Polymer Theory applied to the Nuclear Pore Complex

Physically interesting behaviour can arise when soft matter is confined to nanoscale dimensions. A highly relevant biological example of such a phenomenon is the Nuclear Pore Complex (NPC), found perforating the Nuclear Envelope of all eukaryotic cells. In the central conduit of the NPC, of 30-60 nm diameter, a disordered arrangement of proteins regulates all macromolecular transport between the nucleus and the cytoplasm. Its selectivity for larger macromolecules relies on changes in a permeability barrier that is formed by these unstructured proteins, induced by interactions of these proteins with molecules called Nuclear Transport Receptors (NTRs), which can chaperone larger macromolecules through the NPC. The exact mechanism for the transport selectivity is unknown. To model these unstructured proteins in the nanoscale channel of the NPC, a density functional theory approach is developed that treats the proteins as interacting polymers. This new method is tested against Monte Carlo to show its validity. A detailed comparison between this model system and those previously proposed in the literature is provided. In a parameter range relevant for the NPC, the system shows bimodal behaviour The polymers can alternate between two condensed states: An open state, in which this condensation takes place at the channel wall, and a closed state in which it occurs at the channel centre. We then extend this model by including explicitly the effect of Nuclear Transport Receptors on the conformations of the polymers. The model takes into account the finite size of the transport receptors relative to the NPC diameter. Mapping the polymer and transport receptor behaviour over a set of physiologically relevant parameters gives different structural scenarios for the various hypothesized transport mechanisms. Further to this, the transport rates for each parameter set can be obtained, showing whether such parameters are consistent with experimental evidence. In addition to this, we study the effect of relaxing some of the assumptions of our model, specifically by looking at azimuthal symmetry breaking effects in two dimensions. We also compare our model to experimental results measuring the thickness of planar polymer brushes comprised of NPC proteins to further justify parameter choices

Bistable collective behavior of polymers tethered in a nanopore.

Polymer-coated pores play a crucial role in nucleo-cytoplasmic transport and in a number of biomimetic and nanotechnological applications. Here we present Monte Carlo and Density Functional Theory approaches to identify different collective phases of end-grafted polymers in a nanopore and to study their relative stability as a function of intermolecular interactions. Over a range of system parameters that is relevant for nuclear pore complexes, we observe two distinct phases: one with the bulk of the polymers condensed at the wall of the pore, and the other with the polymers condensed along its central axis. The relative stability of these two phases depends on the interpolymer interactions. The existence the two phases suggests a mechanism in which marginal changes in these interactions, possibly induced by nuclear transport receptors, cause the pore to transform between open and closed configurations, which will influence transport through the pore

Antimicrobial Activity and Docking Study of Synthesized Xanthen-3-on Derivatives

Twelve previously synthesized biologically active 2,6,7-trihydroxy-9-aryl-3H-xanthen-3-one derivatives (1-12) were evaluated in vitro for their antimicrobial activity against four bacteria, S. aureus, B. subtilis P. aeruginosa and E. coli, and two fungi strains, C. albicans and S. cerevisiae. The most potent compound were derivatives 1 which possess hydroxyl group and bromine as substituent and 11 with bromine as substituent on phenyl ring. The results indicate that bromine increase antimicrobial activity of 2,6,7-trihydroxy-9-aryl-3-Hxanthen-3-one derivatives. Compound 7 with ethoxy substituent on phenyl ring showed the least activity against tested bacteria and fungi strains, which is in line with an earlier observation that ethoxy substitution decreases antimicrobial activity. The most and the least potent compounds were subjected to molecular docking simulations to preliminary find out the potential molecular target and at the same moment further support the experimental antimicrobial test of xanthen derivatives

Antimicrobial Activity and Docking Study of Synthesized Xanthen-3-on Derivatives

Twelve previously synthesized biologically active 2,6,7-trihydroxy-9-aryl-3H-xanthen-3-one derivatives (1-12) were evaluated in vitro for their antimicrobial activity against four bacteria, S. aureus, B. subtilis P. aeruginosa and E. coli, and two fungi strains, C. albicans and S. cerevisiae. The most potent compound were derivatives 1 which possess hydroxyl group and bromine as substituent and 11 with bromine as substituent on phenyl ring. The results indicate that bromine increase antimicrobial activity of 2,6,7-trihydroxy-9-aryl-3-Hxanthen-3-one derivatives. Compound 7 with ethoxy substituent on phenyl ring showed the least activity against tested bacteria and fungi strains, which is in line with an earlier observation that ethoxy substitution decreases antimicrobial activity. The most and the least potent compounds were subjected to molecular docking simulations to preliminary find out the potential molecular target and at the same moment further support the experimental antimicrobial test of xanthen derivatives

Physical modelling of the nuclear pore complex

Physically interesting behaviour can arise when soft matter is confined to nanoscale dimensions. A highly relevant biological example of such a phenomenon is the Nuclear Pore Complex (NPC) found perforating the nuclear envelope of eukaryotic cells. In the central conduit of the NPC, of [similar]30–60 nm diameter, a disordered network of proteins regulates all macromolecular transport between the nucleus and the cytoplasm. In spite of a wealth of experimental data, the selectivity barrier of the NPC has yet to be explained fully. Experimental and theoretical approaches are complicated by the disordered and heterogeneous nature of the NPC conduit. Modelling approaches have focused on the behaviour of the partially unfolded protein domains in the confined geometry of the NPC conduit, and have demonstrated that within the range of parameters thought relevant for the NPC, widely varying behaviour can be observed. In this review, we summarise recent efforts to physically model the NPC barrier and function. We illustrate how attempts to understand NPC barrier function have employed many different modelling techniques, each of which have contributed to our understanding of the NPC

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology