The polymorphic fungus Candida albicans is a member of the normal human microbiome. In most individuals, C. albicans resides as a lifelong, harmless commensal. Under certain circumstances, however, ...C. albicans can cause infections that range from superficial infections of the skin to life-threatening systemic infections. Several factors and activities have been identified which contribute to the pathogenic potential of this fungus. Among them are molecules which mediate adhesion to and invasion into host cells, the secretion of hydrolases, the yeast-to-hypha transition, contact sensing and thigmotropism, biofilm formation, phenotypic switching and a range of fitness attributes. Our understanding of when and how these mechanisms and factors contribute to infection has significantly increased during the last years. In addition, novel virulence mechanisms have recently been discovered. In this review we present an update on our current understanding of the pathogenicity mechanisms of this important human pathogen.
Sensory processing atypicalities are a common feature in Autism Spectrum Disorders (ASD) and have previously been linked to a range of behaviours in individuals with ASD and atypical neurological ...development. More recently research has demonstrated a relationship between autistic traits in the neurotypical (NT) population and increased levels of atypical sensory behaviours. The aim of the present study is to extend previous research by examining specific patterns across aspects of autistic traits and sensory behaviours within both ASD and NT populations. The present study recruited 580 NT adults and 42 high-functioning ASD adults with a confirmed diagnosis to investigate the relationship between specific aspects of autistic traits and sensory processing using the subscales of the autism spectrum quotient (AQ) and adult/adolescent sensory profile (AASP). Results showed a significant relationship between all subscales except for attention to detail and imagination on the AQ and provided the first evidence that the strength and pattern of this relationship is identical between NT and ASD adults. These data also provided support for the broader autism phenotype, uncovering a clear progression of sensory atypicalities in line with an increase in autistic traits, regardless of diagnostic status, which has potential implications for the spectrum approach to ASD and how sensory behaviours across the whole of the neurotypical population are conceptualised.
We review the current status of knowledge concerning the early phases of star formation during cosmic dawn. This includes the first generations of stars forming in the lowest mass dark matter halos ...in which cooling and condensation of gas with primordial composition is possible at very high redshift (
z
>
20
), namely metal-free Population III stars, and the first generation of massive black holes forming at such early epochs, the so-called black hole seeds. The formation of black hole seeds as end states of the collapse of Population III stars, or via direct collapse scenarios, is discussed. In particular, special emphasis is given to the physics of supermassive stars as potential precursors of direct collapse black holes, in light of recent results of stellar evolution models, and of numerical simulations of the early stages of galaxy formation. Furthermore, we discuss the role of the cosmic radiation produced by the early generation of stars and black holes at high redshift in the process of reionization.
The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted previously prevalent variants and become a dominant strain worldwide. We report the structure, ...function, and antigenicity of its full-length spike (S) trimer as well as those of the Gamma and Kappa variants, and compare their characteristics with the G614, Alpha, and Beta variants. Delta S can fuse membranes more efficiently at low levels of cellular receptor angiotensin converting enzyme 2 (ACE2), and its pseudotyped viruses infect target cells substantially faster than the other five variants, possibly accounting for its heightened transmissibility. Each variant shows different rearrangement of the antigenic surface of the amino-terminal domain of the S protein but only makes produces changes in the receptor binding domain (RBD), making the RBD a better target for therapeutic antibodies.
The rapid assembly of the massive black holes that power the luminous quasars observed at z ∼ 6–7 remains a puzzle. Various direct collapse models have been proposed to head-start black hole growth ...from initial seeds with masses ∼105 M⊙, which can then reach a billion solar mass while accreting at the Eddington limit. Here, we propose an alternative scenario based on radiatively inefficient supercritical accretion of stellar-mass holes embedded in the gaseous circumnuclear discs (CNDs) expected to exist in the cores of high-redshift galaxies. Our sub-pc resolution hydrodynamical simulations show that stellar-mass holes orbiting within the central 100 pc of the CND bind to very high density gas clumps that arise from the fragmentation of the surrounding gas. Owing to the large reservoir of dense cold gas available, a stellar-mass black hole allowed to grow at super-Eddington rates according to the ‘slim-disc’ solution can increase its mass by three orders of magnitudes within a few million years. These findings are supported by simulations run with two different hydro codes, ramses based on the Adaptive Mesh Refinement technique and gizmo based on a new Lagrangian Godunov-type method, and with similar, but not identical, sub-grid recipes for star formation, supernova feedback, black hole accretion and feedback. The low radiative efficiency of supercritical accretion flows are instrumental to the rapid mass growth of our black holes, as they imply modest radiative heating of the surrounding nuclear environment.
Gasdermin proteins form large membrane pores in human cells that release immune cytokines and induce lytic cell death. Gasdermin pore formation is triggered by caspase-mediated cleavage during ...inflammasome signaling and is critical for defense against pathogens and cancer. We discovered gasdermin homologs encoded in bacteria that defended against phages and executed cell death. Structures of bacterial gasdermins revealed a conserved pore-forming domain that was stabilized in the inactive state with a buried lipid modification. Bacterial gasdermins were activated by dedicated caspase-like proteases that catalyzed site-specific cleavage and the removal of an inhibitory C-terminal peptide. Release of autoinhibition induced the assembly of large and heterogeneous pores that disrupted membrane integrity. Thus, pyroptosis is an ancient form of regulated cell death shared between bacteria and animals.
Native glutamate receptor ion channels are tetrameric assemblies containing two or more different subunits. NMDA receptors are obligate heteromers formed by coassembly of two or three divergent gene ...families. While some AMPA and kainate receptors can form functional homomeric ion channels, the KA1 and KA2 subunits are obligate heteromers which function only in combination with GluR5–7. The mechanisms controlling glutamate receptor assembly involve an initial step in which the amino terminal domains (ATD) assemble as dimers. Here, we establish by sedimentation velocity that the ATDs of GluR6 and KA2 coassemble as a heterodimer of Kd 11 nM, 32,000-fold lower than the Kd for homodimer formation by KA2; we solve crystal structures for the GluR6/KA2 ATD heterodimer and heterotetramer assemblies. Using these structures as a guide, we perform a mutant cycle analysis to probe the energetics of assembly and show that high-affinity ATD interactions are required for biosynthesis of functional heteromeric receptors.
► Control of glutamate receptor assembly by selective formation of ATD heterodimers ► Ultrahigh affinity for ATD heterodimer generates an extremely stable assembly ► Crystal structures of heteromeric kainate receptor tetramers ► Widely distributed contacts on both lobes of the ATD mediate heteromer assembly
Little is known about the molecular mechanisms underlying differences in the ligand binding properties of AMPA, kainate, and NMDA subtype glutamate receptors. Crystal structures of the GluR5 and ...GluR6 kainate receptor ligand binding cores in complexes with glutamate, 2S,4R-4-methylglutamate, kainate, and quisqualate have now been solved. The structures reveal that the ligand binding cavities are 40% (GluR5) and 16% (GluR6) larger than for GluR2. The binding of AMPA- and GluR5-selective agonists to GluR6 is prevented by steric occlusion, which also interferes with the high-affinity binding of 2S,4R-4-methylglutamate to AMPA receptors. Strikingly, the extent of domain closure produced by the GluR6 partial agonist kainate is only 3° less than for glutamate and 11° greater than for the GluR2 kainate complex. This, together with extensive interdomain contacts between domains 1 and 2 of GluR5 and GluR6, absent from AMPA receptors, likely contributes to the high stability of GluR5 and GluR6 kainate complexes.
Observations of distant quasars indicate that supermassive black holes of billions of solar masses already existed less than a billion years after the Big Bang. Models in which the 'seeds' of such ...black holes form by the collapse of primordial metal-free stars cannot explain the rapid appearance of these supermassive black holes because gas accretion is not sufficiently efficient. Alternatively, these black holes may form by direct collapse of gas within isolated protogalaxies, but current models require idealized conditions, such as metal-free gas, to prevent cooling and star formation from consuming the gas reservoir. Here we report simulations showing that mergers between massive protogalaxies naturally produce the conditions for direct collapse into a supermassive black hole with no need to suppress cooling and star formation. Merger-driven gas inflows give rise to an unstable, massive nuclear gas disk of a few billion solar masses, which funnels more than 108 solar masses of gas to a sub-parsec-scale gas cloud in only 100,000 years. The cloud undergoes gravitational collapse, which eventually leads to the formation of a massive black hole. The black hole can subsequently grow to a billion solar masses on timescales of about 108 years by accreting gas from the surrounding disk.
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