Well-Behavior, Well-Posedness and Nonsmooth Analysis

AMS subject classification: 90C30, 90C33.

Implicit task sequence learning in patients with Parkinson's disease, frontal lesions and amnesia: The critical role of fronto–striatal loops

The purpose of this study was to investigate the role of the fronto–striatal system for implicit task sequence learning. We tested performance of patients with compromised functioning of the fronto–striatal loops, that is, patients with Parkinson's disease and patients with lesions in the ventromedial or dorsolateral prefrontal cortex. We also tested amnesic patients with lesions either to the basal forebrain/orbitofrontal cortex or to thalamic/medio-temporal regions. We used a task sequence learning paradigm involving the presentation of a sequence of categorical binary-choice decision tasks. After several blocks of training, the sequence, hidden in the order of tasks, was replaced by a pseudo-random sequence. Learning (i.e., sensitivity to the ordering) was assessed by measuring whether this change disrupted performance. Although all the patients were able to perform the decision tasks quite easily, those with lesions to the fronto–striatal loops (i.e., patients with Parkinson's disease, with lesions in the ventromedial or dorsolateral prefrontal cortex and those amnesic patients with lesions to the basal forebrain/orbitofrontal cortex) did not show any evidence of implicit task sequence learning. In contrast, those amnesic patients with lesions to thalamic/medio-temporal regions showed intact sequence learning. Together, these results indicate that the integrity of the fronto–striatal system is a prerequisite for implicit task sequence learning.

Critical reappraisal of Late Mesozoic-Cenozoic Central and North Atlantic, Caribbean and Mediterranean evolution

(l) The Pacific basin (Pacific area) may be regarded as moving eastwards like a double zip fastener relative to the continents and their respective plates (Pangaea area): opening in the East and closing in the West. This movement is tracked by a continuous mountain belt, the collision ages of which increase westwards. (2) The relative movements between the Pacific area and the Pangaea area in the W-EfE-W direction are generated by tidal forces (principle of hypocycloid gearing), whereby the lower mantle and the Pacific basin or area (Pacific crust = roof of the lower mantle?) rotate somewhat faster eastwards around the Earth's spin axis relative to the upper mantle/crust system with the continents and their respective plates (Pangaea area) (differential rotation). (3) These relative West to East/East to West displacements produce a perpetually existing sequence of distinct styles of opening and closing oeean basins, exemplified by the present East to West arrangement of ocean basins around the globe (Oceanic or Wilson Cycle: Rift/Red Sea style; Atlantic style; Mediterranean/Caribbean style as eastwards propagating tongue of the Pacific basin; Pacific style; Collision/Himalayas style). This sequence of ocean styles, of which the Pacific ocean is a part, moves eastwards with the lower mantle relative to the continents and the upper-mantle/crust of the Pangaea area. (4) Similarly, the collisional mountain belt extending westwards from the equator to the West of the Pacific and representing a chronological sequence of collision zones (sequential collisions) in the wake of the passing of the Pacific basin double zip fastener, may also be described as recording the history of oceans and their continental margins in the form of successive Wilson Cycles. (5) Every 200 to 250 m.y. the Pacific basin double zip fastener, the sequence of ocean styles of the Wilson Cycle and the eastwards growing collisional mountain belt in their wake complete one lap around the Earth. Two East drift lappings of 400 to 500 m.y. produce a two-lap collisional mountain belt spiral around a supercontinent in one hemisphere (North or South Pangaea). The Earth's history is subdivided into alternating North Pangaea growth/South Pangaea breakup eras and South Pangaea growth/North Pangaea breakup eras. Older North and South Pangaeas and their collisional mountain belt spirals may be reconstructed by rotating back the continents and orogenic fragments of a broken spiral (e.g. South Pangaea, Gondwana) to their previous Pangaea growth era orientations. In the resulting collisional mountain belt spiral, pieced together from orogenic segments and fragments, the collision ages have to increase successively towards the West. (6) With its current western margin orientated in a West-East direction North America must have collided during the Late Cretaceous Laramide orogeny with the northern margin of South America (Caribbean Andes) at the equator to the West of the Late Mesozoic Pacific. During post-Laramide times it must have rotated clockwise into its present orientation. The eastern margin of North America has never been attached to the western margin of North Africa but only to the western margin of Europe. (7) Due to migration eastwards of the sequence of ocean styles of the Wilson Cycle, relative to a distinct plate tectonic setting of an ocean, a continent or continental margin, a future or later evolutionary style at the Earth's surface is always depicted in a setting simultaneously developed further to the West and a past or earlier style in a setting simultaneously occurring further to the East. In consequence, ahigh probability exists that up to the Early Tertiary, Greenland (the ArabiaofSouth America?) occupied a plate tectonic setting which is comparable to the current setting of Arabia (the Greenland of Africa?). The Late Cretaceous/Early Tertiary Eureka collision zone (Eureka orogeny) at the northern margin of the Greenland Plate and on some of the Canadian Arctic Islands is comparable with the Middle to Late Tertiary Taurus-Bitlis-Zagros collision zone at the northern margin of the Arabian Plate.

