GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons

Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia

Search for composite and exotic fermions at LEP 2

A search for unstable heavy fermions with the DELPHI detector at LEP is reported. Sequential and non-canonical leptons, as well as excited leptons and quarks, are considered. The data analysed correspond to an integrated luminosity of about 48 pb^{-1} at an e^+e^- centre-of-mass energy of 183 GeV and about 20 pb^{-1} equally shared between the centre-of-mass energies of 172 GeV and 161 GeV. The search for pair-produced new leptons establishes 95% confidence level mass limits in the region between 70 GeV/c^2 and 90 GeV/c^2, depending on the channel. The search for singly produced excited leptons and quarks establishes upper limits on the ratio of the coupling of the excited fermio

Search for charginos in e+e- interactions at sqrt(s) = 189 GeV

An update of the searches for charginos and gravitinos is presented, based on a data sample corresponding to the 158 pb^{-1} recorded by the DELPHI detector in 1998, at a centre-of-mass energy of 189 GeV. No evidence for a signal was found. The lower mass limits are 4-5 GeV/c^2 higher than those obtained at a centre-of-mass energy of 183 GeV. The (\mu,M_2) MSSM domain excluded by combining the chargino searches with neutralino searches at the Z resonance implies a limit on the mass of the lightest neutralino which, for a heavy sneutrino, is constrained to be above 31.0 GeV/c^2 for tan(beta) \geq 1.Comment: 22 pages, 8 figure

Search for lightest neutralino and stau pair production in light gravitino scenarios with stau NLSP

Promptly decaying lightest neutralinos and long-lived staus are searched for in the context of light gravitino scenarios. It is assumed that the stau is the next to lightest supersymmetric particle (NLSP) and that the lightest neutralino is the next to NLSP (NNLSP). Data collected with the Delphi detector at centre-of-mass energies from 161 to 183 \GeV are analysed. No evidence of the production of these particles is found. Hence, lower mass limits for both kinds of particles are set at 95% C.L.. The mass of gaugino-like neutralinos is found to be greater than 71.5 GeV/c^2. In the search for long-lived stau, masses less than 70.0 to 77.5 \GeVcc are excluded for gravitino masses from 10 to 150 \eVcc . Combining this search with the searches for stable heavy leptons and Minimal Supersymmetric Standard Model staus a lower limit of 68.5 \GeVcc may be set for the stau mas

Hadronization properties of b quarks compared to light quarks in e+e- -> q qbar from 183 to 200 GeV

The DELPHI detector at LEP has collected 54 pb^{-1} of data at a centre-of-mass energy around 183 GeV during 1997, 158 pb^{-1} around 189 GeV during 1998, and 187 pb^{-1} between 192 and 200 GeV during 1999. These data were used to measure the average charged particle multiplicity in e+e- -> b bbar events, _{bb}, and the difference delta_{bl} between _{bb} and the multiplicity, _{ll}, in generic light quark (u,d,s) events: delta_{bl}(183 GeV) = 4.55 +/- 1.31 (stat) +/- 0.73 (syst) delta_{bl}(189 GeV) = 4.43 +/- 0.85 (stat) +/- 0.61 (syst) delta_{bl}(200 GeV) = 3.39 +/- 0.89 (stat) +/- 1.01 (syst). This result is consistent with QCD predictions, while it is inconsistent with calculations assuming that the multiplicity accompanying the decay of a heavy quark is independent of the mass of the quark itself.Comment: 13 pages, 2 figure

Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions

Most monogenic disorders have a primary clinical presentation. Inherited ISG15 deficiency, however, has manifested with two distinct presentations to date: susceptibility to mycobacterial disease and intracranial calcifications from hypomorphic interferon-II (IFN-II) production and excessive IFN-I response, respectively. Accordingly, these patients were managed for their infectious and neurologic complications. Herein, we describe five new patients with six novel ISG15 mutations presenting with skin lesions who were managed for dermatologic disease. Cellularly, we denote striking specificity to the IFN-I response, which was previously assumed to be universal. In peripheral blood, myeloid cells display the most robust IFN-I signatures. In the affected skin, IFN-I signaling is observed in the keratinocytes of the epidermis, endothelia, and the monocytes and macrophages of the dermis. These findings define the specific cells causing circulating and dermatologic inflammation and expand the clinical spectrum of ISG15 deficiency to dermatologic presentations as a third phenotype co-dominant to the infectious and neurologic manifestations.Fil: Martin Fernandez, Marta. Icahn School Of Medicine At Mount Sinai; Estados Unidos. King Saud University; Arabia SauditaFil: Bravo García Morato, María. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Gruber, Conor. Icahn School Of Medicine At Mount Sinai; Estados Unidos. King Saud University; Arabia SauditaFil: Murias Loza, Sara. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Malik, Muhammad Nasir Hayat. Twincore; Alemania. University Of Lahore; Países Bajos. Leibniz Universitat Hannover; Alemania. Helmholtz Gemeinschaft; AlemaniaFil: Alsohime, Fahad. King Saud University; Arabia SauditaFil: Alakeel, Abdullah. King Saud University; Arabia SauditaFil: Valdez, Rita. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Buta, Sofija. Icahn School Of Medicine At Mount Sinai; Estados UnidosFil: Buda, Guadalupe. Bitgenia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Biología Celular e Histología; ArgentinaFil: Marti, Marcelo Adrian. Bitgenia; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Biología Celular e Histología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Larralde, Margarita. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Boisson, Bertrand. L'institut Des Maladies Génétiques Imagine; Francia. The Rockefeller University; Estados Unidos. Universite de Paris; FranciaFil: Feito Rodriguez, Marta. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Qiu, Xueer. Icahn School Of Medicine At Mount Sinai; Estados UnidosFil: Chrabieh, Maya. L'institut Des Maladies Génétiques Imagine; FranciaFil: Al Ayed, Mohammed. Najran University; Arabia SauditaFil: Al Muhsen, Saleh. King Saud University; Arabia SauditaFil: Desai, Jigar V.. National Institutes of Health; Estados UnidosFil: Ferre, Elise M.N.. National Institutes of Health; Estados UnidosFil: Rosenzweig, Sergio D.. National Institutes of Health; Estados UnidosFil: Amador-Borrero, Blanca. Icahn School Of Medicine At Mount Sinai; Estados UnidosFil: Bravo-Gallego, Luz Yadira. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Olmer, Ruth. Hannover Medical School; Alemania. German Center for Lung Research; AlemaniaFil: Merkert, Sylvia. Hannover Medical School; Alemania. German Center for Lung Research; AlemaniaFil: Bret, Montserrat. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Sood, Amika K.. University of North Carolina; Estados UnidosFil: Al-rabiaah, Abdulkarim. King Saud University; Arabia SauditaFil: Temsah, Mohamad Hani. King Saud University; Arabia SauditaFil: Halwani, Rabih. University of Sharjah; Emiratos Arabes UnidosFil: Hernandez, Michelle Marilyn. University of North Carolina; Estados UnidosFil: Pessler, Frank. Twincore; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Casanova, Jean Laurent. The Rockefeller University; Estados Unidos. Necker Hospital for Sick Children; Francia. Howard Hughes Medical Institute; Estados Unidos. Universite de Paris; FranciaFil: Bustamante, Jacinta. The Rockefeller University; Estados Unidos. Necker Hospital for Sick Children; Francia. Universite de Paris; FranciaFil: Lionakis, Michail S.. National Institutes of Health; Estados UnidosFil: Bogunovic, Dusan. Icahn School Of Medicine At Mount Sinai; Estados Unido

