MicroRNA-122 modulates the rhythmic expression profile of the circadian deadenylase Nocturnin in mouse liver.

Nocturnin is a circadian clock-regulated deadenylase thought to control mRNA expression post-transcriptionally through poly(A) tail removal. The expression of Nocturnin is robustly rhythmic in liver at both the mRNA and protein levels, and mice lacking Nocturnin are resistant to diet-induced obesity and hepatic steatosis. Here we report that Nocturnin expression is regulated by microRNA-122 (miR-122), a liver specific miRNA. We found that the 3'-untranslated region (3'-UTR) of Nocturnin mRNA harbors one putative recognition site for miR-122, and this site is conserved among mammals. Using a luciferase reporter construct with wild-type or mutant Nocturnin 3'-UTR sequence, we demonstrated that overexpression of miR-122 can down-regulate luciferase activity levels and that this effect is dependent on the presence of the putative miR-122 recognition site. Additionally, the use of an antisense oligonucleotide to knock down miR-122 in vivo resulted in significant up-regulation of both Nocturnin mRNA and protein expression in mouse liver during the night, resulting in Nocturnin rhythms with increased amplitude. Together, these data demonstrate that the normal rhythmic profile of Nocturnin expression in liver is shaped in part by miR-122. Previous studies have implicated Nocturnin and miR-122 as important post-transcriptional regulators of both lipid metabolism and circadian clock controlled gene expression in the liver. Therefore, the demonstration that miR-122 plays a role in regulating Nocturnin expression suggests that this may be an important intersection between hepatic metabolic and circadian control.

Estudi de la connectivitat de l’illa de Menorca

Com a objectius generals: Analitzar la connectivitat ecològica a nivell paisatgístic de Menorca a partir d’una diagnosi que permeti determinar els espais d’interès connector i els punts crítics. Desenvolupar un pla d’acció amb propostes per millorar la connectivitat actual. Objectius específics: Aplicar una metodologia capaç de parametritzar els diferents conceptes relacionats amb la connectivitat ecològica i que sigui aplicable en la planificació territorial. Identificar els espais i elements d’interès per a la correcta circulació dels fluxos ecològics (flora i fauna) i socials, clau pel manteniment del paisatge i de la connectivitat funcional, definint connectors fluvials, espais naturals protegits, matrius (forestal, agrícola i urbana), unitats paisatgístiques, patrimoni arquitectònic i arqueològic, senders i camins ramaders, etc. que permetin determinar Espais o Elements d’Interès Estratègic per a la Connectivitat (EIEC). Definir els punts clau per a la connectivitat i identificar els punts crítics, on les barreres i els elements de fragmentació (carreteres, torrents, sòl urbà, etc.) intercepten els EIEC

Anti-Nogo-A Antibody Treatment Promotes Recovery of Manual Dexterity after Unilateral Cervical Lesion in Adult Primates--re-examination and Extension of Behavioral Data.

In rodents and nonhuman primates subjected to spinal cord lesion, neutralizing the neurite growth inhibitor Nogo-A has been shown to promote regenerative axonal sprouting and functional recovery. The goal of the present report was to re-examine the data on the recovery of the primate manual dexterity using refined behavioral analyses and further statistical assessments, representing secondary outcome measures from the same manual dexterity test. Thirteen adult monkeys were studied; seven received an anti-Nogo-A antibody whereas a control antibody was infused into the other monkeys. Monkeys were trained to perform the modified Brinkman board task requiring opposition of index finger and thumb to grasp food pellets placed in vertically and horizontally oriented slots. Two parameters were quantified before and following spinal cord injury: (i) the standard 'score' as defined by the number of pellets retrieved within 30 s from the two types of slots; (ii) the newly introduced 'contact time' as defined by the duration of digit contact with the food pellet before successful retrieval. After lesion the hand was severely impaired in all monkeys; this was followed by progressive functional recovery. Remarkably, anti-Nogo-A antibody-treated monkeys recovered faster and significantly better than control antibody-treated monkeys, considering both the score for vertical and horizontal slots (Mann-Whitney test: P = 0.05 and 0.035, respectively) and the contact time (P = 0.008 and 0.005, respectively). Detailed analysis of the lesions excluded the possibility that this conclusion may have been caused by differences in lesion properties between the two groups of monkeys.

