Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of p62/SQSTM1 beyond autophagy: a lesson learned from drug‐induced toxicity in vitro

SQSTM1/p62 is a multifunctional, stress‐induced, scaffold protein involved in multiple cellular processes including autophagic clearance, regulation of inflammatory responses and redox homeostasis. Its altered function has been associated with different human pathologies, such as neurodegenerative, metabolic and bone diseases (down‐regulation), and cancerogenesis (up‐regulation). However, its role in the off‐target effects of clinically used drugs is still not understood.
The Factors Affecting the Adversity Quotient of Nurses and Office Workers

This is a descriptive research to identify the factors affecting the adversity experienced by nurses and office workers. The research was conducted among 270 nurses at a general hospital and 192 office workers in the metropolitan area, and the collected data were analyzed using an SPSS 20.0 program. Statistically significant differences were found in emotional intelligence and the adversity quotient between nurses and office workers. Nurses had both variables at lower levels compared to office workers. Statistically significant correlation was found between the adversity quotient and emotional intelligence in each group. In each group, emotional intelligence significantly affected statistically the adversity quotient. It accounted for 19.0% for nurses and 26.0% for office workers. On the basis of these results, it is necessary to develop and employ a program to improve emotional intelligence, which was found to affect the level of adversity quotient, and develop an intervention strategy to raise the adversity quotient, particularly a customized intervention strategy for nurses who had emotional intelligence and adversity quotient at lower levels compared to office workers. The objective is to help them cope efficiently with their changing job environment and to improve the quality of each work service, the nurses’ and office workers’ job satisfaction, and their quality of life.
Effects of mechanical loading on cortical defect repair using a novel mechanobiological model of bone healing

Mechanical loading is an important aspect of post-surgical care. The timing of load application relative to the injury event is thought to differentially regulate repair depending on the stage of healing. Here, we show using a novel mechanobiological model of cortical defect repair that daily loading (5 N peak load, 2 Hz, 60 cycles, 4 consecutive days) during hematoma consolidation and inflammation disrupts the injury site and activates cartilage formation on the periosteal surface adjacent to the defect. We also show that daily loading during the matrix deposition phase enhances both bone and cartilage formation at the defect site, while loading during the remodeling phase results in an enlarged woven bone regenerate. All loading regimens resulted in abundant cellular proliferation within the regenerate and at the periosteal surface and fibrous tissue formation directly above the defect. Stress was concentrated at the edges of the defect during exogenous loading, and finite element (FE)-modeled longitudinal strain (εzz) values along the anterior and posterior borders of the defect (~2200 με) were an order of magnitude larger than strain values on the proximal and distal borders (~50-100 με). These findings demonstrate that all phases of cortical defect healing are sensitive to physical stimulation. In addition, the proposed novel mechanobiological model offers several advantages including its technical simplicity and its well-characterized and spatially confined repair program, making effects of physical and biological interventions more easily assessed.
Lost in translation? A critical look at the role that animal models of obsessive compulsive disorder play in current drug discovery strategies

ABSTRACT Introduction: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric illness estimated to affect between 1–3% of the population. In today’s literature, there are a number well-validated and convincing animal models of OCD described. Areas covered: Herein, the authors look at the role that animal models of OCD (including transgenic models, deer mouse stereotypy, quinpirole sensitization, post-training signal attenuation, and mouse marble burying) have played in determining the current directions of OCD drug discovery. Specifically, the article reviews new OCD drug therapies currently under investigation including drugs that target glutamate, dopamine, serotonin, and endocannabinoid systems. The authors review the published results of these clinical trials, and critically examine the contribution of animal models to the development of these novel therapies. Expert opinion: Nitric oxide inhibitors, oxycarbazepine, and modulators of serotonin and metabotropic glutamate receptors should be further explored in animal models as well as in clinical trials. Pregabalin, topiramate, lamotrigine, sarcosine, minocycline, L-carnosine, celecoxib, and ondansetron, which have shown promise in clinical trials, should be explored in animal models with the goal of understanding the neurobiology of their effects. A multidisciplinary, interactive approach to OCD drug discovery, where animal models generate neurobiological hypotheses that can be tested in the clinic, and vice versa, should be cultivated.
Estimation of Reference Values for PFOS and PFOA in Human Biomonitoring and Relevance of Exposure among Family Members in China

