarily associated with the outcome Fine-tuning (number of components) was performed manually from one to the maximum number of components selecting the best number of components according to the maximal mean area under the precision-recall curve (AUPRC) observed across repetitions The final PLS-DA model was fit on the entire training set Model performance was then evaluated on test set by calculating AUROC and its CI (bootstrap method A descriptive analysis of patient outcomes according to worsening status defined by the IPP model was performed Analyses were performed using R software Version 3.6.2 (R Foundation for Statistical Computing with caret v6.0.84 and pls v2.7.3 packages for machine learning; ggsurvfit v0.2.0 and survival v3.4.0 for incidence plot Median [Q1–Q3] age was 67 [57–77] years old and 64% of patients were male the median SOFA score was 9 [7–12] and the median SAPS II was 55 [42–67] The proportion of community-acquired initial infections was 67% of patients and lung was the primary site of infections in 50% of patients 67% of patients were mechanically ventilated and 14% had renal replacement therapy 20% (n = 66) of patients were deceased at day 28 36% of patients experienced worsening until day 28: 16% died without any HAI and 20% developed an HAI We observed that 20% of patients who died had an HAI (13/66 patients) The median day 28 ICU free days was 16 [0–22] days management and outcomes were not different between the train and the test cohorts The final trained model combining the expression level of the 11 IPP genes set was optimized for the identification of worsening status patients' class (who will develop an HAI and/or die within 15 days after ICU admission) Cumulative incidence curves of worsening events in the test set in the two groups of patients identified by the IPP model Worsening is defined by the occurrence of death or healthcare-associated infection Using a composite endpoint combining both HAI and mortality we identified two groups of patients with different proportions of worsening using a machine-learned combination of gene’s expression levels worsening occurred in almost 50% of patients at day 28 versus only 28% in the low-risk group Patients from the high-risk group had also significantly longer length of ICU stay and mechanical ventilation The implementation of such stratification approach could help in clinical trial design and may contribute to facilitate therapeutic success there is no guidelines providing the minimal performances to reach for such demonstration this new result provides clinically relevant information considering the competing risk between HAI and death This exploratory pilot study acknowledges several limitations the retrospective design limits the conclusion that could be inferred from our results The differences in the design of the two cohorts as well as the variations in patient management guidelines over time induced a great heterogeneity that we had to smooth by merging the two cohorts even if the results were obtained in a train/test approach they need to be confirmed in a new independent multicenter study as we performed gene expression measurement in whole blood we cannot exclude that our model reflects differences in leukocyte subpopulations distribution rather than regulation of gene expression we built a machine-learned model based on the combination of the expression of genes simultaneously assessed in blood that identifies a subgroup of patients at high risk to worsen at day 28 These preliminary results are under evaluation in a large prospective ongoing international observational trial (IMPACCT The datasets generated and/or analysed in the current study are available from the corresponding author upon reasonable request Heterogeneity in sepsis: New biological evidence with clinical applications Sepsis and septic shock in France: Incidences Torres, L. K., Pickkers, P. & Van der Poll, T. Sepsis-Induced Immunosuppression. Ann. Rev. Physiol. 84, 157–181. https://doi.org/10.1146/annurev-physiol-061121-040214 (2021) and attributable mortality of secondary infections in the intensive care unit after admission for sepsis Sepsis therapies: Learning from 30 years of failure of translational research to propose new leads Prognostic and predictive enrichment in sepsis Gaps and opportunities in sepsis translational research elevated PD-1/CD28 ratio rather than PD-1 expression in CD8+ T cells predicts nosocomial infection in sepsis patients: A prospective observational cohort study A community approach to mortality prediction in sepsis via gene expression analysis Prediction of mortality in adult patients with sepsis using six biomarkers: A systematic review and meta-analysis Identification of a sub-group of critically ill patients with high risk of intensive care unit-acquired infections and poor clinical course using a transcriptomic score a specific marker of neutrophil activation is associated with coronavirus disease 2019 severity and death Transcriptomic correlates of organ failure extent in sepsis The pathophysiology of sepsis and precision-medicine-based immunotherapy Immune Profiling Panel: A proof-of-concept study of a new multiplex molecular tool to assess the immune status of critically Ill patients Immune Profiling Panel gene set identifies critically ill patients with low monocyte human leukocyte antigen-Dr expression: preliminary results from the REAnimation low immune status marker (REALISM) study Decreased CX3CR1 messenger RNA expression is an independent molecular biomarker of early