ES-62 is a secreted parasitic worm-derived immunomodulator that exhibits therapeutic potential in allergy by downregulating aberrant MyD88 signalling to normalise the inflammatory phenotype and mast cell responses. IL-33 plays an important role in driving mast cell responses and promoting type-2 allergic inflammation, particularly with respect to asthma, via MyD88-integrated crosstalk amongst the IL-33 receptor (ST2), TLR4 and FcεRI. We have now investigated whether ES-62 targets this pathogenic network by subverting ST2-signalling, specifically by characterising how the functional outcomes of crosstalk amongst ST2, TLR4 and FcεRI are modulated by the worm product in wild type and ST2-deficient mast cells. This analysis showed that whilst ES-62 inhibits IL-33/ST2 signalling, the precise functional modulation observed varies with receptor usage and/or mast cell phenotype. Thus, whilst ES-62's harnessing of the capacity of ST2 to sequester MyD88 appears sufficient to mediate its inhibitory effects in peritoneal-derived serosal mast cells, downregulation of MyD88 expression appears to be required to dampen the higher levels of cytokine production typically released by bone marrow-derived mucosal mast cells.

Autophagy plays a central role in degrading misfolded proteins such as mutated superoxide dismutase 1 (SOD1), which forms aggregates in motor neurons and is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is activated when UNC-51-like kinase 1 (ULK1) is phosphorylated at S555 and activated by AMP-activated protein kinase (AMPK). Autophagy is suppressed when ULK1 is phosphorylated at S757 by the mechanistic target of rapamycin (mTOR). Whether p70 S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, can also regulate autophagy remains uncertain. Here we report that inhibition of S6K1 by A77 1726, the active metabolite of an anti-inflammatory drug leflunomide, induced mTOR feedback activation and ULK1S757 phosphorylation in NSC34 cells, a hybrid mouse motoneuron cell line. Unexpectedly, A77 1726 did not suppress but rather induced autophagy by increasing AMPKT172 and ULK1S555 phosphorylation. Similar observations were made with PF-4708671, a specific S6K1 inhibitor, or with S6K1 siRNA. Further studies showed that A77 1726 induced AMPK phosphorylation by activating the TGF-β-activated kinase 1 (TAK1). Functional studies revealed that A77 1726 induced co-localization of mutant SOD1G93A protein aggregates with autophagosomes and accelerated SOD1G93A protein degradation, which was blocked by inhibition of autophagy through autophagy-related protein 7 (ATG7) siRNA. Our study suggests that S6K1 inhibition induces autophagy through TAK1-mediated AMPK activation in NSC34 cells, and that blocking S6K1 activity by a small molecule inhibitor such as leflunomide may offer a new strategy for ALS treatment.

Electrolytic copper is a well-known form of pure, oxygen free copper that is used for industrial applications. In this work, the catalytic potential of this relatively cheap material was studied. The addition of less than 0.015 mol equivalent of copper powder effectively catalysed the one-pot synthesis of triazoles from a diverse range of organic halides and alkynes. Quantitative conversions in aqueous solvents can be achieved within minutes. The heterogenous nature of the catalyst afforded a low level of copper contamination in the products, thus meeting the rigorous criteria of the pharmaceutical industry.

To identify the variations in fusion (F) protein gene of RSV in China, a molecular epidemiological study was conducted. A total of 553 RSV positive specimens were collected from 2338 pediatric patients hospitalized with community-acquired pneumonia during a multi-center study conducted during 2014-2016. A total of 252 samples (183 RSV A, 69 RSV B) were selected for F gene sequencing, and analyzed together with 142 F gene sequences downloaded from GenBank. The result showed that all the Chinese RSV A and RSV B strains could be divided respectively into three branches. Compared with RSV A/B prototype sequences respectively, there were significant amino acid (AA) mutations at multiple antigenic sites. For RSV A, changes were found at AA residues 122, 124, 125, 276 and 384, and for RSV B at AA residues 45, 116, 125, 172, 173 and 202. Variations in human histocompatibility leukocyte antigen-restricted CTL epitopes were also observed. In total, 56 amino acid differences for the complete F protein were found between the RSV A and B groups in China, while several mutations were only found in the RSV B strains during 2015-2016. The RSV F gene is relatively conserved in China, however, limited mutations are still occurring with time.

Anhedonia (hyposensitivity to rewards) and negative bias (hypersensitivity to punishments) are core features of major depressive disorder (MDD), which could stem from abnormal reinforcement learning. Emerging evidence highlights blunted reward learning and reward prediction error (RPE) signaling in the striatum in MDD, although inconsistencies exist. Preclinical studies have clarified that ventral tegmental area (VTA) neurons encode RPE and habenular neurons encode punishment prediction error (PPE), which are then transmitted to the striatum and cortex to guide goal-directed behavior. However, few studies have probed striatal activation, and functional connectivity between VTA-striatum and VTA-habenula during reward and punishment learning respectively, in unmedicated MDD. To fill this gap, we acquired fMRI data from 25 unmedicated MDD and 26 healthy individuals during a monetary instrumental learning task and utilized a computational modeling approach to characterize underlying neural correlates of RPE and PPE. Relative to controls, MDD individuals showed impaired reward learning, blunted RPE signal in the striatum and overall reduced VTA-striatal connectivity to feedback. Critically, striatal RPE signal was increasingly blunted with more major depressive episodes (MDEs). No group differences emerged in PPE signals in the habenula and VTA or in connectivity between these regions. However, PPE signals in the habenula correlated positively with number of MDEs. These results highlight impaired reward learning, disrupted RPE signaling in the striatum (particularly among individuals with more lifetime MDEs) as well as reduced VTA-striatal connectivity in MDD. Collectively, these findings highlight reward-related learning deficits in MDD and their underlying pathophysiology.

The current study adopted McAdams' multilayer framework as the basis to develop a psychological portrait of an elite athlete who was identified as being particularly 'mentally tough'. The aim was to use this single case as an exemplar to demonstrate the utility of McAdams' framework for understanding the complexity of sport performers across three domains of personality: dispositional traits, characteristic adaptations, and narrative identity. We operationalised these domains through the development of specific research questions and, subsequently, the collection and integration of the participant's Big Five traits, personal strivings, coping strategies, and response to a life story interview. The results offered a comprehensive insight into the nature of one athlete's personality that, in turn, informed conceptual perspectives of mental toughness in sport psychology literature and qualitatively supported emerging evidence of the validity of a three-layer framework in personality psychology. Specifically, the study's design showed how a holistic approach to personality analysis can lead to a more complete psychological representation of competitors in sport, and people generally. It demonstrated how motivational, sociocultural, and meaning-making aspects of personality can complement a trait profile to achieving a satisfying assessment of the whole person.

Rab11 family-interacting protein 2 (Rab11-FIP2) can interact with MYO5B and plays an important role in regulating plasma membrane recycling. However, little is known about the clinical significance of DUSP2 in colorectal cancer (CRC).

Gastric cancer (GC) is a malignant tumor worldwide. As primary pathway for metastasis, the lymphatic system is an important prognostic factor for GC patients. Although the metabolic changes of gastric cancer have been investigated in extensive studies, little effort focused on the metabolic profiling of lymph node metastasis (LNM)-positive or negative GC patients.

This paper presents an accurate nonlinear classification method that can help physicians diagnose seizure in electroencephalographic (EEG) signal characterized by a disturbance in temporal and spectral content. This is accomplished by applying four steps. First, different EEG signals containing healthy, ictal and seizure-free (inter-ictal) activities are decomposed by empirical mode decomposition method. The instantaneous amplitudes and frequencies of resulted bands (intrinsic mode functions, IMF) are then tracked by the direct quadrature method (DQ). In contrast to other approaches, DQ cancels the effect of amplitude modulation on frequency calculation. The dissociation between instantaneous amplitude and frequency information is therefore fully achieved to avoid features confusion. Afterwards, the Shannon entropy values of both sets of instantaneous values (amplitudes and frequencies)-related to every IMF-are calculated. Finally, the obtained entropy values are classified by random forest tree. The proposed procedure yields 100% accuracy for (healthy)/(ictal) and 98.3-99.7% for (healthy)/(ictal)/(interictal) classification problems. The suggested method is hence robust, accurate, fast, user-friendly, data driven with open access interpretability.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) signaling pathway was reported to exert an important role in neuronal apoptosis. The present study was designed to investigate the roles of the PERK signaling pathway in the secondary brain injury (SBI) induced by intracerebral hemorrhage (ICH) and its potential mechanisms. Sprague-Dawley rats were used to establish ICH models by injecting autologous blood (100 μl), and cultured primary rat cortical neurons were exposed to oxyhemoglobin (10 μM) to mimic ICH in vitro. The PERK antagonist, GSK2606414, and inhibitor of eukaryotic translation initiation factor 2 subunit α (eIF2α) dephosphorylation, salubrinal, were used to study the roles of PERK signaling pathway in ICH-induced SBI. Our results showed that the protein levels of p-eIF2α and ATF4 were upregulated following ICH, peaking at 48 h. Application of GSK2606414 reversed this increase in vivo and in vitro, thereby preventing ICH-induced neuronal apoptosis. On the contrary, salubrinal inhibited the dephosphorylation of eIF2α, resulting in the elevation of p-eIF2α, which could activate downstream of PERK signaling and induce neuronal apoptosis and necrosis following ICH in vitro and in vivo. Thus, PERK signaling pathway plays an important role in ICH-induced apoptosis and blocking its activation has neuroprotective effects that alleviates SBI, suggesting that targeting this pathway could be a promising therapeutic strategy for improving patient outcome after ICH.

Patients with autism spectrum disorder (ASD) display abnormalities in neuronal development, synaptic function and neural circuits. The imbalance of excitatory and inhibitory (E/I) synaptic transmission has been proposed to cause the main behavioral characteristics of ASD. Repetitive transcranial magnetic stimulation (rTMS) can directly or indirectly induce excitability and synaptic plasticity changes in the brain noninvasively. However, whether rTMS can ameliorate autistic-like behaviors in animal model via regulating the balance of E/I synaptic transmission is unknown. By using our recent reported animal model with autistic-like behaviors induced by neonatal isolation (postnatal days 1-9), we found that low-frequency rTMS (LF-rTMS, 1 Hz) treatment for 2 weeks effectively alleviated the acquired autistic-like symptoms, as reflected by an increase in social interaction and decrease in self-grooming, anxiety- and depressive-like behaviors in young adult rats compared to those in untreated animals. Furthermore, the amelioration in autistic-like behavior was accompanied by a restoration of the balance between E/I activity, especially at the level of synaptic transmission and receptors in synaptosomes. These findings indicated that LF-rTMS may alleviate the symptoms of ASD-like behaviors caused by neonatal isolation through regulating the synaptic GABA transmission, suggesting that LF-rTMS may be a potential therapeutic technique to treat ASD.

This study evaluated the participation of host cell Rho-family GTPases and their effector proteins in the actin-dependent invasion by Trypanosoma cruzi extracellular amastigotes (EAs). We observed that all proteins were recruited and colocalized with actin at EA invasion sites in live or fixed cells. EA internalization was inhibited in cells depleted in Rac1, N-WASP, and WAVE2. Time-lapse experiments with Rac1, N-WASP and WAVE2 depleted cells revealed that EA internalization kinetics is delayed even though no differences were observed in the proportion of EA-induced actin recruitment in these groups. Overexpression of constitutively active constructs of Rac1 and RhoA altered the morphology of actin recruitments to EA invasion sites. Additionally, EA internalization was increased in cells overexpressing CA-Rac1 but inhibited in cells overexpressing CA-RhoA. WT-Cdc42 expression increased EA internalization, but curiously, CA-Cdc42 inhibited it. Altogether, these results corroborate the hypothesis of EA internalization in non-phagocytic cells by a phagocytosis-like mechanism and present Rac1 as the key Rho-family GTPase in this process.