The reference values of serum perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations were evaluated based on the human blood samples collected from Kashi, Xinjiang. And human serum samples of family members from Liaoning were evaluated for levels of PFOS and PFOA with the purpose to compare exposure pathways for family members. Among the 110 blood specimens from Kashi, the detection frequency of PFOS and PFOA was 93% and 6%, respectively. Reference values of serum PFOS, evaluated as the 90th percentiles of the concentrations, were determined to be 6.44 ug/L. Significant positive correlations were observed for serum levels of PFOS and PFOA among family members in Liaoning. Specially, stronger correlation between mother and offspring was observed than that between father and offspring. And stronger correlation of serum PFOS and PFOA levels was observed among fam- ily members in rural areas than those in big and small-medium cities. Difference in the association of serum PFOS and PFOA level among family members suggested that exposure in the outdoor and working environment of different oc- cupations should be evaluated. Present study provides reference values for exposure assessment in China and potential pathways of human exposure to PFOS and PFOA.
Construction and Evaluation of Hierarchical Parcellation of the Brain using fMRI with Prewhitening

Brain atlases are a ubiquitous tool used for analyzing and interpreting brain imaging datasets. Traditionally, brain atlases divided the brain into regions separated by anatomical landmarks. In the last decade, several attempts have been made to parcellate the brain into regions with distinct functional activity using fMRI. To construct a brain atlas using fMRI, data driven algorithms are used to group voxels with similar functional activity together to form regions. Hierarchical clustering is one parcellation method that has been used for functional parcellation of the brain, resulting in parcellations that align well with cytoarchitectonic divisions of the brain. However, few rigorous data driven evaluations of the method have been performed. Moreover, the effect of removing autocorrelation trends from fMRI time series (prewhitening) on the structure of the resultant atlas has not been previously explored. In this paper, we use hierarchical clustering to produce functional parcellations of the brain using hierarchical clustering. We use both prewhitened and raw fMRI time series to construct the atlas. The resultant atlases were then evaluated for their homogeneity, separation between regions, reproducibility across subjects, and reproducibility across scans.
Intranasal Histamine Challenge in Normal Subjects and Allergic Rhinitis before and after Intranasal Budesonide Studied with Rhinostereometry and Micromanipulator-Guided Laser D oppler Flowmetry

Ten healthy subjects and 10 patients suffering from allergic rhinitis to birch pollen were investigated with the combination of rhinostereometry and laser Doppler flowmetry, thus simultaneously measuring changes in mucosal swelling and microcirculation, following intranasal histamine challenge. Compared to normals, the allergics had a higher degree of congestion and a lower increase in perfusion and velocity of flow. In the allergics there was a decrease in CMBC (concentration of moving blood cells) that was not seen in normals. The decrease in CMBC seen in allergics could be attributed to an increase in vascular permeability producing an interstitial edema, a well-known effect of histamine. After treatment with 1 week of intranasal steroid, most of the differences in the reaction pattern between normals and allergics had disappeared.
Fibrosis and Altered Matrix Degradation

Liver fibrosis occurs as a result of the net deposition of excess collagen types I and III and other matrix proteins, which are synthesized by activated hepatic stellate cells (HSCs). These cells are also able to synthesize enzymes, called metalloproteinases, which can degrade matrix proteins in the extracellular space. The activity of the metalloproteinases is carefully regulated by controlling their conversion from pro-enzymes to the catalytic form and by a family of specific inhibitors, called tissue inhibitors of metalloproteinases (TIMPs). Recent evidence indicates that HSCs play a key role in regulating matrix degradation in the liver: (i) they express several metalloproteinases; (ii) they express cell-surface-associated metalloand serine proteinases that can cleave prometalloproteinases to the active form, and (iii) they express TIMPs which inhibit extracellular degradative activity. It is suggested that the complex interplay of these different factors plays an important role in the pathogenesis of liver fibrosis.
ARHGEF19 interacts with BRAF to activate MAPK signaling during the tumorigenesis of non‐small cell lung cancer

Rho guanine nucleotide exchange factors (RhoGEFs) are proteins that activate Rho GTPases in response to extracellular stimuli and regulate various biologic processes. ARHGEF19, one of RhoGEFs, was reported to activate RhoA in the Wnt‐PCP pathway controlling convergent extension in Xenopus gastrulation. The goal of our study was to identify the role and molecular mechanisms of ARHGEF19 in the tumorigenesis of non‐small cell lung cancer (NSCLC). ARHGEF19 expression was significantly elevated in NSCLC tissues, and ARHGEF19 levels were significantly associated with lymph node status, distant metastasis and TNM stage; Patients with high ARHGEF19 levels had poor overall survival (OS) and progression‐free survival (PFS). Our investigations revealed that ARHGEF19 overexpression promoted the cell proliferation, invasion and metastasis of lung cancer cells, whereas knockdown of this gene inhibited these processes. Mechanistically, ARHGEF19 activated the mitogen‐activated protein kinase (MAPK) pathway in a RhoA‐independent manner: ARHGEF19 interacted with BRAF and facilitated the phosphorylation of its downstream kinase MEK1/2; both the Dbl homology (DH) and Pleckstrin homology (PH) domains of ARHGEF19 were indispensable for the phosphorylation of MEK1/2. Furthermore, downregulation of miR‐29b was likely responsible for the increased expression of ARHGEF19 in lung cancer tissues and, consequently, the abnormal activation of MAPK signaling. These findings suggest that ARHGEF19 upregulation, due to the low expression of miR‐29 in NSCLC tissues, may play a crucial role in NSCLC tumorigenesis by activating MAPK signaling. ARHGEF19 could serve as a negative prognostic marker as well as a therapeutic target for NSCLC patients.
Mycorrhiza-Triggered Transcriptomic and Metabolomic Networks Impinge on Herbivore Fitness1

Ectomycorrhiza-induced systemic defenses in leaves involve aldoxime metabolism and improve poplar fitness by fending off the leaf herbivore Chrysomela populi. Symbioses between plants and mycorrhizal fungi are ubiquitous in ecosystems and strengthen the plants’ defense against aboveground herbivores. Here, we studied the underlying regulatory networks and biochemical mechanisms in leaves induced by ectomycorrhizae that modify herbivore interactions. Feeding damage and oviposition by the widespread poplar leaf beetle Chrysomela populi were reduced on the ectomycorrhizal hybrid poplar Populus × canescens. Integration of transcriptomics, metabolomics, and volatile emission patterns via mass difference networks demonstrated changes in nitrogen allocation in the leaves of mycorrhizal poplars, down-regulation of phenolic pathways, and up-regulation of defensive systems, including protease inhibitors, chitinases, and aldoxime biosynthesis. Ectomycorrhizae had a systemic influence on jasmonate-related signaling transcripts. Our results suggest that ectomycorrhizae prime wounding responses and shift resources from constitutive phenol-based to specialized protective compounds. Consequently, symbiosis with ectomycorrhizal fungi enabled poplars to respond to leaf beetle feeding with a more effective arsenal of defense mechanisms compared with nonmycorrhizal poplars, thus demonstrating the importance of belowground plant-microbe associations in mitigating aboveground biotic stress.
Comparative immunity of antigen recognition, differentiation, and other functional molecules: similarities and differences among common marmosets, humans, and mice

The common marmoset (CM; Callithrix jacchus) is a small New World monkey with a high rate of pregnancy and is maintained in closed colonies as an experimental animal species. Although CMs are used for immunological research, such as studies of autoimmune disease and infectious disease, their immunological characteristics are less defined than those of other nonhuman primates. We and others have analyzed antigen recognition-related molecules, the development of hematopoietic stem cells (HSCs), and the molecules involved in the immune response. CMs systemically express Caja-G, a major histocompatibility complex class I molecule, and the ortholog of HLA-G, a suppressive nonclassical HLA class I molecule. HSCs express CD117, while CD34 is not essential for multipotency. CD117+ cells developed into all hematopoietic cell lineages, but compared with human HSCs, B cells did not extensively develop when HSCs were transplanted into an immunodeficient mouse. Although autoimmune models have been successfully established, sensitization of CMs with some bacteria induced a low protective immunity. In CMs, B cells were observed in the periphery, but IgG levels were very low compared with those in humans and mice. This evidence suggests that CM immunity is partially suppressed systemically. Such immune regulation might benefit pregnancy in CMs, which normally deliver dizygotic twins, the placentae of which are fused and the immune cells of which are mixed. In this review, we describe the CM immune system and discuss the possibility of using CMs as a model of human immunity.
Elevated estimated arterial age is associated with metabolic syndrome and low-grade inflammation

