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Abigail C Burr,1,* Jalene V Velazquez,1,* Arzu Ulu,1 Rohan Kamath,1 Sang Yong Kim,1 Amanpreet K Bilg,1 Aileen Najera,1 Iman Sultan,1 Jon K Botthoff,2 Emma Aronson,3 Meera G Nair,1 Tara M Nordgren1 1Division of Biomedical Sciences, University of California Riverside, Riverside, CA, 92521, USA; 2Center for Conservation Biology, University of California Riverside, Riverside, CA, 92521, USA; 3Department of Plant Pathology and Microbiology, University of California Riverside, Riverside, CA, 92521, USA*These authors contributed equally to this workCorrespondence: Tara M NordgrenDivision of Biomedical Sciences, University of California Riverside, 92521 University Avenue, Riverside, CA, 92521, USATel +1 951 827 3148Email tmnordgren@gmail.comPurpose: The Salton Sea, California’s largest lake, is designated as an agricultural drainage reservoir. In recent years, the lake has experienced shrinkage due to reduced water sources, increasing levels of aerosolized dusts in surrounding regions. Communities surrounding the Salton Sea have increased asthma prevalence versus the rest of California; however, a connection between dust inhalation and lung health impacts has not been defined.Methods: We used an established intranasal dust exposure murine model to study the lung inflammatory response following single or repetitive (7-day) exposure to extracts of dusts collected in regions surrounding the Salton Sea (SSDE), complemented with in vitro investigations assessing SSDE impacts on the airway epithelium.Results: In these investigations, single or repetitive SSDE exposure induced significant lung inflammatory cytokine release concomitant with neutrophil influx. Repetitive SSDE exposure led to significant lung eosinophil recruitment and altered expression of genes associated with allergen-mediated immune response, including Clec4e. SSDE treatment of human bronchial epithelial cells (BEAS-2B) induced inflammatory cytokine production at 5- and 24-hours post-treatment. When BEAS-2B were exposed to protease activity-depleted SSDE (PDSSDE) or treated with SSDE in the context of protease-activated receptor-1 and − 2 antagonism, inflammatory cytokine release was decreased. Furthermore, repetitive exposure to PDSSDE led to decreased neutrophil and eosinophilic influx and IL-6 release in mice compared to SSDE-challenged mice.Conclusion: These investigations demonstrate potent lung inflammatory responses and tissue remodeling in response to SSDE, in part due to environmental proteases found within the dusts. These studies provide the first evidence supporting a link between environmental dust exposure, protease-mediated immune activation, and respiratory disease in the Salton Sea region.Keywords: Salton Sea, dust exposure, lung inflammation, asthma, proteases, protease-activated receptors

Background: Osteoarthritis of the knee is one of the most common ailments worldwide, and pain management of this condition is critical. Methods: A multicentre randomized controlled trial RCT with three months of follow-up, conducted in parallel groups: hyaluronic acid (HA), dry needling (DN) and ultrasound (US) and isometrics of quadriceps. 60 participants took part in the RCT who were diagnosed with osteoarthritis (Grade 3) of the knee by MRI and active adults (age: 23.41 ± 1.68 years; height: 1.79 ± 0.08 m; body mass: 78.33 ± 9.03 kg; body mass index (BMI): 24.14 ± 1.45 kg/m 2 ). After the assigned intervention, VAS, WOMAC, IPAQ and the Star Excursion Balance test were measured at baseline. At 24 h, 15 days, 30 days, 90 days and 180 days follow-up, all variables were measured again. Results: Comparing statistically significant differences between groups, VAS scores were significant at post-test measurement (HA vs. US + isometric and DN vs. US + isometric) at 24 h (HA vs. DN), at 15 days (HA vs. US + isometric and DN vs. US + isometric) and at 1 month (US + isometric vs. HA and US + isometric vs. DN). Conclusions: There is an improvement in pain intensity in knee osteoarthritis in the short term in patients undergoing DN and conventional US + isometric treatment, but in the long term the HA group shows an improvement in pain intensity. There is also a significant difference in the improvement of knee function at different phases of the study in the various intervention groups. The combination of DN and HA in clinical practice is the best option for the treatment of osteoarthritis.

