When to hold that thought: an experimental study showing reduced inhibition of pre-trained associations in schizophrenia.

Schizophrenia encompasses a wide variety of cognitive dysfunctions, a number of which can be understood as deficits of inhibition. To date, no research has examined ‘conditioned inhibition’ in schizophrenia - the ability of a stimulus that signals the absence of an expected outcome to counteract the conditioned response produced by a signal for that outcome (a conditioned excitor). A computer-based task was used to measure conditioned excitation and inhibition in the same discrimination procedure, in 25 patients with a confirmed diagnosis of schizophrenia and a community-based comparison sample. Conditioned inhibition was measured by a ratio score, which compared the degree to which the inhibitory stimulus and a neutral control stimulus reduced conditioned responding to the excitatory cue: the lower the ratio, the greater the inhibitory learning. At test the ratios were 0.45 and 0.39 for patient and control groups respectively, and the relevant interaction term of the ANOVA confirmed that the degree of inhibition was reduced in the patient group, with an effect size of r = 0.28. These results demonstrate for the first time that inhibitory learning is impaired in schizophrenia. Such an impairment provides an attractive framework for the interpretation of the positive symptoms of schizophrenia. However, we were unable to demonstrate any relationship between the level of conditioned inhibition and medication. Similarly, in the present study it must be emphasised that the available data did not demonstrate any relationship between individual variation in inhibitory learning and the level of positive symptoms as measured by the PANSS. In fact inhibitory learning impairment was relatively greater in participants with a predominantly negative symptom profile and their excitatory learning was also reduced. Accordingly the next step will be to investigate such relationships in a larger sample with a priori defined sub-groups displaying predominantly positive versus predominantly negative symptoms

High performing and stable supported nano-alloys for the catalytic hydrogenation of levulinic acid to γ-valerolactone

The catalytic hydrogenation of ​levulinic acid, a key platform molecule in many biorefinery schemes, into ​γ-valerolactone is considered as one of the pivotal reactions to convert lignocellulose-based biomass into renewable fuels and chemicals. Here we report on the development of highly active, selective and stable supported metal catalysts for this reaction and on the beneficial effects of metal nano-alloying. Bimetallic random alloys of ​gold-palladium and ​ruthenium-palladium supported on ​titanium dioxide are prepared with a modified metal impregnation method. ​Gold-palladium/​titanium dioxide shows a marked,~27-fold increase in activity (that is, turnover frequency of 0.1 s−1) compared with its monometallic counterparts. Although ​ruthenium-palladium/​titanium dioxide is not only exceptionally active (that is, turnover frequency of 0.6 s−1), it shows excellent, sustained selectivity to ​γ-valerolactone (99%). The dilution and isolation of ruthenium by palladium is thought to be responsible for this superior catalytic performance. Alloying, furthermore, greatly improves the stability of both supported nano-alloy catalysts

Toll-like receptor 5-mediated IL-17C expression in intestinal epithelial cells enhances epithelial host defense against F4+ ETEC infection

International audienceAbstractEnterotoxigenic Escherichia coli (ETEC) are an important cause of post-weaning diarrhea (PWD) in piglets. The IL-17 cytokine family is well known to play important roles in the host defense against bacterial infections at the mucosa. Previously, we reported the potential role of IL-17A in clearing an ETEC infection in piglets. IL-17C, another member of the IL-17 family, is highly expressed in the intestinal epithelium, however, its role during an ETEC infection is still unclear. In this study, we demonstrate that F4+ ETEC induce IL-17C mRNA and protein expression in intestinal tissues as well as in porcine intestinal epithelial cells (IPEC-J2). This IL-17C production is largely dependent on TLR5 signaling in IPEC-J2 cells. Both F4+ ETEC infection and exogenous IL-17C increased the expression of antimicrobial peptides and tight junction proteins, such as porcine beta-defensin (pBD)-2, claudin-1, claudin-2 and occludin in IPEC-J2 cells. Taken together, our data demonstrate that TLR5-mediated IL-17C expression in intestinal epithelial cells enhances mucosal host defense responses in a unique autocrine/paracrine manner in the intestinal epithelium against ETEC infection