Class-switch recombination (CSR) and somatic hypermutation (SHM) occur during the differentiation of germinal center B cells (GCBs). Activation-induced cytidine deaminase (AID) is responsible for both CSR and SHM in GCBs. Here, we show that ablation of PTEN through the Cγ1-Cre mediated recombination significantly influences the CSR and SHM responses. The GCs fail to produce the IgG1 B cells, the high affinity antibodies and nearly lost the dark zone (DZ) in Ptenfl/flCγ1Cre/+ mice after immunization, suggesting the impaired GC structure. Further mechanistic investigations show that LPS- and interleukin-4 stimulation induced the transcription of Cγ1 in IgM-BCR expressing B cells, which efficiently disrupts PTEN transcription, results in the hyperphosphorylated AKT and FoxO1 and in turn the suppression of AID transcription. Additionally, the reduced transcription of PTEN and AID is also validated by investigating the IgM-BCR expressing GCBs from Ptenfl/flCγ1Cre/+ mice upon immunization. In conclusion, PTEN regulated AID transcription in GCBs is essential for the CSR and IgG antibody responses.

A bioinformatic analysis of previously published RNA-Seq studies on Huanglongbing (HLB) response and tolerance in leaf tissues was performed. The aim was to identify genes commonly modulated between studies and genes, pathways and gene set categories strongly associated with this devastating Citrus disease. Bioinformatic analysis of expression data of four datasets present in NCBI provided 46-68 million reads with an alignment percentage of 72.95-86.76%. Only 16 HLB-regulated genes were commonly identified between the three leaf datasets. Among them were key genes encoding proteins involved in cell wall modification such as CESA8, pectinesterase, expansin8, expansin beta 3.1, and a pectate lyase. Fourteen HLB-regulated genes were in common between all four datasets. Gene set enrichment analysis showed some different gene categories affected by HLB disease. Although sucrose and starch metabolism was highly linked with disease symptoms, different genes were significantly regulated depending on leaf growth and infection stages and experimental conditions. Histone-related transcription factors were highly affected by HLB in the analyzed RNA-Seq datasets. HLB tolerance was linked with induction of proteins involved in detoxification. Protein-protein interaction (PPI) network analysis confirmed a possible role for heat shock proteins in curbing disease progression.

Adults with intellectual disabilities (ID) often live a sedentary lifestyle and have higher rates of overweight and obesity. The purpose of this report is to describe the design and methods of a multi-component physical activity (PA) intervention program that aims to increase PA levels in adults with ID who live in group homes. The study employed a multi-component delayed treatment control group design involving adults with ID who lived in two group homes. Interventions included 30 exercise sessions in groups over a 10-week period and three educational lessons based on social cognitive theory that aimed to improve self-efficacy and social support for PA in the participants. In addition, staff training in exercise and advice on institutional PA policies were provided to the caregivers working in the group homes. Outcome measures on three aspects were collected: (1) physical fitness, (2) PA as assessed by an ActiGraph accelerometer, and (3) self-efficacy and social support for PA. Our major objective was to develop the intervention protocol, and the successful completion of this study will provide valuable evidence on how to promote active lifestyles in adults with ID.

This article aims to assess the effects of ginger (Zingiber officinale Roscoe) on type 2 diabetes mellitus (T2DM) and/or components of the metabolic syndrome (MetS).

