899 research outputs found
An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly
Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays
Habitat structure: a fundamental concept and framework for urban soil ecology
Habitat structure is defined as the composition and arrangement of physical matter at a location. Although habitat structure is the physical template underlying ecological patterns and processes, the concept is relatively unappreciated and underdeveloped in ecology. However, it provides a fundamental concept for urban ecology because human activities in urban ecosystems are often targeted toward management of habitat structure. In addition, the concept emphasizes the fine-scale, on-the-ground perspective needed in the study of urban soil ecology. To illustrate this, urban soil ecology research is summarized from the perspective of habitat structure effects. Among the key conclusions emerging from the literature review are: (1) habitat structure provides a unifying theme for multivariate research about urban soil ecology; (2) heterogeneous urban habitat structures influence soil ecological variables in different ways; (3) more research is needed to understand relationships among sociological variables, habitat structure patterns and urban soil ecology. To stimulate urban soil ecology research, a conceptual framework is presented to show the direct and indirect relationships among habitat structure and ecological variables. Because habitat structure serves as a physical link between sociocultural and ecological systems, it can be used as a focus for interdisciplinary and applied research (e.g., pest management) about the multiple, interactive effects of urbanization on the ecology of soils
Antibodies from rabbits immunized with HIV-1 clade B SOSIP trimers can neutralize multiple clade B viruses by destabilizing the envelope glycoprotein
The high HIV-1 viral diversity is a formidable hurdle for the development of an HIV-1 vaccine. Elicitation of broadly neutralizing antibodies (bNAbs) would offer a solution, but so far immunization strategies have failed to elicit bNAbs efficiently. To overcome the obstacles, it is important to understand the immune responses elicited by current HIV-1 envelope glycoprotein (Env) immunogens. To gain more insight, we characterized monoclonal antibodies (mAbs) isolated from rabbits immunized with Env SOSIP trimers based on the clade B isolate AMC008. Four rabbits that were immunized three times with AMC008 trimer developed robust autologous and sporadic low-titer heterologous neutralizing responses. Seventeen AMC008 trimer-reactive mAbs were isolated using antigen-specific single B cell sorting. Four of these mAbs neutralized the autologous AMC008 virus and several other clade B viruses. When visualized by electron microscopy, the complex of the neutralizing mAbs with the AMC008 trimer showed binding to the gp41 subunit with unusual approach angles and we observed that their neutralization ability depended on their capacity to induce Env trimer dissociation. Thus, AMC008 SOSIP trimer immunization induced clade B neutralizing mAbs with unusual approach angles with neutralizing effects that involve trimer destabilization. Optimizing these responses might provide an avenue to the induction of trimer dissociating bNAbs. IMPORTANCE Roughly 32 million people have died as a consequence of HIV-1 infection since the start of the epidemic and still 1.7 million people get infected with HIV-1 annually. Therefore, a vaccine to prevent HIV-1 infection is urgently needed. Current HIV-1 immunogens are not able to elicit the broad immune responses needed to provide protection against the large variation of HIV-1 strains circulating globally. A better understanding of the humoral immune responses elicited by immunization with state-of-the-art HIV-1 immunogens should facilitate the design of improved HIV-1 vaccine candidates. We identified antibodies with the ability to neutralize multiple HIV-1 viruses by destabilization of the envelope glycoprotein. Their weak but consistent cross-neutralization ability indicates the potential of this epitope to elicit broad responses. The trimer-destabilizing effect of the neutralizing mAbs combined with detailed characterization of the neutralization epitope can be used to shape the next generation of HIV-1 immunogens to elicit improved humoral responses after vaccination
Dynamics and transport near quantum-critical points
The physics of non-zero temperature dynamics and transport near
quantum-critical points is discussed by a detailed study of the O(N)-symmetric,
relativistic, quantum field theory of a N-component scalar field in spatial
dimensions. A great deal of insight is gained from a simple, exact solution of
the long-time dynamics for the N=1 d=1 case: this model describes the critical
point of the Ising chain in a transverse field, and the dynamics in all the
distinct, limiting, physical regions of its finite temperature phase diagram is
obtained. The N=3, d=1 model describes insulating, gapped, spin chain
compounds: the exact, low temperature value of the spin diffusivity is
computed, and compared with NMR experiments. The N=3, d=2,3 models describe
Heisenberg antiferromagnets with collinear N\'{e}el correlations, and
experimental realizations of quantum-critical behavior in these systems are
discussed. Finally, the N=2, d=2 model describes the superfluid-insulator
transition in lattice boson systems: the frequency and temperature dependence
of the the conductivity at the quantum-critical coupling is described and
implications for experiments in two-dimensional thin films and inversion layers
are noted.Comment: Lectures presented at the NATO Advanced Study Institute on "Dynamical
properties of unconventional magnetic systems", Geilo, Norway, April 2-12,
1997, edited by A. Skjeltorp and D. Sherrington, Kluwer Academic, to be
published. 46 page
Yukawa hierarchies at the point of in F-theory
We analyse the structure of Yukawa couplings in local SU(5) F-theory models
with enhancement. In this setting the symmetry is broken down to
SU(5) by a 7-brane configuration described by T-branes, all the Yukawa
couplings are generated in the vicinity of a point and only one family of
quarks and leptons is massive at tree-level. The other two families obtain
their masses when non-perturbative effects are taken into account, being
hierarchically lighter than the third family. However, and contrary to previous
results, we find that this hierarchy of fermion masses is not always
appropriate to reproduce measured data. We find instead that different T-brane
configurations breaking to SU(5) give rise to distinct hierarchical
patterns for the holomorphic Yukawa couplings. Only some of these patterns
allow to fit the observed fermion masses with reasonable local model parameter
values, adding further constraints to the construction of F-theory GUTs. We
consider an model where such appropriate hierarchy is realised and
compute its physical Yukawas, showing that realistic charged fermions masses
can indeed be obtained in this case.Comment: 46 pages + appendices, 5 figures. v2, added references and typos
corrected, version accepted on JHEP. v3, typos correcte
Antibody responses induced by SHIV infection are more focused than those induced by soluble native HIV-1 envelope trimers in non-human primates
The development of an effective human immunodeficiency virus (HIV-1) vaccine is a high
global health priority. Soluble native-like HIV-1 envelope glycoprotein trimers (Env), including those based on the SOSIP design, have shown promise as vaccine candidates by inducing neutralizing antibody responses against the autologous virus in animal models.
