Proliferative Hypothalamic Neurospheres Express NPY, AGRP, POMC, CART and Orexin-A and Differentiate to Functional Neurons

Some pathological conditions with feeding pattern alterations, including obesity and Huntington disease (HD) are associated with hypothalamic dysfunction and neuronal cell death. Additionally, the hypothalamus is a neurogenic region with the constitutive capacity to generate new cells of neuronal lineage, in adult rodents

Plasma lipidome and risk of atrial fibrillation: results from the PREDIMED trial

The potential role of the lipidome in atrial fibrillation (AF) development is still widely unknown. We aimed to assess the association between lipidome profiles of the Prevenci\uf3n con Dieta Mediterr\ue1nea (PREDIMED) trial participants and incidence of AF. We conducted a nested case–control study (512 incident centrally adjudicated AF cases and 735 controls matched by age, sex, and center). Baseline plasma lipids were profiled using a Nexera X2 U-HPLC system coupled to an Exactive Plus orbitrap mass spectrometer. We estimated the association between 216 individual lipids and AF using multivariable conditional logistic regression and adjusted the p values for multiple testing. We also examined the joint association of lipid clusters with AF incidence. Hitherto, we estimated the lipidomics network, used machine learning to select important network-clusters and AF-predictive lipid patterns, and summarized the joint association of these lipid patterns weighted scores. Finally, we addressed the possible interaction by the randomized dietary intervention. Forty-one individual lipids were associated with AF at the nominal level (p < 0.05), but no longer after adjustment for multiple-testing. However, the network-based score identified with a robust data-driven lipid network showed a multivariable-adjusted ORper+1SD of 1.32 (95% confidence interval: 1.16–1.51; p < 0.001). The score included PC plasmalogens and PE plasmalogens, palmitoyl-EA, cholesterol, CE 16:0, PC 36:4;O, and TG 53:3. No interaction with the dietary intervention was found. A multilipid score, primarily made up of plasmalogens, was associated with an increased risk of AF. Future studies are needed to get further insights into the lipidome role on AF. Current Controlled Trials number, ISRCTN35739639

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

TIA-1 Cytotoxic Granule-Associated RNA Binding Protein Improves the Prognostic Performance of CD8 in Mismatch Repair-Proficient Colorectal Cancer

Evidence suggests a confounding effect of mismatch repair (MMR) status on immune response in colorectal cancer. The identification of innate and adaptive immune cells, that can complement the established prognostic effect of CD8 in MMR-proficient colorectal cancers patients, representing 85% of all cases, has not been performed

Effects of 3,4-Methylenedioxymethamphetamine Administration on Retinal Physiology in the Rat

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is known to produce euphoric states, but may also cause adverse consequences in humans, such as hyperthermia and neurocognitive deficits. Although MDMA consumption has been associated with visual problems, the effects of this recreational drug in retinal physiology have not been addressed hitherto. In this work, we evaluated the effect of a single MDMA administration in the rat electroretinogram (ERG). Wistar rats were administered MDMA (15 mg/kg) or saline and ERGs were recorded before (Baseline ERG), and 3 h, 24 h, and 7 days after treatment. A high temperature (HT) saline-treated control group was also included. Overall, significantly augmented and shorter latency ERG responses were found in MDMA and HT groups 3 h after treatment when compared to Baseline. Twenty-four hours after treatment some of the alterations found at 3 h, mainly characterized by shorter latency, tended to return to Baseline values. However, MDMA-treated animals still presented increased scotopic a-wave and b-wave amplitudes compared to Baseline ERGs, which were independent of temperature elevation though the latter might underlie the acute ERG alterations observed 3 h after MDMA administration. Seven days after MDMA administration recovery from these effects had occurred. The effects seem to stem from specific changes observed at the a-wave level, which indicates that MDMA affects subacutely (at 24 h) retinal physiology at the outer retinal (photoreceptor/bipolar) layers. In conclusion, we have found direct evidence that MDMA causes subacute enhancement of the outer retinal responses (most prominent in the a-wave), though ERG alterations resume within one week. These changes in photoreceptor/bipolar cell physiology may have implications for the understanding of the subacute visual manifestations induced by MDMA in humans