Critical reappraisal of Late Mesozoic-Cenozoic Central and North Atlantic, Caribbean and Mediterranean evolution

(l) The Pacific basin (Pacific area) may be regarded as moving eastwards like a double zip fastener relative to the continents and their respective plates (Pangaea area): opening in the East and closing in the West. This movement is tracked by a continuous mountain belt, the collision ages of which increase westwards. (2) The relative movements between the Pacific area and the Pangaea area in the W-E/E-W direction are generated by tidal forces (principle of hypocycloid gearing), whereby the lower mantle and the Pacific basin or area (Pacific crust = roof of the lower mantle?) rotate somewhat faster eastwards around the Earth's spin axis relative to the upper mantle/crust system with the continents and their respective plates (Pangaea area) (differential rotation). (3) These relative West to East/East to West displacements produce a perpetually existing sequence of distinct styles of opening and closing ocean basins, exemplified by the present East to West arrangement of ocean basins around the globe (Oceanic or Wilson Cycle: Rift/Red Sea style; Atlantic style; Mediterranean/Caribbean style as eastwards propagating tongue of the Pacific basin; Pacific style; Collision/Himalayas style). This sequence of ocean styles, of which the Pacific ocean is a part, moves eastwards with the lower mantle relative to the continents and the upper-mantle/crust of the Pangaea area. (4) Similarly, the collisional mountain belt extending westwards from the equator to the West of the Pacific and representing a chronological sequence of collision zones (sequential collisions) in the wake of the passing of the Pacific basin double zip fastener, may also be described as recording the history of oceans and their continental margins in the form of successive Wilson Cycles. (5) Every 200 to 250 m.y. the Pacific basin double zip fastener, the sequence of ocean styles of the Wilson Cycle and the eastwards growing collisional mountain belt in their wake complete one lap around the Earth. Two East drift lappings of 400 to 500 m.y. produce a two-lap collisional mountain belt spiral around a supercontinent in one hemisphere (North or South Pangaea). The Earth's history is subdivided into alternating North Pangaea growth/South Pangaea breakup eras and South Pangaea growth/North Pangaea breakup eras. Older North and South Pangaeas and their collisional mountain belt spirals may be reconstructed by rotating back the continents and orogenic fragments of a broken spiral (e.g. South Pangaea, Gondwana) to their previous Pangaea growth era orientations. In the resulting collisional mountain belt spiral, pieced together from orogenic segments and fragments, the collision ages have to increase successively towards the West. (6) With its current western margin orientated in a West-East direction North America must have collided during the Late Cretaceous Laramide orogeny with the northern margin of South America (Caribbean Andes) at the equator to the West of the Late Mesozoic Pacific. During post-Laramide times it must have rotated clockwise into its present orientation. The eastern margin of North America has never been attached to the western margin of North Africa but only to the western margin of Europe. (7) Due to migration eastwards of the sequence of ocean styles of the Wilson Cycle, relative to a distinct plate tectonic setting of an ocean, a continent or continental margin, a future or later evolutionary style at the Earth's surface is always depicted in a setting simultaneously developed further to the West and a past or earlier style in a setting simultaneously occurring further to the East. In consequence, ahigh probability exists that up to the Early Tertiary, Greenland (the ArabiaofSouth America?) occupied a plate tectonic setting which is comparable to the current setting of Arabia (the Greenland of Africa?). The Late Cretaceous/Early Tertiary Eureka collision zone (Eureka orogeny) at the northern margin of the Greenland Plate and on some of the Canadian Arctic Islands is comparable with the Middle to Late Tertiary Taurus-Bitlis-Zagros collision zone at the northern margin of the Arabian Plate.

Media(ted) discourse and society: rethinking the framework of critical discourse analysis

The analysis of journalistic discourse and its social embeddedness has known significant advances in the last two decades, especially due to the emergence and development of Critical Discourse Analysis. However, three important aspects remain under-researched: the time plane in discourse analysis, the discursive strategies of social actors, and the extra- and supra-textual effects of mediated discourse. Firstly, understanding the biography of public matters requires a longitudinal examination of mediated texts and their social contexts but most forms of analysis of journalistic discourse do not account for the time sequence of texts and its implications. Secondly, as the media representation of social issues is, to a large extent, a function of the discursive construction of events, problems and positions by social actors, the discursive strategies that they employ in a variety of arenas and channels ‘‘before’’ and ‘‘after’’ journalistic texts need to be examined. Thirdly, the fact that many of the modes of operation of discourse are extra- or supra-textual calls for a consideration of various social processes ‘‘outside’’ the text. This paper aims to produce a theoretical and methodological contribution to the integration of these issues in discourse analysis by proposing a framework that combines a textual dimension with a contextual one

Real-Time decision support using data mining to predict blood pressure critical events in intensive medicine patients

Patient blood pressure is an important vital signal to the physicians take a decision and to better understand the patient condition. In Intensive Care Units is possible monitoring the blood pressure due the fact of the patient being in continuous monitoring through bedside monitors and the use of sensors. The intensivist only have access to vital signs values when they look to the monitor or consult the values hourly collected. Most important is the sequence of the values collected, i.e., a set of highest or lowest values can signify a critical event and bring future complications to a patient as is Hypotension or Hypertension. This complications can leverage a set of dangerous diseases and side-effects. The main goal of this work is to predict the probability of a patient has a blood pressure critical event in the next hours by combining a set of patient data collected in real-time and using Data Mining classification techniques. As output the models indicate the probability (%) of a patient has a Blood Pressure Critical Event in the next hour. The achieved results showed to be very promising, presenting sensitivity around of 95%.

Macrophage migration inhibitory factor: a counter-regulator of glucocorticoid action and critical mediator of septic shock.

Recent studies have led to the discovery of a mediator that acts as an endogenous counter-regulator of glucocorticoid action within the immune system. Isolated as a product of anterior pituitary cells, this protein was found to have the sequence of macrophage migration inhibitory factor (MIF), one of the first cytokine activities to be described. Macrophages and T cells release MIF in response both to various inflammatory stimuli and upon incubation with low concentrations of glucocorticoids. The glucocorticoid-induced secretion of MIF is tightly regulated and decreases at high, anti-inflammatory steroid concentrations. Once secreted, MIF "overrides" the anti-inflammatory and immunosuppressive effects of steroids on macrophage and T-cell cytokine production. The physiological role of MIF thus appears to be to counter-balance steroid inhibition of the inflammatory response. Anti-MIF antibodies fully protect animals from experimentally induced gram-negative or gram-positive septic shock, an effect that may be the result of the increased anti-inflammatory effects of glucocorticoids after neutralization of endogenous MIF. Anti-MIF therapeutic strategies are presently under development and may prove to be a means to modulate cytokine production in septic shock as well as in other inflammatory disease states.

Ezrin-Radixin-Moesin-binding Sequence of PSGL-1 Glycoprotein Regulates Leukocyte Rolling on Selectins and Activation of Extracellular Signal-regulated Kinases.

P-selectin glycoprotein ligand-1 (PSGL-1) mediates the capture (tethering) of free-flowing leukocytes and subsequent rolling on selectins. PSGL-1 interactions with endothelial selectins activate Src kinases and spleen tyrosine kinase (Syk), leading to α(L)β(2) integrin-dependent leukocyte slow rolling, which promotes leukocyte recruitment into tissues. In addition, but through a distinct pathway, PSGL-1 engagement activates ERK. Because ezrin, radixin and moesin proteins (ERMs) link PSGL-1 to actin cytoskeleton and because they serve as adaptor molecules between PSGL-1 and Syk, we examined the role of PSGL-1 ERM-binding sequence (EBS) on cell capture, rolling, and signaling through Syk and MAPK pathways. We carried out mutational analysis and observed that deletion of EBS severely reduced 32D leukocyte tethering and rolling on L-, P-, and E-selectin and slightly increased rolling velocity. Alanine substitution of Arg-337 and Lys-338 showed that these residues play a key role in supporting leukocyte tethering and rolling on selectins. Importantly, EBS deletion or Arg-337 and Lys-338 mutations abrogated PSGL-1-induced ERK activation, whereas they did not prevent Syk phosphorylation or E-selectin-induced leukocyte slow rolling. These studies demonstrate that PSGL-1 EBS plays a critical role in recruiting leukocytes on selectins and in activating the MAPK pathway, whereas it is dispensable to phosphorylate Syk and to lead to α(L)β(2)-dependent leukocyte slow rolling.

Critical role of the transcriptional repressor neuron-restrictive silencer factor in the specific control of connexin36 in insulin-producing cell lines.

Connexin36 (Cx36) is specifically expressed in neurons and in pancreatic beta-cells. Cx36 functions as a critical regulator of insulin secretion and content in beta-cells. In order to identify the molecular mechanisms that control the beta-cell expression of Cx36, we initiated the characterization of the human 5' regulatory region of the CX36 gene. A 2043-bp fragment of the human CX36 promoter was identified from a human BAC library and fused to a luciferase reporter gene. This promoter region was sufficient to confer specific expression to the reporter gene in insulin-secreting cell lines. Within this 5' regulatory region, a putative neuron-restrictive silencer element conserved between rodent and human species was recognized and binds the neuron-restrictive silencing factor (NRSF/REST). This factor is not expressed in insulin-secreting cells and neurons; it functions as a potent repressor through the recruitment of histone deacetylase to the promoter of neuronal genes. The NRSF-mediated repression of Cx36 in HeLa cells was abolished by trichostatin A, confirming the functional importance of histone deacetylase activity. Ectopic expression, by viral gene transfer, of NRSF/REST in different insulin-secreting beta-cell lines induced a marked reduction in Cx36 mRNA and protein content. Moreover, mutations in the Cx36 neuron-restrictive silencer element relieved the low transcriptional activity of the human CX36 promoter observed in HeLa cells and in INS-1 cells expressing NRSF/REST. The data showed that cx36 gene expression in insulin-producing beta-cell lines is strictly controlled by the transcriptional repressor NRSF/REST indicating that Cx36 participates to the neuronal phenotype of the pancreatic beta-cells.

Evidence from glut2-null mice that glucose is a critical physiological regulator of feeding.

A role for glucose in the control of feeding has been proposed, but its precise physiological importance is unknown. Here, we evaluated feeding behavior in glut2-null mice, which express a transgenic glucose transporter in their beta-cells to rescue insulin secretion (ripglut1;glut2-/- mice). We showed that in the absence of GLUT2, daily food intake was increased and feeding initiation and termination following a fasting period were abnormal. This was accompanied by suppressed regulation of hypothalamic orexigenic and anorexigenic neuropeptides expression during the fast-to-refed transition. In these conditions, however, there was normal regulation of the circulating levels of insulin, leptin, or glucose but a loss of regulation of plasma ghrelin concentrations. To evaluate whether the abnormal feeding behavior was due to suppressed glucose sensing, we evaluated feeding in response to intraperitoneal or intracerebroventricular glucose or 2-deoxy-D-glucose injections. We showed that in GLUT2-null mice, feeding was no longer inhibited by glucose or activated by 2-deoxy-D-glucose injections and the regulation of hypothalamic neuropeptide expression by intracerebroventricular glucose administration was lost. Together, these data demonstrate that absence of GLUT2 suppressed the function of central glucose sensors, which control feeding probably by regulating the hypothalamic melanocortin pathway. Furthermore, inactivation of these glucose sensors causes overeating.

A repeated GGA motif is critical for the activity and stability of the riboregulator RsmY of Pseudomonas fluorescens.

The riboregulator RsmY of Pseudomonas fluorescens strain CHA0 is an example of small regulatory RNAs belonging to the global Rsm/Csr regulatory systems controlling diverse cellular processes such as glycogen accumulation, motility, or formation of extracellular products in various bacteria. By binding multiple molecules of the small regulatory protein RsmA, RsmY relieves the negative effect of RsmA on the translation of several target genes involved in the biocontrol properties of strain CHA0. RsmY and functionally related riboregulators have repeated GGA motifs predicted to be exposed in single-stranded regions, notably in the loops of hairpins. The secondary structure of RsmY was corroborated by in vivo cleavage with lead acetate. RsmY mutants lacking three or five (out of six) of the GGA motifs showed reduced ability to derepress the expression of target genes in vivo and failed to bind the RsmA protein efficiently in vitro. The absence of GGA motifs in RsmY mutants resulted in reduced abundance of these transcripts and in a shorter half-life (< or = 6 min as compared with 27 min for wild type RsmY). These results suggest that both the interaction of RsmY with RsmA and the stability of RsmY strongly depend on the GGA repeats and that the ability of RsmY to interact with small regulatory proteins such as RsmA may protect this RNA from degradation.

