Striatal cholinergic interneurons generate beta and gamma oscillations in the corticostriatal circuit and produce motor deficits

Cortico-basal ganglia-thalamic (CBT) neural circuits are critical modulators of cognitive and motor function. When compromised, these circuits contribute to neurological and psychiatric disorders, such as Parkinson's disease (PD). In PD, motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the CBT network. However, little is known about how specific cell types within individual CBT brain regions support the generation, propagation, and interaction of oscillatory dynamics throughout the CBT circuit or how specific oscillatory dynamics are related to motor function. Here, we investigated the role of striatal cholinergic interneurons (SChIs) in generating beta and gamma oscillations in cortical-striatal circuits and in influencing movement behavior. We found that selective stimulation of SChIs via optogenetics in normal mice robustly and reversibly amplified beta and gamma oscillations that are supported by distinct mechanisms within striatal-cortical circuits. Whereas beta oscillations are supported robustly in the striatum and all layers of primary motor cortex (M1) through a muscarinic-receptor mediated mechanism, gamma oscillations are largely restricted to the striatum and the deeper layers of M1. Finally, SChI activation led to parkinsonian-like motor deficits in otherwise normal mice. These results highlight the important role of striatal cholinergic interneurons in supporting oscillations in the CBT network that are closely related to movement and parkinsonian motor symptoms.DP2 NS082126 - NINDS NIH HHS; R01 NS081716 - NINDS NIH HHS; R21 NS078660 - NINDS NIH HHShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896681/Published versio

The UNC-6/Netrin receptors UNC-40/DCC and UNC-5 inhibit growth cone filopodial protrusion via UNC-73/Trio, Rac-like GTPases and UNC-33/CRMP

UNC-6/Netrin is a conserved axon guidance cue that can mediate both attraction and repulsion. We previously discovered that attractive UNC-40/DCC receptor signaling stimulates growth cone filopodial protrusion and that repulsive UNC-40–UNC-5 heterodimers inhibit filopodial protrusion in C. elegans. Here, we identify cytoplasmic signaling molecules required for UNC-6-mediated inhibition of filopodial protrusion involved in axon repulsion. We show that the Rac-like GTPases CED-10 and MIG-2, the Rac GTP exchange factor UNC-73/Trio, UNC-44/Ankyrin and UNC-33/CRMP act in inhibitory UNC-6 signaling. These molecules were required for the normal limitation of filopodial protrusion in developing growth cones and for inhibition of growth cone filopodial protrusion caused by activated MYR::UNC-40 and MYR::UNC-5 receptor signaling. Epistasis studies using activated CED-10 and MIG-2 indicated that UNC-44 and UNC-33 act downstream of the Rac-like GTPases in filopodial inhibition. UNC-73, UNC-33 and UNC-44 did not affect the accumulation of full-length UNC-5::GFP and UNC-40::GFP in growth cones, consistent with a model in which UNC-73, UNC-33 and UNC-44 influence cytoskeletal function during growth cone filopodial inhibition.We thank E. Struckhoff for technical assistance and J. Culotti for kindly providing the pU5GFP plasmid. Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs [P40OD010440]

Differential effects of two-pore channel protein 1 and 2 silencing in MDA-MB-468 breast cancer cells

Two-pore channel proteins, TPC1 and TPC2, are calcium permeable ion channels found localized to the membranes of endolysosomal calcium stores. There is increasing interest in the role of TPC-mediated intracellular signaling in various pathologies; however their role in breast cancer has not been extensively evaluated. TPC1 and TPC2 mRNA was present in all non-tumorigenic and tumorigenic breast cell lines assessed. Silencing of TPC2 but not TPC1 attenuated epidermal growth factor-induced vimentin expression in MDA-MB-468 breast cancer cells. This effect was not due to a general inhibition of epithelial to mesenchymal transition (EMT) as TPC2 silencing had no effect on epidermal growth factor (EGF)-induced changes on E-cadherin expression. TPC1 and TPC2 were also shown to differentially regulate cyclopiazonic acid (CPA)-mediated changes in cytosolic free Ca. These findings indicate potential differential regulation of signaling processes by TPC1 and TPC2 in breast cancer cells

Exact solution for scalar field collapse

We give an exact spherically symmetric solution for the Einstein-scalar field system. The solution may be interpreted as an inhomogeneous dynamical scalar field cosmology. The spacetime has a timelike conformal Killing vector field and is asymptotically conformally flat. It also has black or white hole-like regions containing trapped surfaces. We describe the properties of the apparent horizon and comment on the relevance of the solution to the recently discovered critical behaviour in scalar field collapse.Comment: 10 pages(Latex) (2 figures available upon request), Alberta-Thy-4-9

DynaSim: a MATLAB toolbox for neural modeling and simulation

[EN] DynaSim is an open-source MATLAB/GNU Octave toolbox for rapid prototyping of neural models and batch simulation management. It is designed to speed up and simplify the process of generating, sharing, and exploring network models of neurons with one or more compartments. Models can be specified by equations directly (similar to XPP or the Brian simulator) or by lists of predefined or custom model components. The higher-level specification supports arbitrarily complex population models and networks of interconnected populations. DynaSim also includes a large set of features that simplify exploring model dynamics over parameter spaces, running simulations in parallel using both multicore processors and high-performance computer clusters, and analyzing and plotting large numbers of simulated data sets in parallel. It also includes a graphical user interface (DynaSim GUI) that supports full functionality without requiring user programming. The software has been implemented in MATLAB to enable advanced neural modeling using MATLAB, given its popularity and a growing interest in modeling neural systems. The design of DynaSim incorporates a novel schema for model specification to facilitate future interoperability with other specifications (e.g., NeuroML, SBML), simulators (e.g., NEURON, Brian, NEST), and web-based applications (e.g., Geppetto) outside MATLAB. DynaSim is freely available at http://dynasimtoolbox.org. This tool promises to reduce barriers for investigating dynamics in large neural models, facilitate collaborative modeling, and complement other tools being developed in the neuroinformatics community.This material is based upon research supported by the U.S. Army Research Office under award number ARO W911NF-12-R-0012-02, the U.S. Office of Naval Research under award number ONR MURI N00014-16-1-2832, and the National Science Foundation under award number NSF DMS-1042134 (Cognitive Rhythms Collaborative: A Discovery Network)Sherfey, JS.; Soplata, AE.; Ardid-Ramírez, JS.; Roberts, EA.; Stanley, DA.; Pittman-Polletta, BR.; Kopell, NJ. (2018). DynaSim: a MATLAB toolbox for neural modeling and simulation. Frontiers in Neuroinformatics. 12:1-15. https://doi.org/10.3389/fninf.2018.00010S11512Bokil, H., Andrews, P., Kulkarni, J. E., Mehta, S., & Mitra, P. P. (2010). Chronux: A platform for analyzing neural signals. Journal of Neuroscience Methods, 192(1), 146-151. doi:10.1016/j.jneumeth.2010.06.020Brette, R., Rudolph, M., Carnevale, T., Hines, M., Beeman, D., Bower, J. M., … Destexhe, A. (2007). Simulation of networks of spiking neurons: A review of tools and strategies. Journal of Computational Neuroscience, 23(3), 349-398. doi:10.1007/s10827-007-0038-6Börgers, C., & Kopell, N. (2005). Effects of Noisy Drive on Rhythms in Networks of Excitatory and Inhibitory Neurons. Neural Computation, 17(3), 557-608. doi:10.1162/0899766053019908Ching, S., Cimenser, A., Purdon, P. L., Brown, E. N., & Kopell, N. J. (2010). Thalamocortical model for a propofol-induced  -rhythm associated with loss of consciousness. Proceedings of the National Academy of Sciences, 107(52), 22665-22670. doi:10.1073/pnas.1017069108Delorme, A., & Makeig, S. (2004). EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. Journal of Neuroscience Methods, 134(1), 9-21. doi:10.1016/j.jneumeth.2003.10.009Durstewitz, D., Seamans, J. K., & Sejnowski, T. J. (2000). Neurocomputational models of working memory. Nature Neuroscience, 3(S11), 1184-1191. doi:10.1038/81460EatonJ. W. BatemanD. HaubergS. WehbringR. GNU Octave Version 4.2.0 Manual: A High-Level Interactive Language for Numerical Computations2016Ermentrout, B. (2002). Simulating, Analyzing, and Animating Dynamical Systems. doi:10.1137/1.9780898718195FitzHugh, R. (1955). Mathematical models of threshold phenomena in the nerve membrane. The Bulletin of Mathematical Biophysics, 17(4), 257-278. doi:10.1007/bf02477753Gewaltig, M.