Local deformation in a hydrogel induced by an external magnetic field

The aim of this study is to prove the feasibility of a system able to apply local mechanical loading on cells seeded in a hydrogel for tissue engineering applications. This experimental study is based on a previously developed artificial cartilage model with different concentrations of poly(vinyl alcohol) (PVA) that simulates the cartilage extracellular matrix (ECM). Poly(l-lactic acid) (PLLA) microspheres with dispersed magnetic nanoparticles (MNPs) were produced with an emulsion method. These microspheres were embedded in aqueous PVA solutions with varying concentration to resemble increased viscosity of growing tissue during regeneration. The ability to induce a local deformation in the ECM was assessed by applying a steady or an oscillatory magnetic field gradient to different PVA solutions containing the magnetic microparticles, similarly as in ferrogels. PLLA microparticle motion was recorded, and the images were analyzed. Besides, PVA gels and PLLA microparticles were introduced into the pores of a polycaprolactone scaffold, and the microparticle distribution and the mechanical properties of the construct were evaluated. The results of this experimental model show that the dispersion of PLLA microparticles containing MNPs, together with cells in a supporting gel, will allow applying local mechanical stimuli to cells during tissue regeneration. This local stimulation can have a positive effect on the differentiation of seeded cells and improve tissue regeneration.The authors gratefully acknowledge the financial support from the Spanish Ministry of Economy and Competitiveness through the MAT2013-46467-C4-1-R project, including the Feder funds. CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program. CIBER Actions are financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. The authors thank "Servicio de Microscopia Electronica" of Universitat Politecnica de Valencia for their invaluable help. The translation of this paper was funded by the Universitat Politecnica de Valencia, Spain.Vikingsson, L.; Vinals Guitart, Á.; Valera Martínez, A.; Riera Guasp, J.; Vidaurre Garayo, AJ.; Gallego Ferrer, G.; Gómez Ribelles, JL. (2016). Local deformation in a hydrogel induced by an external magnetic field. Journal of Materials Science. 51(22):9979-9990. https://doi.org/10.1007/s10853-016-0226-8S997999905122Eyre D (2002) Collagen of articular cartilage. Arthritis Res 4:30–35Roughley PJ, Lee ER (1994) Cartilage proteoglycans: structure and potential functions. Microsc Res Tech 28:385–397Gillard GC, Reilly HC, Bell-Booth PG, Flint MH (1979) The influence of mechanical forces on the glycosaminoglycan content of the rabbit flexor digitorum profundus tendon. Connect Tissue Res 7:37–46Quinn TM, Grodzinsky AJ, Buschmann MD, Kim YJ, Hunziker EB (1998) Mechanical compression alters proteoglycan deposition and matrix deformation around individual cells in cartilage explants. J Cell Sci 111:573–583Banes AJ, Tsuzaki M, Yamamoto J, Fischer T, Brigman B, Brown T, Miller L (1995) Mechanoreception at the cellular level: the detection, interpretation, and diversity of responses to mechanical signals. Biochem Cell Biol 73:349–365Appelman T, Mizrahi J, Elisseeff J, Seliktar D (2011) The influence of biological motifs and dynamic mechanical stimulation in hydrogel scaffold systems on the phenotype of chondrocytes. Biomaterials 32:1508–1516Mow VC, Ratcliffe A, Poole AR (1992) Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials 13:67–97Mow VC, Huiskes R (2005) Basic orthopaedic biomechanics and mechano-biology. Lippincott Williams and Wilkins, PhiladelphiaBrady MA, Waldman SD, Ethier CR (2015) The application of multiple biophysical cues to engineer functional neocartilage for treatment of osteoarthritis. Part I: cellular response. Tissue Eng Part B Rev 21:1–19Valhmu WB, Stazzone EJ, Bachrach NM, Saed-Nejad F, Fischer SG, Mow VC, Ratcliffe A (1998) Load-controlled compression of articular cartilage induces a transient stimulation of aggrecan gene expression. Arch Biochem Biophys 353:29–36Ingber DE (1997) Tensegrity: the architectural basis of cellular mechanotransduction. Ann Rev Physiol 59:575–599Khan S, Sheetz MP (1997) Force effects on biochemical kinetics. Ann Rev Biochem 66:785–805Hutmacher DW (2000) Scaffolds in tissue engineering bone and cartilage. Biomaterials 21:2529–2543Crick FHC, Hughes AFW (1950) The physical properties of cytoplasm: a study by means of the magnetic particle method. Exp Cell Res 1:37–80Valberg PA, Albertini DF (1985) Cytoplasmic motions, rheology, and structure probed by a novel magnetic particle method. J Cell Biol 101:130–140Valberg PA, Feldman HA (1987) Magnetic particle motions within living cells. Measurement of cytoplasmic viscosity and motile activity. Biophys J 52:551–561Wang N, Ingber DE (1995) Probing transmembrane mechanical coupling and cytomechanics using magnetic twisting cytometry. Biochem Cell Biol 73:327–335Pommerenke H, Schreiber E, Durr F, Nebe B, Hahnel C, Moller W, Rychly J (1996) Stimulation of integrin receptors using a magnetic drag force device induces an intracellular free calcium response. Eur J Cell Biol 70:157–164Bausch AR, Hellerer U, Essler M, Aepfelbacher M, Sackmann E (2001) Rapid stiffening of integrin receptor-actin linkages in endothelial cells stimulated with thrombin: a magnetic bead microrheology study. Biophys J 80:2649–2657Li L, Yang G, Li J, Ding S, Zhou S (2014) Cell behaviors on magnetic electrospun poly-d, l-lactide nano fibers. Mater Sci Eng, C 34:252–261Fuhrer R, Hofmann S, Hild N, Vetsch JR, Herrmann IK, Grass RN, Stark WJ (2013) Pressureless mechanical induction of stem cell differentiation is dose and frequency dependent. PLoS One 8:e81362Cezar CA, Roche ET, Vandenburgh HH, Duda GN, Walsh CJ, Mooney DJ (2016) Biologic-free mechanically induced muscle regeneration. Proc Natl Acad Sci USA 113:1534–1539Vikingsson L, Gallego Ferrer G, Gómez-Tejedor JA, Gómez Ribelles JL (2014) An in vitro experimental model to predict the mechanical behaviour of macroporous scaffolds implanted in articular cartilage. J Mech Behav Biomed Mater 32:125–131Vikingsson L, Gomez-Tejedor JA, Gallego Ferrer G, Gomez Ribelles JL (2015) An experimental fatigue study of a porous scaffold for the regeneration of articular cartilage. J Biomech 48:1310–1317Vikingsson L, Claessens B, Gómez-Tejedor JA, Gallego Ferrer G, Gómez Ribelles JL (2015) Relationship between micro-porosity, water permeability and mechanical behavior in scaffolds for cartilage engineering. J Mech Behav Biomed Mater 48:60–69Li F, Su YL, Shi DF, Wang CT (2010) Comparison of human articular cartilage and polyvinyl alcohol hydrogel as artificial cartilage in microstructure analysis and unconfined compression. Adv Mater Res Trans Tech Publ 87:188–193Grant C, Twigg P, Egan A, Moody A, Eagland D, Crowther N, Britland S (2006) Poly(vinyl alcohol) hydrogel as a biocompatible viscoelastic mimetic for articular cartilage. Biotechnol Prog 22:1400–1406Weeber R, Kantorovich S, Holm C (2015) Ferrogels cross-linked by magnetic nanoparticles—Deformation mechanisms in two and three dimensions studied by means of computer simulations. J Magn Magn Mater 383:262–266Lebourg M, Suay Antón J, Gómez Ribelles JL (2008) Porous membranes of PLLA–PCL blend for tissue engineering applications. Eur Polym J 44:2207–2218Santamaría VA, Deplaine H, Mariggió D, Villanueva-Molines AR, García-Aznar JM, Gómez Ribelles JL, Doblaré M, Gallego Ferrer G, Ochoa I (2012) Influence of the macro and micro-porous structure on the mechanical behavior of poly (l-lactic acid) scaffolds. J Non Cryst Solids 358:3141–3149Panadero JA, Vikingsson L, Gomez Ribelles JL, Lanceros-Mendez S, Sencadas V (2015) In vitro mechanical fatigue behaviour of poly-ε-caprolactone macroporous scaffolds for cartilage tissue engineering. Influence of pore filling by a poly(vinyl alcohol) gel. J Biomed Mater Res Part B Appl Biomater 103:1037–1043Hassan CM, Peppas NA (2000) Structure and applications of poly(vinyl alcohol) hydrogels produced by conventional crosslinking or by freezing/thawing methods. Adv Polym Sci 153:37–65Labet M, Thielemans W (2009) Synthesis of polycaprolactone: a review. Chem Soc Rev 38:3484–3504Mano JF, Gómez Ribelles JL, Alves NM, Salmerón Sanchez M (2005) Glass transition dynamics and structural relaxation of PLLA studied by DSC: influence of crystallinity. Polymer 46:8258–8265Eckstein F, Lemberger B, Gratzke C, Hudelmaier M, Glaser C, Englmeier KH, Reiser M (2005) In vivo cartilage deformation after different types of activity and its dependence on physical training status. Ann Rheum Dis 64:291–295Garlotta D (2001) A literature review of poly(lactic acid). J Polym Eng 9:63–84Kovacs AJ, Aklonis JJ, Hutchinson JM, Ramos AR (1979) Isobaric volume and enthalpy recovery of glasses. II. A transparent multiparameter theory. J Polym Sci Polym Phys 17:1097–1162Hernández F, Molina Mateo J, Romero Colomer F, Salmerón Sánchez M, Gómez Ribelles JL, Mano J (2005) Influence of low-temperature nucleation on the crystallization process of poly(l-lactide). Biomacromolecules 6:3291–3299Wang Y, Gómez Ribelles JL, Salmerón Sánchez M, Mano JF (2005) Morphological contribution to glass transition in poly(l-lactic acid). Macromolecules 38:4712–4718Salmerón Sánchez M, Vincent BM, Vanden Poel G, Gómez-Ribelles JL (2007) Effect of the cooling rate on the nucleation kinetics of poly(l-lactic acid) and its influence on morphology. Macromolecules 40:7989–7997Nobuyuki O (1975) A threshold selection method from gray-level histograms. Automatica 11:23–2

