23 research outputs found
VectorBase: a home for invertebrate vectors of human pathogens
VectorBase () is a web-accessible data repository for information about invertebrate vectors of human pathogens. VectorBase annotates and maintains vector genomes providing an integrated resource for the research community. Currently, VectorBase contains genome information for two organisms: Anopheles gambiae, a vector for the Plasmodium protozoan agent causing malaria, and Aedes aegypti, a vector for the flaviviral agents causing Yellow fever and Dengue fever
Single Molecule Conformational Memory Extraction: P5ab RNA Hairpin
Extracting kinetic models from single
molecule data is an important
route to mechanistic insight in biophysics, chemistry, and biology.
Data collected from force spectroscopy can probe discrete hops of
a single molecule between different conformational states. Model extraction
from such data is a challenging inverse problem because single molecule
data are noisy and rich in structure. Standard modeling methods normally
assume (i) a prespecified number of discrete states and (ii) that
transitions between states are Markovian. The data set is then fit
to this predetermined model to find a handful of rates describing
the transitions between states. We show that it is unnecessary to
assume either (i) or (ii) and focus our analysis on the zipping/unzipping
transitions of an RNA hairpin. The key is in starting with a very
broad class of non-Markov models in order to let the data guide us
toward the best model from this very broad class. Our method suggests
that there exists a folding intermediate for the P5ab RNA hairpin
whose zipping/unzipping is monitored by force spectroscopy experiments.
This intermediate would not have been resolved if a Markov model had
been assumed from the onset. We compare the merits of our method with
those of others
Genetic mechanisms of critical illness in COVID-19.
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, PÂ =Â 1.65Â ĂÂ 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, PÂ =Â 2.3Â ĂÂ 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, PÂ =Â 3.98Â ĂÂ Â 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, PÂ =Â 4.99Â ĂÂ 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
Tryptophan 207 is crucial to the unique properties of the human voltage-gated proton channel, hH1
Part of the âsignature sequenceâ that defines the voltage-gated proton channel (HV1) is a tryptophan residue adjacent to the second Arg in the S4 transmembrane helix: RxWRxxR, which is perfectly conserved in all high confidence HV1 genes. Replacing Trp207 in human HV1 (hHV1) with Ala, Ser, or Phe facilitated gating, accelerating channel opening by 100-fold, and closing by 30-fold. Mutant channels opened at more negative voltages than wild-type (WT) channels, indicating that in WT channels, Trp favors a closed state. The Arrhenius activation energy, Ea, for channel opening decreased to 22 kcal/mol from 30â38 kcal/mol for WT, confirming that Trp207 establishes the major energy barrier between closed and open hHV1. CationâÏ interaction between Trp207 and Arg211 evidently latches the channel closed. Trp207 mutants lost proton selectivity at pHo >8.0. Finally, gating that depends on the transmembrane pH gradient (ÎpH-dependent gating), a universal feature of HV1 that is essential to its biological functions, was compromised. In the WT hHV1, ÎpH-dependent gating is shown to saturate above pHi or pHo 8, consistent with a single pH sensor with alternating access to internal and external solutions. However, saturation occurred independently of ÎpH, indicating the existence of distinct internal and external pH sensors. In Trp207 mutants, ÎpH-dependent gating saturated at lower pHo but not at lower pHi. That Trp207 mutation selectively alters pHo sensing further supports the existence of distinct internal and external pH sensors. Analogous mutations in HV1 from the unicellular species Karlodinium veneficum and Emiliania huxleyi produced generally similar consequences. Saturation of ÎpH-dependent gating occurred at the same pHo and pHi in HV1 of all three species, suggesting that the same or similar group(s) is involved in pH sensing. Therefore, Trp enables four characteristic properties: slow channel opening, highly temperature-dependent gating kinetics, proton selectivity, and ÎpH-dependent gating
Self-reported memory strategies and their relationship to immediate and delayed text recall and working memory capacity
The aim of this study was to examine the performance of fifth-grade children in the reproduction of the content of a new text - directly, after they had read it (immediate recall), and one week later (delayed recall) - and to investigate the relationship between performance, self-reported memory strategies, and working memory capacity (WMC). The results revealed that more complex strategies are associated with better performances, and that children with high WMC outperformed children with lower WMC in immediate and delayed text recall tasks. Hierarchical regression analyses showed that memory strategy and WMC are the strongest predictors for both immediate and delayed recall tasks. It is argued that self-reported memory strategies are possible to use as estimates of strategy proficiency. The awareness of the importance of memory strategies and childrenâs WMC in education are further discussed