-O., & Diesmann, M. (2007). NEST (NEural Simulation Tool). Scholarpedia, 2(4), 1430. doi:10.4249/scholarpedia.1430Gleeson, P., Crook, S., Cannon, R. C., Hines, M. L., Billings, G. O., Farinella, M., … Silver, R. A. (2010). NeuroML: A Language for Describing Data Driven Models of Neurons and Networks with a High Degree of Biological Detail. PLoS Computational Biology, 6(6), e1000815. doi:10.1371/journal.pcbi.1000815Goodman, D. (2008). Brian: a simulator for spiking neural networks in Python. Frontiers in Neuroinformatics, 2. doi:10.3389/neuro.11.005.2008Goodman, D. F. M. (2009). The Brian simulator. Frontiers in Neuroscience, 3(2), 192-197. doi:10.3389/neuro.01.026.2009Hines, M. L., & Carnevale, N. T. (1997). The NEURON Simulation Environment. Neural Computation, 9(6), 1179-1209. doi:10.1162/neco.1997.9.6.1179Hodgkin, A. L., & Huxley, A. F. (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. The Journal of Physiology, 117(4), 500-544. doi:10.1113/jphysiol.1952.sp004764Hucka, M., Finney, A., Sauro, H. M., Bolouri, H., Doyle, J. C., Kitano, H., … Wang. (2003). The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics, 19(4), 524-531. doi:10.1093/bioinformatics/btg015Izhikevich, E. M. (2003). Simple model of spiking neurons. IEEE Transactions on Neural Networks, 14(6), 1569-1572. doi:10.1109/tnn.2003.820440Kopell, N., Ermentrout, G. B., Whittington, M. A., & Traub, R. D. (2000). Gamma rhythms and beta rhythms have different synchronization properties. Proceedings of the National Academy of Sciences, 97(4), 1867-1872. doi:10.1073/pnas.97.4.1867Kramer, M. A., Roopun, A. K., Carracedo, L. M., Traub, R. D., Whittington, M. A., & Kopell, N. J. (2008). Rhythm Generation through Period Concatenation in Rat Somatosensory Cortex. PLoS Computational Biology, 4(9), e1000169. doi:10.1371/journal.pcbi.1000169Lorenz, E. N. (1963). Deterministic Nonperiodic Flow. Journal of the Atmospheric Sciences, 20(2), 130-141. doi:10.1175/1520-0469(1963)0202.0.co;2Markram, H., Meier, K., Lippert, T., Grillner, S., Frackowiak, R., Dehaene, S., … Saria, A. (2011). Introducing the Human Brain Project. Procedia Computer Science, 7, 39-42. doi:10.1016/j.procs.2011.12.015McDougal, R. A., Morse, T. M., Carnevale, T., Marenco, L., Wang, R., Migliore, M., … Hines, M. L. (2016). Twenty years of ModelDB and beyond: building essential modeling tools for the future of neuroscience. Journal of Computational Neuroscience, 42(1), 1-10. doi:10.1007/s10827-016-0623-7Meng, L., Kramer, M. A., Middleton, S. J., Whittington, M. A., & Eden, U. T. (2014). A Unified Approach to Linking Experimental, Statistical and Computational Analysis of Spike Train Data. PLoS ONE, 9(1), e85269. doi:10.1371/journal.pone.0085269Morris, C., & Lecar, H. (1981). Voltage oscillations in the barnacle giant muscle fiber. Biophysical Journal, 35(1), 193-213. doi:10.1016/s0006-3495(81)84782-0Rudolph, M., & Destexhe, A. (2007). How much can we trust neural simulation strategies? Neurocomputing, 70(10-12), 1966-1969. doi:10.1016/j.neucom.2006.10.138Stimberg, M., Goodman, D. F. M., Benichoux, V., & Brette, R. (2014). Equation-oriented specification of neural models for simulations. Frontiers in Neuroinformatics, 8. doi:10.3389/fninf.2014.00006Traub, R. D., Buhl, E. H., Gloveli, T., & Whittington, M. A. (2003). Fast Rhythmic Bursting Can Be Induced in Layer 2/3 Cortical Neurons by Enhancing Persistent Na+Conductance or by Blocking BK Channels. Journal of Neurophysiology, 89(2), 909-921. doi:10.1152/jn.00573.200

The Initial Economic Burden of Femur Fractures on Informal Caregivers in Dar es Salaam, Tanzania

BackgroundFemur fracture patients require significant in-hospital care. The burden incurred by caregivers of such patients amplifies the direct costs of these injuries and remains unquantified. Aim Here we aim to establish the in-hospital economic burden faced by informal caregivers of femur fracture patients. Methods 70 unique caregivers for 46 femoral shaft fracture patients were interviewed. Incurred economic burden was determined by the Human Capital Approach, using standardized income data to quantify productivity loss (in $USD). Linear regression assessed the relationship between caregiver burden and patient time-in-hospital.ResultsThe average economic burden incurred was$149, 9% of a caregiver’s annual income and positively correlated with patient time in hospital (p<0.01). Conclusion Caregivers of patients treated operatively for femur fractures lost a large portion of their annual income, and this loss increased with patient time in hospital. These indirect costs of femur fracture treatment constitute an important component of the total injury burden

The rice EP3 and OsFBK1 E3 ligases alter plant architecture and flower development, and affect transcript accumulation of microRNA pathway genes and their targets

ERECTA PANICLE 3 (EP3) and ORYZA SATIVA F-BOX KELCH 1 (OsFBK1) proteins share 57% and 54% sequence identity with the Arabidopsis F-box protein HAWAIIAN SKIRT (HWS). Previously we showed that EP3 is a functional orthologue of HWS. Here we demonstrate that OsFBK1 is another functional orthologue of HWS and show the complexity of interaction between EP3 and OsFBK1 genes at different developmental stages of the plant. qRT-PCR expression analyses and studies of EP3-GFP and OsFBK1-RFP promoter reporter lines demonstrate that although EP3 and OsFBK1 expression can be detected in the same tissues some cells exclusively express EP3 or OsFBK1 whilst others co-express both genes. Loss, reduction or gain-of-function lines for EP3 and OsFBK1, show that EP3 and OsFBK1 affect plant architecture, organ size, floral organ number and size, floral morphology, pollen viability, grain size and weight. We have identified the putative orthologue genes of the rice microRNA pathway for ORYZA SATIVA DAWDLE (OsDDL) and ORYZA SATIVA SERRATE (OsSE), and demonstrated that EP3 and OsFBK1 affect their transcript levels as well as those of CROWN ROOT DEFECT 1/ORYZA SATIVA Exportin-5 HASTY (CRD1/OsHST), ORYZA SATIVA DICER-LIKE 1 (OsDCL) and ORYZA SATIVA WEAVY LEAF1 (OsWAF1). We show that EP3 affects OsPri-MIR164, OsNAM1 and OsNAC1 transcript levels. OsNAC1 transcripts are modified by OsFBK1, suggesting two independent regulatory pathways, one via EP3 and OsMIR164 and the other via OsFBK1. Our data propose that EP3 and OsFBK1 conjointly play similar roles in rice to how HWS does in Arabidopsis

The Swift/UVOT catalogue of NGC4321 star forming sources: A case against density wave theory

We study the star forming regions in the spiral galaxy NGC4321, taking advantage of the spatial resolution (2.5 arcsec FWHM) of the Swift/UVOT camera and the availability of three UV passbands in the region 1600-3000 A, in combination with optical and IR imaging from SDSS, KPNO/Ha and Spitzer/IRAC, to obtain a catalogue of 787 star forming regions out to three disc scale lengths. We determine the properties of the young stellar component and its relationship with the spiral arms. The Ha luminosities of the sources have a strong decreasing radial trend, suggesting more massive star forming regions in the central part of the galaxy. When segregated with respect to NUV-optical colour, blue sources have a significant excess of flux in the IR at 8 micron, revealing the contribution from PAHs, although the overall reddening of these sources stays below E(B-V)=0.2 mag. The distribution of distances to the spiral arms is compared for subsamples selected according to Ha luminosity, NUV-optical colour, or ages derived from a population synthesis model. An offset is expected between these subsamples as a function of radius if the pattern speed of the spiral arm were constant - as predicted by classic density wave theory. No significant offsets are found, favouring instead a mechanism where the pattern speed has a radial dependence.Comment: 12 pages, 11 figures, 4 tables. MNRAS, in pres

Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia

PURPOSE: In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH. METHODS: After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab. RESULTS: Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9 ± 0.1 (least squares mean ± SE; P < 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline P < 0.0001). Most adverse events were mild to moderate in severity. MAIN CONCLUSIONS: In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab. CLINICALTRIALS.GOV: NCT0216357

Pedestrian Road Traffic Injuries in Urban Peruvian Children and Adolescents: Case Control Analyses of Personal and Environmental Risk Factors

BACKGROUND: Child pedestrian road traffic injuries (RTIs) are an important cause of death and disability in poorer nations, however RTI prevention strategies in those countries largely draw upon studies conducted in wealthier countries. This research investigated personal and environmental risk factors for child pedestrian RTIs relevant to an urban, developing world setting. METHODS: This is a case control study of personal and environmental risk factors for child pedestrian RTIs in San Juan de Miraflores, Lima, Perú. The analysis of personal risk factors included 100 cases of serious pedestrian RTIs and 200 age and gender matched controls. Demographic, socioeconomic, and injury data were collected. The environmental risk factor study evaluated vehicle and pedestrian movement and infrastructure at the sites in which 40 of the above case RTIs occurred and 80 control sites. FINDINGS: After adjustment, factors associated with increased risk of child pedestrian RTIs included high vehicle volume (OR 7.88, 95%CI 1.97-31.52), absent lane demarcations (OR 6.59, 95% CI 1.65-26.26), high vehicle speed (OR 5.35, 95%CI 1.55-18.54), high street vendor density (OR 1.25, 95%CI 1.01-1.55), and more children living in the home (OR 1.25, 95%CI 1.00-1.56). Protective factors included more hours/day spent in school (OR 0.52, 95%CI 0.33-0.82) and years of family residence in the same home (OR 0.97, 95%CI 0.95-0.99). CONCLUSION: Reducing traffic volumes and speeds, limiting the number of street vendors on a given stretch of road, and improving lane demarcation should be evaluated as components of child pedestrian RTI interventions in poorer countries