Ipsilesional trajectory control is related to contralesional arm paralysis after left hemisphere damage

We have recently shown ipsilateral dynamic deficits in trajectory control are present in left hemisphere damaged (LHD) patients with paresis, as evidenced by impaired modulation of torque amplitude as response amplitude increases. The purpose of the current study is to determine if these ipsilateral deficits are more common with contralateral hemiparesis and greater damage to the motor system, as evidenced by structural imaging. Three groups of right-handed subjects (healthy controls, LHD stroke patients with and without upper extremity paresis) performed single-joint elbow movements of varying amplitudes with their left arm in the left hemispace. Only the paretic group demonstrated dynamic deficits characterized by decreased modulation of peak torque (reflected by peak acceleration changes) as response amplitude increased. These results could not be attributed to lesion volume or peak velocity as neither variable differed across the groups. However, the paretic group had damage to a larger number of areas within the motor system than the non-paretic group suggesting that such damage increases the probability of ipsilesional deficits in dynamic control for modulating torque amplitude after left hemisphere damage

Do Worry and Brooding Predict Health Behaviors? A Daily Diary Investigation

Background Meta-analyses have reported associations between perseverative cognition (both worry and brooding) and increased engagement in health-risk behaviors, poorer sleep, and poorer physiological health outcomes. Method Using a daily diary design, this study investigated the within- and between-person relationships between state and trait perseverative cognition and health behaviors (eating behavior, physical activity, alcohol consumption, and sleep) both crosssectionally and prospectively. Participants (n = 273, 93% students, Mage = 20.2, SD = 4.11, 93% female) completed morning and evening diaries across 7 consecutive days. Results Multilevel modeling analyses revealed that, cross-sectionally, higher levels of state worry were associated with more time spent sitting and higher levels of state brooding predicted less daily walking. Conclusion Worry and brooding may represent useful intervention targets for improving inactivity and walking levels, respectively

Tsetse GmmSRPN10 has anti-complement activity and is important for successful establishment of trypanosome infections in the fly midgut

The complement cascade in mammalian blood can damage the alimentary tract of haematophagous arthropods. As such, these animals have evolved their own repertoire of complement-inactivating factors, which are inadvertently exploited by blood-borne pathogens to escape complement lysis. Unlike the bloodstream stages, the procyclic (insect) stage of Trypanosoma brucei is highly susceptible to complement killing, which is puzzling considering that a tsetse takes a bloodmeal every 2–4 days. In this study, we identified four tsetse (Glossina morsitans morsitans) serine protease inhibitors (serpins) from a midgut expressed sequence tag (EST) library (GmmSRPN3, GmmSRPN5, GmmSRPN9 and GmmSRPN10) and investigated their role in modulating the establishment of a T. brucei infection in the midgut. Although not having evolved in a common blood-feeding ancestor, all four serpins have an active site sharing remarkable homology with the human complement C1-inhibitor serpin, SerpinG1. RNAi knockdown of individual GmmSRPN9 and GmmSRPN10 genes resulted in a significant decreased rate of infection by procyclic form T. brucei. Furthermore, recombinant GmmSRPN10 was both able to inhibit the activity of human complement-cascade serine proteases, C1s and Factor D, and to protect the in vitro killing of procyclic trypanosomes when incubated with complement-activated human serum. Thus, the secretion of serpins, which may be part of a bloodmeal complement inactivation system in tsetse, is used by procyclic trypanosomes to evade an influx of fresh trypanolytic complement with each bloodmeal. This highlights another facet of the complicated relationship between T. brucei and its tsetse vector, where the parasite takes advantage of tsetse physiology to further its chances of propagation and transmission