Assessment of the Anthelmintic Efficacy of Albendazole in School Children in Seven Countries Where Soil-Transmitted Helminths Are Endemic

Soil-transmitted helminths (roundworms, whipworms and hookworms) infect millions of children in (sub)tropical countries, resulting in malnutrition, growth stunting, intellectual retardation and cognitive deficits. Currently, there is a need to closely monitor anthelmintic drug efficacy and to develop standard operating procedures, as highlighted in a World Health Organization–World Bank meeting on “Monitoring of Drug Efficacy in Large Scale Treatment Programs for Human Helminthiasis” in Washington DC at the end of 2007. Therefore, we have evaluated the efficacy of a commonly used treatment against these parasitic infections in school children in Africa, Asia and South-America using a standardized protocol. In addition, different statistical approaches to analyzing the data were evaluated in order to develop standardized procedures for data analysis. The results demonstrate that the applied treatment was highly efficacious against round- and hookworms, but not against whipworms. However, there was large variation in efficacy across the different trials which warrants further attention. This study also provides new insights into the statistical analysis of efficacy data, which should be considered in future monitoring and evaluation studies of large scale anthelmintic treatment programs. Finally, our findings emphasize the need to update the World Health Organization recommended efficacy threshold for the treatment of STH

Gene Expression Profiling of Two Distinct Neuronal Populations in the Rodent Spinal Cord

BACKGROUND: In the field of neuroscience microarray gene expression profiles on anatomically defined brain structures are being used increasingly to study both normal brain functions as well as pathological states. Fluorescent tracing techniques in brain tissue that identifies distinct neuronal populations can in combination with global gene expression profiling potentially increase the resolution and specificity of such studies to shed new light on neuronal functions at the cellular level. METHODOLOGY/PRINCIPAL FINDINGS: We examine the microarray gene expression profiles of two distinct neuronal populations in the spinal cord of the neonatal rat, the principal motor neurons and specific interneurons involved in motor control. The gene expression profiles of the respective cell populations were obtained from amplified mRNA originating from 50-250 fluorescently identified and laser microdissected cells. In the data analysis we combine a new microarray normalization procedure with a conglomerate measure of significant differential gene expression. Using our methodology we find 32 genes to be more expressed in the interneurons compared to the motor neurons that all except one have not previously been associated with this neuronal population. As a validation of our method we find 17 genes to be more expressed in the motor neurons than in the interneurons and of these only one had not previously been described in this population. CONCLUSIONS/SIGNIFICANCE: We provide an optimized experimental protocol that allows isolation of gene transcripts from fluorescent retrogradely labeled cell populations in fresh tissue, which can be used to generate amplified aRNA for microarray hybridization from as few as 50 laser microdissected cells. Using this optimized experimental protocol in combination with our microarray analysis methodology we find 49 differentially expressed genes between the motor neurons and the interneurons that reflect the functional differences between these two cell populations in generating and transmitting the motor output in the rodent spinal cord

Updated precision measurement of the average lifetime of B hadrons

The measurement of the average lifetime of B hadrons using inclusively reconstructed secondary vertices has been updated using both an improved processing of previous data and additional statistics from new data. This has reduced the statistical and systematic uncertainties and gives \tau_{\mathrm{B}} = 1.582 \pm 0.011\ \mathrm{(stat.)} \pm 0.027\ \mathrm{(syst.)}\ \mathrm{ps.} Combining this result with the previous result based on charged particle impact parameter distributions yields \tau_{\mathrm{B}} = 1.575 \pm 0.010\ \mathrm{(stat.)} \pm 0.026\ \mathrm{(syst.)}\ \mathrm{ps.

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon