2,377 research outputs found
The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1 : contributions of the pore domains
We have investigated the contribution to ionic
selectivity of residues in the selectivity filter and pore
helices of the P1 and P2 domains in the acid sensitive
potassium channel TASK-1. We used site directed mutagenesis
and electrophysiological studies, assisted by structural
models built through computational methods. We have
measured selectivity in channels expressed in Xenopus
oocytes, using voltage clamp to measure shifts in reversal
potential and current amplitudes when Rb+ or Na+ replaced
extracellular K+. Both P1 and P2 contribute to selectivity,
and most mutations, including mutation of residues in the
triplets GYG and GFG in P1 and P2, made channels nonselective.
We interpret the effects of these—and of other
mutations—in terms of the way the pore is likely to be
stabilised structurally. We show also that residues in the
outer pore mouth contribute to selectivity in TASK-1.
Mutations resulting in loss of selectivity (e.g. I94S, G95A)
were associated with slowing of the response of channels to
depolarisation. More important physiologically, pH sensitivity
is also lost or altered by such mutations. Mutations
that retained selectivity (e.g. I94L, I94V) also retained their
response to acidification. It is likely that responses both to
voltage and pH changes involve gating at the selectivity filter
Inhibitor binding mode and allosteric regulation of Na+-glucose symporters.
Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5
Increased capability gas generator for Space Shuttle APU. Development/hot restart test report
The design, fabrication, and testing of an increased capability gas generator for use in space shuttles are described. Results show an unlimited hot restart capability in the range of feed pressures from 400 psi to 80 psi. Effects of vacuum on hot restart were not addressed, and only beginning-of-life bed conditions were tested. No starts with bubbles were performed. A minimum expected life of 35 hours or more is projected, and the design will maintain a surface temperature of 350 F or more
West Virginia coal fly ash sorption of BTEX
Sorption is a term used in the environmental field to describe how chemical contaminants in soil and groundwater adhere to solid particles such as: clay, peat and activated carbon for the purposes of remediation, fate and transport. A potential surrogate for sorption of chemical contaminants in groundwater is coal fly ash. Batch test experiments have demonstrated coal fly ash\u27s ability to remove hydrophobic, organic petroleum contaminants including: benzene, toluene, ethylbenzene and xylenes (BTEX) in groundwater through the processes of sorption. Coal fly ash is a byproduct material of coal fired power plants that is often disposed of on-site or at landfills. A beneficial use of coal fly ash is for the sorption of BTEX in groundwater
MirGeneDB 2.1: toward a complete sampling of all major animal phyla
B.F. is supported by the Tromso forskningsstiftelse (TFS) [20 SG BF `MIRevolution']; Strategic Research Area (SFO) program of the Swedish Research Council (to V.R.) through Stockholm University (to B.F., W.K., E.M.-S. and M.R.F.); M.R.F. is additionally supported by ERC [758397 `miRCell']; South-Eastern Norway Regional Health Authority support is acknowledged [2018014 to E.H.]; P.J. Chabot is supported by the Junior Scholars Program (Dartmouth College); V.O.'s research funding was awarded to Dr Mary J. O'Connell (Associate Professor) from the School of Life Sciences University of Nottingham; M.H. is supported by the Spanish Government [AGL2017-88702C2-2-R]; University of Granada [A-BIO-481-UGR18, FEDER 18]; K.J.P. has been supported by the National Science Foundation; NASA Ames; Dartmouth College.We describe an update of MirGeneDB, the manually
curated microRNA gene database. Adhering to
uniform and consistent criteria for microRNA
annotation and nomenclature, we substantially
expanded MirGeneDB with 30 additional species
representing previously missing metazoan phyla
such as sponges, jellyfish, rotifers and flatworms.
