Category label and response location shifts in category learning

The category shift literature suggests that rule-based classification, an important form of explicit learning, is mediated by two separate learned associations: a stimulus-to-label association that associates stimuli and category labels, and a label-to-response association that associates category labels and responses. Three experiments investigate whether information–integration classification, an important form of implicit learning, is also mediated by two separate learned associations. Participants were trained on a rule-based or an information–integration categorization task and then the association between stimulus and category label, or between category label and response location was altered. For rule-based categories, and in line with previous research, breaking the association between stimulus and category label caused more interference than breaking the association between category label and response location. However, no differences in recovery rate emerged. For information–integration categories, breaking the association between stimulus and category label caused more interference and led to greater recovery than breaking the association between category label and response location. These results provide evidence that information–integration category learning is mediated by separate stimulus-to-label and label-to-response associations. Implications for the neurobiological basis of these two learned associations are discussed

Protein profiling in hepatocellular carcinoma by label-free quantitative proteomics in two west african populations.

Background Hepatocellular Carcinoma is the third most common cause of cancer related death worldwide, often diagnosed by measuring serum AFP; a poor performance stand-alone biomarker. With the aim of improving on this, our study focuses on plasma proteins identified by Mass Spectrometry in order to investigate and validate differences seen in the respective proteomes of controls and subjects with LC and HCC. Methods Mass Spectrometry analysis using liquid chromatography electro spray ionization quadrupole time-of-flight was conducted on 339 subjects using a pooled expression profiling approach. ELISA assays were performed on four significantly differentially expressed proteins to validate their expression profiles in subjects from the Gambia and a pilot group from Nigeria. Results from this were collated for statistical multiplexing using logistic regression analysis. Results Twenty-six proteins were identified as differentially expressed between the three subject groups. Direct measurements of four; hemopexin, alpha-1-antitrypsin, apolipoprotein A1 and complement component 3 confirmed their change in abundance in LC and HCC versus control patients. These trends were independently replicated in the pilot validation subjects from Nigeria. The statistical multiplexing of these proteins demonstrated performance comparable to or greater than ALT in identifying liver cirrhosis or carcinogenesis. This exercise also proposed preliminary cut offs with achievable sensitivity, specificity and AUC statistics greater than reported AFP averages. Conclusions The validated changes of expression in these proteins have the potential for development into high-performance tests usable in the diagnosis and or monitoring of HCC and LC patients. The identification of sustained expression trends strengthens the suggestion of these four proteins as worthy candidates for further investigation in the context of liver disease. The statistical combinations also provide a novel inroad of analyses able to propose definitive cut-offs and combinations for evaluation of performance

Efficacy of Combined Therapy with Amantadine, Oseltamivir, and Ribavirin In Vivo against Susceptible and Amantadine-Resistant Influenza A Viruses

The limited efficacy of existing antiviral therapies for influenza – coupled with widespread baseline antiviral resistance – highlights the urgent need for more effective therapy. We describe a triple combination antiviral drug (TCAD) regimen composed of amantadine, oseltamivir, and ribavirin that is highly efficacious at reducing mortality and weight loss in mouse models of influenza infection. TCAD therapy was superior to dual and single drug regimens in mice infected with drug-susceptible, low pathogenic A/H5N1 (A/Duck/MN/1525/81) and amantadine-resistant 2009 A/H1N1 influenza (A/California/04/09). Treatment with TCAD afforded >90% survival in mice infected with both viruses, whereas treatment with dual and single drug regimens resulted in 0% to 60% survival. Importantly, amantadine had no activity as monotherapy against the amantadine-resistant virus, but demonstrated dose-dependent protection in combination with oseltamivir and ribavirin, indicative that amantadine's activity had been restored in the context of TCAD therapy. Furthermore, TCAD therapy provided survival benefit when treatment was delayed until 72 hours post-infection, whereas oseltamivir monotherapy was not protective after 24 hours post-infection. These findings demonstrate in vivo efficacy of TCAD therapy and confirm previous reports of the synergy and broad spectrum activity of TCAD therapy against susceptible and resistant influenza strains in vitro

Transcriptional Control in Cardiac Progenitors: Tbx1 Interacts with the BAF Chromatin Remodeling Complex and Regulates Wnt5a

Mutations of the Wnt5a gene, encoding a ligand of the non-canonical Wnt pathway, and the Ror2 gene, encoding its receptor, have been found in patients with cardiac outflow tract defects. We found that Wnt5a is expressed in the second heart field (SHF), a population of cardiac progenitor cells destined to populate the cardiac outflow tract and the right ventricle. Because of cardiac phenotype similarities between Wnt5a and Tbx1 mutant mice, we tested potential interactions between the two genes. We found a strong genetic interaction in vivo and determined that the loss of both genes caused severe hypoplasia of SHF–dependent segments of the heart. We demonstrated that Wnt5a is a transcriptional target of Tbx1 and explored the mechanisms of gene regulation. Tbx1 occupies T-box binding elements within the Wnt5a gene and interacts with the Baf60a/Smarcd1 subunit of a chromatin remodeling complex. It also interacts with the Setd7 histone H3K4 monomethyltransferase. Tbx1 enhances Baf60a occupation at the Wnt5a gene and enhances its H3K4 monomethylation status. Finally, we show that Baf60a is required for Tbx1–driven regulation of target genes. These data suggest a model in which Tbx1 interacts with, and probably recruits a specific subunit of, the BAF complex as well as histone methylases to activate or enhance transcription. We speculate that this may be a general mechanism of T-box function and that Baf60a is a key component of the transcriptional control in cardiac progenitors

Internet-based treatment for adults with depressive symptoms: the protocol of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Depression is a highly prevalent condition, affecting more than 15% of the adult population at least once in their lives. Guided self-help is effective in the treatment of depression. The purpose of this study is to investigate the effectiveness of two Internet-based guided self-help treatments with adults reporting elevated depressive symptoms. Other research questions concern the identification of potential mediators and the search for subgroups who respond differently to the interventions.</p> <p>Methods</p> <p>This study is a randomized controlled trial with three conditions: two treatment conditions and one waiting list control group. The two treatment conditions are Internet-based cognitive behavior therapy and Internet-based problem-solving therapy. They consist of 8 and 5 weekly lessons respectively. Both interventions are combined with support by e-mail. Participants in the waiting list control group receive the intervention three months later.</p> <p>The study population consists of adults from the general population. They are recruited through advertisements in local and national newspapers and through banners on the Internet. Subjects with symptoms of depression (≥ 16 on the Center for Epidemiological Studies Depression scale) are included. Other inclusion criteria are having sufficient knowledge of the Dutch language, access to the Internet and an e-mail address.</p> <p>Primary outcome is depressive symptoms. Secondary outcomes are anxiety, quality of life, dysfunctional cognitions, worrying, problem solving skills, mastery, absence at work and use of healthcare. We will examine the following variables as potential mediators: dysfunctional cognitions, problem solving skills, worrying, anxiety and mastery. Potential moderating variables are: socio-demographic characteristics and symptom severity. Data are collected at baseline and at 5 weeks, 8 weeks, 12 weeks and 9 months after baseline. Analyses will be conducted on the intention-to-treat sample.</p> <p>Discussion</p> <p>This study evaluates two Internet-based treatments for depression, namely cognitive behavioral therapy and problem-solving therapy. The effectiveness of Internet-based problem-solving therapy suggest that this may be a worthwhile alternative to other more intensive treatment options. Strengths and limitations of this study are discussed.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN16823487</p

Susceptibility to Ebbinghaus and Muller-Lyer illusions in autistic children: a comparison of three different methods

Background Studies reporting altered susceptibility to visual illusions in autistic individuals compared to that typically developing individuals have been taken to reflect differences in perception (e.g. reduced global processing), but could instead reflect differences in higher-level decision-making strategies. Methods We measured susceptibility to two contextual illusions (Ebbinghaus, Müller-Lyer) in autistic children aged 6–14 years and typically developing children matched in age and non-verbal ability using three methods. In experiment 1, we used a new two-alternative-forced-choice method with a roving pedestal designed to minimise cognitive biases. Here, children judged which of two comparison stimuli was most similar in size to a reference stimulus. In experiments 2 and 3, we used methods previously used with autistic populations. In experiment 2, children judged whether stimuli were the ‘same’ or ‘different’, and in experiment 3, we used a method-of-adjustment task. Results Across all tasks, autistic children were equally susceptible to the Ebbinghaus illusion as typically developing children. Autistic children showed a heightened susceptibility to the Müller-Lyer illusion, but only in the method-of-adjustment task. This result may reflect differences in decisional criteria. Conclusions Our results are inconsistent with theories proposing reduced contextual integration in autism and suggest that previous reports of altered susceptibility to illusions may arise from differences in decision-making, rather than differences in perception per se. Our findings help to elucidate the underlying reasons for atypical responses to perceptual illusions in autism and call for the use of methods that reduce cognitive bias when measuring illusion susceptibility

Immuno-epidemiology of human Schistosoma haematobium infection: preferential IgG3 antibody responsiveness to a recombinant antigen dependent on age and parasite burden