Background: Arterial age can be estimated from equations relating arterial stiffness to age and blood pressure in large cohorts. We investigated whether estimated arterial age (eAA) was elevated in patients with the metabolic syndrome and/or known cardiovascular disease (CVD), which factors were associated with eAA and whether eAA added prognostic information. Methods: In 1993, 2366 study participants, 41, 51, 61, and 71 years old, had traditional cardiovascular risk factors and carotid–femoral pulse wave velocity (cfPWV) measured. Risk groups were identified based on known CVD and components of metabolic syndrome, Systematic COronary Risk Evaluation, or Framingham risk score. From age, mean blood pressure, and cfPWV, eAA and estimated cfPWV (ePWV) were calculated. In 2006, the combined cardiovascular endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for ischemic heart disease was registered. Results: cfPWV and ePWV increased with ageing and cardiovascular risk (all P < 0.001), but ePWV increased more with ageing than cfPWV. The difference between eAA and chronological age was associated with male sex (&bgr; = 0.14), higher heart rate (&bgr; = 0.16 both P < 0.001), fasting glucose (&bgr; = 0.08) soluble urokinase plasminogen activator receptor (&bgr; = 0.06, both P < 0.01), and known CVD (&bgr; = 0.06, P < 0.05) independently of age, SBP, and heart rate. Independently of Systematic COronary Risk Evaluation, eAA (hazard ratio = 1.20, P < 0.01) predicted CEP, but not as accurately as ePWV (hazard ratio = 1.58, P < 0.001) and cfPWV (hazard ratio = 1.32, P < 0.001) among apparently healthy study participants. Conclusion: Elevated eAA was associated with male sex, higher plasma glucose, and soluble urokinase plasminogen activator receptor and known CVD independently of age, SBP, and heart rate.
PARP1 Trapping and DNA Replication Stress Enhance Radiosensitization with Combined WEE1 and PARP Inhibitors

KRAS mutations in non–small cell lung cancer (NSCLC) cause increased levels of DNA damage and replication stress, suggesting that inhibition of the DNA damage response (DDR) is a promising strategy for radiosensitization of NSCLC. This study investigates the ability of a WEE1 inhibitor (AZD1775) and a PARP inhibitor (olaparib) to radiosensitize KRAS-mutant NSCLC cells and tumors. In addition to inhibiting the DDR, these small-molecule inhibitors of WEE1 and PARP induce DNA replication stress via nucleotide exhaustion and PARP trapping, respectively. As monotherapy, AZD1775 or olaparib alone modestly radiosensitized a panel of KRAS-mutant NSCLC lines. The combination of agents, however, significantly increased radiosensitization. Furthermore, AZD1775-mediated radiosensitization was rescued by nucleotide repletion, suggesting a mechanism involving AZD1775-mediated replication stress. In contrast, radiosensitization by the combination of AZD1775 and olaparib was not rescued by nucleosides. Whereas both veliparib, a PARP inhibitor that does not efficiently trap PARP1 to chromatin, and PARP1 depletion radiosensitized NSCLC cells as effectively as olaparib, which does efficiently trap PARP, only olaparib potentiated AZD1775-mediated radiosensitization. Taken together, these mechanistic data demonstrate that although nucleotide depletion is sufficient for radiosensitization by WEE1 inhibition alone, and inhibition of PARP catalytic activity is sufficient for radiosensitization by olaparib alone, PARP1 trapping is required for enhanced radiosensitization by the combination of WEE1 and PARP inhibitors. Implications: This study highlights DNA replication stress caused by nucleotide depletion and PARP1 trapping as an important mechanism of radiosensitization in KRAS-mutant tumors and supports further development of DNA replication as a therapeutic target. Mol Cancer Res; 16(2); 222–32. ©2017 AACR.
Evaluation of Radius Microstructure and Areal Bone Mineral Density Improves Fracture Prediction in Postmenopausal Women