and late mortality in critically ill patients The REAnimation low immune status markers (REALISM) project: A protocol for broad characterisation and follow-up of injury-induced immunosuppression in intensive care unit (ICU) critically ill patients Immune profiling demonstrates a common immune signature of delayed acquired immunodeficiency in patients with various etiologies of severe injury European surveillance of ICU-acquired infections (HELICS-ICU): Methods and main results Immune Profiling Panel gene set identifies critically Ill patients with low monocyte human leukocyte antigen-DR expression: Preliminary results from the REAnimation low immune status marker (REALISM) study Association between mRNA expression of CD74 and IL10 and risk of ICU-acquired infections: A multicenter cohort study an automated nested multiplex PCR system for multi-pathogen detection: Development and application to respiratory tract infection Heterogeneity in the definition of mechanical ventilation duration and ventilator-free days SMOTE: Synthetic minority over-sampling technique The third international consensus definitions for sepsis and septic shock (Sepsis-3) Differences in impact of definitional elements on mortality precludes international comparisons of sepsis epidemiology—A cohort study illustrating the need for standardized reporting Genetic factors of the disease course after sepsis: A genome-wide study for 28day mortality Genomic landscape of the individual host response and outcomes in sepsis: A prospective cohort study Classification of patients with sepsis according to blood genomic endotype: A prospective cohort study Developing a new definition and assessing new clinical criteria for septic shock: For the third international consensus definitions for sepsis and septic shock (Sepsis-3) An adjudication protocol for severe pneumonia An evaluation of the role of gene expression in the prediction and diagnosis of ventilator-associated pneumonia Transcriptomic depression of immunological synapse as a signature of ventilator-associated pneumonia Estimating attributable mortality due to nosocomial infections acquired in intensive care units Download references MIP Réa study group: HCL: Bernard Allaouchiche ESPCI: Andrew Griffiths and Stephanie Toetsch This work was supported by funds from bioMérieux and Hospices Civils de Lyon The MIP Réa study was part of Advanced Diagnostics for New Therapeutic Approaches (ADNA) a program dedicated to personalized medicine coordinated by Institut Mérieux and supported by the French public agency BPI France The REALISM study received funding from the Agence Nationale de la Recherche through a grant awarded to BIOASTER (Grant number #ANR-10-AIRT-03) and from bioMérieux EA 7426 “Pathophysiology of Injury-Induced Immunosuppression” (Université Claude Bernard Lyon 1 – Hospices Civils de Lyon Guillaume Monneret & Jean-François Llitjos Open Innovation and Partnerships (OI&P) Aurore Fleurie & Jean-François Llitjos Anaesthesia and Critical Care Medicine Department Thomas Rimmelé & Anne-Claire Lukaszewicz Edouard Herriot Hospital – Hospices Civils de Lyon All authors read and approved the final manuscript co-funded by the Hospices Civils de Lyon and bioMérieux GM and FV are co-inventors in patent applications covering the following markers: CX3CR1 and S100A9 GM and FV are co-inventors in patent applications covering the following markers: CX3CR1 BioFire – a bioMérieux company - holds patents on the technology Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41598-024-62202-z Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology You don't have permission to access the page you requested What is this page?The website you are visiting is protected.For security reasons this page cannot be displayed Metrics details a family of high-affinity dopamine transporter ligands are molecules that exhibit pharmacological and behavioral characteristics predictive of significant therapeutic potential in cocaine addiction we examined in mice the effects of 3α-[bis(4′-fluorophenyl)metoxy]-tropane (AHN-1055) on motor activity conditioned place preference (CPP) and c-Fos expression in the striatum AHN-1055 produced mild attenuation of spontaneous locomotor activity at a low dose (1 mg/kg) and weak stimulation at a higher dose (10 mg/kg) the BZT analog significantly increased c-Fos expression in the dorsolateral caudoputamen at the high dose whereas producing marginal decreases at low and moderate doses (1 3 mg/kg) in both dorsal and ventral striatum Interaction assays showed that cocaine's ability to stimulate locomotor activity was decreased by AHN-1055 treatment Such reduced ability did not result from an increase in stereotyped behavior decreased cocaine-induced locomotor activity but evoked by itself intense motor stereotypies the BZT analog dose-dependently blocked cocaine-induced CPP without producing CPP when given alone and blocked in conditioned mice cocaine-stimulated early-gene activation in the nucleus accumbens and dorsomedial striatum These observations provide evidence that AHN-1055 does not behave as a classical psychomotor stimulant and that some of its properties including attenuation of cocaine-induced striatal c-Fos expression and that of structurally related molecules as possible pharmacotherapies in cocaine addiction suggesting that the pharmacokinetic/dynamic characteristics of cocaine and other psychoactive compounds that share DAT activity might be critical for their addictive properties and support the claim that they might offer a lead