Observation of an Efimov spectrum in an atomic system

In 1970 V. Efimov predicted a puzzling quantum-mechanical effect that is still of great interest today. He found that three particles subjected to a resonant pairwise interaction can join into an infinite number of loosely bound states even though each particle pair cannot bind. Interestingly, the properties of these aggregates, such as the peculiar geometric scaling of their energy spectrum, are universal, i.e. independent of the microscopic details of their components. Despite an extensive search in many different physical systems, including atoms, molecules and nuclei, the characteristic spectrum of Efimov trimer states still eludes observation. Here we report on the discovery of two bound trimer states of potassium atoms very close to the Efimov scenario, which we reveal by studying three-particle collisions in an ultracold gas. Our observation provides the first evidence of an Efimov spectrum and allows a direct test of its scaling behaviour, shedding new light onto the physics of few-body systems.Comment: 10 pages, 3 figures, 1 tabl

Defective Gpsm2/G alpha(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome

Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues

Pretreatment CD4 Cell Slope and Progression to AIDS or Death in HIV-Infected Patients Initiating Antiretroviral Therapy—The CASCADE Collaboration: A Collaboration of 23 Cohort Studies

Analyzing data from several thousand cohort study participants, Marcel Wolbers and colleagues find that the rate of CD4 T cell decline is not useful in deciding when to start HIV treatment

Author Correction: Defective Gpsm2/G alpha(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome (vol 8, 14907, 2017)

Author Correction: Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrom

Computational methodology to determine fluid related parameters on non regular three-dimensional scaffolds

The application of three-dimensional (3D) biomaterials to facilitate the adhesion, proliferation, and differentiation of cells has been widely studied for tissue engineering purposes. The fabrication methods used to improve the mechanical response of the scaffold produce complex and non regular structures. Apart from the mechanical aspect, the fluid behavior in the inner part of the scaffold should also be considered. Parameters such as permeability (k) or wall shear stress (WSS) are important aspects in the provision of nutrients, the removal of metabolic waste products or the mechanically-induced differentiation of cells attached in the trabecular network of the scaffolds. Experimental measurements of these parameters are not available in all labs. However, fluid parameters should be known prior to other types of experiments. The present work compares an experimental study with a computational fluid dynamics (CFD) methodology to determine the related fluid parameters (k and WSS) of complex non regular poly(L-lactic acid) scaffolds based only on the treatment of microphotographic images obtained with a microCT (lCT). The CFD analysis shows similar tendencies and results with low relative difference compared to those of the experimental study, for high flow rates. For low flow rates the accuracy of this prediction reduces. The correlation between the computational and experimental results validates the robustness of the proposed methodology.The authors gratefully acknowledge research support from the Spanish Ministry of Science and Innovation through research project DPI2010-20399-C04-01. The Instituto de Salud Carlos III (ISCIII) through the CIBER initiative and the Platform for Biological Tissue Characterization of the Centro de Investigacion Biomedica en Red en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN) are also gratefully acknowledged.Acosta Santamaría, VA.; Malvé, M.; Duizabo, A.; Mena Tobar, A.; Gallego Ferrer, G.; García Aznar, J.; Doblare Castellano, M.... (2013). Computational methodology to determine fluid related parameters on non regular three-dimensional scaffolds. Annals of Biomedical Engineering. 41(11):2367-2380. https://doi.org/10.1007/s10439-013-0849-8S236723804111Acosta Santamaría, V., H. Deplaine, D. Mariggió, A. R. Villanueva-Molines, J. M. García-Aznar, J. L. Gómez Ribelles, M. Doblaré, G. Gallego Ferrer, and I. Ochoa. Influence of the macro and micro-porous structure on the mechanical behavior of poly(l-lactic acid) scaffolds. J. Non-Cryst. Solids 358(23):3141–3149, 2012.Adachi, T., Y. Osako, M. Tanaka, M. Hojo, and S. J. Hollister. Framework for optimal design of porous scaffold microstructure by computational simulation of bone regeneration. Biomaterials 27(21):3964–3972, 2006.Adamczyk, Z., and T. G. M. Vandeven. Deposition of particles under external forces in laminar-flow through parallel-plate and cylindrical channels. J. Colloid Interface Sci. 80(2):340–356, 1981.Alberich, B. A., D. Moratal, J. L. Escobar, J. C. Rodríguez, A. Vallés-Lluch, L. Martí-Bonmatí, et al. Microcomputed tomography and microfinite element modeling for evaluating polymer scaffolds architecture and their mechanical properties. J. Biomed. Mater. Res. B Appl. Biomater. 91B(1):191–202, 2009.Al-Munajjed, A., M. Hien, R. Kujat, J. P. Gleeson, and J. Hammer. Influence of pore size on tensile strength, permeability and porosity of hyaluronan-collagen scaffolds. J. Mater. Sci. Mater. Med. 19(8):2859–2864, 2008.Alves da Silva, M. L., A. Martins, A. R. Costa-Pinto, V. M. Correlo, P. Sol, M. Bhattacharya, S. Faria, R. L. Reis, and N. M. Neves. Chondrogenic differentiation of human bone marrow mesenchymal stem cells in chitosan-based scaffolds using a flow-perfusion bioreactor. J. Tissue Eng. Regen. Med. 5(9):722–732, 2011.Ansys (2010) CFX Theory User Manual. Canonsburg, PA: Ansys Software.Brígido, R. D., J. M. Estellés, J. A. Sanz, J. M. García-Aznar, and M. S. Sánchez. Polymer scaffolds with interconnected spherical pores and controlled architecture for tissue engineering: fabrication, mechanical properties, and finite element modeling. J. Biomed. Mater. Res. B Appl. Biomater. 81B(2):448–455, 2007.Byrne, P. D., D. Lacroix, J. A. Planell, D. J. Kelly, and P. J. Prendergast. Simulation of tissue differentiation in a scaffold as a function of porosity, Young’s modulus and dissolution rate: application of mechanobiological models in tissue engineering. Biomaterials 28:5544–5554, 2007.Chor, M. V., and W. Li. A permeability measurement system for tissue engineering scaffolds. Meas. Sci. Technol. 18(1):208–216, 2007.Cozensroberts, C., J. A. Quinn, and D. A. Lauffenburger. Receptor-mediated adhesion phenomena—model studies with the radial-flow detachment assay. Biophys. J. 58(1):107–125, 1990.Davisson, T., R. L. Sah, and A. Ratcliffe. Perfusion increases cell content and matrix synthesis in chondrocyte three-dimensional cultures. Tissue Eng. 8(5):807–816, 2002.Deplaine, H., M. Lebourg, P. Ripalda, A. Vidaurre, P. Sanz-Ramos, G. Mora, F. Prósper, I. Ochoa, M. Doblaré, J. L. Gómez Ribelles, I. Izal-Azcárate, and G. Gallego Ferrer. Biomimetic hydroxyapatite coating on pore walls improves osteointegration of poly(l-lactic acid) scaffolds. J. Biomed. Mater. Res. B Appl. Biomater. 101(1):173–186, 2013.Dias, M. R., P. R. Fernandes, J. M. Guedes, and S. J. Hollister. Permeability analysis of scaffolds for bone tissue engineering. J. Biomech. 45(6):938–944, 2012.Freyman, T. M., I. V. Yannas, and L. J. Gibson. Cellular materials as porous scaffolds for tissue engineering. Prog. Mater Sci. 46:273–282, 2001.Gong, S., H. Wang, Q. Sun, S. T. Xue, and J. Wang. Mechanical properties and in vitro biocompatibility of porous zein scaffolds. Biomaterials 27(20):3793–3799, 2006.Gutierrez, R. A., and E. T. Crumpler. Potential effect of geometry on wall shear stress distribution across scaffold surfaces. Ann. Biomed. Eng. 36(1):77–85, 2008.Hammer, D. A., and D. Lauffenburger. A dynamic-model for receptor-mediated cell adhesion to surfaces. Biophys. J. 52(3):475–487, 1987.Ho, S. T., and D. W. Hutmacher. A comparison of micro CT with other techniques used in the characterization of scaffolds. Biomaterials 27(8):1362–1376, 2006.Ho, M. H., P. Y. Kuo, H. J. Hsieh, T. Y. Hsien, L. T. Hou, J. Y. Lai, and D. M. Wang. Preparation of porous scaffolds by using freeze-extraction and freeze-gelation methods. Biomaterials 25(1):129–138, 2004.Hutmacher, D. W., J. T. Schantz, C. X. Lam, K. C. Tan, and T. C. Lim. State of the art and future directions of scaffold-based bone engineering from a biomaterials perspective. J. Tissue Eng. Regen. Med. 1(4):245–260, 2007.Izal, I., P. Aranda, P. Sanz-Ramos, P. Ripalda, G. Mora, F. Granero-Moltó, H. Deplaine, J. L. Gómez-Ribelles, G. G. Ferrer, V. Acosta, I. Ochoa, J. M. García-Aznar, E. J. Andreu, M. Monleón-Pradas, M. Doblaré, and F. Prósper. Culture of human bone marrow-derived mesenchymal stem cells on of poly(l-lactic acid) scaffolds: potential application for the tissue engineering of cartilage. Knee Surg. Sports Traumatol. Arthrosc., 2012.Kapur, S., D. J. Baylink, and K. H. Lau. Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways. Bone 32(3):241–251, 2003.Karande, T. S., J. L. Ong, and C. M. Agrawal. Diffusion in musculoskeletal tissue engineering scaffolds: design issues related to porosity, permeability, architecture, and nutrient mixing. Ann. Biomed. Eng. 32(12):1728–1743, 2004.Kelly, D. J., and P. J. Prendergast. Mechano-regulation of stem cell differentiation and tissue regeneration in osteochondral defects. J. Biomech. 38(7):1413–1422, 2005.Kreke, M. R., L. A. Sharp, Y. W. Lee, and A. S. Goldstein. Effect of intermittent shear stress on mechanotransductive signaling and osteoblastic differentiation of bone marrow stromal cells. Tissue Eng. Part A 14(4):529–537, 2008.Lacroix, D., A. Chateau, M. P. Ginebra, and J. A. Planell. Micro-finite element models of bone tissue-engineering scaffolds. Biomaterials 27(30):5326–5334, 2006.Lacroix, D., and P. J. Prendergast. A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J. Biomech. 35(9):1163–1171, 2002.Li, S., J. R. De Wijn, J. Li, P. Layrolle, and K. De Groot. Macroporous biphasic calcium phosphate scaffold with high permeability/porosity ratio. Tissue Eng. 9:535–548, 2003.Melchels, F. P. W., B. Tonnarelli, A. L. Olivares, I. Martin, D. Lacroix, J. Feijen, et al. The influence of the scaffold design on the distribution of adhering cells after perfusion cell seeding. Biomaterials 32(11):2878–2884, 2011.O’Brien, F. J., B. A. Harley, M. A. Waller, I. Yannas, L. J. Gibson, and P. Prendergast. The effect of pore size on permeability and cell attachment in collagen scaffolds for tissue engineering. Technol. Health Care 15(1):3–17, 2007.Ochoa, I., J. A. Sanz, J. M. Garcia-Aznar, M. Doblare, D. M. Yunos, and A. R. Boccaccini. Permeability evaluation of 45S5 bioglass-based scaffolds for bone tissue engineering. J. Biomech. 42:257–260, 2009.Porter, B., R. Zauel, H. Stockman, R. Guldberg, and D. Fyhrie. 3-D computational modeling of media flow through scaffolds in a perfusion bioreactor. Mater. Res. 38:543–549, 2005.Sandino, C., S. Checa, P. J. Prendergast, and D. Lacroix. Simulation of angiogenesis and cell differentiation in a CaP scaffold subjected to compressive strains using a lattice modeling approach. Biomaterials 31(8):2446–2452, 2010.Sanz, J. A., J. M. García-Aznar, and M. Doblaré. On scaffold designing for bone regeneration: a computational multiscale approach. Acta Biomater. 5(1):219–229, 2009.Sanz, J. A., C. Kasper, M. van Griensven, J. M. Garcia-Aznar, I. Ochoa, and M. Doblare. Mechanical and flow characterization of Sponceram® carriers: evaluation by homogenization theory and experimental validation. J. Biomed. Mater. Res. B Appl. Biomater. 87B(1):42–48, 2008.Singh, H., S. H. Teoh, H. T. Low, and D. W. Hutmacher. Flow modelling within a scaffold under the influence of uni-axial and bi-axial bioreactor rotation. J. Biotechnol. 119:181–196, 2005.Sjollema, J., and H. J. Busscher. Deposition of polystyrene latex-particles toward polymethylmethacrylate in a parallel plate flow cell. J. Colloid Interface Sci. 132(2):382–394, 1989.Truscello, S., G. Kerckhofs, S. Van Bael, G. Pyka, J. Schrooten, and H. Van Oosterwyck. Prediction of permeability of regular scaffolds for skeletal tissue engineering: a combined computational and experimental study. Acta Biomater. 8(4):1648–1658, 2012.Woodfield, T. B., J. Malda, J. Wijn, F. Péters, J. Riesle, and C. A. van Blitterswijk. Design of porous scaffolds for cartilage tissue engineering using a three-dimensional fiber-deposition technique. Biomaterials 25(18):4149–4161, 2004

