Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity

Ciliary Neurotrophic Factor (CNTF) was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CNTF acts via receptors that are not only related to leptin receptors, but also similarly distributed within hypothalamic nuclei involved in feeding. However, although CNTF mimics the ability of leptin to cause fat loss in mice that are obese because of genetic deficiency of leptin (ob/ob mice), CNTF is also effective in diet-induced obesity models that are more representative of human obesity, and which are resistant to leptin. This discordance again raised the possibility that CNTF might be acting via nonleptin pathways, perhaps more analogous to those activated by cachectic cytokines. Arguing strongly against this possibility, we now show that CNTF can activate hypothalamic leptin-like pathways in diet-induced obesity models unresponsive to leptin, that CNTF improves prediabetic parameters in these models, and that CNTF acts very differently than the prototypical cachectic cytokine, IL-1. Further analyses of hypothalamic signaling reveals that CNTF can suppress food intake without triggering hunger signals or associated stress responses that are otherwise associated with food deprivation; thus, unlike forced dieting, cessation of CNTF treatment does not result in binge overeating and immediate rebound weight gain.

Flightless brown kiwis of New Zealand possess extremely subdivided population structure and cryptic species like small mammals.

Using allozymes and mtDNA sequences from the cytochrome b gene, we report that the brown kiwi has the highest levels of genetic structuring observed in birds. Moreover, the mtDNA sequences are, with two minor exceptions, diagnostic genetic markers for each population investigated, even though they are among the more slowly evolving coding regions in this genome. A major unexpected finding was the concordant split in molecular phylogenies between brown kiwis in the southern South Island and elsewhere in New Zealand. This basic phylogeographic boundary halfway down the South Island coincides with a fixed allele difference in the Hb nuclear locus and strongly suggests that two morphologically cryptic species are currently merged under one polytypic species. This is another striking example of how molecular genetic assays can detect phylogenetic discontinuities that are not reflected in traditional morphologically based taxonomies. However, reanalysis of the morphological characters by using phylogenetic methods revealed that the reason for this discordance is that most are primitive and thus are phylogenetically uninformative. Shared-derived morphological characters support the same relationships evident in the molecular phylogenies and, in concert with the molecular data, suggest that as brown kiwis colonized northward from the southern South Island, they retained many primitive characters that confounded earlier systematists. Strong subdivided population structure and cryptic species in brown kiwis seem to have evolved relatively recently as a consequence of Pleistocene range disjunctions, low dispersal power, and genetic drift in small populations.

46,XX doença do desenvolvimento sexual testicular : a propósito de um caso clínico

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

DAS GESPRÄCH ZWISCHEN HÖLDERLIN, HEGEL UND SCHELLING ÜBER KANTS ANTINOMIEN

«Die Art, wie er den Mechanismus der Natur mit ihrer Zweckmäßigkeit vereiniget, scheint mir eigentlich den ganzen Geist seines Systems zu enthalten»: This quotation, which originated the present essay, is solely extracted from a letter sent by Hölderlin to Hegel, and yet, it condensates three different approaches from the three Tübingen friends to the problem of Kant’s philosophy of religion and to its possible resolution between 1795 and 1796. From this epistolary dialogue emerges a simultaneous study of Kant, originated by the growing dissension towards the orthodox thought of the Stift. The turning point – or the maximum cumulative point – of this discordance happens precisely with the discovery of the «spirit of Kant’s system», as a combined explanation of the religious and philosophical phenomena [«Die Art, wie er den Mechanismus der Natur mit ihrer Zweckmässigkeit vereiniget»]. This, I think, is something which the three friends discover gradually and not independently from the concept of «providence», which Kant himself, according to Hölderlin, had used to «attenuate his antinomies», which Hegel uses in his first religious writings and the initial formation of his own philosophy and which Schelling will later explore in his System of Transcendental Idealism. In a word, providence is consensually the comprehension axis between man, God and nature and, thus, the explanatory link between the antinomical poles which regulate human existence. On the other hand, however – this being the aspect I would like to stress –, this decisive moment for a whole generation, for the history of philosophy itself, means the consummation of a new revolutionary perspective born in Kant, a new vision of the absolute and the divine and, therefore, a new way to write philosophy about philosophy, less philosophical than before, to the extent that the new situation of man and his reflection within the problem ultimately destined them – as is the case in the three young philosophers – to silence and death. The final aim of this essay is, therefore, to know what this «last step of philosophy» is and what dies along with it, what such a step may have meant and what it already foretold in terms of the development of philosophy.

EU Mission in Kosovo (EULEX): Constructing Ambiguity or Constructive Disunity? Transatlantic Security Paper No. 3, June 2011

In which skies should auspices about the future of EU foreign policy be looked for, Libya’s or Kosovo’s? Many commentators have been prompt in digging the grave for EU Security and Defense Policy after Member States’ discordance over taking military action against the Qaddafi regime1. However, as this paper will emphasize through the case of Kosovo, unanimity is not always an indispensable prerequisite – and should not be regarded as the sole criteria – to EU action in regional security. Overly focusing on the ‘speak with one voice’ mantra sometimes leads to stop short of assessing actual outcomes.

Bulk geochemistry, mass change and alteration intensity of basalts from ODP Leg 187 sites and survey dredges

Shipboard studies during Ocean Drilling Program Leg 187 (Australian Antarctic Discordance, AAD) suggested that there was no discernible coincidence between the interpreted age of rocks recovered and the intensity of alteration observed. Samples from the oldest sites occupied appeared to exhibit the least overall effects of alteration, and the intensity of alteration varied from site to site. Previous investigations of low-temperature alteration in oceanic basement samples have been restricted by the myopic perspective provided by single drill holes or dredge collections. Combining core samples from Leg 187 and dredge samples from the AAD collection at Oregon State University (USA) offers the unique opportunity to investigate mineral and bulk chemical changes attending alteration of basalt over a range of ages from 0 to 28 Ma. Results of this research indicate that there is a general increase in the intensity of alteration as the basalts age and mosve off axis, but that this relationship is somewhat veiled by the dominating control on alteration intensity dictated by variations in permeability.

Paleomagnetic and age determinations on rocks from Nares Strait

The Nares Strait controversy concerns the debate about whether or not a major sinistral transcurrent fault (the Wegener Fault) separates northern Greenland and Canada. To date no firm evidence has been found for the proposed 200 km sinistral offset, and to the contrary, geological correlations, mainly involving Paleozoic rocks across the Nares Strait, suggest that total left-lateral motion is no more than 70 km. The E-W trending Thule (Greenland) and Devon Island (Canada) dyke swarms lie on opposite sides of Baffin Bay and are offset sinistrally about 200 km, suggesting that if their correlation is established a convincing case for the Wegener Fault can be made. Paleomagnetic, geochemical and petrographic data allow, but do not yet establish, the correlation. Paleomagnetic results for Canadian sites (VGP = 6.9°N, 181.8 °E, A95 = 12.7°, N = 5) and Greenland sites (VGP = 11.5 °N, 178.3 °E, A95 = 13.8°, N = 4) are not significantly different at the 95 % confidence level. These levels are too large to resolve whether or not the Thule and Devon Island swarms have been offset. Geochemical data reveal a distinct and identical pattern in incompatible elements, while petrographically, the dykes are indistinguishable. U-Pb geochronological results for a Canadian dyke (720.2 ±2.0 Ma) and a Thule dyke (720.4 ±2.7 Ma) are identical within error and clearly identify the two sets of dykes as being parts of the same magmatic episode.

Patient Variability in Sciatic Nerve Branch Point Distance Using Ultrasound Guided Localization

Background and Objectives: Improved ultrasound and needle technology make popliteal sciatic nerve blockade a popular anesthetic technique and imaging to localize the branch point of the common peroneal and posterior tibial components is important because successful blockade techniques vary with respect to injection of the common trunk proximally or separate injections distally. Nerve stimulation, ultrasound, cadaveric and magnetic resonance studies demonstrate variability in distance and discordance between imaging and anatomic examination of the branch point. The popliteal crease and imprecise, inaccessible landmarks render measurement of the branch point variable and inaccurate. The purpose of this study was to use the tibial tuberosity, a fixed bony reference, to measure the distance of the branch point. Method: During popliteal sciatic nerve blockade in the supine position the branch point was identified by ultrasound and the block needle was inserted. The vertical distance from the tibial tuberosity prominence and needle insertion point was measured. Results: In 92 patients the branch point is a mean distance of 12.91 cm proximal to the tibial tuberosity and more proximal in male (13.74 cm) than female patients (12.08 cm). Body height is related to the branch point distance and is more proximal in taller patients. Separation into two nerve branches during local anesthetic injection supports notions of more proximal neural anatomic division. Limitations: Imaging of the sciatic nerve division may not equal its true anatomic separation. Conclusion: Refinements in identification and resolution of the anatomic division of the nerve branch point will determine if more accurate localization is of any clinical significance for successful nerve blockade.

Molecular analysis of the psa permease complex of Streptococcus pneumoniae

The psaBCA locus of Streptococcus pneumoniae encodes a putative ABC Mn2+-permease complex. Downstream of the operon is psaD, which may be co-transcribed and encodes a thiol peroxidase. Previously, there has been discordance concerning the phenotypic impact of mutations in the psa locus, resolution of which has been complicated by differences in mutant construction and the possibility of polar effects. Here, we constructed unmarked, in frame deletion mutants DeltapsaB, DeltapsaC, DeltapsaA, DeltapsaD, DeltapsaBC, DeltapsaBCA and DeltapsaBCAD in S. pneumoniae D39 to examine the role of each gene within the locus in Mn2+ uptake, susceptibility to oxidative stress, virulence, nasopharyngeal colonization and chain morphology. The requirement for Mn2+ for growth and transformation was also investigated for all mutants. Inductively coupled plasma mass spectrometry (ICP-MS) analysis provided the first direct evidence that PsaBCA is indeed a Mn2+ transporter. However, this study did not substantiate previous reports that the locus plays a role in choline-binding protein pro-duction or chain morphology. We also confirmed the importance of the Psa permease in systemic virulence and resistance to superoxide and hydrogen peroxide, as well as demonstrating a role in nasopharyngeal colonization for the first time. Further evi-dence is provided to support the requirement for Mn2+ supplementation for growth and transformation of DeltapsaB, DeltapsaC, DeltapsaA, DeltapsaBC, DeltapsaBCA and DeltapsaBCAD mutants. However, transformation, as well as growth, of the DeltapsaD mutant was not dependent upon Mn2+ supplementation. We also show that, apart from sensitivity to hydrogen peroxide, the DeltapsaD mutant exhibited essentially similar phenotypes to those of the wild type. Western blot analysis with a PsaD antiserum showed that deleting any of the genes upstream of psaD did not affect its expression. However, we found that deleting psaB resulted in decreased expression of PsaA relative to that in D39, whereas deleting both psaB and psaC resulted in at least wild-type levels of PsaA.

Increased DNA Methylation at the AXIN1 Gene in a Monozygotic Twin from a Pair Discordant for a Caudal Duplication Anomaly

The AXIN1 gene has been implicated in caudal duplication anomalies. Its coding region was sequenced in both members of a monozygotic ( MZ) twin pair discordant for a caudal duplication anomaly, but no mutation was found. Using bisulfite sequencing, we examined methylation at the promoter region of the AXIN1 gene in these twins and in twin and age-matched singleton controls. Methylation of the promoter region in peripheral blood mononucleated cells was variable among individuals, including MZ pairs. In the MZ pair discordant for the caudal duplication, this region of the affected twin was significantly more methylated than that of the unaffected twin (), which was significantly more P < .0001 methylated than those of the controls (). We have confirmed that this CpG island does function as a promoter P = .02 in vitro and that its activity is inversely proportional to the extent of methylation. This finding raises the possibility that hypermethylation of the AXIN1 promoter, by mechanisms as yet undetermined, is associated with the malformation. This case may be paradigmatic for some cases of MZ discordance.

Finding fact by using fiction

This study was to explore the psychoanalytic process that writers experience when they write memoirs. With psychoanalytic theory, the findings were that when writers compose memoirs which include repressed information, the writer's word choice or word block is heavily influenced by his/her own moral code. This idea led to the assertions that first, we are fragmented because of the discordance that arises between the structures of morality and language, the latter which includes good and evil; second, when we write memoirs, we must create a fictional identity that allows the different fragments of identity to operate under the illusion of continuity that language provides; and third, the language we use may transcend our repressed information into consciousness. The conclusion was that when past immoral truths are uncovered, the various fragments with their selfish aims and the fictional identity cease to exist in the wake of being. ^

Caracterização morfológica-sedimentar do vale inciso Apodi-Mossoró e plataforma continental adjacente - Bacia Potiguar Offshore

Systems of incised valleys have been studied in different continental shelves, including the Brazilian continental margin. The interest to characterize this feature is given by the information that it can provide variations on sea level, as well as the ability to host economically significant quantities of hydrocarbons in reservoirs located in deposits filling of the incised valleys. This thesis has the overall objective to characterize the morphology and sedimentary cover of the incised valley Apodi-Mossoró, located in the Northern Continental shelf of Rio Grande do Norte state, adjacent to Areia Branca city. The methodology included the integration of satellite imagery, bathymetric data, sedimentological data, shallow seismic, and the identification of foraminifera. The results indicate that the ApodiMossró incised valley is currently formed by two channels, shallow channel and deep channel, which have distinct morphological and sedimentological characteristics. The deep channel has connection with one of the heads of the Apodi Canyon, located in the slope area. The acquisition, processing and interpretation of shallow seismic data allowed the recognition of the depositional surface, erosional surface, discordance, and sismofaceis. The erosional surface mapped from shallow seismic sections is possibly a indicative of an ancient surface of valley incision, where it would probably be associated with the limit Pleistocene/Holocene. Different sismofaceis were identified and reflect the rise in sea level with standards sometimes agradacional, sometimes progradational. The thickness of sediments on this surface was estimated at a maximum of 22m thick in the central portion of the incised valley. Statistically, there are differences between the adjacent continental shelf and channels, and between these channels, for the content of calcium carbonate, organic matter, sand and mud perceptual, except for the gravel grain size. The analysis of living and dead foraminifera showed the presence of fifty species distributed in regards to morphology, depth and type of sediment. Four type of seismic echocharacteres were identified and mapped, as well as their bedforms, indicating different sedimentary processes along the incised valley. The integration of results suggests an activation of the Apodi-Mossoró incised valley in the Late Pleistocene.

Molecular analysis of evolutionary relationships of Phaseolus dumosus with the gene pool of common bean

Valuable genetic variation for bean breeding programs is held within the common bean secondary gene pool which consists of Phaseolus albescens, P. coccineus, P. costaricensis, and P. dumosus. However, the use of close relatives for bean improvement is limited due to the lack of knowledge about genetic variation and genetic plasticity of many of these species. Characterisation and analysis of the genetic diversity is necessary among beans' wild relatives; in addition, conflicting phylogenies and relationships need to be understood and a hypothesis of a hybrid origin of P. dumosus needs to be tested. This thesis research was orientated to generate information about the patterns of relationships among the common bean secondary gene pool, with particular focus on the species Phaseolus dumosus. This species displays a set of characteristics of agronomic interest, not only for the direct improvement of common bean but also as a source of valuable genes for adaptation to climate change. Here I undertake the first comprehensive study of the genetic diversity of P. dumosus as ascertained from both nuclear and chloroplast genome markers. A germplasm collection of the ancestral forms of P. dumosus together with wild, landrace and cultivar representatives of all other species of the common bean secondary gene pool, were used to analyse genetic diversity, phylogenetic relationships and structure of P. dumosus. Data on molecular variation was generated from sequences of cpDNA loci accD-psaI spacer, trnT-trnL spacer, trnL intron and rps14-psaB spacer and from the nrDNA the ITS region. A whole genome DArT array was developed and used for the genotyping of P. dumosus and its closes relatives. 4208 polymorphic markers were generated in the DArT array and from those, 742 markers presented a call rate >95% and zero discordance. DArT markers revealed a moderate genetic polymorphism among P. dumosus samples (13% of polymorphic loci), while P. coccineus presented the highest level of polymorphism (88% of polymorphic loci). At the cpDNA one ancestral haplotype was detected among all samples of all species in the secondary genepool. The ITS region of P. dumosus revealed high homogeneity and polymorphism bias to P. coccineus genome. Phylogenetic reconstructions made with Maximum likelihood and Bayesian methods confirmed previously reported discrepancies among the nuclear and chloroplast genomes of P. dumosus. The outline of relationships by hybridization networks displayed a considerable number of interactions within and between species. This research provides compelling evidence that P. dumosus arose from hybridisation between P. vulgaris and P. coccineus and confirms that P. costaricensis has likely been involved in the genesis or backcrossing events (or both) in the history of P. dumosus. The classification of the specie P. persistentus was analysed based on cpDNA and ITS sequences, the results found this species to be highly related to P. vulgaris but not too similar to P. leptostachyus as previously proposed. This research demonstrates that wild types of the secondary genepool carry a significant genetic variation which makes this a valuable genetic resource for common bean improvement. The DArT array generated in this research is a valuable resource for breeding programs since it has the potential to be used in several approaches including genotyping, discovery of novel traits, mapping and marker-trait associations. Efforts should be made to search for potential populations of P. persistentus and to increase the collection of new populations of P. dumosus, P. albescens and P. costaricensis that may provide valuable traits for introgression into common bean and other Phaseolus crops.