Revisiting the reactivity between HCO and CH3_3 on interstellar grain surfaces

Formation of interstellar complex organic molecules is currently thought to be dominated by the barrierless coupling between radicals on the interstellar icy grain surfaces. Previous standard DFT results on the reactivity between CH$_3$ and HCO on amorphous water surfaces, showed that formation of CH$_4$ + CO by H transfer from HCO to CH$_3$ assisted by water molecules of the ice was the dominant channel. However, the adopted description of the electronic structure of the biradical (i.e., CH$_3$/HCO) system was inadequate (without the broken-symmetry (BS) approach). In this work, we revisit the original results by means of BS-DFT both in gas phase and with one water molecule simulating the role of the ice. Results indicate that adoption of BS-DFT is mandatory to describe properly biradical systems. In the presence of the single water molecule, the water-assisted H transfer exhibits a high energy barrier. In contrast, CH$_3$CHO formation is found to be barrierless. However, direct H transfer from HCO to CH$_3$ to give CO and CH$_4$ presents a very low energy barrier, hence being a potential competitive channel to the radical coupling and indicating, moreover, that the physical insights ofthe original work remain valid.Comment: Submitted to MNRAS main journal. For associated supporting material refer to the publication in MNRAS. Accepted 2020 February 14. Received 2020 February 1

Structural representations of DNA regulatory substrates can enhance sequence-based algorithms by associating functional sequence variants

The nucleotide sequence representation of DNA can be inadequate for resolving protein-DNA binding sites and regulatory substrates, such as those involved in gene expression and horizontal gene transfer. Considering that sequence-like representations are algorithmically very useful, here we fused over 60 currently available DNA physicochemical and conformational variables into compact structural representations that can encode single DNA binding sites to whole regulatory regions. We find that the main structural components reflect key properties of protein-DNA interactions and can be condensed to the amount of information found in a single nucleotide position. The most accurate structural representations compress functional DNA sequence variants by 30% to 50%, as each instance encodes from tens to thousands of sequences. We show that a structural distance function discriminates among groups of DNA substrates more accurately than nucleotide sequence-based metrics. As this opens up a variety of implementation possibilities, we develop and test a distance-based alignment algorithm, demonstrating the potential of using the structural representations to enhance sequence-based algorithms. Due to the bias of most current bioinformatic methods to nucleotide sequence representations, it is possible that considerable performance increases might still be achievable with such solutions.Comment: 20 pages, 8 figures, 3 tables, conferenc

Diagnosis, Treatment, and Outcomes in Children With Congenital Nephrogenic Diabetes Insipidus: A Pediatric Nephrology Research Consortium Study

© Copyright © 2020 D\u27Alessandri-Silva, Carpenter, Ayoob, Barcia, Chishti, Constantinescu, Dell, Goodwin, Hashmat, Iragorri, Kaspar, Mason, Misurac, Muff-Luett, Sethna, Shah, Weng, Greenbaum and Mahan. Background and Objectives: Congenital or primary nephrogenic diabetes insipidus (NDI) is a rare genetic disorder that severely impairs renal concentrating ability, resulting in massive polyuria. There is limited information about prognosis or evidence guiding the management of these patients, either in the high-risk period after diagnosis, or long-term. We describe the clinical presentation, genetic etiology, treatment and renal outcomes in a large group of children (89%) and white (67%). Median age at diagnosis was 4.2 months interquartile range (IQR 1.1, 9.8). A desmopressin acetate loading test was administered to 46% of children at a median age of 4.8 months (IQR 2.8, 7.6); only 15% had a water restriction test. Genetic testing or a known family history was present in 70% of the patients; out of those genetically tested, 89 and 11% had mutations in AVPR2 and AQP2, respectively. No positive family history or genetic testing was available for 30%. The most common treatments were thiazide diuretics (74%), potassium-sparing diuretics (67%) and non-steroidal anti-inflammatory drugs (42%). At the time of first treatment, 70 and 71% of children were below −2 standard deviations (SD) for weight and height, respectively. At last follow-up, median age was 72.3 months (IQR 40.9, 137.2) and the percentage below −2 SD improved to 29% and 38% for weight and height, respectively. Adverse outcomes included inpatient hospitalizations (61%), urologic complications (37%), and chronic kidney disease (CKD) stage 2 or higher in 23%. Conclusion: We found the majority of patients were treated with thiazides with either a potassium sparing diuretic and/or NSAIDs. Hospitalizations, urologic complications, short stature, and CKD were common. Prospective trials to evaluate different treatment strategies are needed to attempt to improve outcomes

Bridges of biomaterials promote nigrostriatal pathway regeneration

[EN] Repair of central nervous system (CNS) lesions is difficulted by the lack of ability of central axons to regrow, and the blocking by the brain astrocytes to axonal entry. We hypothesized that by using bridges made of porous biomaterial and permissive olfactory ensheathing glia (OEG), we could provide a scaffold to permit restoration of white matter tracts. We implanted porous polycaprolactone (PCL) bridges between the substantia nigra and the striatum in rats, both with and without OEG. We compared the number of tyrosine-hydroxylase positive (TH+) fibers crossing the striatal-graft interface, and the astrocytic and microglial reaction around the grafts, between animals grafted with and without OEG. Although TH+ fibers were found inside the grafts made of PCL alone, there was a greater fiber density inside the graft and at the striatal-graft interface when OEG was cografted. Also, there was less astrocytic and microglial reaction in those animals. These results show that these PCL grafts are able to promote axonal growth along the nigrostriatal pathway, and that cografting of OEG markedly enhances axonal entry inside the grafts, growth within them, and re-entry of axons into the CNS. These results may have implications in the treatment of diseases such as Parkinson's and others associated with lesions of central white matter tracts.Contract grant sponsor: Regional Government Health Department (Conselleria de Sanitat, Generalitat Valenciana) and Carlos III Health Institute of the Ministry of Health and Consumer Affairs (Spain) (Regenerative Medicine Programme) Contract grant sponsor: Spanish ministry of Education and Science; contract grant number: MAT 2006-13554-C02-02 Contract grant sponsor: Red de Terapia Celular TERCEL (RETICS), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion (ISCIII); contract grant number: RD12/0019/0010 (to J.A.) Contract grant sponsor: Spanish Science & Innovation Ministery; contract grant number: MAT2008-06434 (to M.M.P.) Contract grant sponsor: "Convenio de Colaboracion para la Investigacion Basica y Traslacional en Medicina Regenerativa," Instituto Nacional de Salud Carlos III, the Conselleria de Sanidad of the Generalitat Valenciana, and the Foundation Centro de Investigacion Principe FelipeGómez Pinedo, U.; Sanchez-Rojas, L.; Vidueira, S.; Sancho, FJ.; Martínez-Ramos, C.; Lebourg, M.; Monleón Pradas, M.... (2019). Bridges of biomaterials promote nigrostriatal pathway regeneration. Journal of Biomedical Materials Research Part B Applied Biomaterials. 107(1):190-196. https://doi.org/10.1002/jbm.b.34110S1901961071Pekny, M., Wilhelmsson, U., & Pekna, M. (2014). The dual role of astrocyte activation and reactive gliosis. Neuroscience Letters, 565, 30-38. doi:10.1016/j.neulet.2013.12.071Bliss, T. M., Andres, R. H., & Steinberg, G. K. (2010). Optimizing the success of cell transplantation therapy for stroke. Neurobiology of Disease, 37(2), 275-283. doi:10.1016/j.nbd.2009.10.003Tam, R. Y., Fuehrmann, T., Mitrousis, N., & Shoichet, M. S. (2013). Regenerative Therapies for Central Nervous System Diseases: a Biomaterials Approach. Neuropsychopharmacology, 39(1), 169-188. doi:10.1038/npp.2013.237Skop, N. B., Calderon, F., Cho, C. H., Gandhi, C. D., & Levison, S. W. (2014). Improvements in biomaterial matrices for neural precursor cell transplantation. Molecular and Cellular Therapies, 2(1), 19. doi:10.1186/2052-8426-2-19Yasuhara, T., Kameda, M., Sasaki, T., Tajiri, N., & Date, I. (2017). Cell Therapy for Parkinson’s Disease. Cell Transplantation, 26(9), 1551-1559. doi:10.1177/0963689717735411Orive, G., Anitua, E., Pedraz, J. L., & Emerich, D. F. (2009). Biomaterials for promoting brain protection, repair and regeneration. Nature Reviews Neuroscience, 10(9), 682-692. doi:10.1038/nrn2685Walker, P. A., Aroom, K. R., Jimenez, F., Shah, S. K., Harting, M. T., Gill, B. S., & Cox, C. S. (2009). Advances in Progenitor Cell Therapy Using Scaffolding Constructs for Central Nervous System Injury. Stem Cell Reviews and Reports, 5(3), 283-300. doi:10.1007/s12015-009-9081-1Zhong, Y., & Bellamkonda, R. V. (2008). Biomaterials for the central nervous system. Journal of The Royal Society Interface, 5(26), 957-975. doi:10.1098/rsif.2008.0071Pérez‐GarnezM BarciaJA Gómez‐PinedoU Monleón‐PradasM Vallés‐LluchA.Materials for Central Nervous System Tissue Engineering Cells and Biomaterials in Regenerative Medicine. InTech;2014. Chap 7.Sinha, V. R., Bansal, K., Kaushik, R., Kumria, R., & Trehan, A. (2004). Poly-ϵ-caprolactone microspheres and nanospheres: an overview. International Journal of Pharmaceutics, 278(1), 1-23. doi:10.1016/j.ijpharm.2004.01.044Raisman, G. (2001). Olfactory ensheathing cells — another miracle cure for spinal cord injury? 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Annals of Neurology, 45(2), 207-215. doi:10.1002/1531-8249(199902)45:23.0.co;2-kGómez-Pinedo, U., Félez, M. C., Sancho-Bielsa, F. J., Vidueira, S., Cabanes, C., Soriano, M., … Barcia, J. A. (2008). Improved technique for stereotactic placement of nerve grafts between two locations inside the rat brain. Journal of Neuroscience Methods, 174(2), 194-201. doi:10.1016/j.jneumeth.2008.07.008HowardCV ReedMG.Unbiased Stereology: Three‐Dimensional Measurement in Microscopy. Oxford: Bioimaging Group;1998.Collier, T. J., & Springer, J. E. (1991). Co-grafts of embryonic dopamine neurons and adult sciatic nerve into the denervated striatum enhance behavioral and morphological recovery in rats. Experimental Neurology, 114(3), 343-350. doi:10.1016/0014-4886(91)90160-eBourke, J. L., Coleman, H. A., Pham, V., Forsythe, J. S., & Parkington, H. C. (2014). Neuronal Electrophysiological Function and Control of Neurite Outgrowth on Electrospun Polymer Nanofibers Are Cell Type Dependent. Tissue Engineering Part A, 20(5-6), 1089-1095. doi:10.1089/ten.tea.2013.0295Nga, V. D. W., Lim, J., Choy, D. K. S., Nyein, M. A., Lu, J., Chou, N., … Teoh, S.-H. (2015). Effects of Polycaprolactone-Based Scaffolds on the Blood–Brain Barrier and Cerebral Inflammation. Tissue Engineering Part A, 21(3-4), 647-653. doi:10.1089/ten.tea.2013.0779Pérez-Garnés, M., Martínez-Ramos, C., Barcia, J. A., Escobar Ivirico, J. L., Gómez-Pinedo, U., Vallés-Lluch, A., & Monleón Pradas, M. (2012). One-Dimensional Migration of Olfactory Ensheathing Cells on Synthetic Materials: Experimental and Numerical Characterization. Cell Biochemistry and Biophysics, 65(1), 21-36. doi:10.1007/s12013-012-9399-1Diban, N., Ramos-Vivas, J., Remuzgo-Martinez, S., Ortiz, I., & Urtiaga, A. (2015). Poly(ε-caprolactone) Films with Favourable Properties for Neural Cell Growth. Current Topics in Medicinal Chemistry, 14(23), 2743-2749. doi:10.2174/156802661466614121515393

Dynamic risk control by human nucleus accumbens

Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established

The ambivalent shadow of the pre-Wilsonian rise of international law

The generation of American international lawyers who founded the American Society of International Law in 1906 and nurtured the soil for what has been retrospectively called a “moralistic legalistic approach to international relations” remains little studied. A survey of the rise of international legal literature in the U.S. from the mid-19th century to the eve of the Great War serves as a backdrop to the examination of the boosting effect on international law of the Spanish American War in 1898. An examination of the Insular Cases before the US Supreme Court is then accompanied by the analysis of a number of influential factors behind the pre-war rise of international law in the U.S. The work concludes with an examination of the rise of natural law doctrines in international law during the interwar period and the critiques addressed.by the realist founders of the field of “international relations” to the “moralistic legalistic approach to international relation

A movie of a star: multi-epoch VLBA imaging of the SiO masers towards the Mira variable TX Cam

We describe an observing campaign using the Very Long Baseline Array (VLBA) to monitor the time-evolution of the v=1, J=1-0 SiO maser emission towards the Mira variable TX Cam. The data reported here cover the period 1997 May 24 to 1999 February 19, during which the SiO maser emission was imaged at approximately bi-weekly intervals. The result is an animated movie at an angular resolution of ~500 microarcsec, over a full pulsation period, of the gas motions in the near circumstellar environment of this star, as traced by the SiO maser emission. This paper serves to release the movie and is the first in a series concerning the scientific results from this observing campaign. In this paper, we discuss the global proper motion of the SiO maser emission as a function of pulsation phase. We measure a dominant expansion mode between optical phases $\phi \sim 0.7-1.5$ confirming ballistic deceleration, and compare this to predictions from existing pulsation models for late-type, evolved stars. Local infall and outflow motions are superimposed on the dominant expansion mode, and non-radial local gas motions are also evident for individual SiO maser components. The overall morphology and evolution of the SiO emission deviates significantly from spherical symmetry, with important implications for models of pulsation kinematics in the near-circumstellar environments of Mira variables.Comment: Mpeg movie can be obtained from http://www.jb.man.ac.uk/~pdiamond/txcam_movie.mpe

T Cells' Immunological Synapses Induce Polarization of Brain Astrocytes In Vivo and In Vitro: A Novel Astrocyte Response Mechanism to Cellular Injury

Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown.Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes.Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV infection), anti-transplant, autoimmune, or anti-tumor immune responses in vivo and in vitro

A Unified Functional Network Target for Deep Brain Stimulation in Obsessive-Compulsive Disorder

BACKGROUND: Multiple deep brain stimulation (DBS) targets have been proposed for treating intractable obsessive-compulsive disorder (OCD). Here, we investigated whether stimulation effects of different target sites would be mediated by one common or several segregated functional brain networks. METHODS: First, seeding from active electrodes of 4 OCD patient cohorts (N = 50) receiving DBS to anterior limb of the internal capsule or subthalamic nucleus zones, optimal functional connectivity profiles for maximal Yale-Brown Obsessive Compulsive Scale improvements were calculated and cross-validated in leave-one-cohort-out and leave-one-patient-out designs. Second, we derived optimal target-specific connectivity patterns to determine brain regions mutually predictive of clinical outcome for both targets and others predictive for either target alone. Functional connectivity was defined using resting-state functional magnetic resonance imaging data acquired in 1000 healthy participants. RESULTS: While optimal functional connectivity profiles showed both commonalities and differences between target sites, robust cross-predictions of clinical improvements across OCD cohorts and targets suggested a shared network. Connectivity to the anterior cingulate cortex, insula, and precuneus, among other regions, was predictive regardless of stimulation target. Regions with maximal connectivity to these commonly predictive areas included the insula, superior frontal gyrus, anterior cingulate cortex, and anterior thalamus, as well as the original stereotactic targets. CONCLUSIONS: Pinpointing the network modulated by DBS for OCD from different target sites identified a set of brain regions to which DBS electrodes associated with optimal outcomes were functionally connected-regardless of target choice. On these grounds, we establish potential brain areas that could prospectively inform additional or alternative neuromodulation targets for obsessive-compulsive disorder