Introduction: Insomnia is the most common of sleep disorders, it induces a wide variety of organic symptoms, including somatic and cognitive impairments. There are pharmacological drugs nowadays that help diminish sleep impairments due to insomnia. However, most of them seem to be worsening cognitive impairments, benzodiazepine receptor agonists, in particular, seem to induce an even worst deterioration of cognitive function. On the other hand, cognitive behavioral therapy for insomnia (CBT-I) has shown to be a reliable tool to improve the whole picture of insomnia., Objectives: To analyze the effect of CBT-I on insomnia symptoms and cognitive performance in patients suffering from chronic insomnia., Material and Methods: Ten subjects with a diagnosis of insomnia and no pharmacological treatment were evaluated pre- and post-six biweekly sessions of CBT-I with two neuropsychological batteries, BANFE and NEUROPSI attention and memory., Results: CBT-I significantly improves both the symptoms of insomnia, measured subjectively with a sleep diary and the Athens insomnia scale, and the cognitive performance measured with the neuropsychological batteries., Discussion: CBT-I is not only an effective tool for the treatment of insomnia but also helps to ameliorate cognitive performance.

Nek2 (NIMA-related kinase 2) is a serine/threonine-protein kinase that localizes to centrosomes and kinetochores, controlling centrosome separation, chromosome attachments to kinetochores, and the spindle assembly checkpoint. These processes prevent centrosome amplification (CA), mitotic dysfunction, and chromosome instability (CIN). Our group and others have suggested that Nek2 maintains high levels of CA/CIN, tumor growth, and drug resistance. We identified that Nek2 overexpression correlates with poor survival of breast cancer. However, the mechanisms driving these phenotypes are unknown. We now report that overexpression of Nek2 in MCF10A cells drives CA/CIN and aneuploidy. Besides, enhanced levels of Nek2 results in larger 3D acinar structures, but could not initiate tumors in a p53 +/+ or a p53 -/- xenograft model. Nek2 overexpression induced the epithelial-to-mesenchymal transition (EMT) while its downregulation reduced the expression of the mesenchymal marker vimentin. Furthermore, either siRNA-mediated downregulation or INH6's chemical inhibition of Nek2 in MDA-MB-231 and Hs578t cells showed important EMT changes and decreased invasion and migration. We also showed that Slug and Zeb1 are involved in Nek2 mediated EMT, invasion, and migration. Besides its role in CA/CIN, Nek2 contributes to breast cancer progression through a novel EMT mediated mechanism.

Background: Obesity is one of the main challenges in the first world nowadays. New alternatives are needed and endoscopic endoluminal approaches are gaining importance against the risky surgery and the non-efficient pharmacological treatments. Nevertheless, these techniques seem to be inefficient in obese III patients. The aim of the study is to demonstrate the safety and efficiency of the new reinforced POSE 18-plication protocol., Methods: Mean body mass index (BMI) ≈ 47 kg/m 2 obese type III patients were treated in different Spanish centers with the new POSE method consisting of 18 plications in the stomach body. On the other hand, 15 lower body mass patients BMI ≈ 40 kg/m 2 were treated with the standard POSE method previously described., Results: Three months follow-up shows an overall % total weight loss (TWL) and % excess weight loss (EWL) of 15% and 41% respectively for standard POSE and 17% and 36% for the new reinforced POSE18. Both are equally safe and the endpoint weight loss objectives are reached. Endoluminal procedures have been demonstrated to be useful in overweight and obese type I/II. However, bariatric surgery is recommended for higher BMI > 40 kg/m 2 . We successfully applied a non-standard POSE protocol and the patients reached 17%TWL in 3 months., Conclusions: Our study shows that reinforced POSE 18 can be successfully applied in obese type III; it is safer than bariatric surgery and there are no associated risks when compared with standard endoscopic surgery.

SH2-containing-inositol-5-phosphatases (SHIPs) dephosphorylate the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P 3 ) and play important roles in regulating the PI3K/Akt pathway in physiology and disease. Aiming to uncover interdomain regulatory mechanisms in SHIP2, we determined crystal structures containing the 5-phosphatase and a proximal region adopting a C2 fold. This reveals an extensive interface between the two domains, which results in significant structural changes in the phosphatase domain. Both the phosphatase and C2 domains bind phosphatidylserine lipids, which likely helps to position the active site towards its substrate. Although located distant to the active site, the C2 domain greatly enhances catalytic turnover. Employing molecular dynamics, mutagenesis and cell biology, we identify two distinct allosteric signaling pathways, emanating from hydrophobic or polar interdomain interactions, differentially affecting lipid chain or headgroup moieties of PI(3,4,5)P 3 . Together, this study reveals details of multilayered C2-mediated effects important for SHIP2 activity and points towards interesting new possibilities for therapeutic interventions.

