Whereas clathrin-mediated endocytosis (CME) exists in all eukaryotic cells, we first detect classical dynamin in Ichthyosporid, a single-cell, metazoan precursor. Based on a key functional residue in its pleckstrin homology domain, we speculate that the evolution of metazoan dynamin coincided with the specialized need for regulated CME during neurotransmission.

Sperm function generally declines with male age. Paradoxically, females of many species still choose to mate with old males rather than young males. Females choosing old mates may suffer reduced fertilization rates and an increased incidence of birth defects in offspring, lowering fitness which may in turn lead to conflict between the sexes. This apparent paradox has generated much interest from theorists, but whether this paradox presents in nature remains equivocal. Empirical studies have found mixed support for both a decline in fertility with male age and age-based female mate preference. Here, we examine recent evidence for this paradox, identify confounding variables, highlight areas that deserve further investigation, and suggest avenues for future research.

Population genetics is often taught in introductory biology classes, starting with the Hardy-Weinberg principle (HWP) and genetic drift. Here I argue that teaching these two topics first aligns neither with current expert knowledge, nor with good pedagogy. Student difficulties with mathematics in general, and probability in particular, make population genetics difficult to teach and learn. I recommend an alternative, historically inspired ordering of population genetics topics, based on progressively increasing mathematical difficulty. This progression can facilitate just-in-time math instruction. This alternative ordering includes, but does not privilege, the HWP and genetic drift. Stochastic events whose consequences are felt within a single generation, and the deterministic accumulation of the effects of selection across multiple generations, are both taught before tackling the stochastic accumulation of the effects of accidents of sampling.

Leucine-rich repeat-containing 8 (LRRC8) proteins are composed of four transmembrane helices and 17 leucine-rich repeats (LRR). Although LRRC8 proteins have been associated with important processes, like maturation of B cells or adipocyte differentiation, their biology and molecular function are largely unknown. We found that LRRC8 proteins originated from the combination of a pannexin and an LRR domain (most likely related to the SHOC2, LAP, RSU1 and LRRIQ4 protein families) before the diversification of chordates. We propose that, like pannexins, LRRC8 proteins form hexameric channels, which participate in cell-cell communication processes. According to the inferred topological model, and contrary to what was previously assumed, the six LRR domains are located in the cytoplasm, and could participate in the organisation of signalling cascades. By compiling available proteomics and gene expression data, and on the basis of the LRRC8 proposed hexameric channel structure, we present clues to the function of this family. Editor's suggested further reading in BioEssays Pannexins, distant relatives of the connexin family with specific cellular functions? Abstract.

The postsynaptic density (PSD) is a massive multi-protein complex whose functions include positioning signalling molecules for induction of long-term potentiation (LTP) and depression (LTD) of synaptic strength. These processes are thought to underlie memory formation. To understand how the PSD coordinates bidirectional synaptic plasticity with different synaptic activation patterns, it is necessary to determine its three-dimensional structure. A structural model of the PSD is emerging from investigation of its molecular composition and connectivity, in addition to structural studies at different levels of resolution. Technical innovations including mass spectrometry of cross-linked proteins and super-resolution light microscopy can drive progress. Integrating different information relating to PSD structure is challenging since the structure is so large and complex. The reconstruction of a PSD subcomplex anchored by AKAP79 exemplifies on a small scale how integration can be achieved. With its entire molecular structure coming into focus, this is a unique opportunity to study the PSD.

Domains can spread among proteins in a process called domain shuffling and this has been identified as one of the major mechanisms leading to the formation of new proteins throughout evolution. This process has an impact on the topology of protein-protein interaction networks as it may create new hubs and also increase interconnectivity.

How do cells interpret information from their environment and translate it into specific cell fate decisions? We propose that cell fate is already encoded in early signaling events and thus can be predicted from defined signal properties. Specifically, we hypothesize that the time integral of activated key signaling molecules can be correlated to cellular behavior such as proliferation or differentiation. The identification of these decisive key signal mediators and their connection to cell fate is facilitated by mathematical modeling. A possible mechanistic linkage between signaling dynamics and cellular function is the directed control of gene regulatory networks by defined signals. Targeted experiments in combination with mathematical modeling can increase our understanding of how cells process information and realize distinct cell fates.

The innate immune system of mammals encodes several families of immune detector proteins that monitor the cytosol for signs of pathogen invasion. One important but poorly understood family of cytosolic immunosurveillance proteins is the NLR (nucleotide-binding domain, leucine-rich repeat containing) proteins. Recent work has demonstrated that one subfamily of NLRs, the NAIPs (NLR family, apoptosis inhibitory proteins), are activated by specific interaction with bacterial ligands, such as flagellin. NAIP activation leads to assembly of a large multiprotein complex called the inflammasome, which initiates innate immune responses by activation of the Caspase-1 protease. NAIPs therefore appear to detect pathogen molecules via a simple and direct receptor-ligand mechanism. Interestingly, other NLR family members appear to detect pathogens indirectly, perhaps by responding to host cell "stress" caused by the pathogen. Thus, the NLR family may have evolved surprisingly diverse mechanisms for detecting pathogens.

Here we postulate that the adapter protein evolutionarily conserved signalling intermediate in Toll pathway (ECSIT) might act as a molecular sensor in the pathogenesis of Alzheimer's disease (AD). Based on the analysis of our AD-associated protein interaction network, ECSIT emerges as an integrating signalling hub that ascertains cell homeostasis by the specific activation of protective molecular mechanisms in response to signals of amyloid-beta or oxidative damage. This converges into a complex cascade of patho-physiological processes. A failure to repair would generate severe mitochondrial damage and ultimately activate pro-apoptotic mechanisms, promoting synaptic dysfunction and neuronal death. Further support for our hypothesis is provided by increasing evidence of mitochondrial dysfunction in the disease etiology. Our model integrates seemingly controversial hypotheses for familial and sporadic forms of AD and envisions ECSIT as a biomarker to guide future therapies to halt or prevent AD. Editor's suggested further reading in BioEssays Binding of amyloid peptides to domain-swapped dimers of other amyloid-forming protein may prevent their neurotoxicity Abstract Please, also watch the Video Abstract.

Three-dimensional structured illumination microscopy (3D-SIM) has opened up new possibilities to study nuclear architecture at the ultrastructural level down to the ∼100 nm range. We present first results and assess the potential using 3D-SIM in combination with 3D fluorescence in situ hybridization (3D-FISH) for the topographical analysis of defined nuclear targets. Our study also deals with the concern that artifacts produced by FISH may counteract the gain in resolution. We address the topography of DAPI-stained DNA in nuclei before and after 3D-FISH, nuclear pores and the lamina, chromosome territories, chromatin domains, and individual gene loci. We also look at the replication patterns of chromocenters and the topographical relationship of Xist-RNA within the inactive X-territory. These examples demonstrate that an appropriately adapted 3D-FISH/3D-SIM approach preserves key characteristics of the nuclear ultrastructure and that the gain in information obtained by 3D-SIM yields new insights into the functional nuclear organization.