The microscopic environment inside a metazoan organism is highly crowded. Whether individual cells can tailor their behavior to the limited space remains unclear. In this study, we found that cells ...measure the degree of spatial confinement by using their largest and stiffest organelle, the nucleus. Cell confinement below a resting nucleus size deforms the nucleus, which expands and stretches its envelope. This activates signaling to the actomyosin cortex via nuclear envelope stretch-sensitive proteins, up-regulating cell contractility. We established that the tailored contractile response constitutes a nuclear ruler-based signaling pathway involved in migratory cell behaviors. Cells rely on the nuclear ruler to modulate the motive force that enables their passage through restrictive pores in complex three-dimensional environments, a process relevant to cancer cell invasion, immune responses, and embryonic development.
Most non-spherical bacteria rely on the actin-like MreB cytoskeleton to control synthesis of a cell-shaping and primarily rod-like cell wall. Diverging from simple rod shape generally requires ...accessory cytoskeletal elements, which locally interfere with the MreB-guided cell wall synthesis. Conserved and widespread representatives of this accessory cytoskeleton are bactofilins that polymerize into static, non-polar bundles of filaments. Intriguingly, many species of the Actinobacteria and Rhizobiales manage to grow rod-like without MreB by tip extension, yet some of them still possess bactofilin genes, whose function in cell morphogenesis is unknown. An intricate representative of these tip-growing bacteria is Rhodomicrobium vannielii; a member of the hitherto genetically not tractable and poorly studied Hyphomicrobiaceae within the MreB-less Rhizobiales order. R. vannielii displays complex asymmetric cell shapes and differentiation patterns including filamentous hyphae to produce offspring and to build dendritic multicellular arrays. Here, we introduce techniques to genetically access R. vannielii, and we elucidate the role of bactofilins in its sophisticated morphogenesis. By targeted mutagenesis and fluorescence microscopy, protein interaction studies and peptidoglycan incorporation analysis we show that the R. vannielii bactofilins are associated with the hyphal growth zones and that one of them is essential to form proper hyphae. Another paralog is suggested to represent a novel hybrid and co-polymerizing bactofilin. Notably, we present R. vannielii as a powerful new model to understand prokaryotic cell development and control of multipolar cell growth in the absence of the conserved cytoskeletal element, MreB.
With the steady increase in the precision of flavour physics measurements collected during LHC Run 2, the LHCb experiment requires simulated data samples of larger and larger sizes to study the ...detector response in detail. The simulation of the detector response is the main contribution to the time needed to simulate full events. This time scales linearly with the particle multiplicity. Of the dozens of particles present in the simulation only the few participating in the signal decay under study are of interest, while all remaining particles mainly affect the resolutions and efficiencies of the detector. This paper presents a novel development for the LHCb simulation software which re-uses the rest of the event from previously simulated events. This approach achieves an order of magnitude increase in speed and the same quality compared to the nominal simulation.
In the last two decades we have witnessed sizable progress in defining the role of gastrointestinal signals in the control of glucose and energy homeostasis. Specifically, the molecular basis of the ...huge metabolic benefits in bariatric surgery is emerging while novel incretin-based medicines based on endogenous hormones such as glucagon-like peptide 1 and pancreas-derived amylin are improving diabetes management. These and related developments have fostered the discovery of novel insights into endocrine control of systemic metabolism, and in particular a deeper understanding of the importance of communication across vital organs, and specifically the gut-brain-pancreas-liver network. Paradoxically, the pancreatic peptide glucagon has reemerged in this period among a plethora of newly identified metabolic macromolecules, and new data complement and challenge its historical position as a gut hormone involved in metabolic control. The synthesis of glucagon analogs that are biophysically stable and soluble in aqueous solutions has promoted biological study that has enriched our understanding of glucagon biology and ironically recruited glucagon agonism as a central element to lower body weight in the treatment of metabolic disease. This review summarizes the extensive historical record and the more recent provocative direction that integrates the prominent role of glucagon in glucose elevation with its under-acknowledged effects on lipids, body weight, and vascular health that have implications for the pathophysiology of metabolic diseases, and the emergence of precision medicines to treat metabolic diseases.
Tectonic reconstructions of Southeast Asia have given rise to numerous controversies that include the accretionary history of Sundaland and the enigmatic tectonic origin of the proto-South China Sea. ...We assimilate a diversity of geological and geophysical observations into a new regional plate model, coupled to a global model, to address these debates. Our approach takes into account terrane suturing and accretion histories, the location of subducted slabs imaged in mantle tomography in order to constrain the evolution of regional subduction zones, as well as plausible absolute and relative plate velocities and tectonic driving mechanisms. We propose a scenario of rifting from northern Gondwana in the latest Jurassic, driven by northward slab pull from north-dipping subduction of Tethyan crust beneath Eurasia, to detach East Java, Mangkalihat, southeast Borneo and West Sulawesi blocks that collided with a Tethyan intra-oceanic subduction zone in the mid-Cretaceous and subsequently accreted to the Sunda margin (i.e., southwest Borneo core) in the Late Cretaceous. In accounting for the evolution of plate boundaries, we propose that the Philippine Sea plate originated on the periphery of Tethyan crust forming this northward conveyor. We implement a revised model for the Tethyan intra-oceanic subduction zones to reconcile convergence rates, changes in volcanism and the obduction of ophiolites. In our model the northward margin of Greater India collides with the Kohistan-Ladakh intra-oceanic arc at ∼53 Ma, followed by continent-continent collision closing the Shyok and Indus-Tsangpo suture zones between ∼42 and 34 Ma. We also account for the back-arc opening of the proto-South China Sea from ∼65 Ma, consistent with extension along east Asia and the formation of supra-subduction zone ophiolites presently found on the island of Mindoro. The related rifting likely detached the Semitau continental fragment from South China, which accreted to northern Borneo in the mid-Eocene, to account for the Sarawak Orogeny. Rifting then re-initiated along southeast China by 37 Ma to open the South China Sea, resulting in the complete consumption of proto-South China Sea by ∼17 Ma when the collision of the Dangerous Grounds and northern Palawan blocks with northern Borneo choked the subduction zone to result in the Sabah Orogeny and the obduction of ophiolites in Palawan and Mindoro. We conclude that the counterclockwise rotation of Borneo was accommodated by oroclinal bending consistent with paleomagnetic constraints, the curved lithospheric lineaments observed in gravity anomalies of the Java Sea and the curvature of the Cretaceous Natuna paleo-subduction zone. We complete our model by constructing a time-dependent network of topological plate boundaries and gridded paleo-ages of oceanic basins, allowing us to compare our plate model evolution to seismic tomography. In particular, slabs observed at depths shallower than ∼1000 km beneath northern Borneo and the South China Sea are likely to be remnants of the proto-South China Sea basin.
Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, ...thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).
PDF
