Foldamers are non-natural oligomers that mimic the structural behaviour of natural peptides, proteins and nucleotides by folding into a well-defined 3D conformation in solution. Since their first description about two decades ago, numerous studies have been undertaken dealing with the design, synthesis, characterization and application of foldamers. They have huge application potential as antimicrobial, anticancer and anti-HIV agents and in materials science. Despite their importance, there is no publicly available web resource providing comprehensive information on these compounds. Here we describe FoldamerDB, an open-source, fully annotated and manually curated database of peptidic foldamers. FoldamerDB holds the information about the sequence, structure and biological activities of the foldamer entries. It contains the information on over 1319 species and 1018 activities, collected from more than 160 research papers. The web-interface is designed to be clutter-free, user-friendly and it is compatible with devices of different screen sizes. The interface allows the user to search the database, browse and filter the foldamers using multiple criteria. It also offers a detailed help page to assist new users. FoldamerDB is hoped to bridge the gap in the freely available web-based resources on foldamers and will be of interest to diverse groups of scientists from chemists to biologists. The database can be accessed at http://foldamerdb.ttk.hu/.

The development of executive function is linked to maturation of prefrontal cortex (PFC) in childhood. Childhood obesity has been associated with changes in brain structure, particularly in PFC, as well as deficits in executive functions. We aimed to determine whether differences in cortical structure mediate the relationship between executive function and childhood obesity. We analyzed MR-derived measures of cortical thickness for 2700 children between the ages of 9 and 11 years, recruited as part of the NIH Adolescent Brain and Cognitive Development (ABCD) study. We related our findings to measures of executive function and body mass index (BMI). In our analysis, increased BMI was associated with significantly reduced mean cortical thickness, as well as specific bilateral reduced cortical thickness in prefrontal cortical regions. This relationship remained after accounting for age, sex, race, parental education, household income, birth-weight, and in-scanner motion. Increased BMI was also associated with lower executive function. Reduced thickness in the rostral medial and superior frontal cortex, the inferior frontal gyrus, and the lateral orbitofrontal cortex partially accounted for reductions in executive function. These results suggest that childhood obesity is associated with compromised executive function. This relationship may be partly explained by BMI-associated reduced cortical thickness in the PFC.

Enteral feeding by tube in chronic kidney disease (CKD) before 2 years of age improves growth. Whether it is effective after this age is unknown. We assessed whether height and weight SDS changed after tube feeding was started in children with CKD above 2 years of age.

Using Doppler to improve detection of intrapartum fetal heart rate (FHR) abnormalities coupled with appropriate, timely intrapartum care in low- and middle-income countries (LMIC) can save lives.

Pathway Commons (https://www.pathwaycommons.org) is an integrated resource of publicly available information about biological pathways including biochemical reactions, assembly of biomolecular complexes, transport and catalysis events and physical interactions involving proteins, DNA, RNA, and small molecules (e.g. metabolites and drug compounds). Data is collected from multiple providers in standard formats, including the Biological Pathway Exchange (BioPAX) language and the Proteomics Standards Initiative Molecular Interactions format, and then integrated. Pathway Commons provides biologists with (i) tools to search this comprehensive resource, (ii) a download site offering integrated bulk sets of pathway data (e.g. tables of interactions and gene sets), (iii) reusable software libraries for working with pathway information in several programming languages (Java, R, Python and Javascript) and (iv) a web service for programmatically querying the entire dataset. Visualization of pathways is supported using the Systems Biological Graphical Notation (SBGN). Pathway Commons currently contains data from 22 databases with 4794 detailed human biochemical processes (i.e. pathways) and ∼2.3 million interactions. To enhance the usability of this large resource for end-users, we develop and maintain interactive web applications and training materials that enable pathway exploration and advanced analysis.

Octoploid strawberry (Fragaria × ananassa Duch.) is a model plant for research and one of the most important non-climacteric fruit crops throughout the world. The associations between regulatory networks and metabolite composition were explored for one of the most critical agricultural properties in octoploid strawberry, fruit colour. Differences in the levels of flavonoids are due to the differences in the expression of structural and regulatory genes involved in flavonoid biosynthesis. The molecular mechanisms underlying differences in fruit colour were compared between red and white octoploid strawberry varieties. FaMYB genes had combinatorial effects in determining the red colour of fruit through the regulation of flavonoid biosynthesis in response to the increase in endogenous ABA at the final stage of fruit development. Analysis of alleles of FaMYB10 and FaMYB1 in red and white strawberry varieties led to the discovery of a white-specific variant allele of FaMYB10, FaMYB10-2. Its coding sequence possessed an ACTTATAC insertion in the genomic region encoding the C-terminus of the protein. This insertion introduced a predicted premature termination codon, which suggested the loss of intact FaMYB10 protein playing a critical role in the loss of red colour in white octoploid strawberry.