A majority of low‐trauma fractures occur in subjects with only moderate decrease of areal bone mineral density (aBMD), ie, osteopenia, assessed by dual‐energy X‐ray absorptiometry (DXA) or low fracture probability assessed by FRAX. We investigated whether peripheral bone microstructure and estimated strength improve the prediction of incident fractures beyond central DXA and FRAX. In this population‐based study of 740 postmenopausal women (aged 65.0 ± 1.4 years) from the Geneva Retirees Cohort (ISRCTN registry 11865958), we assessed at baseline cortical (Ct) and trabecular (Tb) volumetric bone mineral density (vBMD) and microstructure by peripheral quantitative computed tomography (HR‐pQCT); bone strength by micro‐finite element analysis; aBMD and trabecular bone score (TBS) by DXA; and FRAX fracture probability. Eighty‐five low‐trauma fractures occurred in 68 women over a follow‐up of 5.0 ± 1.8 years. Tb and Ct vBMD and microstructure predicted incident fractures, independently of each other and of femoral neck (FN) aBMD and FRAX (with BMD ± TBS). However, the associations were markedly attenuated after adjustment for ultra‐distal radius aBMD (same bone site). The best discrimination between women with and without fracture was obtained at the radius with total vBMD, the combination of a Tb with a Ct parameter, or with failure load, which improved the area under the curve (AUC) for major osteoporotic fracture when added to FN aBMD (0.760 versus 0.695, p = 0.022) or to FRAX‐BMD (0.759 versus 0.714, p = 0.015). The replacement of failure load by ultra‐distal aBMD did not significantly decrease the AUC (0.753, p = 0.747 and 0.750, p = 0.509, respectively). In conclusion, peripheral bone microstructure and strength improve the prediction of fractures beyond central DXA and FRAX but are partially captured in aBMD measured by DXA at the radius. Because HR‐pQCT is not widely available for clinical purposes, assessment of ultra‐distal radius aBMD by DXA may meanwhile improve fracture risk estimation. © 2017 American Society for Bone and Mineral Research.
Angiotensin II and ACTH release: site of action and potency relative to corticotropin releasing factor and vasopressin.

The present studies were designed to test, using a combination of in vivo and in vitro paradigms, the potency of angiotensin II (AII) to release ACTH, in relation to that of other neural peptides with corticotropin-releasing activity (CRA), such as synthetic corticotropin releasing factor (CRF), arginine vasopressin (AVP) and oxytocin (OXY); and to determine whether a central or peripheral locus is the primary site of action of the peptide. Injection of AII (1 and 5 micrograms, i.p.) in intact unanesthetized male rats, resulted in an increase in plasma ACTH and beta-endorphin-like immunoreactivity (beta-end-LI) levels after the largest dose. The responses, however, were not as pronounced as those elicited by 0.5 microgram of CRF or 1 micrograms of AVP. Injection of AII (i.v., 1 or 5 micrograms) in centrally blocked rats (pretreated with chlorpromazine-morphine-nembutal) failed to elicit any increase in either ACTH or bet a-end-LI levels, whereas 0.5 microgram of either CRF or AVP increased both hormones several fold. In vitro studies using dispersed anterior pituitary cells obtained from male donor rats showed that AII as well as AIII could increase ACTH release at doses of 10(-8) M or larger. Under the same conditions, CRF and AVP stimulated ACTH release to a greater degree at 10(-10) and 10(-9) M, respectively. On the other hand, OXY was stimulatory at 10(-8) M. Dose-response studies indicated a rank order of CRA as follows: CRF greater than AVP greater than OXY greater than AII = AIII. Both AII and AIII showed additive effects when coincubated with either CRF or AVP. (ABSTRACT TRUNCATED AT 250 WORDS)