Neural Correlates of Ongoing Conscious Experience: Both Task-Unrelatedness and Stimulus-Independence Are Related to Default Network Activity

in PLoS ONE (2011), 6(2), 16997

The default mode network (DMN) is a set of brain regions that consistently shows higher activity at rest compared to tasks requiring sustained focused attention toward externally presented stimuli. The ... [more ▼]

The default mode network (DMN) is a set of brain regions that consistently shows higher activity at rest compared to tasks requiring sustained focused attention toward externally presented stimuli. The cognitive processes that the DMN possibly underlies remain a matter of debate. It has alternately been proposed that DMN activity reflects unfocused attention toward external stimuli or the occurrence of internally generated thoughts. The present study aimed at clarifying this issue by investigating the neural correlates of the various kinds of conscious experiences that can occur during task performance. Four classes of conscious experiences (i.e., being fully focused on the task, distractions by irrelevant sensations/perceptions, interfering thoughts related to the appraisal of the task, and mind-wandering) that varied along two dimensions (“task-relatedness” and “stimulus-dependency”) were sampled using thought-probes while the participants performed a go/no-go task. Analyses performed on the intervals preceding each probe according to the reported subjective experience revealed that both dimensions are relevant to explain activity in several regions of the DMN, namely the medial prefrontal cortex, posterior cingulate cortex/precuneus, and posterior inferior parietal lobe. Notably, an additive effect of the two dimensions was demonstrated for midline DMN regions. On the other hand, lateral temporal regions (also part of the DMN) were specifically related to stimulus-independent reports. These results suggest that midline DMN regions underlie cognitive processes that are active during both internal thoughts and external unfocused attention. They also strengthen the view that the DMN can be fractionated into different subcomponents and reveal the necessity to consider both the stimulus-dependent and the task-related dimensions of conscious experiences when studying the possible functional roles of the DMN. [less ▲]

Bovine tuberculosis prevalence survey on cattle in the rural livestock system of Torodi (Niger).

in PLoS ONE (2011), 6(9), 24629

BACKGROUND: Bovine tuberculosis (BTB) is a widespread zoonosis in developing countries but has received little attention in sub-Saharan Africa, especially in Niger. Recent investigations confirmed the ... [more ▼]

BACKGROUND: Bovine tuberculosis (BTB) is a widespread zoonosis in developing countries but has received little attention in sub-Saharan Africa, especially in Niger. Recent investigations confirmed the high incidence of the disease in cattle slaughtered in an abattoir in Niamey. The fact that most of the animals in which M. bovis has been identified were from the rural area of Torodi implied the existence of a probable source of BTB in this region. This study aimed to determine the prevalence of BTB infection in cattle and to identify risk factors for infection in human and cattle populations in Torodi. METHODS AND PRINCIPAL FINDINGS: A survey was carried out at the level of households keeping livestock (n = 51). The questionnaire was related to the potential risk factors and the presence of clinical signs of TB both in animals and humans. Comparative Intradermal Tuberculin Test was conducted to determine the TB status in cattle (n = 393). The overall apparent individual animal prevalence of tuberculin reactors was 3.6% (CI: 95%, 1.9-5.9), whereas the individual true prevalence was estimated at 0.8% (CI: 95%, 0.0-5.0). Using a multivariate logistic regression analysis and a classification tree analysis, the only household level risk factor that significantly influenced the presence of BTB in cattle was the presence of animals coughing in the herd (OR = 4.7, 95% CI: 1.12-19.71, p-value = 0.034). The lack of the practice of quarantine was borderline significant (OR = 4.2, 95% CI: 0.96-18.40, p-value = 0.056). CONCLUSION/SIGNIFICANCE: The study confirmed that BTB is endemic in cattle in Torodi and the risk of the transmission of the disease to humans is potentially high. For the control of the disease in livestock, slaughtering of infected animals and the compensation of the owners is needed. Collaboration between the veterinary and the medical sectors, in the diagnosis, monitoring, prevention and control of BTB is strongly encouraged. [less ▲]

