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Visualization of cytosolic ribosomes on the surface of mitochondria by electron cryo‐tomography
(2017)
We employed electron cryo‐tomography to visualize cytosolic ribosomes on the surface of mitochondria. Translation‐arrested ribosomes reveal the clustered organization of the TOM complex, corroborating earlier reports of localized translation. Ribosomes are shown to interact specifically with the TOM complex, and nascent chain binding is crucial for ribosome recruitment and stabilization. Ribosomes are bound to the membrane in discrete clusters, often in the vicinity of the crista junctions. This interaction highlights how protein synthesis may be coupled with transport. Our work provides unique insights into the spatial organization of cytosolic ribosomes on mitochondria.
Dendrites form predominantly binary trees that are exquisitely embedded in the networks of the brain. While neuronal computation is known to depend on the morphology of dendrites, their underlying topological blueprint remains unknown. Here, we used a centripetal branch ordering scheme originally developed to describe river networks—the Horton-Strahler order (SO)–to examine hierarchical relationships of branching statistics in reconstructed and model dendritic trees. We report on a number of universal topological relationships with SO that are true for all binary trees and distinguish those from SO-sorted metric measures that appear to be cell type-specific. The latter are therefore potential new candidates for categorising dendritic tree structures. Interestingly, we find a faithful correlation of branch diameters with centripetal branch orders, indicating a possible functional importance of SO for dendritic morphology and growth. Also, simulated local voltage responses to synaptic inputs are strongly correlated with SO. In summary, our study identifies important SO-dependent measures in dendritic morphology that are relevant for neural function while at the same time it describes other relationships that are universal for all dendrites.
Rho GTPases control fundamental cellular processes and Cdc42 is a well-studied member of the family that controls filopodia formation and cell migration. Although the regulation of Cdc42 activity by nucleotide binding is well documented, the mechanisms driving its proteostasis are not clear. Here, we demonstrate that the highly conserved, RING domain containing E3 ubiquitin ligase XIAP controls the protein stability of Cdc42. XIAP binds to Cdc42 and directly conjugates poly ubiquitin chains to the Lysine 166 of Cdc42 targeting it for proteasomal degradation. Depletion of XIAP led to an increased protein stability and activity of Cdc42 in normal and tumor cells. Consistently, loss of XIAP enhances filopodia formation in a Cdc42-dependent manner and this phenomenon phenocopies EGF stimulation. Further, XIAP depletion promotes lung colonization of tumor cells in mice in a Cdc42-dependent manner. These observations shed molecular insights into ubiquitin-dependent regulation of Cdc42 and that of actin cytoskeleton.
Cytokine regulation of high-output nitric oxide (NO) derived from inducible NO synthase (iNOS) is critically involved in inflammation biology and host defense. Herein, we set out to characterize the role of type I interferon (IFN) as potential regulator of hepatic iNOS in vitro and in vivo. In this regard, we identified in murine Hepa1-6 hepatoma cells a potent synergism between pro-inflammatory interleukin-β/tumor necrosis factor-α and immunoregulatory IFNβ as detected by analysis of iNOS expression and nitrite release. Upregulation of iNOS by IFNβ coincided with enhanced binding of signal transducer and activator of transcription-1 to a regulatory region at the murine iNOS promoter known to support target gene expression in response to this signaling pathway. Synergistic iNOS induction under the influence of IFNβ was confirmed in alternate murine Hepa56.1D hepatoma cells and primary hepatocytes. To assess iNOS regulation by type I IFN in vivo, murine acetaminophen (APAP)-induced sterile liver inflammation was investigated. In this model of acute liver injury, excessive necroinflammation drives iNOS expression in diverse liver cell types, among others hepatocytes. Herein, we demonstrate impaired iNOS expression in type I IFN receptor-deficient mice which associated with diminished APAP-induced liver damage. Data presented indicate a vital role of type I IFN within the inflamed liver for fine-tuning pathological processes such as overt iNOS expression.
Neurogenesis of hippocampal granule cells (GCs) persists throughout mammalian life and is important for learning and memory. How newborn GCs differentiate and mature into an existing circuit during this time period is not yet fully understood. We established a method to visualize postnatally generated GCs in organotypic entorhino-hippocampal slice cultures (OTCs) using retroviral (RV) GFP-labeling and performed time-lapse imaging to study their morphological development in vitro. Using anterograde tracing we could, furthermore, demonstrate that the postnatally generated GCs in OTCs, similar to adult born GCs, grow into an existing entorhino-dentate circuitry. RV-labeled GCs were identified and individual cells were followed for up to four weeks post injection. Postnatally born GCs exhibited highly dynamic structural changes, including dendritic growth spurts but also retraction of dendrites and phases of dendritic stabilization. In contrast, older, presumably prenatally born GCs labeled with an adeno-associated virus (AAV), were far less dynamic. We propose that the high degree of structural flexibility seen in our preparations is necessary for the integration of newborn granule cells into an already existing neuronal circuit of the dentate gyrus in which they have to compete for entorhinal input with cells generated and integrated earlier.
