1,699 research outputs found
AlphaFold2-multimer guided high-accuracy prediction of typical and atypical ATG8-binding motifs
Macroautophagy/autophagy is an intracellular degradation process central to cellular homeostasis and defense against pathogens in eukaryotic cells. Regulation of autophagy relies on hierarchical binding of autophagy cargo receptors and adaptors to ATG8/LC3 protein family members. Interactions with ATG8/LC3 are typically facilitated by a conserved, short linear sequence, referred to as the ATG8/LC3 interacting motif/region (AIM/LIR), present in autophagy adaptors and receptors as well as pathogen virulence factors targeting host autophagy machinery. Since the canonical AIM/LIR sequence can be found in many proteins, identifying functional AIM/LIR motifs has proven challenging. Here, we show that protein modelling using Alphafold-Multimer (AF2-multimer) identifies both canonical and atypical AIM/LIR motifs with a high level of accuracy. AF2-multimer can be modified to detect additional functional AIM/LIR motifs by using protein sequences with mutations in primary AIM/LIR residues. By combining protein modelling data from AF2-multimer with phylogenetic analysis of protein sequences and protein-protein interaction assays, we demonstrate that AF2-multimer predicts the physiologically relevant AIM motif in the ATG8-interacting protein 2 (ATI-2) as well as the previously uncharacterized noncanonical AIM motif in ATG3 from potato (Solanum tuberosum). AF2-multimer also identified the AIM/LIR motifs in pathogen-encoded virulence factors that target ATG8 members in their plant and human hosts, revealing that cross-kingdom ATG8-LIR/AIM associations can also be predicted by AF2-multimer. We conclude that the AF2-guided discovery of autophagy adaptors/receptors will substantially accelerate our understanding of the molecular basis of autophagy in all biological kingdoms
Towards a Tetravalent Chemistry of Colloids
We propose coating spherical particles or droplets with anisotropic
nano-sized objects to allow micron-scale colloids to link or functionalize with
a four-fold valence, similar to the sp3 hybridized chemical bonds associated
with, e.g., carbon, silicon and germanium. Candidates for such coatings include
triblock copolymers, gemini lipids, metallic or semiconducting nanorods and
conventional liquid crystal compounds. We estimate the size of the relevant
nematic Frank constants, discuss how to obtain other valences and analyze the
thermal distortions of ground state configurations of defects on the sphere.Comment: Replaced to improve figures. 4 figures Nano Letter
Theory of Melting and the Optical Properties of Gold/DNA Nanocomposites
We describe a simple model for the melting and optical properties of a
DNA/gold nanoparticle aggregate. The optical properties at fixed wavelength
change dramatically at the melting transition, which is found to be higher and
narrower in temperature for larger particles, and much sharper than that of an
isolated DNA link. All these features are in agreement with available
experiments. The aggregate is modeled as a cluster of gold nanoparticles on a
periodic lattice connected by DNA bonds, and the extinction coefficient is
computed using the discrete dipole approximation. Melting takes place as an
increasing number of these bonds break with increasing temperature. The melting
temperature corresponds approximately to the bond percolation threshold.Comment: 5 pages, 4 figure. To be published in Phys. Rev.
Partial derivative automata formalized in Coq
In this paper we present a computer assisted proof of the correctness of a partial derivative automata construction from a regular expression within the Coq proof assistant. This proof is part of a for- malization of Kleene algebra and regular languages in Coq towards their usage in program certification.FundaĆ§Ć£o para a CiĆŖncia e Tecnologia (FCT)
Program POSI, RESCUE (PTDC/EIA/65862/2006), SFRH/BD/33233/2007
Treatment in vitro with PPARĪ± and PPARĪ³ ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice
AbstractTrypanosoma cruzi, the etiological agent of Chagas' disease, induces a persistent inflammatory response. Macrophages are a first line cell phenotype involved in the clearance of infection. Upon parasite uptake, these cells increase inflammatory mediators like NO, TNF-Ī±, IL-1Ī² and IL-6, leading to parasite killing. Although desired, inflammatory response perpetuation and exacerbation may lead to tissue damage. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors that, besides regulating lipid and carbohydrate metabolism, have a significant anti-inflammatory effect. This is mediated through the interaction of the receptors with their ligands. PPARĪ³, one of the PPAR isoforms, has been implicated in macrophage polarization from M1, the classically activated phenotype, to M2, the alternatively activated phenotype, in different models of metabolic disorders and infection. In this study, we show for the first time that, besides PPARĪ³, PPARĪ± is also involved in the in vitro polarization of macrophages isolated from T. cruzi-infected mice. Polarization was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers like Arginase I, Ym1, mannose receptor and TGF-Ī². Besides, macrophage phagocytic activity was significantly enhanced, leading to increased parasite load. We suggest that modulation of the inflammatory response by both PPARs might be due, at least in part, to a change in the profile of inflammatory macrophages. The potential use of PPAR agonists as modulators of overt inflammatory response during the course of Chagas' disease deserves further investigation
Field-effect transistors assembled from functionalized carbon nanotubes
We have fabricated field effect transistors from carbon nanotubes using a
novel selective placement scheme. We use carbon nanotubes that are covalently
bound to molecules containing hydroxamic acid functionality. The functionalized
nanotubes bind strongly to basic metal oxide surfaces, but not to silicon
dioxide. Upon annealing, the functionalization is removed, restoring the
electronic properties of the nanotubes. The devices we have fabricated show
excellent electrical characteristics.Comment: 5 pages, 6 figure
Co-directional replication-transcription conflicts lead to replication restart
August 24, 2011Head-on encounters between the replication and transcription machineries on the lagging DNA strand can lead to replication fork arrest and genomic instability1, 2. To avoid head-on encounters, most genes, especially essential and highly transcribed genes, are encoded on the leading strand such that transcription and replication are co-directional. Virtually all bacteria have the highly expressed ribosomal RNA genes co-directional with replication3. In bacteria, co-directional encounters seem inevitable because the rate of replication is about 10ā20-fold greater than the rate of transcription. However, these encounters are generally thought to be benign2, 4, 5, 6, 7, 8, 9. Biochemical analyses indicate that head-on encounters10 are more deleterious than co-directional encounters8 and that in both situations, replication resumes without the need for any auxiliary restart proteins, at least in vitro. Here we show that in vivo, co-directional transcription can disrupt replication, leading to the involvement of replication restart proteins. We found that highly transcribed rRNA genes are hotspots for co-directional conflicts between replication and transcription in rapidly growing Bacillus subtilis cells. We observed a transcription-dependent increase in association of the replicative helicase and replication restart proteins where head-on and co-directional conflicts occur. Our results indicate that there are co-directional conflicts between replication and transcription in vivo. Furthermore, in contrast to the findings in vitro, the replication restart machinery is involved in vivo in resolving potentially deleterious encounters due to head-on and co-directional conflicts. These conflicts probably occur in many organisms and at many chromosomal locations and help to explain the presence of important auxiliary proteins involved in replication restart and in helping to clear a path along the DNA for the replisome.Biotechnology and Biological Sciences Research Council (Great Britain) (Grant BB/E006450/1)Wellcome Trust (London, England) (Grant 091968/Z/10/Z)National Institutes of Health (U.S.) (Grant GM41934)National Institutes of Health (U.S.) (Postdoctoral Fellowship GM093408)Biotechnology and Biological Sciences Research Council (Great Britain) (Sabbatical Visit
Applied Plasma Research
Contains reports on three research projects.National Science Foundation (Grant GK-18185)M. I. T. Lincoln Laboratory Purchase Order No. CC-55
Structure Formation, Melting, and the Optical Properties of Gold/DNA Nanocomposites: Effects of Relaxation Time
We present a model for structure formation, melting, and optical properties
of gold/DNA nanocomposites. These composites consist of a collection of gold
nanoparticles (of radius 50 nm or less) which are bound together by links made
up of DNA strands. In our structural model, the nanocomposite forms from a
series of Monte Carlo steps, each involving reaction-limited cluster-cluster
aggregation (RLCA) followed by dehybridization of the DNA links. These links
form with a probability which depends on temperature and particle
radius . The final structure depends on the number of monomers (i. e. gold
nanoparticles) , , and the relaxation time. At low temperature, the
model results in an RLCA cluster. But after a long enough relaxation time, the
nanocomposite reduces to a compact, non-fractal cluster. We calculate the
optical properties of the resulting aggregates using the Discrete Dipole
Approximation. Despite the restructuring, the melting transition (as seen in
the extinction coefficient at wavelength 520 nm) remains sharp, and the melting
temperature increases with increasing as found in our previous
percolation model. However, restructuring increases the corresponding link
fraction at melting to a value well above the percolation threshold. Our
calculated extinction cross section agrees qualitatively with experiments on
gold/DNA composites. It also shows a characteristic ``rebound effect,''
resulting from incomplete relaxation, which has also been seen in some
experiments. We discuss briefly how our results relate to a possible sol-gel
transition in these aggregates.Comment: 12 pages, 10 figure
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