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.

HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p<2.4 × 10(-12)). All associated SNPs mapped to the HLA class I region. Clinical relevance of host and pathogen variation was assessed using VL results. We identified two critical advantages to the use of viral variation for identifying host factors: (1) association signals are much stronger for HIV-1 sequence variants than VL, reflecting the 'intermediate phenotype' nature of viral variation; (2) association testing can be run without any clinical data. The proposed genome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host-pathogen interaction. DOI:http://dx.doi.org/10.7554/eLife.01123.001.

Trypsin cleaves acid-sensing ion channel 1a in a domain that is critical for channel gating.

Acid-sensing ion channels (ASICs) are neuronal Na(+) channels that are members of the epithelial Na(+) channel/degenerin family and are transiently activated by extracellular acidification. ASICs in the central nervous system have a modulatory role in synaptic transmission and are involved in cell injury induced by acidosis. We have recently demonstrated that ASIC function is regulated by serine proteases. We provide here evidence that this regulation of ASIC function is tightly linked to channel cleavage. Trypsin cleaves ASIC1a with a similar time course as it changes ASIC1a function, whereas ASIC1b, whose function is not modified by trypsin, is not cleaved. Trypsin cleaves ASIC1a at Arg-145, in the N-terminal part of the extracellular loop, between a highly conserved sequence and a sequence that is critical for ASIC1a inhibition by the venom of the tarantula Psalmopoeus cambridgei. This channel domain controls the inactivation kinetics and co-determines the pH dependence of ASIC gating. It undergoes a conformational change during inactivation, which renders the cleavage site inaccessible to trypsin in inactivated channels.

Diffusion tensor echo planar imaging using surface coil transceiver with a semiadiabatic RF pulse sequence at 14.1T.

Diffusion magnetic resonance studies of the brain are typically performed using volume coils. Although in human brain this leads to a near optimal filling factor, studies of rodent brain must contend with the fact that only a fraction of the head volume can be ascribed to the brain. The use of surface coil as transceiver increases Signal-to-Noise Ratio (SNR), reduces radiofrequency power requirements and opens the possibility of parallel transmit schemes, likely to allow efficient acquisition schemes, of critical importance for reducing the long scan times implicated in diffusion tensor imaging. This study demonstrates the implementation of a semiadiabatic echo planar imaging sequence (echo time=40 ms, four interleaves) at 14.1T using a quadrature surface coil as transceiver. It resulted in artifact free images with excellent SNR throughout the brain. Diffusion tensor derived parameters obtained within the rat brain were in excellent agreement with reported values.

N-Glycosylation and conserved cysteine residues in RAMP3 play a critical role for the functional expression of CRLR/RAMP3 adrenomedullin receptor.

The calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein-3 (RAMP3) can assemble into a CRLR/RAMP3 heterodimeric receptor that exhibits the characteristics of a high affinity adrenomedullin receptor. RAMP3 participates in adrenomedullin (AM) binding via its extracellular N-terminus characterized by the presence of six highly conserved cysteine residues and four N-glycosylation consensus sites. Here, we assessed the usage of these conserved residues in cotranslational modifications of RAMP3 and addressed their role in functional expression of the CRLR/RAMP3 receptor. Using a Xenopus oocyte expression system, we show that (i) RAMP3 is assembled with CRLR as a multiple N-glycosylated species in which two, three, or four consensus sites are used; (ii) elimination of all N-glycans in RAMP3 results in a significant inhibition of receptor [(125)I]AM binding and an increase in the EC(50) value for AM; (iii) several lines of indirect evidence indicate that each of the six cysteines is involved in disulfide bond formation; (iv) when all cysteines are mutated to serines, RAMP3 is N-glycosylated at all four consensus sites, suggesting that disulfide bond formation inhibits N-gylcosylation; and (v) elimination of all cysteines abolishes adrenomedullin binding and leads to a complete loss of receptor function. Our data demonstrate that cotranslational modifications of RAMP3 play a critical role in the function of the CRLR/RAMP3 adrenomedullin receptor.