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

Genetic and functional data indicate that variation in the expression of the neurotrophin-3 receptor gene (NTRK3) may have an impact on neuronal plasticity, suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNA (miRNA) posttranscriptional gene regulators act by base-pairing to specific sequence sites, usually at the 3'UTR of the target mRNA. Variants at these sites might result in gene expression changes contributing to disease susceptibility. We investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by resequencing their 3'UTRs in patients with panic disorder (PD), obsessive-compulsive disorder (OCD), and in controls. We have found the C allele of rs28521337, located in a functional target site for miR-485-3p in the truncated isoform of NTRK3, to be significantly associated with the hoarding phenotype of OCD. We have also identified two new rare variants in the 3'UTR of NTRK3, ss102661458 and ss102661460, each present only in one chromosome of a patient with PD. The ss102661458 variant is located in a functional target site for miR-765, and the ss102661460 in functional target sites for two miRNAs, miR-509 and miR-128, the latter being a brain-enriched miRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the miRNA-mediated regulation of NTRK3, resulting in recovery of gene expression. These data implicate miRNAs as key posttranscriptional regulators of NTRK3 and provide a framework for allele-specific miRNA regulation of NTRK3 in anxiety disorders.

Chroma binary similarity and local alignment applied to cover song identification

We present a new technique for audio signal comparison based on tonal subsequence alignment and its application to detect cover versions (i.e., different performances of the same underlying musical piece). Cover song identification is a task whose popularity has increased in the Music Information Retrieval (MIR) community along in the past, as it provides a direct and objective way to evaluate music similarity algorithms.This article first presents a series of experiments carried outwith two state-of-the-art methods for cover song identification.We have studied several components of these (such as chroma resolution and similarity, transposition, beat tracking or Dynamic Time Warping constraints), in order to discover which characteristics would be desirable for a competitive cover song identifier. After analyzing many cross-validated results, the importance of these characteristics is discussed, and the best-performing ones are finally applied to the newly proposed method. Multipleevaluations of this one confirm a large increase in identificationaccuracy when comparing it with alternative state-of-the-artapproaches.

Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice.

During the initial phases of type 1 diabetes, pancreatic islets are invaded by immune cells, exposing β-cells to proinflammatory cytokines. This unfavorable environment results in gene expression modifications leading to loss of β-cell functions. To study the contribution of microRNAs (miRNAs) in this process, we used microarray analysis to search for changes in miRNA expression in prediabetic NOD mice islets. We found that the levels of miR-29a/b/c increased in islets of NOD mice during the phases preceding diabetes manifestation and in isolated mouse and human islets exposed to proinflammatory cytokines. Overexpression of miR-29a/b/c in MIN6 and dissociated islet cells led to impairment in glucose-induced insulin secretion. Defective insulin release was associated with diminished expression of the transcription factor Onecut2, and a consequent rise of granuphilin, an inhibitor of β-cell exocytosis. Overexpression of miR-29a/b/c also promoted apoptosis by decreasing the level of the antiapoptotic protein Mcl1. Indeed, a decoy molecule selectively masking the miR-29 binding site on Mcl1 mRNA protected insulin-secreting cells from apoptosis triggered by miR-29 or cytokines. Taken together, our findings suggest that changes in the level of miR-29 family members contribute to cytokine-mediated β-cell dysfunction occurring during the initial phases of type 1 diabetes.