Myopalladin (MYPN) is a striated muscle-specific, immunoglobulin-containing protein located in the Z-line and I-band of the sarcomere as well as the nucleus. Heterozygous MYPN gene mutations are associated with hypertrophic, dilated, and restrictive cardiomyopathy, and homozygous loss-of-function truncating mutations have recently been identified in patients with cap myopathy, nemaline myopathy, and congenital myopathy with hanging big toe.

The extent of functional maturation and integration of nonproliferative neuronal precursors, becoming neurons in the adult murine piriform cortex, is largely unexplored. We thus questioned whether precursors eventually become equivalent to neighboring principal neurons or whether they represent a novel functional network element. Adult brain neuronal precursors and immature neurons (complex cells) were labeled in transgenic mice (DCX-DsRed and DCX-CreERT2 /flox-EGFP), and their cell fate was characterized with patch clamp experiments and morphometric analysis of axon initial segments. Young (DCX+) complex cells in the piriform cortex of 2- to 4-month-old mice received sparse synaptic input and fired action potentials at low maximal frequency, resembling neonatal principal neurons. Following maturation, the synaptic input detected on older (DCX-) complex cells was larger, but predominantly GABAergic, despite evidence of glutamatergic synaptic contacts. Furthermore, the rheobase current of old complex cells was larger and the maximal firing frequency was lower than those measured in neighboring age-matched principal neurons. The striking differences between principal neurons and complex cells suggest that the latter are a novel type of neuron and new coding element in the adult brain rather than simple addition or replacement for preexisting network components.

Epidemiologic evidence suggests that exposure to particulate matter of 2.5 μm or less in diameter (PM2.5) aggravates asthma.

The mechanisms leading to the low-grade inflammation observed during obesity are not fully understood. Seeking the initiating events, we tested the hypothesis that the intestine could be damaged by repeated lipid supply and therefore participate in inflammation. In mice, 1-5 palm oil gavages increased intestinal permeability via decreased expression and mislocalization of junctional proteins at the cell-cell contacts; altered the intestinal bacterial species by decreasing the abundance of Akkermansia muciniphila, segmented filamentous bacteria, and Clostridium leptum; and increased inflammatory cytokine expression. This was further studied in human intestinal epithelial Caco-2/TC7 cells using the two main components of palm oil, i.e., palmitic and oleic acid. Saturated palmitic acid impaired paracellular permeability and junctional protein localization, and induced inflammatory cytokine expression in the cells, but unsaturated oleic acid did not. Inhibiting de novo ceramide synthesis prevented part of these effects. Altogether, our data show that short exposure to palm oil or palmitic acid induces intestinal dysfunctions targeting barrier integrity and inflammation. Excessive palm oil consumption could be an early player in the gut alterations observed in metabolic diseases.

Caragana korshinskii Kom. is a legume shrub that is widely distributed across desert habitats with gravely, sandy, and saline soils in Asia and Africa. C. korshinskii has highly developed roots and a strong tolerance to abiotic stress. At present, there are few genetic studies of C. korshinskii because of the limited availability of genomic resources. To understand the comprehensive mechanisms that are associated with drought tolerance, we used RNA-seq to survey the differentially expressed genes (DEGs) in comparisons of drought-treated and control plants. After analysing the sequencing results, we found 440 differentially expressed genes existing in drought-treated and control plants. Among the DEGs, 39 unigenes showed up-regulated expression after drought treatment, while 401 unigenes were down-regulated. We used the KEGG database to annotate these drought-induced genes; 126 unigenes were identified by KEGG pathway annotation, and approximately 28% of the unigenes with known function fell into categories related to fatty acid metabolism, starch, sucrose metabolism, and nitrogen metabolism, suggesting that these pathways or processes may be involved in the drought response. Finally, we confirmed that one gene has a potential function in drought tolerance. Our study is the first to provide transcriptomic resources for Caragana korshinskii and to determine its digital gene expression profile under conditions of drought stress using the assembled transcriptomic data for reference. These data provide a valuable resource for genetic and genomic studies of desert plants under abiotic stress conditions.