BACKGROUND: Schistosomiasis is a major parasitic disease affecting over 200 million people in the developing world with a further 400 million people at risk of infection. The aim of this study was to identify a single antigen from adult Schistosoma haematobium worms and subsequently use this antigen to study the development of schistosome-acquired immunity in a human population. METHODS: The full-length cDNA sequence of a S. haematobium protein, a putative orthologue of the S. mansoni tegumental antigen Sm13, was obtained from a cDNA library of adult S. haematobium worms and named Sh13 following a small-scale expressed sequence tags (EST) project. The recombinant Sh13 protein expressed in E. coli, was used to investigate immuno-epidemiological patterns in 147 Zimbabweans (7–18 years old) exposed to S. haematobium. RESULTS: Sequence analysis of the full-length cDNA sequence of the S. haematobium protein Sh13, indicated that the protein has an N-terminal signal peptide and encodes an 85-amino acid mature protein with a highly conserved predicted transmembrane domain (86 % identity with the S. mansoni tegumental antigen Sm13). The recombinant Sh13 protein was used in ELISA assays to determine the reactivity of sera from the study participants. Antibody responses against Sh13 were predominantly IgG3 isotype compared to responses against crude worm antigens which were predominantly IgG1 and IgG4. The relationship between anti-Sh13 IgG3 levels and infection intensity varied significantly with host age. The youngest children (7–10 years old) had relatively low levels of both infection and anti-Sh13 IgG3. In older children (11–12 years old) rising infection levels were accompanied by a significant increase in anti-Sh13 IgG3 levels. Subsequently, infection intensity declined significantly in 13–18 year olds but levels of the antibody continued to rise. The changing relationship between infection intensity and anti-Sh13 IgG3 levels with host age is consistent with the profile of a protective immune response predicted from theoretical work. CONCLUSION: We have identified and characterised a novel S. haematobium antigen Sh13, a putative tegumental protein, and shown that it is recognised predominantly by IgG3 antibodies from people infected with/exposed to S. haematobium parasites. We have also shown that, the anti-Sh13 IgG3 response is maximal in older individuals with the lowest infection intensity, and that the age profile of the relationship between anti-Sh13 IgG3 and infection intensity is consistent with that predicted by theoretical work for a protective response stimulated by and directed against adult worms

Small-Molecule Activators of Insulin-Degrading Enzyme Discovered through High-Throughput Compound Screening

Background: Hypocatabolism of the amyloid β-protein (Aβ) by insulin-degrading enzyme (IDE) is implicated in the pathogenesis of Alzheimer disease (AD), making pharmacological activation of IDE an attractive therapeutic strategy. However, it has not been established whether the proteolytic activity of IDE can be enhanced by drug-like compounds. Methodology/Principal Findings: Based on the finding that ATP and other nucleotide polyphosphates modulate IDE activity at physiological concentrations, we conducted parallel high-throughput screening campaigns in the absence or presence of ATP and identified two compounds—designated Ia1 and Ia2—that significantly stimulate IDE proteolytic activity. Both compounds were found to interfere with the crosslinking of a photoaffinity ATP analogue to IDE, suggesting that they interact with a bona fide ATP-binding domain within IDE. Unexpectedly, we observed highly synergistic activation effects when the activity of Ia1 or Ia2 was tested in the presence of ATP, a finding that has implications for the mechanisms underlying ATP-mediated activation of IDE. Notably, Ia1 and Ia2 activated the degradation of Aβ by ∼700% and ∼400%, respectively, albeit only when Aβ was presented in a mixture also containing shorter substrates. Conclusions/Significance: This study describes the first examples of synthetic small-molecule activators of IDE, showing that pharmacological activation of this important protease with drug-like compounds is achievable. These novel activators help to establish the putative ATP-binding domain as a key modulator of IDE proteolytic activity and offer new insights into the modulatory action of ATP. Several larger lessons abstracted from this screen will help inform the design of future screening campaigns and facilitate the eventual development of IDE activators with therapeutic utility

Widespread Regulation of miRNA Biogenesis at the Dicer Step by the Cold-Inducible RNA-Binding Protein, RBM3

MicroRNAs (miRNAs) play critical roles in diverse cellular events through their effects on translation. Emerging data suggest that modulation of miRNA biogenesis at post-transcriptional steps by RNA-binding proteins is a key point of regulatory control over the expression of some miRNAs and the cellular processes they influence. However, the extent and conditions under which the miRNA pathway is amenable to regulation at posttranscriptional steps are poorly understood. Here we show that RBM3, a cold-inducible, developmentally regulated RNA-binding protein and putative protooncogene, is an essential regulator of miRNA biogenesis. Utilizing miRNA array, Northern blot, and PCR methods, we observed that over 60% of miRNAs detectable in a neuronal cell line were significantly downregulated by knockdown of RBM3. Conversely, for select miRNAs assayed by Northern blot, induction of RBM3 by overexpression or mild hypothermia increased their levels. Changes in miRNA expression were accompanied by changes in the levels of their ∼70 nt precursors, whereas primary transcript levels were unaffected. Mechanistic studies revealed that knockdown of RBM3 does not reduce Dicer activity or impede transport of pre-miRNAs into the cytoplasm. Rather, we find that RBM3 binds directly to ∼70 nt pre-miRNA intermediates and promotes / de-represses their ability as larger ribonucleoproteins (pre-miRNPs) to associate with active Dicer complexes. Our findings suggest that the processing of a majority of pre-miRNPs by Dicer is subject to an intrinsic inhibitory influence that is overcome by RBM3 expression. RBM3 may thus orchestrate changes in miRNA expression during hypothermia and other cellular stresses, and in the euthermic contexts of early development, differentiation, and oncogenesis where RBM3 expression is highly elevated. Additionally, our data suggest that temperature-dependent changes in miRNA expression mediated by RBM3 may contribute to the therapeutic effects of hypothermia, and are an important variable to consider in in vitro studies of translation-dependent cellular events