Recueil de lettres diplomatiques

Cet insha paraît d'origine indienne. On y trouve : - Une lettre du Nizam Shah à Shah Tahmasp (fol. 7 recto) ;- une lettre du Nizam Shah au Shir Shah de Dehli (fol. 19 recto) ; - Une lettre du roi de Perse Shah Tahmasp (fol. 22 verso) ;- un nishan du Nizam Shah adressé à un nommé Roumi Khan (fol. 27 recto) ; - un billet adressé par le vizir Ghiyas ed-Din Mohammed à Khvadjeh Sadr ed-Din Isfahani (fol. 30 recto) ;- une lette vraissemblablement adressée par un Nizam Shah à Djelal Khan Islam Shah (fol.31 verso) ; - Un billet adressé à Shah Kiwam ed-Din Nourbakhshi (ibid) ;Une lettre du Nizam Shah à l'émir Ghiyas ed-Din Mansour Shirazi (fol. 32 verso) ;- un feth nameh de Shah Hosein Nizam Shah (fol. 40 recto) ;Les premières et les dernières pages sont couvertes de notes parmi lesquels on trouve : - Fol. 3 recto : des vers de Sheikh Mohammed Gandjayi Tebrizi, de l'Imam Fakhr ed-Din, De Maulana Shems-i Mouzaffer, de Shah Rokh Houkmet el-Ain, la date de la mort du vizir Ghiyas ed-Din Mohammed Tebrizi, deux kasida de Molla Hosein Kerbalai Tebrizi et de Khvadjeh A Badamiyari.- Fol. 4 recto : des vers de Khvadjeh Mohammed Khoshnam, d'Afdal ed-Din Kermani, la préface du Divan de Zahir ed-Din Faryabi, la date de la mort de Shaeikh Mohammed Shirin Maghrebi.- Fol. 4 verso : des vers de Kemal-i Khodjendi avec la date de sa mort, celle de la mort du kadi Nedjm ed-Din Mohammed el-Uskubi, de Khvadjeh Djemal ed-Din Selman Savedji.- Fol. 5 recto : des vers de Kotb ed-Din Atiki, Mahmoud Shebisteri, Ala ed-Din Semnani, la date de la mort de Sheikh Diye Allah Kouzekznani, du Khvadjeh Ala ed-Din Tebrizi Nakshibendi, un nisham de Navab Abd Allah Khan Uzbek.- Fol. 6 : des vers de l'émir Seyyed Abd Allah Lala, de Saadi, Seyyed Ali Hamadani, de Fakh ed-Din Fath Allah Kazwini, de Fakhri Gourgani, Mantiki, Nedjm ed-Din Kakas Soureti, Moudjir ed-Din Berlakani, Louloui, Nizami Boukhari, un ghazel de Firdoussi, des vers de Rafik ed-Din Loubnani, Rokn ed-Din Imam Zadeh, Zeki Iraki.A la fin du volume on trouve des vers de Djami, de Assar, une notice sur les soufis.

Health care-associated native valve endocarditis: importance of non-nosocomial acquisition.

BACKGROUND: The clinical profile and outcome of nosocomial and non-nosocomial health care-associated native valve endocarditis are not well defined. OBJECTIVE: To compare the characteristics and outcomes of community-associated and nosocomial and non-nosocomial health care-associated native valve endocarditis. DESIGN: Prospective cohort study. SETTING: 61 hospitals in 28 countries. PATIENTS: Patients with definite native valve endocarditis and no history of injection drug use who were enrolled in the ICE-PCS (International Collaboration on Endocarditis Prospective Cohort Study) from June 2000 to August 2005. MEASUREMENTS: Clinical and echocardiographic findings, microbiology, complications, and mortality. RESULTS: Health care-associated native valve endocarditis was present in 557 (34%) of 1622 patients (303 with nosocomial infection [54%] and 254 with non-nosocomial infection [46%]). Staphylococcus aureus was the most common cause of health care-associated infection (nosocomial, 47%; non-nosocomial, 42%; P = 0.30); a high proportion of patients had methicillin-resistant S. aureus (nosocomial, 57%; non-nosocomial, 41%; P = 0.014). Fewer patients with health care-associated native valve endocarditis had cardiac surgery (41% vs. 51% of community-associated cases; P < 0.001), but more of the former patients died (25% vs. 13%; P < 0.001). Multivariable analysis confirmed greater mortality associated with health care-associated native valve endocarditis (incidence risk ratio, 1.28 [95% CI, 1.02 to 1.59]). LIMITATIONS: Patients were treated at hospitals with cardiac surgery programs. The results may not be generalizable to patients receiving care in other types of facilities or to those with prosthetic valves or past injection drug use. CONCLUSION: More than one third of cases of native valve endocarditis in non-injection drug users involve contact with health care, and non-nosocomial infection is common, especially in the United States. Clinicians should recognize that outpatients with extensive out-of-hospital health care contacts who develop endocarditis have clinical characteristics and outcomes similar to those of patients with nosocomial infection. PRIMARY FUNDING SOURCE: None.

