Integrin activation - the importance of a positive feedback

Integrins mediate cell adhesion and are essential receptors for the development and functioning of multicellular organisms. Integrin activation is known to require both ligand and talin binding and to correlate with cluster formation but the activation mechanism and precise roles of these processes are not yet resolved. Here mathematical modeling, with known experimental parameters, is used to show that the binding of a stabilizing factor, such as talin, is alone insufficient to enable ligand-dependent integrin activation for all observed conditions; an additional positive feedback is required.Comment: in press in Bulletin of Mathematical Biolog

Protein sequence and structure: Is one more fundamental than the other?

We argue that protein native state structures reside in a novel "phase" of matter which confers on proteins their many amazing characteristics. This phase arises from the common features of all globular proteins and is characterized by a sequence-independent free energy landscape with relatively few low energy minima with funnel-like character. The choice of a sequence that fits well into one of these predetermined structures facilitates rapid and cooperative folding. Our model calculations show that this novel phase facilitates the formation of an efficient route for sequence design starting from random peptides.Comment: 7 pages, 4 figures, to appear in J. Stat. Phy

Momentum and Energy Distributions of Nucleons in Finite Nuclei due to Short-Range Correlations

The influence of short-range correlations on the momentum and energy distribution of nucleons in nuclei is evaluated assuming a realistic meson-exchange potential for the nucleon-nucleon interaction. Using the Green-function approach the calculations are performed directly for the finite nucleus $^{16}$O avoiding the local density approximation and its reference to studies of infinite nuclear matter. The nucleon-nucleon correlations induced by the short-range and tensor components of the interaction yield an enhancement of the momentum distribution at high momenta as compared to the Hartree-Fock description. These high-momentum components should be observed mainly in nucleon knockout reactions like $(e,e'p)$ leaving the final nucleus in a state of high excitation energy. Our analysis also demonstrates that non-negligible contributions to the momentum distribution should be found in partial waves which are unoccupied in the simple shell-model. The treatment of correlations beyond the Brueckner-Hartree-Fock approximation also yields an improvement for the calculated ground-state properties.Comment: 12 pages RevTeX, 7 figures postscript files appende

Momentum Distribution in Nuclear Matter and Finite Nuclei

A simple method is presented to evaluate the effects of short-range correlations on the momentum distribution of nucleons in nuclear matter within the framework of the Green's function approach. The method provides a very efficient representation of the single-particle Green's function for a correlated system. The reliability of this method is established by comparing its results to those obtained in more elaborate calculations. The sensitivity of the momentum distribution on the nucleon-nucleon interaction and the nuclear density is studied. The momentum distributions of nucleons in finite nuclei are derived from those in nuclear matter using a local-density approximation. These results are compared to those obtained directly for light nuclei like $^{16}O$.Comment: 17 pages REVTeX, 10 figures ps files adde

PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis

Patients infected by Leishmania braziliensis develop debilitating skin lesions. The role of inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in both CD4^{+} and CD8^{+} T cell subsets. Moreover, PDL-1/PDL-2 ligands were increased on skin macrophages compared to healthy controls. The proportions PD1^{+}, but not TIM-3 or CTLA-4 expressing T cells in the circulation were positively correlated with those in the lesions of the same patients, suggesting that PD-1 may regulate T cell function equally in both compartments. Blocking PD-1 signaling in circulating T cells enhanced their proliferative capacity and IFN-γ production, but not TNF-α secretion in response to L. braziliensis recall antigen challenge in vitro. While we previously showed a significant correlation between the accumulation of senescent CD8^{+}CD45RA^{+}CD27^{-} T cells in the circulation and skin lesion size in the patients, there was no such correlation between the extent of PD-1 expression by circulating on T cells and the magnitude of skin lesions suggesting that exhausted-like T cells may not contribute to the cutaneous immunopathology. Nevertheless, we identified exhausted-like T cells in both skin lesions and in the blood. Targeting this population by PD-1 blockade may improve T cell function and thus accelerate parasite clearance that would reduce the cutaneous pathology in cutaneous leishmaniasis

A multi-decade record of high quality fCO2 data in version 3 of the Surface Ocean CO2 Atlas (SOCAT)

The Surface Ocean CO2 Atlas (SOCAT) is a synthesis of quality-controlled fCO2 (fugacity of carbon dioxide) values for the global surface oceans and coastal seas with regular updates. Version 3 of SOCAT has 14.7 million fCO2 values from 3646 data sets covering the years 1957 to 2014. This latest version has an additional 4.6 million fCO2 values relative to version 2 and extends the record from 2011 to 2014. Version 3 also significantly increases the data availability for 2005 to 2013. SOCAT has an average of approximately 1.2 million surface water fCO2 values per year for the years 2006 to 2012. Quality and documentation of the data has improved. A new feature is the data set quality control (QC) flag of E for data from alternative sensors and platforms. The accuracy of surface water fCO2 has been defined for all data set QC flags. Automated range checking has been carried out for all data sets during their upload into SOCAT. The upgrade of the interactive Data Set Viewer (previously known as the Cruise Data Viewer) allows better interrogation of the SOCAT data collection and rapid creation of high-quality figures for scientific presentations. Automated data upload has been launched for version 4 and will enable more frequent SOCAT releases in the future. High-profile scientific applications of SOCAT include quantification of the ocean sink for atmospheric carbon dioxide and its long-term variation, detection of ocean acidification, as well as evaluation of coupled-climate and ocean-only biogeochemical models. Users of SOCAT data products are urged to acknowledge the contribution of data providers, as stated in the SOCAT Fair Data Use Statement. This ESSD (Earth System Science Data) “living data” publication documents the methods and data sets used for the assembly of this new version of the SOCAT data collection and compares these with those used for earlier versions of the data collection (Pfeil et al., 2013; Sabine et al., 2013; Bakker et al., 2014). Individual data set files, included in the synthesis product, can be downloaded here: doi:10.1594/PANGAEA.849770. The gridded products are available here: doi:10.3334/CDIAC/OTG.SOCAT_V3_GRID

PNES around the world: Where we are now and how we can close the diagnosis and treatment gaps-an ILAE PNES Task Force report

An international consensus clinical practice statement issued in 2011 ranked psychogenic nonepileptic seizures (PNES) among the top three neuropsychiatric problems. An ILAE PNES Task Force was founded and initially charged with summarizing the current state of the art in terms of diagnosis and treatment, resulting in two publications. The first described different levels of diagnostic certainty. The second summarized current knowledge of management approaches. The present paper summarizes an international workshop of the ILAE PNES Task Force that focused on the current understanding and management of PNES around the world. We initially provide a knowledge update about the etiology, epidemiology, and prognosis of PNES-in adults and in special patient groups, such as children, older adults, and those with intellectual disability. We then explore clinical management pathways and obstacles to optimal care for this disorder around the world by focusing on a number of countries with different cultural backgrounds and at very different stages of social and economic development (United Kingdom, U.S.A., Zambia, Georgia, China, and Japan). Although evidence-based methods for the diagnosis and treatment of PNES have now been described, and much is known about the biopsychosocial underpinnings of this disorder, this paper describes gaps in care (not only in less developed countries) that result in patients with PNES not having adequate access to healthcare provisions. A range of challenges requiring solutions tailored to different healthcare systems emerges. Continued attention to PNES by the ILAE and other national and international neurologic, psychiatric, and health organizations, along with ongoing international collaboration, should ensure that patients with PNES do not lose out as healthcare services evolve around the world