Knockdown of SF-1 and RNF31 Affects Components of Steroidogenesis, TGFβ, and Wnt/β-catenin Signaling in Adrenocortical Carcinoma Cells

The orphan nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1) is a critical regulator of development and homeostasis of the adrenal cortex and gonads. We recently showed that a complex containing E3 ubiquitin ligase RNF31 and the known SF-1 corepressor DAX-1 (NR0B1) interacts with SF-1 on target promoters and represses transcription of steroidogenic acute regulatory protein (StAR) and aromatase (CYP19) genes. To further evaluate the role of SF-1 in the adrenal cortex and the involvement of RNF31 in SF-1-dependent pathways, we performed genome-wide gene-expression analysis of adrenocortical NCI-H295R cells where SF-1 or RNF31 had been knocked down using RNA interference. We find RNF31 to be deeply connected to cholesterol metabolism and steroid hormone synthesis, strengthening its role as an SF-1 coregulator. We also find intriguing evidence of negative crosstalk between SF-1 and both transforming growth factor (TGF) β and Wnt/β-catenin signaling. This crosstalk could be of importance for adrenogonadal development, maintenance of adrenocortical progenitor cells and the development of adrenocortical carcinoma. Finally, the SF-1 gene profile can be used to distinguish malignant from benign adrenocortical tumors, a finding that implicates SF-1 in the development of malignant adrenocortical carcinoma

The Herbicide Atrazine Activates Endocrine Gene Networks via Non-Steroidal NR5A Nuclear Receptors in Fish and Mammalian Cells