for the design of efficacious replacement medications for cocaine addiction To determine the extent to which AHN-1055 was able to influence the stimulant and rewarding effects of cocaine and to gain insight into its possible application as a pharmacotherapy for cocaine addiction administered alone and in combination with cocaine aged 5–6 weeks and weighting 22–26 g (Charles River Mice were housed in groups of four subjects after arrival at the laboratories and were allowed 4–7 days to acclimatize to the animal facility before experiments began The housing room was maintained under constant conditions of temperature (21±2°C) and humidity (50±5%) and was kept on a 12 h light–dark cycle (lights on at 0900 hours) All experiments were carried out in accordance with the current European directives regulating animal experimentation (86/609/ECC) and were approved by the Ethical Committee (Faculty of Pharmacy) of the University of Valencia Purity of the product was assessed by magnetic resonance sonicated for complete solubilization and injected at doses of 0 Dose selection for the BZT analog was based on pilot experiments Doses higher than 10 mg/kg (20 and 30 mg/kg) were lethal in some mice when combined with cocaine and were not used in these experiments D-amphetamine sulfate and nomifensine (Sigma-Aldrich UK) were dissolved in 0.9% saline and injected at doses of 15 D-amphetamine and nomifensine were selected based on preliminary dose–response locomotor activity and/or CPP assays performed in our laboratories All compounds were prepared fresh daily and were injected at a volume of 10 ml/kg The responses were rated from 1 to 10 for each of the four dimensions The assessment consisted in an average of the four measures Ratings varied from 1 to 10 according to the following parameters: 1 An additional set of animals (n=63) was exposed to the same pharmacological treatments and underwent conditioning but was killed after the last-conditioning session The brains of these mice were used for c-Fos immunocytochemistry For the shell region of nucleus accumbens (N Acc shell) the counting frame was 0.06 mm2 and was placed in the shell region using the most medial part of the anterior commissure as a vertical guide for the right side of the frame For the nucleus accumbens core (N Acc core) the counting frame was adjusted to the contour of the anterior commissure the lateral ventricle and the corpus callosum The size of the counting frame for the N Acc core was 0.18–0.20 mm2 Digital photomicrographs were taken after equalization using the corpus callosum as a blank and were examined with image analysis software (ImageTool Counting frames were applied to the regions under investigation and threshold intensity was set manually within a constant range to remove background and faint stain Positively immunolabelled cells were counted blind to the experimental treatments and results were expressed as density of c-Fos-positive cells (cells/mm2) for each of the regions studied Games–Howell (G–H) post hoc comparisons were made after ANOVA thus preserving the principles of normal distribution and homogeneity of variances Statistical significance was set at α=0.05 per experiment Effects of AHN-1055 on locomotor activity and c-Fos expression in the mouse striatum and comparison with a reference dose of cocaine Panel in (a) shows the time course of the effects induced by AHN-1055 (0 and 10 mg/kg) on locomotor activity over a 2 h period locomotor activity at several time points along the activity curves (a) although variations in accumulated scores (mean distance travelled per unit time) did not reach statistical significance (b) Induction of c-Fos in different striatal regions after treatment with AHN-1055 compared with the reference dose of cocaine (c Cocaine stimulated c-Fos expression in both ventral and dorsal striatum whereas the BZT analog was effective only in the DLst Digital photomicrographs of c-Fos expression in DLst after treatment with vehicle and the high dose of AHN-1055 are shown in (e) The schematic diagram in (e) depicts the striatal regions considered for quantification (*) indicates significant differences (p=0.05) from control values these observations show clear differences between AHN-1055 and cocaine in their ability to stimulate of c-Fos protein in the striatum and nomifensine (20 mg/kg) on cocaine-stimulated locomotor activity and motor stereotypy AHN-1055 reduced cocaine-induced hyperactivity (a b) without potentiating the expression of stereotyped behaviors (c) D-amphetamine showed more effectiveness that the BZT analog at stimulating locomotor activity (d e) and enhanced motor stereotypy evoked by cocaine treatment (f) without decreasing cocaine-induced locomotion (d Nomifensive decreased cocaine-stimulated locomotor activity (g h) but produced strong stereotypies after repeated administration (i) The scores for the five daily sessions are shown in (a and g) and the time course of effects in (b (*) indicates significant differences (p=0.05) from controls (#) indicates significant differences (p=0.05) from cocaine values the effects of AHN-1055 and nomifensine were clearly different with regards to the induction of motor stereotypy and 10 mg/kg) with cocaine on c-Fos induction in conditioned mice AHN-1055 did not increase c-Fos expression in any of the striatal regions investigated the BZT analog prevented cocaine-induced c-Fos expression in the N Acc core Digital photomicrographs of c-Fos expression in the ventral striatum after treatment with vehicle cocaine and the