A Musically aware system for browsing and interacting with audio music collections

In the context of the CompMusic project we are developing methods to automatically describe/annotate audio music recordings pertaining to various music cultures. As away to demonstrate the usefulness of the methods we are also developing a system to browse and interact with specific audio collections. The system is an online web application that interfaces with all the data gathered (audio, scores plus contextual information) and all the descriptions that are automatically generated with the developed methods. In this paper we present the basic architecture of the proposed system, the types of data sources that it includes,and we mention some of the culture specific issues that we are working on for its development. The system is in a preliminary stage but it shows the potential that MIR technologies can have in browsing and interacting with musiccollections of various cultures.

Opportunities for a cultural specific approach in the computational description of music

The current research in Music Information Retrieval (MIR) is showing the potential that the Information Technologies can have in music related applications. Amajor research challenge in that direction is how to automaticallydescribe/annotate audio recordings and how to use the resulting descriptions to discover and appreciate music in new ways. But music is a complex phenomenonand the description of an audio recording has to deal with this complexity. For example, each musicculture has specificities and emphasizes different musicaland communication aspects, thus the musical recordings of each culture should be described differently. At the same time these cultural specificities give us the opportunity to pay attention to musical concepts andfacets that, despite being present in most world musics, are not easily noticed by listeners. In this paper we present some of the work done in the CompMusic project, including ideas and specific examples on how to take advantage of the cultural specificities of differentmusical repertoires. We will use examples from the art music traditions of India, Turkey and China.

An integrated genomic and expression analysis of 7q deletion in splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterised by 7q32 deletion, but the target genes of this deletion remain unknown. In order to elucidate the genetic target of this deletion, we performed an integrative analysis of the genetic, epigenetic, transcriptomic and miRNomic data. High resolution array comparative genomic hybridization of 56 cases of SMZL delineated a minimally deleted region (2.8 Mb) at 7q32, but showed no evidence of any cryptic homozygous deletion or recurrent breakpoint in this region. Integrated transcriptomic analysis confirmed significant under-expression of a number of genes in this region in cases of SMZL with deletion, several of which showed hypermethylation. In addition, a cluster of 8 miRNA in this region showed under-expression in cases with the deletion, and three (miR-182/96/183) were also significantly under-expressed (P<0.05) in SMZL relative to other lymphomas. Genomic sequencing of these miRNA and IRF5, a strong candidate gene, did not show any evidence of somatic mutation in SMZL. These observations provide valuable guidance for further characterisation of 7q deletion.

Fate of rubrospinal neurons after unilateral section of the cervical spinal cord in adult macaque monkeys: effects of an antibody treatment neutralizing Nogo-A.

The present study describes in primates the effects of a spinal cord injury on the number and size of the neurons in the magnocellular part of the red nucleus (RNm), the origin of the rubrospinal tract, and evaluates whether a neutralization of Nogo-A reduces the lesioned-induced degenerative processes observed in RNm. Two groups of monkeys were subjected to unilateral section of the spinal cord affecting the rubrospinal tract; one group was subsequently treated with an antibody neutralizing Nogo-A; the second group received a control antibody. Intact animals were also included in the study. Counting neurons stained with a monoclonal antibody recognizing non-phosphorylated epitopes on neurofilaments (SMI-32) indicated that their number in the contralesional RNm was consistently inferior to that in the ipsilesional RNm, in a proportion amounting up to 35%. The lesion also induced shrinkage of the soma of the neurons detected in the contralesional RNm. Infusing an anti-Nogo-A antibody at the site of the lesion did not increase the proportion of SMI-32 positive rubrospinal neurons in the contralesional RNm nor prevent shrinkage.

La Investigació farmacèutica i les seves dues realitats : malària vs. hipertensió

El món està mal repartit, això és evident. La qüestió és: fins a quin punt? El treball que segueix a continuació pretén estudiar aquest mal repartiment a través d'un àmbit concret: el de la indústria farmacèutica.Els recursos per a la investigació farmacèutica sovint es destinen a finalitats que estan lluny d'aconseguir benestar pel màxim nombre de persones possible. En canvi, es destinen allà on hi ha més possibilitat d'obtenir uns elevats rendiments econòmics. Malgrat no haver-hi dades concretes que evidenciïn aquest fet, sí que n'hi ha d'indirectes que ens ajudaran a esbrinar-ho.En l'estudi es posa en evidència les enormes discriminacions que pateixen diferents tipus de malalties, així com també algunes solucions que permetrien arreglar el problema, però que no es duen a terme. A més, ens endinsem en el món de la indústria farmacèutica a partir de dos països i dues malalties que mostren de primera mà la situació de la indústria farmacèutica mundial.