Atrazine (ATR) remains a widely used broadleaf herbicide in the United States despite the fact that this s-chlorotriazine has been linked to reproductive abnormalities in fish and amphibians. Here, using zebrafish we report that environmentally relevant ATR concentrations elevated zcyp19a1 expression encoding aromatase (2.2 µg/L), and increased the ratio of female to male fish (22 µg/L). ATR selectively increased zcyp19a1, a known gene target of the nuclear receptor SF-1 (NR5A1), whereas zcyp19a2, which is estrogen responsive, remained unchanged. Remarkably, in mammalian cells ATR functions in a cell-specific manner to upregulate SF-1 targets and other genes critical for steroid synthesis and reproduction, including Cyp19A1, StAR, Cyp11A1, hCG, FSTL3, LHß, INHα, αGSU, and 11ß-HSD2. Our data appear to eliminate the possibility that ATR directly affects SF-1 DNA- or ligand-binding. Instead, we suggest that the stimulatory effects of ATR on the NR5A receptor subfamily (SF-1, LRH-1, and zff1d) are likely mediated by receptor phosphorylation, amplification of cAMP and PI3K signaling, and possibly an increase in the cAMP-responsive cellular kinase SGK-1, which is known to be upregulated in infertile women. Taken together, we propose that this pervasive and persistent environmental chemical alters hormone networks via convergence of NR5A activity and cAMP signaling, to potentially disrupt normal endocrine development and function in lower and higher vertebrates

Depletion of Dendritic Cells Enhances Innate Anti-Bacterial Host Defense through Modulation of Phagocyte Homeostasis

Dendritic cells (DCs) as professional antigen-presenting cells play an important role in the initiation and modulation of the adaptive immune response. However, their role in the innate immune response against bacterial infections is not completely defined. Here we have analyzed the role of DCs and their impact on the innate anti-bacterial host defense in an experimental infection model of Yersinia enterocolitica (Ye). We used CD11c-diphtheria toxin (DT) mice to deplete DCs prior to severe infection with Ye. DC depletion significantly increased animal survival after Ye infection. The bacterial load in the spleen of DC-depleted mice was significantly lower than that of control mice throughout the infection. DC depletion was accompanied by an increase in the serum levels of CXCL1, G-CSF, IL-1α, and CCL2 and an increase in the numbers of splenic phagocytes. Functionally, splenocytes from DC-depleted mice exhibited an increased bacterial killing capacity compared to splenocytes from control mice. Cellular studies further showed that this was due to an increased production of reactive oxygen species (ROS) by neutrophils. Adoptive transfer of neutrophils from DC-depleted mice into control mice prior to Ye infection reduced the bacterial load to the level of Ye-infected DC-depleted mice, suggesting that the increased number of phagocytes with additional ROS production account for the decreased bacterial load. Furthermore, after incubation with serum from DC-depleted mice splenocytes from control mice increased their bacterial killing capacity, most likely due to enhanced ROS production by neutrophils, indicating that serum factors from DC-depleted mice account for this effect. In summary, we could show that DC depletion triggers phagocyte accumulation in the spleen and enhances their anti-bacterial killing capacity upon bacterial infection

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. / Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. / Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. / Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic–atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants

A correction for sample overlap in genome-wide association studies in a polygenic pleiotropy-informed framework.

BACKGROUND: There is considerable evidence that many complex traits have a partially shared genetic basis, termed pleiotropy. It is therefore useful to consider integrating genome-wide association study (GWAS) data across several traits, usually at the summary statistic level. A major practical challenge arises when these GWAS have overlapping subjects. This is particularly an issue when estimating pleiotropy using methods that condition the significance of one trait on the signficance of a second, such as the covariate-modulated false discovery rate (cmfdr). RESULTS: We propose a method for correcting for sample overlap at the summary statistic level. We quantify the expected amount of spurious correlation between the summary statistics from two GWAS due to sample overlap, and use this estimated correlation in a simple linear correction that adjusts the joint distribution of test statistics from the two GWAS. The correction is appropriate for GWAS with case-control or quantitative outcomes. Our simulations and data example show that without correcting for sample overlap, the cmfdr is not properly controlled, leading to an excessive number of false discoveries and an excessive false discovery proportion. Our correction for sample overlap is effective in that it restores proper control of the false discovery rate, at very little loss in power. CONCLUSIONS: With our proposed correction, it is possible to integrate GWAS summary statistics with overlapping samples in a statistical framework that is dependent on the joint distribution of the two GWAS