combination of the high dose of AHN-1055 with cocaine are shown in (c) (*) indicates significant differences (p=0.05) from control values and (#) indicates significant deviations (p=0.05) from cocaine values The suppressing effects of the BZT analog on cocaine-induced locomotor activity were homogeneous across sessions When we examined the data averaged for the four sessions we observed a significant inhibitory effect of the low dose of AHN-1055 (p<0.05 by N–K test) which was consistent through the 4 days of administration The high dose was stimulant during the first session but the mice developed tolerance to the activating effects of the BZT analog (data not shown) This finding is at variance with the results obtained in the earlier experiment in which high doses of AHN-1055 did not produce tolerance when administered daily It is noted that the BZT analog prevented the induction of c-Fos in the same regions where cocaine effectively produced significant elevations The design and synthesis of N-substituted BZT analogs has provided new tools to explore the functional correlates of DAT activity new avenues have been opened for reducing the adverse effects caused by the administration of cocaine and other stimulants with functional activity at the DAT These experiments provide an ample set of novel behavioral observations that characterize the behavioral and neurochemical effects of the BZT analog Albeit AHN-1055 and parent compounds were first synthesized more than a decade ago their potential as pharmacotherapies for cocaine addiction has not been sufficiently investigated in preclinical models The data presented showed by means of complementary experiments that the BZT analog despite its ability to bind with high affinity to the DAT does not behave as a classical psychomotor stimulant and the activating effects of cocaine on striatal early-gene expression as well as some clinically relevant behavioral correlates of cocaine administration including locomotor activity and conditioned reward the biphasic pattern of locomotor activity observed after treatment with AHN-1055 is unlike that observed after administration of classical psychomotor stimulants the BZT analog also differed from the DAT inhibitor nomifensine which attenuated cocaine-induced locomotor activity but induced by itself intense stereotypies after repeated exposure these data provide a clear behavioral demonstration that AHN-1055 differs from a prototypical psychomotor stimulant drug A novel finding of these experiments was that pretreatment with the BZT analog blocked cocaine-stimulated CPP It is noted that AHN-1055 also prevented in cocaine-conditioned mice the induction of early-gene activation in the N Acc and DMst a finding that provides insight into the neural mechanisms underlying the ability of AHN-1055 to largely suppress the unconditioned and conditioned effects of cocaine these findings highlight the possibility of designing novel compounds with affinity for the DAT which by virtue of their differential pharmacokinetic/dynamic profile and mode of interaction with the DAT might effectively antagonize the neuronal and behavioral actions of cocaine even if they function as dopamine transport inhibitors except for income received from our primary employers no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest Novel N-substituted 3 alpha-[bis(4′-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter Fos immunoreactivity after stimulation or inhibition of muscarinic receptors indicates anatomical specificity for cholinergic control of striatal efferent neurons and cortical neurons in the rat The binding sites for cocaine and dopamine in the dopamine transporter overlap A novel method for automatic quantification of psychostimulant-evoked route-tracing stereotypy: application to Mus musculus c-Fos and deltaFosB expression are differentially altered in distinct subregions of the nucleus accumbens shell in cocaine-sensitized rats Intermittent cortical stimulation evokes sensitization to cocaine and enduring changes in matrix and striosome neuron responsiveness The role of nigral and thalamic output pathways in the expression of oral stereotypies induced by amphetamine injections into the striatum A measure of striatal function predicts motor stereotypy Behavioural topography in the striatum: differential effects of quinpirole and D-amphetamine microinjections Dynamic dopamine receptor interactions in the core and shell of nucleus accumbens differentially coordinate the expression of unconditioned motor behaviors The nucleus accumbens and reward: neurophysiological investigations in behaving animals Behavioral effects of morphine and 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Rank transformations as a bridge between parametric and non-parametric statistics The Mouse Brain in Stereotaxic Coordinates Download references This work was supported by grants to JJC from Plan Nacional de Biomedicina (Ministerio de Ciencia e Innovación) Plan Nacional Sobre Drogas (Ministerio de Sanidad y Consumo) and FEPAD (Fundación para el Estudio y Prevención de las Adicciones y Drogodependencias CV-S is in receipt of a graduate student contract from Red de Trastornos Adictivos (RETICS We thank Alexandra Arcusa for technical assistance Biopsychology and Comparative Neuroscience Group University of Valencia-FGUV & Red de Trastornos Adictivos-RETICS Vicente Hernández-Rabaza & Juan J Canales Department of Pharmacology and Pharmaceutical Science Department of Organic and Inorganic Chemistry Download citation