Pathogenic Cav3.2 channel mutation in a child with primary generalized epilepsy.

Two paternally-inherited missense variants in CACNA1H were identified and characterized in a 6-year-old child with generalized epilepsy. Febrile and unprovoked seizures were present in this child. Both variants were expressed in cis or isolation using human recombinant Cav3.2 calcium channels in tsA-201 cells. Whole-cell patch-clamp recordings indicated that one variant (c.3844C > T; p.R1282W) caused a significant increase in current density consistent with a pathogenic gain-of-function phenotype; while the other cis-related variant (c.5294C > T; p.A1765V) had a benign profile

Nonanalyticities of the entropy induced by saddle points of the potential energy landscape

The relation between saddle points of the potential of a classical many-particle system and the analyticity properties of its Boltzmann entropy is studied. For finite systems, each saddle point is found to cause a nonanalyticity in the Boltzmann entropy, and the functional form of this nonanalytic term is derived for the generic case of potentials having the Morse property. With increasing system size the order of the nonanalytic term grows unboundedly, leading to an increasing differentiability of the entropy. Nonetheless, a distribution of an unboundedly growing number of saddle points may cause a phase transition in the thermodynamic limit. Analyzing the contribution of the saddle points to the density of states in the thermodynamic limit, conditions on the distribution of saddle points and their curvatures are derived which are necessary for a phase transition to occur. With these results, the puzzling absence of topological signatures in the spherical model is elucidated. As further applications, the phase transitions of the mean-field XY model and the mean-field k-trigonometric model are shown to be induced by saddle points of vanishing curvature.Comment: 24 pages, 2 figure

Coastal Tropical Convection in a Stochastic Modeling Framework

Recent research has suggested that the overall dependence of convection near coasts on large-scale atmospheric conditions is weaker than over the open ocean or inland areas. This is due to the fact that in coastal regions convection is often supported by meso-scale land-sea interactions and the topography of coastal areas. As these effects are not resolved and not included in standard cumulus parametrization schemes, coastal convection is among the most poorly simulated phenomena in global models. To outline a possible parametrization framework for coastal convection we develop an idealized modeling approach and test its ability to capture the main characteristics of coastal convection. The new approach first develops a decision algorithm, or trigger function, for the existence of coastal convection. The function is then applied in a stochastic cloud model to increase the occurrence probability of deep convection when land-sea interactions are diagnosed to be important. The results suggest that the combination of the trigger function with a stochastic model is able to capture the occurrence of deep convection in atmospheric conditions often found for coastal convection. When coastal effects are deemed to be present the spatial and temporal organization of clouds that has been documented form observations is well captured by the model. The presented modeling approach has therefore potential to improve the representation of clouds and convection in global numerical weather forecasting and climate models.Comment: Manuscript submitted for publication in Journal of Advances in Modeling Earth System

The deglacial history of surface and intermediate water of the Bering Sea

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Elsevier B. V. for personal use, not for redistribution. The definitive version was published in Deep Sea Research Part II: Topical Studies in Oceanography 52 (2005): 2163-2173, doi:10.1016/j.dsr2.2005.07.004.The lithology of deglacial sediments from the Bering Sea includes intervals of laminated or dysaerobic sediments. These intervals are contemporaneous with the occurrence of laminated sediments from the California margin and Gulf of California, which suggests widespread low-oxygen conditions at intermediate depths in the North Pacific Ocean. The cause could be reduced intermediate water ventilation, increased organic carbon flux, or a combination of the two. We infer abrupt decreases of planktonic foraminifer δ18O at 14,400 y BP and 11,650 y BP, which may be a combination of both freshening and warming. On the Shirshov Ridge, the abundance of sea-ice diatoms of the genus Nitzschia reach local maxima twice during the deglaciation, the latter of which may be an expression of the Younger Dryas. These findings expand the extent of the expression of deglacial millennial-scale climate events to include the northernmost Pacific.The Oak Foundation of Boston, Massachusetts, and the WHOI Academic Programs Office provided support for Mea Cook. This project was funded by NSF grant OPP-9912122

Computational generation and screening of RNA motifs in large nucleotide sequence pools

Although identification of active motifs in large random sequence pools is central to RNA in vitro selection, no systematic computational equivalent of this process has yet been developed. We develop a computational approach that combines target pool generation, motif scanning and motif screening using secondary structure analysis for applications to 1012–1014-sequence pools; large pool sizes are made possible using program redesign and supercomputing resources. We use the new protocol to search for aptamer and ribozyme motifs in pools up to experimental pool size (1014 sequences). We show that motif scanning, structure matching and flanking sequence analysis, respectively, reduce the initial sequence pool by 6–8, 1–2 and 1 orders of magnitude, consistent with the rare occurrence of active motifs in random pools. The final yields match the theoretical yields from probability theory for simple motifs and overestimate experimental yields, which constitute lower bounds, for aptamers because screening analyses beyond secondary structure information are not considered systematically. We also show that designed pools using our nucleotide transition probability matrices can produce higher yields for RNA ligase motifs than random pools. Our methods for generating, analyzing and designing large pools can help improve RNA design via simulation of aspects of in vitro selection