Some anaerobic archaea and bacteria live on substrates that do not allow the synthesis of one mol of ATP per mol of substrate via substrate level phosphorylation (SLP). Energy conservation in these cases is only possible by a chemiosmotic mechanism that involves the generation of an electrochemical ion gradient across the cytoplasmic membrane that then drives ATP synthesis via an ATP synthase. The minimal amount of energy required for ATP synthesis is thus dependent on the magnitude of the electrochemical ion gradient, the phosphorylation potential in the cell and the ion/ATP ratio of the ATP synthase. It was always thought that the minimum biological energy quantum is defined as the amount of energy required to translocate one ion across the cytoplasmic membrane. We will discuss the thermodynamics of the reactions involved in chemiosmosis and describe the limitations for ion transport and ATP synthesis that led to the proposal that at least −20 kJ/mol are required for ATP synthesis. We will challenge this hypothesis by arguing that the enzyme energizing the membrane may translocate net less than one ion: By using a primary pump connected to an antiporter module a stoichiometry below one can be obtained, implying that the minimum biological energy quantum that sustains life is even lower than assumed to date.
Southern African protected areas (PAs) harbour a great diversity of animals, which represent a large potential for wildlife tourism. In this region, global change is expected to result in vegetation changes, such as bush encroachment and increases in vegetation density. However, little is known on the influence of vegetation structure on wildlife tourists’ wildlife viewing experience and satisfaction. In this study, we collected data on vegetation structure and perceived mammal densities along 196 road transects (each 5 km long) and conducted a social survey with 651 questionnaires across four PAs in three Southern African countries. Our objectives were 1) to assess visitors’ attitude towards vegetation, 2) to test the influence of perceived mammal density and vegetation structure on the easiness to spot animals, and 3) on visitors’ satisfaction during their visit to PAs. Using a Boosted Regression Tree procedure, we found mostly negative non-linear relationships between vegetation density and wildlife tourists’ experience, and positive relationships between perceived mammal densities and wildlife tourists’ experience. In particular, wildlife tourists disliked road transects with high estimates of vegetation density. Similarly, the easiness to spot animals dropped at thresholds of high vegetation density and at perceived mammal densities lower than 46 individuals per road transect. Finally, tourists’ satisfaction declined linearly with vegetation density and dropped at mammal densities smaller than 26 individuals per transect. Our results suggest that vegetation density has important impacts on tourists’ wildlife viewing experience and satisfaction. Hence, the management of PAs in savannah landscapes should consider how tourists perceive these landscapes and their mammal diversity in order to maintain and develop a sustainable wildlife tourism.
Compartmental models are the theoretical tool of choice for understanding single neuron computations. However, many models are incomplete, built ad hoc and require tuning for each novel condition rendering them of limited usability. Here, we present T2N, a powerful interface to control NEURON with Matlab and TREES toolbox, which supports generating models stable over a broad range of reconstructed and synthetic morphologies. We illustrate this for a novel, highly detailed active model of dentate granule cells (GCs) replicating a wide palette of experiments from various labs. By implementing known differences in ion channel composition and morphology, our model reproduces data from mouse or rat, mature or adult-born GCs as well as pharmacological interventions and epileptic conditions. This work sets a new benchmark for detailed compartmental modeling. T2N is suitable for creating robust models useful for large-scale networks that could lead to novel predictions. We discuss possible T2N application in degeneracy studies.
Genetic data in studies of systematics of Amazonian amphibians frequently reveal that purportedly widespread single species in reality comprise species complexes. This means that real species richness may be significantly higher than current estimates. Here we combine genetic, morphological, and bioacoustic data to assess the phylogenetic relationships and species boundaries of two Amazonian species of the Dendropsophus leucophyllatus species group: D. leucophyllatus and D. triangulum. Our results uncovered the existence of five confirmed and four unconfirmed candidate species. Among the confirmed candidate species, three have available names: Dendropsophus leucophyllatus, Dendropsophus triangulum, and Dendropsophus reticulatus, this last being removed from the synonymy of D. triangulum. A neotype of D. leucophyllatus is designated. We describe the remaining two confirmed candidate species, one from Bolivia and another from Peru. All confirmed candidate species are morphologically distinct and have much smaller geographic ranges than those previously reported for D. leucophyllatus and D. triangulum sensu lato. Dendropsophus leucophyllatus sensu stricto occurs in the Guianan region. Dendropsophus reticulatus comb. nov. corresponds to populations in the Amazon basin of Brazil, Ecuador, and Peru previously referred to as D. triangulum. Dendropsophus triangulum sensu stricto is the most widely distributed species; it occurs in Amazonian Ecuador, Peru and Brazil, reaching the state of Pará. We provide accounts for all described species including an assessment of their conservation status.
The transporter associated with antigen processing (TAP) selectively translocates antigenic peptides into the endoplasmic reticulum. Loading onto major histocompatibility complex class I molecules and proofreading of these bound epitopes are orchestrated within the macromolecular peptide-loading complex, which assembles on TAP. This heterodimeric ABC-binding cassette (ABC) transport complex is therefore a major component in the adaptive immune response against virally or malignantly transformed cells. Its pivotal role predestines TAP as a target for infectious diseases and malignant disorders. The development of therapies or drugs therefore requires a detailed comprehension of structure and function of this ABC transporter, but our knowledge about various aspects is still insufficient. This review highlights recent achievements on the structure and dynamics of antigenic peptides in complex with TAP. Understanding the binding mode of antigenic peptides in the TAP complex will crucially impact rational design of inhibitors, drug development, or vaccination strategies.