However, to overcome HIV-1’s extreme diversity a vaccine needs to induce broadly neutralizing antibodies (bNAbs). Such bNAbs can protect non-human primates (NHPs) and
humans from infection. The prototypic BG505 SOSIP.664 immunogen is based on the
BG505 env sequence isolated from an HIV-1-infected infant from Kenya who developed a
bNAb response. Studying bNAb development during natural HIV-1 infection can inform vaccine design, however, it is unclear to what extent vaccine-induced antibody responses to
Env are comparable to those induced by natural infection. Here, we compared Env antibody
responses in BG505 SOSIP-immunized NHPs with those in BG505 SHIV-infected NHPs,
by analyzing monoclonal antibodies (mAbs). We observed three major differences between
BG505 SOSIP immunization and BG505 SHIV infection. First, SHIV infection resulted in
more clonal expansion and less antibody diversity compared to SOSIP immunization, likely because of higher and/or prolonged antigenic stimulation and increased antigen diversity
during infection. Second, while we retrieved comparatively fewer neutralizing mAbs (NAbs)
from SOSIP-immunized animals, these NAbs targeted more diverse epitopes compared to
NAbs from SHIV-infected animals. However, none of the NAbs, either elicited by vaccination
or infection, showed any breadth. Finally, SOSIP immunization elicited antibodies against
the base of the trimer, while infection did not, consistent with the base being placed onto the
virus membrane in the latter setting. Together these data provide new insights into the antibody response against BG505 Env during infection and immunization and limitations that
need to be overcome to induce better responses after vaccination
Ribosomal oxygenases are structurally conserved from prokaryotes to humans
2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components1,2 and in the hydroxylation of transcription factors3 and splicing factor proteins4. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA5,6,7 and ribosomal proteins8 have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy9,10,11,12. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans8 raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone Nε-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases
Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.
The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation
From international health to global health: how to foster a better dialogue between empirical and normative disciplines.
BACKGROUND: Public health recommendations are usually based on a mixture of empirical evidence and normative arguments: to argue that authorities ought to implement an intervention that has proven effective in improving people's health requires a normative position confirming that the authorities are responsible for improving people's health. While public health (at the national level) is based on a widely accepted normative starting point - namely, that it is the responsibility of the state to improve people's health - there is no widely accepted normative starting point for international health or global health. As global health recommendations may vary depending on the normative starting point one uses, global health research requires a better dialogue between researchers who are trained in empirical disciplines and researchers who are trained in normative disciplines. DISCUSSION: Global health researchers with a background in empirical disciplines seem reluctant to clarify the normative starting point they use, perhaps because normative statements cannot be derived directly from empirical evidence, or because there is a wide gap between present policies and the normative starting point they personally support. Global health researchers with a background in normative disciplines usually do not present their work in ways that help their colleagues with a background in empirical disciplines to distinguish between what is merely personal opinion and professional opinion based on rigorous normative research. If global health researchers with a background in empirical disciplines clarified their normative starting point, their recommendations would become more useful for their colleagues with a background in normative disciplines. If global health researchers who focus on normative issues used adapted qualitative research guidelines to present their results, their findings would be more useful for their colleagues with a background in empirical disciplines. Although a single common paradigm for all scientific disciplines that contribute to global health research may not be possible or desirable, global health researchers with a background in empirical disciplines and global health researchers with a background in normative disciplines could present their 'truths' in ways that would improve dialogue. This paper calls for an exchange of views between global health researchers and editors of medical journals
Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model
Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures
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