37 research outputs found
ALA: Naturalness-aware Adversarial Lightness Attack
Most researchers have tried to enhance the robustness of DNNs by revealing
and repairing the vulnerability of DNNs with specialized adversarial examples.
Parts of the attack examples have imperceptible perturbations restricted by Lp
norm. However, due to their high-frequency property, the adversarial examples
can be defended by denoising methods and are hard to realize in the physical
world. To avoid the defects, some works have proposed unrestricted attacks to
gain better robustness and practicality. It is disappointing that these
examples usually look unnatural and can alert the guards. In this paper, we
propose Adversarial Lightness Attack (ALA), a white-box unrestricted
adversarial attack that focuses on modifying the lightness of the images. The
shape and color of the samples, which are crucial to human perception, are
barely influenced. To obtain adversarial examples with a high attack success
rate, we propose unconstrained enhancement in terms of the light and shade
relationship in images. To enhance the naturalness of images, we craft the
naturalness-aware regularization according to the range and distribution of
light. The effectiveness of ALA is verified on two popular datasets for
different tasks (i.e., ImageNet for image classification and Places-365 for
scene recognition).Comment: 9 page
Oat beta-glucan reduces colitis by promoting autophagy flux in intestinal epithelial cells via EPHB6-TFEB axis
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract, mainly including Crohnās disease and ulcerative colitis. Epidemiological findings suggest that inadequate dietary fibers intake may be a risk factor for IBD. Oat beta-glucan is a type of fermentable dietary fiber and has been proved to reduce experimental colitis. However, the mechanism remains unclear. The aim of this study was to explore the role and possible mechanism of oat beta-glucan in reducing experimental colitis. We used a dextran sulfate sodium (DSS)-induced mice acute colitis model to explore the potential mechanism of oat beta-glucan in reducing experimental colitis. As a result, oat beta-glucan upregulated the expressions of Erythropoietin-producing hepatocyte receptor B6 (EPHB6) and transcription factor EB (TFEB), promoted autophagy flux and downregulated the expressions of interleukin 1 beta (IL-1Ī²), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-Ī±) in intestinal epithelial cells (IECs). The role of the EPHB6-TFEB axis was explored using a lipopolysaccharide-induced HT-29 cells inflammation model. The results revealed that EPHB6 regulated the expression of TFEB, and knockdown of EPHB6 decreased the protein level of TFEB. When EPHB6 or TFEB was knocked down, autophagy flux was inhibited, and the anti-inflammatory effect of sodium butyrate, a main metabolite of oat beta-glucan in the gut, was blocked. In summary, our findings demonstrated that oat beta-glucan reduced DSS-induced acute colitis in mice, promoted autophagy flux via EPHB6-TFEB axis and downregulated the expressions of IL-1Ī², IL-6 and TNF-Ī± in IECs, and this effect may be mediated by butyrate
Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice
Acknowledgments and Disclosures This work was supported by the National Institutes of Health (Grant Nos. R01DK093587 and R01DK101379 [to YX], R01DK092605 to [QT], R01DK078056 [to MM]), the Klarman Family Foundation (to YX), the Naman Family Fund for Basic Research (to YX), Curtis Hankamer Basic Research Fund (to YX), American Diabetes Association (Grant Nos. 7-13-JF-61 [to QW] and 1-15-BS-184 [to QT]), American Heart Association postdoctoral fellowship (to PX), Wellcome Trust (Grant No. WT098012 [to LKH]), and Biotechnology and Biological Sciences Research Council (Grant No. BB/K001418/1 [to LKH]). The anxiety tests (e.g., open-field test, light-dark test, elevated plus maze test) were performed in the Mouse Neurobehavior Core, Baylor College of Medicine, which was supported by National Institutes of Health Grant No. P30HD024064. PX and YH were involved in experimental design and most of the procedures, data acquisition and analyses, and writing the manuscript. XC assisted in the electrophysiological recordings; LV-T assisted in the histology study; XY, KS, CW, YY, AH, LZ, and GS assisted in surgical procedures and production of study mice. MGM, QW, QT, and LKH were involved in study design and writing the manuscript. YX is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors report no biomedical financial interests or potential conflicts of interest.Peer reviewedPublisher PD
Distinct Hypothalamic Neurons Mediate Estrogenic Effects on Energy Homeostasis and Reproduction
SummaryEstrogens regulate body weight and reproduction primarily through actions on estrogen receptor-Ī± (ERĪ±). However, ERĪ±-expressing cells mediating these effects are not identified. We demonstrate that brain-specific deletion of ERĪ± in female mice causes abdominal obesity stemming from both hyperphagia and hypometabolism. Hypometabolism and abdominal obesity, but not hyperphagia, are recapitulated in female mice lacking ERĪ± in hypothalamic steroidogenic factor-1 (SF1) neurons. In contrast, deletion of ERĪ± in hypothalamic pro-opiomelanocortin (POMC) neurons leads to hyperphagia, without directly influencing energy expenditure or fat distribution. Further, simultaneous deletion of ERĪ± from both SF1 and POMC neurons causes hypometabolism, hyperphagia, and increased visceral adiposity. Additionally, female mice lacking ERĪ± in SF1 neurons develop anovulation and infertility, while POMC-specific deletion of ERĪ± inhibits negative feedback regulation of estrogens and impairs fertility in females. These results indicate that estrogens act on distinct hypothalamic ERĪ± neurons to regulate different aspects of energy homeostasis and reproduction
Secreted glucose regulated protein78 ameliorates DSS-induced mouse colitis
The secreted form of 78-kDa glucose-regulated protein (sGRP78) has been widely reported for its property in aiding resolution of inflammatory. However, little is known on its potential in the treatment of colitis. To investigate the expression pattern and functional outcome of GRP78 in ulcerative colitis, its expression was measured in human and murine colitis samples. It was found that GRP78 was spontaneously secreted to a high level in gut, which is a physiological site of immune tolerance. During the active phase of DSS-induced colitis, the sGRP78 level was significantly reduced but rebounded quickly during resolving phase, making it a potential candidate for the treatment of colitis. In the following experiments, the administration of sGRP78 was proved to decrease susceptibility to experimental colitis, as indicated by an overall improvement of intestinal symptoms, restoration of TJ integrity, decreased infiltration of immune cells and impaired production of inflammatory cytokines. And specific cleavage of endogenous sGRP78 could aggravate DSS colitis. Adoptive transfer of sGRP78-conditioned BMDMs reduced inflammation in the gut. We linked sGRP78 treatment with altered macrophage biology and skewed macrophage polarization by inhibiting the TLR4-dependent MAP-kinases and NF-ĪŗB pathways. Based on these studies, as a naturally occurring immunomodulatory molecule, sGRP78 might be an attractive novel therapeutic agent for acute intestinal inflammation
Estrogen receptorāĪ± in medial amygdala neurons regulates body weight
Estrogen receptorāĪ± (ERĪ±) activity in the brain prevents obesity in both males and females. However, the ERĪ±-expressing neural populations that regulate body weight remain to be fully elucidated. Here we showed that single-mindedā1 (SIM1) neurons in the medial amygdala (MeA) express abundant levels of ERĪ±. Specific deletion of the gene encoding ERĪ± (Esr1) from SIM1 neurons, which are mostly within the MeA, caused hypoactivity and obesity in both male and female mice fed with regular chow, increased susceptibility to diet-induced obesity (DIO) in males but not in females, and blunted the body weightālowering effects of a glucagon-like peptide-1āestrogen (GLP-1āestrogen) conjugate. Furthermore, selective adeno-associated virus-mediated deletion of Esr1 in the MeA of adult male mice produced a rapid body weight gain that was associated with remarkable reductions in physical activity but did not alter food intake. Conversely, overexpression of ERĪ± in the MeA markedly reduced the severity of DIO in male mice. Finally, an ERĪ± agonist depolarized MeA SIM1 neurons and increased their firing rate, and designer receptors exclusively activated by designer drugāmediated (DREADD-mediated) activation of these neurons increased physical activity in mice. Collectively, our results support a model where ERĪ± signals activate MeA neurons to stimulate physical activity, which in turn prevents body weight gain
Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice
Binge eating afflicts approximately 5% of US adults, though effective treatments are limited. Here, we showed that estrogen replacement substantially suppresses binge-like eating behavior in ovariectomized female mice. Estrogen-dependent inhibition of binge-like eating was blocked in female mice specifically lacking estrogen receptor-Ī± (ERĪ±) in serotonin (5-HT) neurons in the dorsal raphe nuclei (DRN). Administration of a recently developed glucagon-like peptide-1āestrogen (GLP-1āestrogen) conjugate designed to deliver estrogen to GLP1 receptorāenhanced regions effectively targeted bioactive estrogens to the DRN and substantially suppressed binge-like eating in ovariectomized female mice. Administration of GLP-1 alone reduced binge-like eating, but not to the same extent as the GLP-1āestrogen conjugate. Administration of ERĪ±-selective agonist propylpyrazole triol (PPT) to murine DRN 5-HT neurons activated these neurons in an ERĪ±-dependent manner. PPT also inhibited a small conductance Ca2+-activated K+ (SK) current; blockade of the SK current prevented PPT-induced activation of DRN 5-HT neurons. Furthermore, local inhibition of the SK current in the DRN markedly suppressed binge-like eating in female mice. Together, our data indicate that estrogens act upon ERĪ± to inhibit the SK current in DRN 5-HT neurons, thereby activating these neurons to suppress binge-like eating behavior and suggest ERĪ± and/or SK current in DRN 5-HT neurons as potential targets for anti-binge therapies
A potential brain functional biomarker distinguishing patients with Crohnās disease with different disease stages: a resting-state fMRI study
BackgroundThe previous studies have demonstrated that patients with Crohnās disease in remission (CD-R) have abnormal alterations in brain function. However, whether brain function changes in patients with Crohnās disease in activity (CD-A) and the relationship with CD-R are still unclear. In this study, we aimed to investigate whether the different levels of disease activity may differentially affect the brain function and to find the brain functional biomarker distinguishing patients with different disease stages by measuring the amplitude of low frequency fluctuations (ALFF).Methods121 patients with CD and 91 healthy controls (HCs) were recruited. The clinical and psychological assessment of participants were collected. The criteria for the disease activity were the Crohnās disease activity index (CDAI) scores. CD-R refers to CD patients in remission which the CDAI score is less than 150. Conversely, CD-A refers to CD patients in activity which the CDAI score is ā„150. The ALFF was compared among three groups by performing one-way analysis of variance, followed by a post hoc two-sample t-test. Differences among the groups were selected as seeds for functional connectivity analyses. We also investigated the correlation among clinical, psychological scores and ALFF. Binary logistic regression analysis was used to examine the unique contribution of the ALFF characteristics of the disease stages.ResultsThere were widespread differences of ALFF values among the 3 groups, which included left frontal pole (FP_L), right supramarginal gyrus (SG_R), left angular gyrus (AG_L), right cingulate gyrus (CG_R), right intracalcarine cortex (IC_R), right parahippocampal gyrus (PG_R), right lingual gyrus (LG_R), right precuneous cortex (PC_R), left occipital fusiform gyrus (OFG_L). Significant brain regions showing the functional connections (FC) increased in FP_L, SG_R, PC_R and OFG_L between CD-A and HCs. The erythrocyte sedimentation rate had a negative correlation with the ALFF values in PC_R in the patients with CD. The phobic anxiety values had a negative correlation with the ALFF values in OFG_L. The psychoticism values had a negative correlation with ALFF values in the IC_R. And the hostility values had a positive correlation with the ALFF values in CG_R. Significant brain regions showing the FC increased in FP_L, SG_R, CG_R, PG_R, LG_R and OFG_L between CD-R and HCs. In binary logistic regression models, the LG_R (betaā=ā5.138, pā=ā0.031), PC_R (betaā=ā1.876, pā=ā0.002) and OFG_L (betaā=ā3.937, pā=ā0.044) was disease stages predictors.ConclusionThe results indicated the significance of the altered brain activity in the different disease stages of CD. Therefore, these findings present a potential identify neuroimaging-based brain functional biomarker in CD. Additionally, the study provides a better understanding of the pathophysiology of CD
Endoscopic ultrasonography with fine-needle aspiration for histological diagnosis of solid pancreatic masses: a meta-analysis of diagnostic accuracy studies
Uncovering the Novel Role of NR1D1 in Regulating BNIP3-Mediated Mitophagy in Ulcerative Colitis
Background: Ulcerative colitis (UC) is a chronic, incurable condition characterized by mucosal inflammation and intestinal epithelial cell (IEC) damage. The circadian clock gene NR1D1, implicated in UC and the critical mitophagy process for epithelial repair, needs further exploration regarding its role in mitophagy regulation in UC. Methods: We created a jet lag mouse model and induced colitis with dextran sulfate sodium (DSS), investigating NR1D1ās role. Intestinal-specific Nr1d1 knockout mice were also generated. RNA sequencing, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays helped ascertain NR1D1ās regulatory effect on BNIP3 expression. The mitochondrial state in IECs was assessed through transmission electron microscopy, while confocal microscopy evaluated mitophagy-associated protein expression in colon tissue and CCD841 cells. Cell apoptosis and reactive oxygen species (ROS) were measured via flow cytometry. Results: We observed reduced NR1D1 expression in the IECs of UC patients, accentuated under jet lag and DSS exposure in mice. NR1D1 ablation led to disrupted immune homeostasis and declined mitophagy in IECs. NR1D1, usually a transcriptional repressor, was a positive regulator of BNIP3 expression, leading to impaired mitophagy, cellular inflammation, and apoptosis. Administering the NR1D1 agonist SR9009 ameliorated colitis symptoms, primarily by rectifying defective mitophagy. Conclusions: Our results suggest that NR1D1 bridges the circadian clock and UC, controlling BNIP3-mediated mitophagy and representing a potential therapeutic target. Its agonist, SR9009, shows promise in UC symptom alleviation