Characterization of SpPol4, a unique X-family DNA polymerase in Schizosaccharomyces pombe

As predicted by the amino acid sequence, the purified protein coded by Schizosaccharomyces pombe SPAC2F7.06c is a DNA polymerase (SpPol4) whose biochemical properties resemble those of other X family (PolX) members. Thus, this new PolX is template-dependent, polymerizes in a distributive manner, lacks a detectable 3′→5′ proofreading activity and its preferred substrates are small gaps with a 5′-phosphate group. Similarly to Polμ, SpPol4 can incorporate a ribonucleotide (rNTP) into a primer DNA. However, it is not responsible for the 1–2 rNTPs proposed to be present at the mating-type locus and those necessary for mating-type switching. Unlike Polμ, SpPol4 lacks terminal deoxynucleotidyltransferase activity and realigns the primer terminus to alternative template bases only under certain sequence contexts and, therefore, it is less error-prone than Polμ. Nonetheless, the biochemical properties of this gap-filling DNA polymerase are suitable for a possible role of SpPol4 in non-homologous end-joining. Unexpectedly based on sequence analysis, SpPol4 has deoxyribose phosphate lyase activity like Polβ and Polλ, and unlike Polμ, suggesting also a role of this enzyme in base excision repair. Therefore, SpPol4 is a unique enzyme whose enzymatic properties are hybrid of those described for mammalian Polβ, Polλ and Polμ

A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking

Histone lysine methyltransferase complexes are essential for chromatin organization and gene regulation. Whether any of this machinery functions in membrane traffic is unknown. In this study, we report that mammal Dpy-30 (mDpy-30), a subunit of several histone H3 lysine 4 (H3K4) methyltransferase (H3K4MT) complexes, resides in the nucleus and at the trans-Golgi network (TGN). The TGN targeting of mDpy-30 is mediated by BIG1, a TGN-localized guanine nucleotide exchange factor for adenosine diphosphate ribosylation factor GTPases. Altering mDpy-30 levels changes the distribution of cation-independent mannose 6-phosphate receptor (CIMPR) without affecting that of TGN46 or transferrin receptor. Our experiments also indicate that mDpy-30 functions in the endosome to TGN transport of CIMPR and that its knockdown results in the enrichment of internalized CIMPR and recycling endosomes near cell protrusions. Much like mDpy-30 depletion, the knockdown of Ash2L or RbBP5, two other H3K4MT subunits, leads to a similar redistribution of CIMPR. Collectively, these results suggest that mDpy-30 and probably H3K4MT play a role in the endosomal transport of specific cargo proteins

The impact of the North Atlantic Oscillation on the uptake and accumulation of anthropogenic CO2 by North Atlantic Ocean mode waters

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 25 (2011): GB3022, doi:10.1029/2010GB003892.The North Atlantic Ocean accounts for about 25% of the global oceanic anthropogenic carbon sink. This basin experiences significant interannual variability primarily driven by the North Atlantic Oscillation (NAO). A suite of biogeochemical model simulations is used to analyze the impact of interannual variability on the uptake and storage of contemporary and anthropogenic carbon (Canthro) in the North Atlantic Ocean. Greater winter mixing during positive NAO years results in increased mode water formation and subsequent increases in subtropical and subpolar Canthro inventories. Our analysis suggests that changes in mode water Canthro inventories are primarily due to changes in water mass volumes driven by variations in water mass transformation rates rather than local air-sea CO2 exchange. This suggests that a significant portion of anthropogenic carbon found in the ocean interior may be derived from surface waters advected into water formation regions rather than from local gas exchange. Therefore, changes in climate modes, such as the NAO, may alter the residence time of anthropogenic carbon in the ocean by altering the rate of water mass transformation. In addition, interannual variability in Canthro storage increases the difficulty of Canthro detection and attribution through hydrographic observations, which are limited by sparse sampling of subsurface waters in time and space.We would like to acknowledge funding from the NOAA Climate Program under the Office of Climate Observations and Global Carbon Cycle Program (NOAA‐NA07OAR4310098), NSF (OCE‐0623034), NCAR, the WHOI Ocean Climate Institute, a National Defense Science and Engineering Graduate Fellowship and an Environmental Protection Agency STAR graduate fellowship. NCAR is sponsored by the National Science Foundation

Spaceflight Bone Atrophy: Problem Solved?

No abstract availabl