Neuropeptide Y (NPY) exerts a powerful orexigenic effect in the hypothalamus. However, extra-hypothalamic nuclei also produce NPY, but its influence on energy homeostasis is unclear. Here we uncover ...a previously unknown feeding stimulatory pathway that is activated under conditions of stress in combination with calorie-dense food; NPY neurons in the central amygdala are responsible for an exacerbated response to a combined stress and high-fat-diet intervention. Central amygdala NPY neuron-specific Npy overexpression mimics the obese phenotype seen in a combined stress and high-fat-diet model, which is prevented by the selective ablation of Npy. Using food intake and energy expenditure as readouts, we demonstrate that selective activation of central amygdala NPY neurons results in increased food intake and decreased energy expenditure. Mechanistically, it is the diminished insulin signaling capacity on central amygdala NPY neurons under combined stress and high-fat-diet conditions that leads to the exaggerated development of obesity.
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•Central amygdala NPY neurons control feeding•Stress combined with a high-caloric diet increases NPY expression in the central amygdala•Insulin controls NPY expression in central amygdala neurons•Stress combined with a high-caloric diet causes insulin resistance in central amygdala
Hypothalamic NPY neurons stimulate strong feeding behavior when activated. Here Ip et al. show that chronic stress, combined with a high-fat diet, result in insulin de-repression of NPY neurons in the central amygdala, resulting in exaggerated obesity because of increased feeding and decreased energy expenditure.
Abstract
Background
The outbreak and global spread of COVID-19 was accompanied by an increase in reports of stigmatization of Chinese and Asian-looking people. The behavioral immune system provides a ...framework for stigmatization in response to infectious disease threats. Specifically, stigmatization might increase with rising levels of infectious disease threat. The present study aimed to examine this hypothesis during the early phase of the COVID-19 pandemic.
Methods
As part of the “EUCLID” project (
https://euclid.dbvis.de
), a total of 5011 persons from Germany were surveyed via an online-questionnaire between February 2
nd
and April 3
rd
, 2020, covering the progression of the COVID-19 pandemic over three time periods which were defined by critical events.
Results
There was no evidence for an increase in the stigmatization of Chinese and Asian-looking people across three topics, that is personal proximity, air travel, and medical measures upon arrival from China.
Conclusions
The present findings provide good news in that participants showed an adaptive response to the infectious disease threat rather than displaying increased stigmatization. Further research is necessary to specify the conditions that increase the risk of stigmatization in response to infectious disease threats.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neuropeptide FF (NPFF) group peptides belong to the evolutionary conserved RF-amide peptide family. While they have been assigned a role as pain modulators, their roles in other aspects of physiology ...have received much less attention. NPFF peptides and their receptor NPFFR2 have strong and localized expression within the dorsal vagal complex that has emerged as the key centre for regulating glucose homeostasis. Therefore, we investigated the role of the NPFF system in the control of glucose metabolism and the histochemical and molecular identities of NPFF and NPFFR2 neurons.
We examined glucose metabolism in Npff−/− and wild-type (WT) mice using intraperitoneal (i.p.) glucose tolerance and insulin tolerance tests. Body composition and glucose tolerance was further examined in mice after 1-week and 3-week of high-fat diet (HFD). Using RNAScope double ISH, we investigated the neurochemical identity of NPFF and NPFFR2 neurons in the caudal brainstem, and the expression of receptors for peripheral factors in NPFF neurons.
Lack of NPFF signalling in mice leads to improved glucose tolerance without significant impact on insulin excursion after the i.p. glucose challenge. In response to an i.p. bolus of insulin, Npff−/− mice have lower glucose excursions than WT mice, indicating an enhanced insulin action. Moreover, while HFD has rapid and potent detrimental effects on glucose tolerance, this diet-induced glucose intolerance is ameliorated in mice lacking NPFF signalling. This occurs in the absence of any significant impact of NPFF deletion on lean or fat masses, suggesting a direct effect of NPFF signalling on glucose metabolism. We further reveal that NPFF neurons in the subpostrema area (SubP) co-express receptors for peripheral factors involved in glucose homeostasis regulation such as insulin and GLP1. Furthermore, Npffr2 is expressed in the glutamatergic NPFF neurons in the SubP, and in cholinergic neurons of the dorsal motor nucleus of the vagus (DMV), indicating that central NPFF signalling is likely modulating vagal output to innervated peripheral tissues including those important for glucose metabolic control.
NPFF signalling plays an important role in the regulation of glucose metabolism. NPFF neurons in the SubP are likely to receive peripheral signals and mediate the control of whole-body glucose homeostasis via centrally vagal pathways. Targeting NPFF and NPFFR2 signalling may provide a new avenue for treating type 2 diabetes and obesity.