La dependència econòmica des estudiants : comparació entre dues universitats públiques

Com a estudiants tenim moltes obligacions i la universitat ens absorbeix gran part del temps. És freqüent que en nosaltres sorgeixin inquietuds sobre quina seria la nostra situació si estiguéssim en una altra universitat o context que ens donés més marge d’autonomia i poguéssim, per exemple, dedicar part del nostre temps a treballar i obtenir ingressos. Per tant, la nostra percepció és que la majoria d’estudiants universitaris ho podem ser perquè darrere tenim una família que ens dóna suport en l’aspecte econòmic. Estudiar, entre altres coses, representa una inversió. Una inversió de temps el cost d’oportunitat de la qual és igual al total d’ingressos que podríem obtenir durant els anys que duren els estudis. No obstant, aquest elevat cost d’oportunitat es veu recompensat un cop acabats els estudis en forma d’una remuneració superior a aquest. Però, ha d’implicar sempre això? És obligatori renunciar a uns ingressos per tal de poder-se formar? La societat està interessada en que estudiem, però, dóna recursos per a que ho fem? Quines són les opcions que tenim els estudiants per a poder assolir una certa independència econòmica? Quin paper hi juga la universitat? En quin grau influeix el model d’universitat en el grau de dependència?Estudiem en una universitat, la UPF, la filosofia de la qual és que els estudiants han de ser-ho a temps complert, evitant que treballin mentre cursen la carrera:“Els plans d’estudis, dissenyats a partir de […], l’alta exigència acadèmica i de superació personal, la dedicació completa…” (www.upf.edu)La qualitat dels estudis es relaciona directament amb la dedicació absoluta. És difícil objectar el fet que quant més temps es dedica als estudis, millors són els resultats. No obstant i desgraciadament, no tothom pot permetre’s el luxe de invertir el cent per cent del seu temps als estudis i no treballar. El Pacte Internacional pels Drets Econòmics, Socials i Culturals de la ONU ratificat el 1966 i que va entrar en vigor l’any 1976, defensa, a l’article 13, el dret de tota persona a l’educació: “La enseñanza primaria debe ser obligatoria y accesible a todos gratuitamente"; “La enseñanza secundaria, en sus diferentes formas, incluso la enseñanza secundaria técnica y profesional, debe ser generalizada y hacerse accesible a todos, por cuantos medios sean apropiados, y en particular por la implantación progresiva de la enseñanza gratuita" “La enseñanza superior debe hacerse igualmente accesible a todos, sobre la base de la capacidad de cada uno, por cuantos medios sean apropiados, y en particular por la implantación progresiva de la enseñanza gratuita"En aquest treball hem volgut estudiar quins factors influeixen i de quina manera en la independència econòmica que pot assolir un estudiant. Hem volgut donar un fort èmfasi a l’àmbit universitari a l’hora de fer el treball ja que com a estudiants ens trobem en ple procés formatiu i aquesta té un pes rellevant en les nostres vides quotidianes, sobretot en matèria de temps i dedicació.

Circulating microRNAs as biomarkers for detection of autologous blood transfusion.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate various biological processes. Cell-free miRNAs measured in blood plasma have emerged as specific and sensitive markers of physiological processes and disease. In this study, we investigated whether circulating miRNAs can serve as biomarkers for the detection of autologous blood transfusion, a major doping technique that is still undetectable. Plasma miRNA levels were analyzed using high-throughput quantitative real-time PCR. Plasma samples were obtained before and at several time points after autologous blood transfusion (blood bag storage time 42 days) in 10 healthy subjects and 10 controls without transfusion. Other serum markers of erythropoiesis were determined in the same samples. Our results revealed a distinct change in the pattern of circulating miRNAs. Ten miRNAs were upregulated in transfusion samples compared with control samples. Among these, miR-30b, miR-30c, and miR-26b increased significantly and showed a 3.9-, 4.0-, and 3.0-fold change, respectively. The origin of these miRNAs was related to pulmonary and liver tissues. Erythropoietin (EPO) concentration decreased after blood reinfusion. A combination of miRNAs and EPO measurement in a mathematical model enhanced the efficiency of autologous transfusion detection through miRNA analysis. Therefore, our results lay the foundation for the development of miRNAs as novel blood-based biomarkers to detect autologous transfusion.