Protein kinase B (PKB/Akt) is an important mediator of signals that control various cellular processes including cell survival, growth, proliferation, and metabolism. PKB promotes these processes by phosphorylating many cellular targets, which trigger distinct downstream signaling events. However, how PKB is able to selectively target its substrates to induce specific cellular functions remains elusive. Here we perform a systematic study to dissect mechanisms that regulate intrinsic kinase activity versus mechanisms that specifically regulate activity toward specific substrates. We demonstrate that activation loop phosphorylation and the C-terminal hydrophobic motif are essential for high PKB activity in general. On the other hand, we identify membrane targeting, which for decades has been regarded as an essential step in PKB activation, as a mechanism mainly affecting substrate selectivity. Further, we show that PKB activity in cells can be triggered independently of PI3K by initial hydrophobic motif phosphorylation, presumably through a mechanism analogous to other AGC kinases. Importantly, different modes of PKB activation result in phosphorylation of distinct downstream targets. Our data indicate that specific mechanisms have evolved for signaling nodes, like PKB, to select between various downstream events. Targeting such mechanisms selectively could facilitate the development of therapeutics that might limit toxic side effects., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Purpose: In order to explore the potential role of GABA, acetylcholine and glutamate in the caudo-lateral peribrachial area (C-PBL) over Rapid-Eye-Movement sleep (REM) onset and maintenance as well as on synchronized sleep with ponto-geniculo-occipital (PGO) waves (SP) in cats, a muscimol, carbachol and L-glutamate local application was performed and behavioral states were assessed., Methods: Fourteen chronically implanted, adult, male cats underwent a 23 hour polysomnographic recording after 3 pharmacological manipulations: carbachol, muscimol and L-glutamate. Each cat received all three drugs randomly with a seven day interval., Results: 1) Carbachol increases waking, SP and REM sleep while decreases slow wave sleep (SWS). 2) Muscimol decreases SP percentage and number while increases REM sleep onset. 3) Carbachol facilitates PGO activity and increases the latency to both SWS1 and REM sleep but enhances PGO activity while muscimol decreases it., Conclusions: Acetylcholine promotes PGO related states (SP as well as REM sleep), while GABA reduces only SP and specifically PGOs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Sleep disturbances in depression are up to 70%. Patients frequently have difficulty in falling asleep, frequent awakenings during the night and non-restorative sleep. Sleep abnormalities in depression are mainly characterized by increased rapid eye movement (REM) sleep and reduced slow wave sleep. Among the mechanisms of sleep disturbances in depression are hyperactivation of the hypothalamic-pituitary-adrenal axis, CLOCK gene polymorphism and primary sleep disorders. The habenula is a structure regulating the activities of monoaminergic neurons in the brain. The hyperactivation of the habenula has also been implicated, together with sleep disturbances, in depression. The presence of depression in primary sleep disorders is common. Sleep disturbances treatment include pharmacotherapy or Cognitive Behavioral Therapy.

The Staphylococcus aureus Agr system regulates virulence gene expression by responding to cell population density (quorum sensing). When an extracellular peptide signal (AIP-III in strain UAMS-1, used for these experiments) reaches a concentration threshold, the AgrC-AgrA two-component regulatory system is activated through a cascade of phosphorylation events, leading to induction of the divergently transcribed agrBDCA operon and the RNAIII gene. RNAIII is a posttranscriptional regulator of numerous metabolic and pathogenesis genes. CodY, a global regulatory protein, is known to repress agrBDCA and RNAIII transcription during exponential growth in rich medium, but the mechanism of this regulation has remained elusive. Here we report that phosphorylation of AgrA by the AgrC protein kinase is required for the overexpression of the agrBDCA operon and the RNAIII gene in a codY mutant during the exponential-growth phase, suggesting that the quorum-sensing system, which normally controls AgrC activation, is active even in exponential-phase cells in the absence of CodY. In part, such premature expression of RNAIII was attributable to higher-than-normal accumulation of AIP-III in a codY mutant strain, as determined using ultrahigh-performance liquid chromatography coupled to mass spectrometry. Although CodY is a strong repressor of the agr locus, CodY bound only weakly to the agrBDCA-RNAIII promoter region, suggesting that direct regulation by CodY is unlikely to be the principal mechanism by which CodY regulates agr and RNAIII expression. Taken together, these results strongly suggest that cell population density signals inducing virulence gene expression can be overridden by nutrient availability, a condition monitored by CodY.