We have investigated the relationship between the function of the gene hindsight (hnt), which is the Drosophila homolog of Ras Responsive Element Binding protein-1 (RREB-1), and the EGFR signaling pathway. We report that hnt mutant embryos are defective in EGFR signaling dependent processes, namely chordotonal organ recruitment and oenocyte specification. We also show the temperature sensitive hypomorphic allele hntpebbled is enhanced by the hypomorphic MAPK allele rolled (rl1 ). We find that hnt overexpression results in ectopic DPax2 expression within the embryonic peripheral nervous system, and we show that this effect is EGFR-dependent. Finally, we show that the canonical U-shaped embryonic lethal phenotype of hnt, which is associated with premature degeneration of the extraembyonic amnioserosa and a failure in germ band retraction, is rescued by expression of several components of the EGFR signaling pathway (sSpi, Ras85DV12 , pntP1 ) as well as the caspase inhibitor p35 Based on this collection of corroborating evidence, we suggest that an overarching function of hnt involves the positive regulation of EGFR signaling.

Detection of minimal disseminated disease is a validated prognostic factor in ALK-positive anaplastic large cell lymphoma. We previously reported that quantification of minimal disease by quantitative real-time polymerase chain reaction (RQ-PCR) in bone marrow applying a cut-off of 10 copies NPM-ALK/104 copies of ABL1 identifies very high-risk patients. In the present study, we aimed to confirm the prognostic value of quantitative minimal disseminated disease evaluation and to validate digital polymerase chain reaction (dPCR) as an alternative method. Among 91 patients whose bone marrow was analyzed by RQ-PCR, more than 10 normalized copy-numbers correlated with stage III/IV disease, mediastinal and visceral organ involvement and low anti-ALK antibody titers. The cumulative incidence of relapses of 18 patients with more than 10 normalized copy-numbers of NPM-ALK was 61±12% compared to 21±5% for the remaining 73 patients (P=0.0002). Results in blood correlated with those in bone marrow (r=0.74) in 70 patients for whom both materials could be tested. Transcripts were quantified by RQ-PCR and dPCR in 75 bone marrow and 57 blood samples. Copy number estimates using dPCR and RQ-PCR correlated in 132 samples (r=0.85). Applying a cut-off of 30 copies NPM-ALK/104 copies ABL1 for quantification by dPCR, almost identical groups of patients were separated as those separated by RQ-PCR. In summary, the prognostic impact of quantification of minimal disseminated disease in bone marrow could be confirmed for patients with anaplastic large cell lymphoma. Blood can substitute for bone marrow. Quantification of minimal disease by dPCR provides a promising tool to facilitate harmonization of minimal disease measurement between laboratories and for clinical studies.

Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycolysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glutamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both in vitro and in vivo; high sensitivity to L-asp was caused by low expression of asparagine synthetase (ASNS) and L-asp-induced suppression of glutamine metabolism. In addition, samples from patients with EVI1+MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L-asp treatment. Clarification of metabolic reprogramming in EVI1+ leukemia cells may aid development of treatments for EVI1+MF9 refractory leukemia.

Retrospective analysis.

Despite great interest, the mechanism of neutrophil extracellular traps (NETs) release is not fully understood and some aspects of this process, e.g. the role of reactive nitrogen species (RNS), still remain unclear. Therefore, our aim was to investigate the mechanisms underlying RNS-induced formation of NETs and contribution of RNS to NETs release triggered by various physiological and synthetic stimuli. The involvement of RNS in NETs formation was studied in primary human neutrophils and differentiated human promyelocytic leukemia cells (HL-60 cells). RNS (peroxynitrite and nitric oxide) efficiently induced NETs release and potentiated NETs-inducing properties of platelet activating factor and lipopolysaccharide. RNS-induced NETs formation was independent of autophagy and histone citrullination, but dependent on the activity of phosphoinositide 3-kinases (PI3K) and myeloperoxidase, as well as selective degradation of histones H2A and H2B by neutrophil elastase. Additionally, NADPH oxidase activity was required to release NETs upon stimulation with NO, as shown in NADPH-deficient neutrophils isolated from patients with chronic granulomatous disease. The role of RNS was further supported by increased RNS synthesis upon stimulation of NETs release with phorbol 12-myristate 13-acetate and calcium ionophore A23187. Scavenging or inhibition of RNS formation diminished NETs release triggered by these stimuli while scavenging of peroxynitrite inhibited NO-induced NETs formation. Our data suggest that RNS may act as mediators and inducers of NETs release. These processes are PI3K-dependent and ROS-dependent. Since inflammatory reactions are often accompanied by nitrosative stress and NETs formation, our studies shed a new light on possible mechanisms engaged in various immune-mediated conditions.