Structural changes in symbiotic human microorganisms can affect host phenotype. Liver-fire hyperactivity syndrome (LFHS) presents as bitter taste, halitosis, xerostomia, odontalgia, and other oral symptoms. LFHS is associated with hypertension (EH). In this study, tongue flora was analyzed to further understand the intrinsic relationship between tongue flora and LFHS. Samples of tongue coating, from 16 patients with EH-LFHS, 16 with EH-non-LFHS, and 16 controls, were obtained; then, 16S rRNA variable (V3-V4) regions were amplified and sequenced by MiSeq PE300 Sequencing. Tag clustering and Operational Taxonomic Units (OTUs) abundance analysis were used to compare the OTU sequence with the 16S database. The species were classified, and diversity and structure of the bacterial flora were compared between the three groups. Alpha diversity analysis, including Observed Species index and Chao index, indicated significantly higher richness of species in patients with EH-LFHS (p < 0.05). Higher phylogenetic diversity, in patients with EH-non-LFHS, indicates greater differences in evolutionary history than in patients with EH-LFHS. Streptococcus, Rothia, Neisseria, and Sphingomonas were the most prevalent in patients with EH-LFHS, differed from the other two groups. This indicates that richer bacterial diversity, and structure associated with EH-LFHS, may affect the occurrence, development, and outcome of hypertension and syndrome subtypes recognized by TCM.

Natural killer cells (NK cells) are cytotoxic lymphocytes of innate immunity that reveal some immunoregulatory properties, however, their role in the process of ageing is not completely understood. The study aimed to analyze the expression of proteins involved in cellular stress response: sirtuin 1 (SIRT1), heat shock protein 70 (HSP70) and manganese superoxide dismutase (SOD2) in human NK cells with reference to the process of ageing. Non-stimulated and stimulated with IL-2, LPS or PMA with ionomycin cells originated from peripheral blood samples of: seniors aged over 85 ('the oldest'; n = 25; 88.5 ± 0.5 years, mean ± SEM), seniors aged under 85 ('the old'; n = 30; 75.6 ± 0.9 years) and the young (n = 31; 20.9 ± 0.3 years). The relationships between the levels of expression of cellular protective proteins in the studied population were also analyzed. The concentrations of carbonyl groups and 8-isoprostanes, markers of oxidative stress, in both stimulated and non-stimulated cultured NK cells were measured to assess the level of the oxidative stress in the cells.

Microalgae accumulate lipids when exposed to stressful conditions such as nutrient limitation that can be used to generate biofuels. Nitrogen limitation or deprivation is a strategy widely employed to elicit this response. However, this strategy is associated with a reduction in the microalgal growth, leading to overall poor lipid productivities. Here, we investigated the combined effect of a reduced source of nitrogen (ammonium) and super-saturating light intensities on the growth and induction of lipid accumulation in two model but diverse microalgal species, Phaeodactylum tricornutum and Nannochloropsis oceanica. We hypothesized that the lower energy cost of assimilating ammonium would allow the organisms to use more reductant power for lipid biosynthesis without compromising growth and that this would be further stimulated by the effect of high light (1000 µmol m-2 s-1) stress. We studied the changes in growth and physiology of both species when grown in culture media that either contained nitrate or ammonium as the nitrogen source, and an additional medium that contained ammonium with tungsten in place of molybdenum and compared this with growth in media without nitrogen. We focused our investigation on the early stages of exposure to the treatments to correspond to events relevant to induction of lipid accumulation in these two species.

Copy number variants (CNVs) are the genetic bases for microdeletion/ microduplication syndromes (MMSs). Couples with an affected child and desire to have further children are routinely tested for a potential parental origin of a specific CNV either by molecular karyotyping or by two color fluorescence in situ hybridization (FISH), yet. In the latter case a critical region probe (CRP) is combined with a control probe for identification of the chromosome in question. However, CNVs can arise also due to other reasons, like a recombination-event based on a submicroscopic, cryptic inversion in one of the parents.