MirGeneDB 2.1 now consists of 75 species spanning
over ∼800 million years of animal evolution, and
contains a total number of 16 670 microRNAs from
1549 families. Over 6000 microRNAs were added in
this update using ∼550 datasets with ∼7.5 billion
sequencing reads. By adding new phylogenetically
important species, especially those relevant for
the study of whole genome duplication events,
and through updating evolutionary nodes of origin
for many families and genes, we were able to
substantially refine our nomenclature system. All changes are traceable in the specifically developed
MirGeneDB version tracker. The performance of
read-pages is improved and microRNA expression
matrices for all tissues and species are now also
downloadable. Altogether, this update represents
a significant step toward a complete sampling of
all major metazoan phyla, and a widely needed
foundation for comparative microRNA genomics and
transcriptomics studies. MirGeneDB 2.1 is part of
RNAcentral and Elixir Norway, publicly and freely
available at http://www.mirgenedb.org/.Tromso forskningsstiftelse (TFS) 20_SG_BFStrategic Research Area (SFO) program of the Swedish Research Council through Stockholm UniversityEuropean Research Council (ERC)
European Commission 758397South-Eastern Norway Regional Health Authority 2018014Junior Scholars Program (Dartmouth College)School of Life Sciences University of NottinghamSpanish GovernmentEuropean Commission AGL2017-88702-C2-2-RUniversity of Granada A-BIO-481-UGR18
FEDER 18National Science Foundation (NSF)National Aeronautics & Space Administration (NASA)Dartmouth Colleg
Repositori de preguntes per als cursos de moodle del departament d'electricitat d'un centre d'FP del centre de Barcelona
L'Objectiu d'aquest treball és promoure i facilitar la utilització de qüestionaris en la plataforma moodle. Crear un repositori de preguntes amb la finalitat de poder crear qüestionaris amb més facilitat dins dels cursos de moodle. El format escollit serà el banc de preguntes. En aquest projecte es tindran en compte els següents objectius: - Que sigui una eina d'utilitat pels docents. Els docents tindran més facilitat per a poder generar proves, test, exà mens, etc. dins del seu curs del moodle. Aixà com poder generar versions diferenciades d'un alumne a un altre. Tanmateix podran anar afegint noves preguntes al reposi tori de manera que cada cop sigui més ampli i útil. - D'utilitat pels alumnes. Els alumnes podran rebre una retroacció immediata de la prova que han realitzat. També es podran preparar tests per a que posin a prova els seus coneixements. - D'utilitat pels pares. Podran veure les qualificacions de l'alumne i els treballs que tenen, les dates d'entrega i els resultats obtinguts fins al moment. - Que estigui vinculat al currÃculum del mòdul. Cada pregunta que s'introdueixi al repositori es podrà associar als diferents coneixements, resultats d'aprenentatge i criteris d'avaluació de manera que el docent podrà verificar que s'assoleixen els objectius de l'aprenentatge de l'alumne
Prediction of Metabolic Pathways Involvement in Prokaryotic UniProtKB Data by Association Rule Mining
The widening gap between known proteins and their functions has encouraged
the development of methods to automatically infer annotations. Automatic
functional annotation of proteins is expected to meet the conflicting
requirements of maximizing annotation coverage, while minimizing erroneous
functional assignments. This trade-off imposes a great challenge in designing
intelligent systems to tackle the problem of automatic protein annotation. In
this work, we present a system that utilizes rule mining techniques to predict
metabolic pathways in prokaryotes. The resulting knowledge represents
predictive models that assign pathway involvement to UniProtKB entries. We
carried out an evaluation study of our system performance using
cross-validation technique. We found that it achieved very promising results in
pathway identification with an F1-measure of 0.982 and an AUC of 0.987. Our
prediction models were then successfully applied to 6.2 million
UniProtKB/TrEMBL reference proteome entries of prokaryotes. As a result,
663,724 entries were covered, where 436,510 of them lacked any previous pathway
annotations
Survey of variation in human transcription factors reveals prevalent DNA binding changes
Published in final edited form as:
Science. 2016 Mar 25; 351(6280): 1450–1454.
Published online 2016 Mar 24. doi: 10.1126/science.aad2257Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation.National Institutes of Health; NHGRI R01 HG003985; P50 HG004233; A*STAR National Science Scholarship; National Science Foundatio
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