Associations of four biological age markers with child development: a multi-omic analysis in the European HELIX cohort

Background: While biological age in adults is often understood as representing general health and resilience, the conceptual interpretation of accelerated biological age in children and its relationship to development remains unclear. We aimed to clarify the relationship of accelerated biological age, assessed through two established biological age indicators, telomere length and DNA methylation age, and two novel candidate biological age indicators , to child developmental outcomes, including growth and adiposity, cognition, behaviour, lung function and onset of puberty, among European school-age children participating in the HELIX exposome cohort. Methods: The study population included up to 1,173 children, aged between 5 and 12 years, from study centres in the UK, France, Spain, Norway, Lithuania, and Greece. Telomere length was measured through qPCR, blood DNA methylation and gene expression was measured using microarray, and proteins and metabolites were measured by a range of targeted assays. DNA methylation age was assessed using Horvath's skin and blood clock, while novel blood transcriptome and 'immunometabolic' (based on plasma protein and urinary and serum metabolite data) clocks were derived and tested in a subset of children assessed six months after the main follow-up visit. Associations between biological age indicators with child developmental measures as well as health risk factors were estimated using linear regression, adjusted for chronological age, sex, ethnicity and study centre. The clock derived markers were expressed as Δ age (i.e., predicted minus chronological age). Results: Transcriptome and immunometabolic clocks predicted chronological age well in the test set (r= 0.93 and r= 0.84 respectively). Generally, weak correlations were observed, after adjustment for chronological age, between the biological age indicators. Among associations with health risk factors, higher birthweight was associated with greater immunometabolic Δ age, smoke exposure with greater DNA methylation Δ age and high family affluence with longer telomere length. Among associations with child developmental measures, all biological age markers were associated with greater BMI and fat mass, and all markers except telomere length were associated with greater height, at least at nominal significance (p<0.05). Immunometabolic Δ age was associated with better working memory (p = 4e -3) and reduced inattentiveness (p= 4e -4), while DNA methylation Δ age was associated with greater inattentiveness (p=0.03) and poorer externalizing behaviours (p= 0.01). Shorter telomere length was also associated with poorer externalizing behaviours (p=0.03). Conclusions: In children, as in adults, biological ageing appears to be a multi-faceted process and adiposity is an important correlate of accelerated biological ageing. Patterns of associations suggested that accelerated immunometabolic age may be beneficial for some aspects of child development while accelerated DNA methylation age and telomere attrition may reflect early detrimental aspects of biological ageing, apparent even in children. Funding: UK Research and Innovation (MR/S03532X/1); European Commission (grant agreement numbers: 308333; 874583)

Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination.

Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria

Supported bimetallic nano-alloys as highly active catalysts for the one-pot tandem synthesis of imines and secondary amines from nitrobenzene and alcohols

The synthesis and functionalization of imines and amines are key steps in the preparation of many fine chemicals and for pharmaceuticals in particular. Traditionally, metal complexes are used as homogeneous catalysts for these organic transformations. Here we report gold-palladium and ruthenium-palladium nano-alloys supported on TiO2 acting as highly efficient heterogeneous catalysts for the one-pot synthesis of the imine N-benzylideneaniline and the secondary amine N-benzylaniline directly from the easily available and stable nitrobenzene and benzyl alcohol precursors using a hydrogen auto-transfer strategy. These reactions were carried out without any added external hydrogen, sacrificial hydrogen donor or a homogeneous base. The bimetallic catalysts were prepared by the recently developed modified impregnation strategy, giving efficient control of size and nano-alloy composition. Both bimetallic catalysts were found to be far more active than their monometallic analogues due to a synergistic effect. Based on the turnover numbers the catalytic activities follow the order Ru < Pd < Au << Au-Pd < Ru-Pd. Aberration corrected scanning transmission electron microscopy (AC-STEM) and X-ray absorption spectroscopy (XAFS) studies of these catalysts revealed that the reason for the observed synergistic effect is the electronic modification of the metal sites in the case of the Au-Pd system and a size stabilisation effect in the case of the Ru-Pd catalyst

IgH gene rearrangements as plasma biomarkers in Non-Hodgkin's Lymphoma patients

New biomarkers with improved accuracy could be helpful for monitoring disease in patients with Non-Hodgkin's lymphomas (NHL). Towards this end, we have explored the feasibility of identifying the sequence of rearranged IgH genes using next-generation sequencing, then using PCR to detect specific rearranged DNA fragments in patients' plasma. By capturing and sequencing the IgH genomic regions (IgCap), we were able to detect and precisely determine the sequence of rearranged IgH loci in the tumors of three NHL patients. Moreover, circulating rearranged DNA fragments could be identified in the plasma of all three patients. Even in cases wherein tumor biopsies were unavailable, we were able to use the IgH capture approach to identify rearranged DNA loci in the plasma of 8 of 14 patients. IgCap may enable a more informed management of selected patients with NHL and other B-cell malignancies in the future

The state-of-the-art of urban climate change modeling and observations

As an effect of climate change, cities need detailed information on urban climates at decision scale that cannot be easily delivered using current observation networks, nor global and even regional climate models. A review is presented of the recent literature and recommendations are formulated for future work. In most cities, historical observational records are too short, discontinuous, or of too poor quality to support trend analysis and climate change attribution. For climate modeling, on the other hand, specific dynamical and thermal parameterization dedicated to the exchange of water and energy between the atmosphere and the urban surfaces have to be implemented. Therefore, to fully understand how cities are impacted by climate change, it is important to have (1) simulations of the urban climate at fine spatial scales (including coastal hazards for coastal cities) integrating global climate scenarios with urban expansion and population growth scenarios and their associated uncertainty estimates, (2) urban climate observations, especially in Global South cities, and (3) spatial data of high resolution on urban structure and form, human behavior, and energy consumption

An epigenomic approach to therapy for tamoxifen-resistant breast cancer

Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer

To screen or not to screen for peripheral arterial disease in subjects aged 80 and over in primary health care: a cross-sectional analysis from the BELFRAIL study

<p>Abstract</p> <p>Background</p> <p>Peripheral arterial disease (PAD) is common in older people. An ankle-brachial index (ABI) < 0.9 can be used as an indicator of PAD. Patients with low ABI have increased mortality and a higher risk of serious cardiovascular morbidity. However, because 80% of the patients are asymptomatic, PAD remains unrecognised in a large group of patients. The aims of this study were 1) to examine the prevalence of reduced ABI in subjects aged 80 and over, 2) to determine the diagnostic accuracy of the medical history and clinical examination for reduced ABI and 3) to investigate the difference in functioning and physical activity between patients with and without reduced ABI.</p> <p>Methods</p> <p>A cross-sectional study embedded within the BELFRAIL study. A general practitioner (GP) centre, located in Hoeilaart, Belgium, recruited 239 patients aged 80 or older. Only three criteria for exclusion were used: urgent medical need, palliative situation and known serious dementia. The GP recorded the medical history and performed a clinical examination. The clinical research assistant performed an extensive examination including Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS-15), Activities of Daily Living (ADL), Tinetti test and the LASA Physical Activity Questionnaire (LAPAQ). ABI was measured using an automatic oscillometric appliance.</p> <p>Results</p> <p>In 40% of patients, a reduced ABI was found. Cardiovascular risk factors were unable to identify patients with low ABI. A negative correlation was found between the number of cardiovascular morbidities and ABI. Cardiovascular morbidity had a sensitivity of 65.7% (95% CI 53.4-76.7) and a specificity of 48.6% (95% CI 38.7-58.5). Palpation of the peripheral arteries showed the highest negative predictive value (77.7% (95% CI 71.8-82.9)). The LAPAQ score was significantly lower in the group with reduced ABI.</p> <p>Conclusion</p> <p>The prevalence of PAD is very high in patients aged 80 and over in general practice. The clinical examination, cardiovascular risk factors and the presence of cardiovascular morbidity were not able to identify patients with a low ABI. A screening strategy for PAD by determining ABI could be considered if effective interventions for those aged 80 and over with a low ABI become available through future research.</p