There is growing interest in the use of "distributionally-sensitive" forms of economic evaluation that capture both the impact of an intervention upon average population health and the distribution of that health amongst the population. This review aims to inform the conduct of distributionally sensitive evaluations in the UK by answering three questions: (1) How averse are the UK public towards inequalities in lifetime health between socioeconomic groups? (2) Does this aversion differ depending upon the type of health under consideration? (3) Are the UK public as averse to inequalities in health between socioeconomic groups as they are to inequalities in health between neutrally framed groups? EMBASE, MEDLINE, EconLit, and SSCI were searched for stated preference studies relevant to these questions in October 2017. Of the 2155 potentially relevant papers identified, 15 met the predefined hierarchical eligibility criteria. Seven elicited aversion to inequalities in health between socioeconomic groups, and eight elicited aversion between neutrally labelled groups. We find general, although not universal, evidence for aversion to inequalities in lifetime health between socioeconomic groups, albeit with significant variation in the strength of that preference across studies. Second, limited evidence regarding the impact of the type of health upon aversion. Third, some evidence that the UK public are more averse to inequalities in lifetime health when those inequalities are presented in the context of socioeconomic inequality than when presented in isolation.

The Montreal Cognitive Assessment (MoCA) is an increasingly used screening tool for cognitive impairment. While it has been validated in multiple settings and languages, most studies have used a biased case-control design including healthy controls as comparisons not representing a clinical setting. The purpose of the present cross-sectional study is to test the criterion validity of the MoCA for mild cognitive impairment (MCI) and mild dementia (MD) in an old age psychiatry cohort (n = 710). The reference standard consists of a multidisciplinary, consensus-based diagnosis in accordance with international criteria. As a secondary outcome, the use of healthy community older adults as additional comparisons allowed us to underscore the effects of case-control spectrum-bias.

Variation in methotrexate (MTX) efficacy represents a significant barrier to early and effective disease control in the treatment of autoimmune arthritis. We hypothesize that the utilization of metabolomic techniques will allow for an improved understanding of the biochemical basis for the pharmacological activity of MTX, and can promote the identification and evaluation of novel molecular biomarkers of MTX response. In this work, erythroblastoid cells were exposed to MTX at the physiologic concentration of 1,000 nM and analyzed using three metabolomic platforms to give a broad spectrum of cellular metabolites. MTX pharmacological activity, defined as cellular growth inhibition, was associated with an altered cellular metabolomic profile based on the analysis of 724 identified metabolites. By discriminant analysis, MTX treatment was associated with increases in ketoisovaleric acid, fructose, galactose, and 2-deoxycytidine, and corresponding reductions in 2-deoxyuridine, phosphatidylinositol 32:0, orotic acid, and inosine monophosphate. Inclusion of data from analysis of folate metabolism in combination with chemometric and metabolic network analysis demonstrated that MTX treatment is associated with dysregulated folate metabolism and nucleotide biosynthesis, which is in line with its known mechanism of action. However, MTX treatment was also associated with alterations in a diversity of metabolites, including intermediates of amino acid, carbohydrate, and lipid metabolism. Collectively, these findings support a robust metabolic response following exposure to physiologic concentrations of MTX. They also identify various metabolic intermediates that are associated with the pharmacological activity of MTX, and are, therefore, potential molecular biomarker candidates in future preclinical and clinical studies of MTX efficacy in autoimmune arthritis.

Cell-based influenza vaccines can solve the problem of the frequent occurrence of egg adaptation-associated antigenic changes observed in egg-based vaccines. Seed viruses for cell-based vaccines can be prepared from clinical specimens by cell culture; however, clinical samples risk harboring respiratory viruses other than influenza virus. Therefore, it is necessary to investigate the patterns of co-infection in clinical samples and explore whether cell culture technology can selectively propagate influenza viruses from samples containing other respiratory viruses.