•Lack of NPFF signalling improves glucose tolerance and enhance insulin actions.•Lack of NPFF signalling ameliorates diet-induced glucose intolerance.•NPFF neurons co-express receptors for circulating factors involved in glucose homeostatic control.•NPFF neurons and NPFFR2 neurons in the dorsal vagal complex are predominantly glutamatergic and cholinergic, respectively.•The central NPFF system modulates glucose metabolism most likely via controlling parasympathetic output.
Although most people are aware of the health benefits of consuming sufficient amounts of fruit and vegetables, many do not adhere to current dietary recommendations. Recent studies have suggested ...meal colour variety as an intuitive cue for healthy and enjoyable lunch meal choices. The present study extends this research by testing the "colourful = healthy" association across meal types. Using smartphone-based Ecological Momentary Assessment, 110 participants recorded 2818 eating occasions over a period of eight days. For each eating occasion, a picture, a short written description of the meal, the meal type (breakfast, lunch, afternoon tea, dinner, snack) and the perceived meal colour variety were recorded. Foods were classified into seven food groups based on the pictures and descriptions. Data were analysed using multilevel modelling. For all meal types except afternoon tea which did not include vegetables, perceived that meal colour variety was positively related to vegetable consumption (
s ≥ 0.001,
s ≥ 3.27,
s ≤ 0.002, quasi-R
s ≥ 0.06). Moreover, perceived meal colour variety was negatively associated with sweets consumption for breakfast, dinner and snacks (
s ≤ -0.001,
s ≤ -2.82,
s ≤ 0.006, quasi-R
s ≥ 0.01). The "colourful = healthy" association can be generalized across meal types and thus may be a promising strategy to promote a healthier diet.
•Behavioral changes and governmental strategies are needed to address COVID-19.•Protective behaviors and support for measures are often studied separately.•However, these individual and collective ...pathways are cross-amplifying.•Research should address connections between individual and collective pathways.
In times of unprecedented infectious disease threats, it is essential to understand how to increase individual protective behaviors and support for collective measures. The present study therefore examines factors associated with individual and collective pathways.
Data was collected through an online survey from 4483 participants (70.8% female, M = 41.2 years) across 10 countries from April 15, 2020 to June 2, 2020 as part of the "EUCLID" project (https://euclid.dbvis.de). Structural equation modeling was used to examine individual and collective pathways across and within countries.
Overall, the adoption of individual protective behaviors and support for collective measures were high. Risk perception on the individual level and perceived effectiveness at the collective level were positively associated with both individual protective behaviors and support for collective measures. Furthermore, the model explained considerable variance in individual (40.7%) and collective protective behaviors (40.8%) and was largely replicated across countries.
The study extends previous research by demonstrating that individual risk perception and perceived effectiveness of collective measures jointly affect individual protective health behaviors and support for collective measures. These findings highlight the need to jointly consider a variety of behavioral actions against infectious disease threats, acknowledging interactions between individual and collective pathways.
This is special type of abstract that is so short and could be inserted after main abstract of article, as a blurb or inserted as annotations into a Table of contents
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•Proposing BRDTI method for per-drug ranking of DTIs.•Performed comparative evaluation of BRDTI w.r.t. AUC and per-drug nDCG.•BRDTI achieved best average results on predicting new targets for ...existing drugs.
In silico prediction of drug-target interactions (DTI) could provide valuable information and speed-up the process of drug repositioning – finding novel usage for existing drugs. In our work, we focus on machine learning algorithms supporting drug-centric repositioning approach, which aims to find novel usage for existing or abandoned drugs. We aim at proposing a per-drug ranking-based method, which reflects the needs of drug-centric repositioning research better than conventional drug-target prediction approaches.
We propose Bayesian Ranking Prediction of Drug-Target Interactions (BRDTI). The method is based on Bayesian Personalized Ranking matrix factorization (BPR) which has been shown to be an excellent approach for various preference learning tasks, however, it has not been used for DTI prediction previously. In order to successfully deal with DTI challenges, we extended BPR by proposing: (i) the incorporation of target bias, (ii) a technique to handle new drugs and (iii) content alignment to take structural similarities of drugs and targets into account.
Evaluation on five benchmark datasets shows that BRDTI outperforms several state-of-the-art approaches in terms of per-drug nDCG and AUC. BRDTI results w.r.t. nDCG are 0.929, 0.953, 0.948, 0.897 and 0.690 for G-Protein Coupled Receptors (GPCR), Ion Channels (IC), Nuclear Receptors (NR), Enzymes (E) and Kinase (K) datasets respectively. Additionally, BRDTI significantly outperformed other methods (BLM-NII, WNN-GIP, NetLapRLS and CMF) w.r.t. nDCG in 17 out of 20 cases. Furthermore, BRDTI was also shown to be able to predict novel drug-target interactions not contained in the original datasets. The average recall at top-10 predicted targets for each drug was 0.762, 0.560, 1.000 and 0.404 for GPCR, IC, NR, and E datasets respectively.
Based on the evaluation, we can conclude that BRDTI is an appropriate choice for researchers looking for an in silico DTI prediction technique to be used in drug-centric repositioning scenarios. BRDTI Software and supplementary materials are available online at www.ksi.mff.cuni.cz/∼peska/BRDTI.
State-of-the-art approaches for the prediction of drug-target interactions (DTI) are based on various techniques, such as matrix factorisation, restricted Boltzmann machines, network-based inference ...and bipartite local models (BLM). In this paper, we propose the framework of Asymmetric Loss Models (ALM) which is more consistent with the underlying chemical reality compared with conventional regression techniques. Furthermore, we propose to use an asymmetric loss model with BLM to predict drug-target interactions accurately. We evaluate our approach on publicly available real-world drug-target interaction datasets. The results show that our approach outperforms state-of-the-art DTI techniques, including recent versions of BLM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To contain the spread of Covid-19, engagement in protective behaviors across the population is of great importance. The present study investigated protective behavior intentions during the early ...phases of Covid-19 in Germany (February 2–April 3, 2020) as a function of threat level and age using data from 4,940 participants in the EUCLID project. Results indicated that the intention to engage in social distancing increased sharply with threat level. Intentions for personal hygiene also increased, although to a lesser extent. While age only had a small overall effect on behavioral intentions, differential patterns emerged. After the lockdown was introduced, the impact of age decreased for social distancing and hygiene behavior intentions but increased for seeing a doctor. Since containing the Covid-19 pandemic depends on high adoption rates of protective behaviors, future research should track sustained phases of the pandemic, including the easing of restrictions and possible new waves of infections.
The Birt-Hogg-Dube disease occurs as a result of germline mutations in the human Folliculin gene (FLCN), and is characterized by clinical features including fibrofolliculomas, lung cysts and ...multifocal renal neoplasia. Clinical and genetic evidence suggest that FLCN acts as a tumor suppressor gene. The human cell line UOK257, derived from the renal cell carcinoma of a patient with a germline mutation in the FLCN gene, harbors a truncated version of the FLCN protein. Reconstitution of the wild type FLCN protein into UOK257 cells delays cell cycle progression, due to a slower progression through the late S and G2/M-phases. Similarly, Flcn (-/-) mouse embryonic fibroblasts progress more rapidly through the cell cycle than wild type controls (Flcn (flox/flox)). The reintroduction of tumor-associated FLCN mutants (FLCN ΔF157, FLCN 1-469 or FLCN K508R) fails to delay cell cycle progression in UOK257 cells. Additionally, FLCN phosphorylation (on Serines 62 and 73) fluctuates throughout the cell cycle and peaks during the G2/M phase in cells treated with nocodazole. In keeping with this observation, the reintroduction of a FLCN phosphomimetic mutant into the UOK257 cell line results in faster progression through the cell cycle compared to those expressing the wild type FLCN protein. These findings suggest that the tumor suppression function of FLCN may be linked to its impact on the cell cycle and that FLCN phosphorylation is important for this activity. Additionally, these observations describe a novel in vitro assay for testing the functional significance of FLCN mutations and/or genetic polymorphisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Histone deacetylase inhibitors are promising anti-tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies. However, little is known about any effects ...of these drugs on the central nervous system. The aim of the present study was to analyze the effects of trichostatin A (TSA)—a broad-spectrum histone deacetylase inhibitor—on the transcriptional regulation of several genes involved in dopamine- and serotonergic neurotransmission. To this end, short-term parallel cultures of SK-NF-I neuroblastoma cells were treated with TSA either alone or in combination with hypoxia, and mRNA levels of dopamine receptor D3 (DRD3) and D4 (DRD4), dopamine transporter (DAT), dopamine hydroxylase (DBH), dopamine receptor regulating factor (DRRF), catechol-O-methyltransferase (COMT), serotonin receptor 1A (HTR1A), monoamino oxidase A (MAO-A), serotonin transporter (SLC6A4) and tryptophan hydroxylase 2 (TPH2) were determined by quantitative PCR. We found that TSA did not antagonize the hypoxia-induced activation of D3 and D4 dopamine receptor genes, implying that induction of these genes is not mediated directly by hypoxia inducible factor-1alpha. On the other hand, TSA dramatically upregulated the expression of DAT and SLC6A4 (45-fold and 15-fold, respectively), while transcript levels of MAO-A and COMT were significantly reduced (by 70% and by more than 90%, respectively). Induction of DAT protein expression was detected by western blotting. These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons.
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