Own song selectivity in the songbird auditory pathway: Suppression by norepinephrine

in PLoS ONE (2011), 6(5), 20131

New noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria.

in PloS one (2011), 6(5), 19418

BACKGROUND: Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs beta-lactams inhibit transpeptidase ... [more ▼]

BACKGROUND: Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs beta-lactams inhibit transpeptidase activity of PBPs by forming a covalent penicilloyl-enzyme complex that blocks the normal transpeptidation reaction; this finally results in bacterial death. In some resistant bacteria the resistance is acquired by active-site distortion of PBPs, which lowers their acylation efficiency for beta-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs. METHODOLOGY/PRINCIPAL FINDINGS: Our in-house bank of compounds was screened for inhibition of three PBPs from resistant bacteria: PBP2a from Methicillin-resistant Staphylococcus aureus (MRSA), PBP2x from Streptococcus pneumoniae strain 5204, and PBP5fm from Enterococcus faecium strain D63r. Initial hit inhibitor obtained by screening was then used as a starting point for computational similarity searching for structurally related compounds and several new noncovalent inhibitors were discovered. Two compounds had promising inhibitory activities of both PBP2a and PBP2x 5204, and good in-vitro antibacterial activities against a panel of Gram-positive bacterial strains. CONCLUSIONS: We found new noncovalent inhibitors of PBPs which represent important starting points for development of more potent inhibitors of PBPs that can target penicillin-resistant bacteria. [less ▲]

Enhanced Activity of Meprin-a, a Pro-Migratory and Pro- Angiogenic Protease, in Colorectal Cancer

in PLoS ONE (2011), 6(11), 26450

Meprin-α is a metalloprotease overexpressed in cancer cells, leading to the accumulation of this protease in a subset of colorectal tumors. The impact of increased meprin-α levels on tumor progression is ... [more ▼]

Meprin-α is a metalloprotease overexpressed in cancer cells, leading to the accumulation of this protease in a subset of colorectal tumors. The impact of increased meprin-α levels on tumor progression is not known. We investigated the effect of this protease on cell migration and angiogenesis in vitro and studied the expression of meprin-α mRNA, protein and proteolytic activity in primary tumors at progressive stages and in liver metastases of patients with colorectal cancer, as well as inhibitory activity towards meprin-α in sera of cancer patient as compared to healthy controls. We found that the hepatocyte growth factor (HGF)- induced migratory response of meprin-transfected epithelial cells was increased compared to wild-type cells in the presence of plasminogen, and that the angiogenic response in organ-cultured rat aortic explants was enhanced in the presence of exogenous human meprin-α. In patients, meprin-α mRNA was expressed in colonic adenomas, primary tumors UICC (International Union Against Cancer) stage I, II, III and IV, as well as in liver metastases. In contrast, the corresponding protein accumulated only in primary tumors and liver metastases, but not in adenomas. However, liver metastases lacked meprin-α activity despite increased expression of the corresponding protein, which correlated with inefficient zymogen activation. Sera from cancer patients exhibited reduced meprin-α inhibition compared to healthy controls. In conclusion, meprin-α activity is regulated differently in primary tumors and metastases, leading to high proteolytic activity in primary tumors and low activity in liver metastases. By virtue of its pro-migratory and pro-angiogenic activity, meprin-α may promote tumor progression in colorectal cancer. [less ▲]

Refinement of 1p36 alterations not involving PRDM16 in myeloid and lymphoid malignancies.

in PLoS ONE (2011), 6(10), 26311

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups ... [more ▼]

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (N = 27) and telomeric rearrangements (N = 15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (N = 39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis. [less ▲]

Covert waking brain activity reveals instantaneous sleep depth.

in PLoS ONE (2011), 6(3), 17351

The neural correlates of the wake-sleep continuum remain incompletely understood, limiting the development of adaptive drug delivery systems for promoting sleep maintenance. The most useful measure for ... [more ▼]

The neural correlates of the wake-sleep continuum remain incompletely understood, limiting the development of adaptive drug delivery systems for promoting sleep maintenance. The most useful measure for resolving early positions along this continuum is the alpha oscillation, an 8-13 Hz electroencephalographic rhythm prominent over posterior scalp locations. The brain activation signature of wakefulness, alpha expression discloses immediate levels of alertness and dissipates in concert with fading awareness as sleep begins. This brain activity pattern, however, is largely ignored once sleep begins. Here we show that the intensity of spectral power in the alpha band actually continues to disclose instantaneous responsiveness to noise--a measure of sleep depth--throughout a night of sleep. By systematically challenging sleep with realistic and varied acoustic disruption, we found that sleepers exhibited markedly greater sensitivity to sounds during moments of elevated alpha expression. This result demonstrates that alpha power is not a binary marker of the transition between sleep and wakefulness, but carries rich information about immediate sleep stability. Further, it shows that an empirical and ecologically relevant form of sleep depth is revealed in real-time by EEG spectral content in the alpha band, a measure that affords prediction on the order of minutes. This signal, which transcends the boundaries of classical sleep stages, could potentially be used for real-time feedback to novel, adaptive drug delivery systems for inducing sleep. [less ▲]

Thiamine Status in Humans and Content of Phosphorylated Thiamine Derivatives in Biopsies and Cultured Cells

in PLoS ONE (2010), 5(10), 13616

Background Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine ... [more ▼]

Background Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines. Methodology and Principal Findings Thiamine derivatives were determined by HPLC. In human tissues, the total thiamine content is lower than in other animal species. ThDP is the major thiamine compound and tissue levels decrease at high age. In semen, ThDP content correlates with the concentration of spermatozoa but not with their motility. The proportion of ThTP is higher in humans than in rodents, probably because of a lower 25-kDa ThTPase activity. The expression and activity of this enzyme seems to correlate with the degree of cell differentiation. ThTP was present in nearly all brain and muscle samples and in ~60% of other tissue samples, in particular fetal tissue and cultured cells. A low ([ThTP]+[ThMP])/([Thiamine]+[ThMP]) ratio was found in cardiovascular tissues of patients with cardiac insufficiency. AThTP was detected only sporadically in adult tissues but was found more consistently in fetal tissues and cell lines. Conclusions and Significance The high sensitivity of humans to thiamine deficiency is probably linked to low circulating thiamine concentrations and low ThDP tissue contents. ThTP levels are relatively high in many human tissues, as a result of low expression of the 25-kDa ThTPase. Another novel finding is the presence of ThTP and AThTP in poorly differentiated fast-growing cells, suggesting a hitherto unsuspected link between these compounds and cell division or differentiation. [less ▲]

Transfer of Communication Skills to the Workplace during Clinical Rounds : Impact of a Program for Residents

in PLoS ONE (2010), 5(8), 1-9

Does plasminogen activator inhibitor-1 drive lymphangiogenesis?

in PLoS ONE (2010), 5(3), 9653

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators ... [more ▼]

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and by regulating endothelial cell survival and migration. Protease system's role in lymphangiogenesis is unknown yet. Thus, based on its important pro-angiogenic effect, we hypothesized that PAI-1 may regulate lymphangiogenesis associated at least with metastatic dissemination of cancer cells. To address this issue, we studied the impact of PAI-1 deficiency in various murine models of tumoral lymphangiogenesis. Wild-type PAI-1 proficient mice were used as controls. We provide for the first time evidence that PAI-1 is dispensable for tumoral lymphangiogenesis associated with breast cancers either induced by mammary carcinoma cell injection or spontaneously appearing in transgenic mice expressing the polyomavirus middle T antigen (PymT) under the control of a mouse mammary tumor virus long-terminal repeat promoter (MMTV-LTR). We also investigated inflammation-related lymphatic vessel recruitment by using two inflammatory models. PAI-1 deficiency did neither affect the development of lymphangioma nor burn-induced corneal lymphangiogenesis. These novel data suggest that vascular remodelling associated with lymphangiogenesis and angiogenesis involve different molecular determinants. PAI-1 does not appear as a potential therapeutic target to counteract pathological lymphangiogenesis. [less ▲]