Structural Convergence Among Diverse, Toxic β-Sheet Ion Channels

Recent studies show that an array of -sheet peptides, including N-terminally truncated A peptides (A11-42/17-42), K3 (a 2-microglobulin fragment), and protegrin-1 (PG-1) peptides form ion channel-like structures and elicit single channel ion conductance when reconstituted in lipid bilayers and induce cell damage through cell calcium overload. Striking similarities are observed in the dimensions of these toxic channels irrespective of their amino acid sequences. However, the intriguing question of preferred channel sizes is still unresolved. Here, exploiting ssNMR-based, U-shaped, -strand-turn--strand coordinates, we modeled truncated A peptide (p3) channels with different sizes (12- to 36-mer). Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer. This observation is in good agreement with channel dimensions imaged by AFM for A9-42, K3 fragment, and PG-1 channels and highlights the bilayer-supported preferred toxic -channel sizes and organization, regardless of the peptide sequence

The electron–proton bottleneck of photosynthetic oxygen evolution

Photosynthesis fuels life on Earth by storing solar energy in chemical form. Today’s oxygen-rich atmosphere has resulted from the splitting of water at the protein-bound manganese cluster of photosystem II during photosynthesis. Formation of molecular oxygen starts from a state with four accumulated electron holes, the S4 state—which was postulated half a century ago1 and remains largely uncharacterized. Here we resolve this key stage of photosynthetic O2 formation and its crucial mechanistic role. We tracked 230,000 excitation cycles of dark-adapted photosystems with microsecond infrared spectroscopy. Combining these results with computational chemistry reveals that a crucial proton vacancy is initally created through gated sidechain deprotonation. Subsequently, a reactive oxygen radical is formed in a single-electron, multi-proton transfer event. This is the slowest step in photosynthetic O2 formation, with a moderate energetic barrier and marked entropic slowdown. We identify the S4 state as the oxygen-radical state; its formation is followed by fast O–O bonding and O2 release. In conjunction with previous breakthroughs in experimental and computational investigations, a compelling atomistic picture of photosynthetic O2 formation emerges. Our results provide insights into a biological process that is likely to have occurred unchanged for the past three billion years, which we expect to support the knowledge-based design of artificial water-splitting systems

Characterization of Treponema denticola pyrF encoding orotidine-5′-monophosphate decarboxylase

The Treponema denticola ATCC 35405 genome annotation contains most of the genes for de novo pyrimidine biosynthesis. To initiate characterization of pyrimidine synthesis in Treponema , we focused on TDE2110 (the putative pyrF , encoding orotidine-5′-monophosphate decarboxlyase). Unlike the parent strain, an isogenic pyrF mutant was resistant to 5-fluoroorotic acid. In complex medium, growth of the pyrF mutant was independent of added uracil, indicating activity of a uracil uptake/salvage pathway. Transcription of pyrF was greatly reduced in T. denticola grown in excess uracil, demonstrating that de novo pyrimidine synthesis is regulated and suggesting a feedback mechanism. Treponema denticola PyrF complemented uracil auxotrophy in an Escherichia coli pyrF mutant. This study provides biochemical confirmation of T. denticola genome predictions of de novo and salvage pyrimidine pathways and provides proof of concept that pyrF has potential as a selectable marker in T. denticola .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75261/1/j.1574-6968.2006.00589.x.pd

Análisis comparativo de eventos hidrometeorológicos en la provincia de Córdoba monitoreados mediante estaciones meteorológicas automáticas y sensores remotos (Radar meteorológico y satélite)

En este trabajo se describe el monitoreo de cuatro eventos hidrometeorológicos relevantes ocurridos entre 2015 y 2018 en la Provincia de Córdoba, Argentina, que han sido monitoreados por estaciones meteorológicas automáticas (EMAs) de superficie administradas por diferentes organismos, simultáneamente por el radar RMA1 instalado a fines del año 2014 en la ciudad de Córdoba, perteneciente al Sistema Nacional de Radares Meteorológicos (Sinarame), e imágenes satelitales de GOES 16. A través del análisis de estos eventos se puede apreciar la evolución de las capacidades disponibles en el Observatorio Hidro-Meteorológico de Córdoba (OHMC), tanto en lo que hace a los sensores propiamente dicho como a la calidad de sus productos, cuya finalidad precisamente es integrar la información hidrometeorológica relevada en la Provincia por diferentes organismos del área de recursos hídricos. La Provincia de Córdoba se caracteriza por la ocurrencia de eventos extremos, como las tormentas de tipo convectivas que se desarrollan principalmente en época estival y que se caracterizan por una gran variabilidad espacial y temporal, con picos de lluvia de gran intensidad. La reconstrucción de este tipo de eventos, particularmente la estimación de la tasa de precipitación a partir de mediciones de un radar meteorológico, es un tema de interés para una amplia gama de aplicaciones hidrológicas.This paper describes the monitoring of four relevant hydrometeorological events that occurred between 2015 and 2018 in the Province of Córdoba, Argentina, which have been monitored by automatic weather stations (EMAs) administered by different agencies, simultaneously by the RMA1 radar installed at end of 2014 in the city of Córdoba, belonging to the National System of Meteorological Radar (Sinarame), and satellite images of GOES 16. Through the analysis of these events you can see the evolution of the capabilities available at the Hydro-Meteorological Observatory of Córdoba (OHMC), both in what it does to the sensors themselves and to the quality of their products, whose purpose is precisely to integrate the hydrometeorological information collected in the Province by different organisms in the area of water resources. The Province of Córdoba is characterized by the occurrence of extreme events, such as convective type storms that develop mainly during the summer and that are characterized by great spatial and temporal variability, with high intensity rain peaks. The reconstruction of this type of events, particularly the estimation of the precipitation rate from meteorological radar measurements, is a topic of interest for a wide range of hydrological applications.Fil: Testa Tacchino, Alejo Juan Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Estudios Avanzados en Ingeniería y Tecnología. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Estudios Avanzados en Ingeniería y Tecnología; ArgentinaFil: Ingaramo, Ricardo Daniel. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Lighezzolo, Andrés. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Montamat, Ignacio Adolfo. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Saffe, Jorge Nicolás. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Martina, Agustín. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Poffo, Denis. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Capone, María Eugenia. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Rodriguez, Andres. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Estudios Avanzados en Ingeniería y Tecnología. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Estudios Avanzados en Ingeniería y Tecnología; Argentin

All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers

Alzheimer’s disease (AD) is the most common type of senile dementia in aging populations. Amyloid β (Aβ)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Aβ-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Aβ binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Aβ effects even in the absence of receptor–peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Aβ isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn2+, a known blocker of l-Aβ isomer channels. MD simulations further verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca2+ leaking, unregulated channels in AD, and suggest that Aβ toxicity is mediated through a receptor-independent, nonstereoselective mechanism

Opportunities, barriers, and recommendations in down syndrome research

Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy